Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[C:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)[O:9][CH2:10][CH2:11]I)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH3:28]>C(=O)=O>[NH2:28][CH2:11][CH2:10][O:9][C:8](=[C:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Reactant: N
Agent: O=C=O
Solvent: C1CCOC1
Product: NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1
Temperature: 40 °C
Yield: 90 %

Procedure:
A solution of [(3-hydroxyphenyl)(2-iodoethoxy)methylene]adamantane (3.0 g, 0.01 mol)in a minimum amount of THF was added into 10 mL of liquid ammonia in a sealed tube which was kept in dry ice. After sealing the tube this was heated at 40° C. in an oil bath for 17 h. The reaction mixture was cooled down and solvent evaporated to obtain a white solid. This material was extracted with methylene chloride. The combined organic layers were washed with water, dried over MgSO4, and concentrated to give 2.0 g (90%) of the product as a white solid: mp 55° C.; 1H NMR (CDCl3) δ1.77-1.96 (m, 12H), 2.68 (bs, 1H), 2.85 (t, 2H, J=4.8 MHz), 3.23 (bs, 1H), 3.48 (t, 2H, J=4.8 MHz), 4.46 (bs, 2H), 6.70-7.17 (m, 4 H); 13C NMR (CDCl3) δ28.16, 30.28, 32.19, 36.99, 38.88, 39.04, 41.33, 70.45, 114.97, 116.17, 120.63, 129.02, 131.89, 136.69, 141.79, 156.86; MS m/e (rel intensity) 299 (10), 256 (100), 239 (5), 199 (6), 135 (12), 121 (27), 93 (12), 77(5). Exact mass: calcd 299.1885, found: 299.1891. ##STR31##
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH2:22])[CH2:19]2.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH:22][C:8](=[O:10])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:19]2
Reactant: O=C(O)c1cccc(Br)n1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), 2-adamantylamine hydrochloride (558 mg, 2.97 mmol), N,N-diisopropylethylamine (1.30 ml, 7.44 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 602 mg of white solid (73%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH2:16])[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=2)=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)#[N:30]>CN(C)C=O>[NH2:16][C:14]1[C:13]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:12][N:11]=[C:10]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:1]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[C:29]#[N:30])[N:2]=2)[N:15]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Nc1nc(-c2n[nH]c3ncccc23)ncc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cn1nc(-c2ncc(-c3ccncc3)c(N)n2)c2cccnc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
60 mg (0.21 mmol) of 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(4-pyridinyl)-4-pyrimidinylamine from Example 35 A are suspended in 6 ml of dimethylformamide under argon. Addition of 26.38 mg (0.25 mmol) of sodium carbonate is followed by stirring at 50° C. for one hour. Then 40.66 mg (0.21 mmol) of 2-cyanobenzyl bromide are added thereto, and the mixture is stirred at 50° C. overnight. For work up, the mixture is filtered and the filtrate is adjusted to pH 4–5 with 1 normal hydrochloric acid and purified by preparative RP-HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.8 %

Procedure:
To a solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) in pyridine (3.00 mL) was added benzenesulfonyl chloride (0.75 mL, 5.78 mmol) dropwise at 0° C. The mixture was stirred for 40 min at room temperature. The resulting solid was filtered, washed with water, and dried under vacuum to give N-(5-bromopyridin-3-yl)benzenesulfonamide (1.39 g, 77%) as a brown solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.58-7.68 (4H, m), 7.79-7.81 (2H, m), 8.27 (1H, d, J=2.4 Hz), 8.37 (1H, d, J=2.0 Hz), 10.91 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][OH:23])=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(CO)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution (30 mL) of ethyl 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (2.85 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/l toluene solution (12.8 mL) of diisobutylaluminum hydride was added dropwise over 30 min, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a brown oil (yield 2.29 g, 91%).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl>C1C=CC=CC=1>[C:10]([CH:9]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([F:17])[CH:19]=1)[C:8]([O:14][CH2:15][CH3:16])=[O:13])(=[O:11])[CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1cccc(F)c1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mL of 10% dimethylformamide in benzene was added 58.6% NaH (41 g, 1.0 mol) cooled in an ice bath was added ethyl acetoacetate (130 g, 1.0 mol) was added. The reaction was stirred at room temperature for 30 minutes, and m-fluorobenzyl chloride (145 g, 1.0 mol) was added. The reaction was heated to reflux for 3 hours and gave an NaCl precipitate which was then removed by filtration. The filtrated was poured into H2O, acidified with concentrated HCl and was extracted with a mixture of ether and benzene. The organic layer was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by distillation (112-119° C./25 mmHg) to give compound A (133 g, 56%).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16]([O-:19])(O)=[O:17].[Na+]>N1C=CC=CC=1.CCCCCC>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][C:16]([O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:17])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC(=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of triethylsilyloxy keto diol 6 (883 mg, 2.31 mmol) in 35 mL of pyridine under nitrogen at 0° C. was added dropwise 0.485 mL(2.771 mmol) of TBSOTf. The solution was then warmed to room temperature. After 2 h at room temperature, the solution was diluted with 100 mL of hexane and poured into 150 mL of a saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with two 100 mL portions of hexane. The organic layers were combined, and washed with 50 mL of a 10% aqueous CuSO4 solution followed by 20 mL of H2O, and dried over anhydrous Na2SO4. Removal of the solvent followed by flash chromatography purification (2.5% EtOAc/hexane) to give 1.122 g of t-butyldimethylsilyloxy ketone 7 (98% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+]([C:17]1C=CC=C[C:18]=1C(O)=O)([O-])=O.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[C:9]2[C:10]=1[NH:11][CH:18]=[CH:17]2
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1Cl
Temperature: -45 °C
Yield: 90 %

