Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][O:4][CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[Si:27]([O:15][CH2:14][CH:2]([OH:1])[CH2:3][O:4][CH2:5][P:6](=[O:13])([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CCOP(=O)(COCC(O)CO)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(COCC(O)CO[Si](C)(C)C(C)(C)C)OCC
Yield: 71.2 %

Procedure:
To a solution of diethyl 2,3-dihydroxypropoxymethylphosphonate (4.15 g, 17.lmmol), triethylamine (1.9 g, 2.62 ml, 18.81 mmol), 4-dimethylaminopyridine (84mg, 0.7 mmol) and t-butyldimethylchlorosilane (2.92 g, 19.4 mmol) in dichloromethane (50 ml) was stirred for 16 hours at 20° C. under nitrogen. The solution was washed with water (50 ml), saturated ammonium chloride (50 ml) and dried (Na2SO4). The solvents was evaporated to leave a yellow oil which was chromatographed on silica eluting with ethyl acetate affording diethyl 3-t-butyldimethylsilyloxy-2-hydroxypropoxymethylphosphonate (4.35 g, 71%) as a pale lemon liquid. νmax (film) 3400, 1460 , 1240, 1100, 1020 and 960 cm-1 ; δH (CDCl3) 0.05(6H, s, (CH3)2Si), 0.86(9H, s,(CH3)3C), 1.31(6H, t, J7.3 Hz, 2×CH2CH3), 2.50 (1H, br.s, D2O exchangeable, OH), 3.70(7H, m, CH2OSi+CHOH+CH2OCH2P), 4.12(4H, m, 2×CH2CH3); m/z 357(MH+,3%), 341 (M-CH3+,4%); Found: C,46.89; H,9.23%; C14H33O6PSi requires C,47 17; H,9.33%
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:18]([CH2:20][C:21](OCC)=[O:22])=[O:19].[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:18]([C:20]1[C:21](=[O:22])[NH:4][C:3]2[C:2]([C:1]=1[OH:10])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:19]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc(C(=O)c2c(O)c3ccccc3[nH]c2=O)cc1OC
Yield: 17.6 %

Procedure:
Ethyl anthranilate (1.44 grams) and 2.2 grams of ethyl 3,4-dimethoxybenzoylacetate are dissolved in 100 ml of xylene and heated to reflux for five hours with 200 mg of sodium ethoxide. After cooling, crystals are separated out and collected by filtration and recrystallized from methanol to give 0.5 grams of 3-(3,4-dimethoxybenzoyl)-4-hydroxy-2-quinolone, pale yellow needles, melting point 235° to 236° C.
Reaction SMILES: [C:1]([CH2:8][C:9]([OH:11])=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C([Cl:15])=O>CCCCCC>[C:1]([CH2:8][C:9]([Cl:15])=[O:11])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(=O)CC(=O)O
Solvent: CCCCCC
Product: CCCCCC(=O)CC(=O)Cl
Reaction time: 1 h
Yield: 96.8 %

Procedure:
8.7 g (0.05 m) of hexanoylacetic acid and 12.7 g (0.10 m) of oxalyl chloride were mixed together at room temperature. The reaction was heated gradually over one hour to 50°-60° C., then to 60°-70° C. under aspirator pressure for one hour. The reaction mixture was diluted with 125 ml hexane, washed with 3×100 ml ice water, dried over 20 g MgSO4, and roto-vapped at 50° C. to yield an oil (9.4 g, 98% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.O>CN(C)C=O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][N:4]1[C:5](=[O:16])[C:6]2[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:17]
Reactant: BrCc1nc2ccccc2s1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3ccccc3s1)c(=O)n2C
Yield: 90 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (327 mg, 1 mmol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (221 mg, 1.6 mmol) and 2-bromomethyl-1,3-benzothiazole (228 mg, 1 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 2b (400 mg, yellow solid), yield: 90%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:19][CH:18]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NCC(F)(F)F)s1
Yield: 79 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (72 mg, 79%) which was obtained as an off white solid MS: m/e=397.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[NH:19][CH3:20].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.IC>CO>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:19]([CH3:20])[C:3]3[CH:4]=[C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=4)[CH:17]=[CH:18][C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(NC)c2)ccn1
Solvent: CI
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Br)cc4)n(C)c3c2)ccn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the {4-[4-amino-3-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C. for 2 hours. The reaction mixture was cooled down to room temperature and iodomethane (1 eq) was added and stirred overnight at 60° C. The reaction was concentrated and preparative chromatography gave (4-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-6-yloxy)-(2-pyridyl)-N-methylcarboxamide. MS: MH+=452.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[CH2:38])[CH:31]3[CH2:37][NH:36][CH2:35][CH:32]3[C:33]=2[CH:34]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:30]([CH3:38])[CH:31]3[CH2:37][NH:36][CH2:35][CH:32]3[C:33]=2[CH:34]=1
Reactant: C=C1c2ccc(Cl)cc2C2CNCC12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1c2ccc(Cl)cc2C2CNCC12
Reaction time: 2 h

Procedure:
Di-tert-butyl dicarbonate (0.43 g, 2.00 mmol) and DIEA (1.0 mL, 6.0 mmol) were added to a solution of 5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.0 mmol) in CH2Cl2 (10 mL) at 0° C. The reaction mixture was stirred for 2 hours at from 0° C. to room temperature, then quenched with aqueous HCl (10 mL, 0.1 M). The organic extracts were washed with brine, dried over MgSO4, and concentrated to afford the subtitle compound in quantitative yield. MS calculated for C17H20ClNO2+H: 306, observed: 306.
Reaction SMILES: [Cl:1]Cl.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Reactant: ClCl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Cl)cc21

Procedure:
A cold solution of chlorine in chloroform is added dropwise at from 0° to 5° C., while stirring, to a mixture of 14.7 g (0.063 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 100 ml of chloroform until no more educt is visible in the thin layer chromatograph. The reaction mixture is diluted with methylene chloride and washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-chloro-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 103°-105° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[NH2:26][C:24]([C:23]1[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][C:28]=2[F:37])[S:20][C:19]=1[NH:18][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:7]=1)=[O:25]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: NC(=O)c1ccc(Cl)nc1CN1CCOCC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(N)=O)c(CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 6-chloro-2-(morpholin-4-ylmethyl)pyridine-3-carboxamide (87 mg, 0.34 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) as the starting materials.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>CN(C=O)C>[OH:68][C@@H:67]([CH3:69])[C:66]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:70]
Reactant: C[C@H](O)C(=O)O
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and L-lactic acid (21.02 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the crude dissolved in MeOH and acetonitrile, filtered and purified by preparative HPLC yielding (S)-2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (30.0 mg, 26%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:5])=[O:4]
Reactant: CCOC(=O)CCCCCO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To the suspension of poly(4-methylpyridine) (2.24 g, 2 eq) in newly dried dichloromethane (25 mL ) at 0° C. was added trifluoromethanesulfonic anhydride (5 g, 1 eq) drop wise over 30 mins. Ethyl 6-hydroxyhexanoate (2.76 g, 0.95 eq) was then added in drop wise via a syringe. The mixture was stirred at 0° C. for 4 hrs and the polymer was filtered off by a frit. The solvent was evaporated under reduced pressure (without heating) and the crude product was subjected to a short silica gel pad with 1:4 (v/v) diethyl ether/hexane as the eluent solvent. The solvent was evaporated (without heating) and the product was used directly in the following step. (3.9 g, 75% yield based on ethyl 6-hydroxyhexanoate.) See FIG. 10.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][C:17]([F:19])=[CH:16][CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccc(F)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-fluorobenzamide (3.65 g, 11.3 mmol) in THF (50 mL) was treated with triphosgene (3.69 g, 12.4 mmol) at room temperature. The solution was stirred at room temperature for 2 h, then was treated slowly with saturated aqueous NaHCO3 and stirred until no more gas evolution was observed. The resulting mixture was extracted twice with EtOAc. The combined organic phases were washed twice with water, then with brine, dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H) -dione (4.20 g), used without further purification. Mass spectrum m/z 349, 351 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[N:5]=1.[CH3:39]O>>[CH3:39][O:23][C:22]([C:16]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:8]3[CH:7]=[C:6]([NH:25][CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=4)[N:5]=[C:4]([O:3][CH3:2])[N:9]=3)[CH:11]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:24]
Reactant: CO
Reactant: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Agent: Cl
Product: COC(=O)C1(c2cccc(-c3cc(NCCc4ccc(OC(F)(F)F)cc4)nc(OC)n3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 43.5 μL, 0.17 mmol) is added to a solution of N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid (45 mg, 0.09 mmol) in methyl alcohol (4 mL) and the reaction mixture is stirred overnight at 70° C. The reaction is cooled to room temperature, quenched with water. The volatiles are removed in vacuo. The aqeous is extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluted with ethyl acetate/heptane to afford 4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester [86 mg, Example 84(b)]. LCMS: RT=2.48 minutes, MS: 532 (M+H). IC50=70 nM
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:24]1[CH3:33]
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 27c using 2-(4-fluorobenzenesulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[CH2:22]([CH:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[S:8][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)sc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzothiazole-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 196-199° C. (diethylether)
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B(F)(F)[F:16].F>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([F:16])[CH:7]=1
Reactant: Nc1cc(Br)ccc1-c1ccccc1
Reactant: FB(F)F
Agent: F
Product: Fc1cc(Br)ccc1-c1ccccc1

Procedure:
2-Amino-4-bromo-biphenyl was subjected to a Schiemann reaction using hydrofluoroboric acid. The product had a b.p. of 106°-109°C./0.6mm, and a m.p. of 38°-39°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.O1CCCC1>C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)N=C=S
Reactant: OCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)OCc1ccc(Cl)cc1
Yield: 58.2 %

Procedure:
90 g of ethoxycarbonyl isothiocyanate were added dropwise to a mixture of 85 g of p-chlorobenzyl alcohol, 600 ml of tetrahydrofuran and 4 ml of triethylamine and the mixture was refluxed for 24 hours and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl alcohol and the precipitate formed was recovered by vacuum filtration to obtain 95 g of p-chlorobenzyl N-carbethoxy-thiocarbamate melting at 95° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:29][OH:30]>CCO.O>[OH:30]/[N:29]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=N/O)cc2)CC1
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (3.89 g, 13.41 mmol, prepared as described in Example 10) and K2CO3 (1.02 g, 7.38 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (1.4 g, 20.1 mmol) in water (saturated, approx. 2 mL) and the reaction mixture stirred overnight. The reaction was filtered, concentrated in vacuo, water was added and the product filtered to afford tert-butyl 4-{4-[(E)-(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:24]([CH2:27][CH3:28])[CH2:23][CH2:22][NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)=[CH:3][N:4]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19])[CH3:26]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 85, step 1, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-(2-diethylaminoethyl)benzenesulfonamide (100 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (17 mg, 0.086 mmol), Pd(PPh3)4 (9 mg, 0.007 mmol) and NaOtBu (27 mg, 0.29 mmol) in DMF:water (3:1, 6 mL). The crude residue is chromatographed on silica gel, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH). The fractions containing the desired product are combined and evaporated, to afford the title compound as a yellow solid. HPLC (254 nm): Rt 2.04 min (97.2%); m/z (APCI) 455 (M+H)+
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1([C:15]([F:22])([F:21])[C:16]([O:18]CC)=O)[C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[C:8](=[O:10])[C:7]([F:13])([F:14])[C:2]2([S:1][CH2:6][CH2:5][CH2:4][S:3]2)[C:15]([F:21])([F:22])[C:16]1=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(F)(F)C1(C(F)(F)C(=O)OCC)SCCCS1
Product: O=C1N(Cc2ccccc2)C(=O)C(F)(F)C2(SCCCS2)C1(F)F

Procedure:
React 7.2 mmol of the product of Example 20 with benzylamine using the general procedure set forth in Example 8, and purify by silica gel chromatography using ethyl acetate/hexane as eluant to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:48][OH:49]>C1COCC1>[F:30][CH:29]([F:31])[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:17]([N:13]2[C:14](=[O:16])[C:15]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12]2)[CH2:18][C:19](=[O:20])[NH:48][OH:49])=[CH:23][C:24]=1[O:32][CH2:33][CH3:34]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 72.1 %

Procedure:
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 8 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and hydroxylamine hydrochloride (0.23 g, 3.6 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.60 g, 80% yield): mp 116-118° C.; 1H NMR (CDCl3): δ 0.82 (m, 2H, c-CH2), 1.02 (m, 2H, c-CH2), 1.36 (t, J=6.8 Hz, 3H, OCH2CH3), 1.58 (m, 1H, c-CH), 2.86 (dd, J=5, 15 Hz, 1H, CH2), 3.15 (dd, J=10, 15 Hz, 1H, CH2), 3.30 (broad, 1H, NHOH), 4.01 (q, J=7.0 Hz, 2H, OCH2CH3), 4.02 (d, J=17.5 Hz, 1H, CH2N), 4.34 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.71 (m, 1H, CHN), 6.07 (broad, 1H, NHOH), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 6.88 (m, 3H, Ar), 7.07 (d, J=7.5 Hz, 1H, Ar), 7.30 (t, J=7.5 Hz, 1H, Ar), 8.28 (d, J=8 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.27, 8.39, 14.5, 16.0, 35.4, 47.3, 52.4, 64.8, 111.8, 113.3, 115.9, 116.9, 117.0, 118.9, 120.0, 122.6, 133.3, 136.6, 137.6, 140.0, 141.5, 150.8, 167.5, 169.7, 172.8; Anal. Calcd. for C24H25F2N3O6+0.34H2O: C, 58.16; H, 5.22; N, 8.48; Found: C, 58.25; H, 5.37; N, 8.58, 1.25H2O