Procedure:
A two liter 3-neck flask was assembled with an overhead stir, flame dried and flushed with nitrogen. To this was added 1.0 equivalent of 2-chloro-3-nitrobenzoic acid (30 grams, 148.8 mmol) in 300 mL dry THF. The flask was then cooled to −45° C. with the aid of an ethanol/dry ice bath. 4.0 equivalents of cold Vinyl Grignard reagent (Aldrich, 1M Sure/Seal™ bottles) was then cannulated into the solution of nitrobenzoic acid. An additional 100 mL of dry THF was then added via cannula to the very thick solution. The flask was allowed to slowly warm to room temperature overnight. In the morning, the flask was cooled to 0° C. with an ice bath and 400 mL of saturated NH4Cl was added in four portions. The mixture was stirred for one hour then transferred to a separatory funnel and extracted with ethyl acetate (300 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4 and evaporated to dryness on the rotovap. The aqueous layer was acidified to pH=2 with 2M HCl. The resulting solid was filtered, combined with the above isolated solid and dried in a vacuum desiccator over night to yield 26.32 grams (90%) of a tan powder that was used without further purification. 1H NMR (300 MHz): (CD3OD) δ 7.59 (d, J=8.42 Hz, 1H), 7.49 (d, J=8.42 Hz, 1H), 7.42 (d, J=2.93 Hz, 1H), 6.53 (d, J=2.93 Hz, 1H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=195.92, 197.92, HPLC Rt=1.018 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)C3CC3)ccc2n1
Yield: 79 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (64 mg, 0.2 mmol) was converted, using cyclopropancarboxylic acid instead of cyclopropylacetic acid, to the title compound (57 mg, 79%) which was obtained as a light brown solid. MS: m/e=359.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2c(Cl)cccc2Cl)c1

Procedure:
Alkylation reaction of phenol 58 with 2,6-dichlorobenzylbromide gave 2-(3-(3-(2,6-dichlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.780 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.82-7.85 (m, 2H), 7.69-7.72 (m, 2H), 7.35-7.38 (m, 1H), 6.86-6.79 (m, 2H), 6.81 (s, 1H), 6.80 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 3.76 (t, J=6.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.00-2.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:29]=O)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:29][NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: Cn1cc(F)cc(C=O)c1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cn(C)c4=O)nc3F)c2c1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 3.99 g, 15.59 mmol) and 5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (33, 2.66 g, 17.15 mmol) in 50 mL of acetonitrile, triethylsilane (9.96 mL, 62.4 mmol) and trifluoroacetic acid (4.80 mL, 62.4 mmol) were added. The reaction was stirred at 80° C. for several hours, then concentrated under vacuum and the residue was taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum, and the residue purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the residue triturated with methanol to provide the desired compound (P-2156, 3.1 g, 7.84 mmol, 50.3% yield).
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]=[O:25]>>[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]=[C:24]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][O:25]1
Reactant: CC(C)CN[C@H](CCl)CC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OC[C@H](CC(C)C)N1CC(C)C

Procedure:
(L)-Leucine methyl ester was reduced to (1S)-1-(hydroxymethyl)-3-methylbutylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-3-methylbutylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-3-methylbutylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-oxazolidine.
Reaction SMILES: [CH:1]1([C:7]([C:9](=[CH:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[C:10]([O:12]CC)=O)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C:7]([C:9]2[C:10](=[O:12])[C:22]3[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C1CCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c(=O)c(C(=O)C3CCCCC3)c[nH]c12
Yield: 35 %

Procedure:
Ethyl 2-cyclohexylcarbonyl-3-(2-methoxyphenylamino)acrylate (20 g, 0.06 mol) was added in portions to boiling diphenyl ether (200 ml) and the mixture was heated under reflux for 1.5 hours. When cool, the mixture was diluted with petroleum ether and allowed to crystallise overnight to give 3-cyclohexylcarbonyl-8-methoxy-4(1H)-quinolone (6.0 g, 35.2%), m.p. 168°-70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[C:29]=4[F:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4F)c3O2)cc1
Yield: 16.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-difluorophenyl)boronic acid (0.618 g, 3.91 mmol) generally according to the procedure described for Intermediate 184 provided 0.090 g (77%) of (±)-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:23])=[CH:14][CH:13]=1>ClCCl>[O-:6][N+:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:23])=[CH:14][CH:13]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Chloroperoxybenzoic acid (2.06 g of 70%, 8.4 mmol) is added to a stirred mixture of 2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (Example 14; 1.86 g, 5 mmol) in dichloromethane (50 mL) at 0° C. The resulting mixture is then stirred at room temperature for 15 hours. The mixture is diluted with dichloromethane (100 mL) and washed sequentially with aqueous sodium hydroxide (2×100 mL) and aqueous sodium thiosulphate (2×50 mL of 10%). The organic phase is dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethanol in ethyl acetate, and recrystallised from ethyl acetate-hexane to give the title compound as a colourless crystalline solid, m.p. 181-184° C.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)=O)(C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:19]1([CH2:18][CH:17]([C:15]2[NH:14][C:11]3=[N:12][CH:13]=[C:8]([C:6]#[N:5])[CH:9]=[C:10]3[CH:16]=2)[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)NC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C#N)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 17.4 %

Procedure:
To a stirred solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid tert-butylamide (240 mg, 0.51 mmol) in chloroform (5 mL) was added phosphorus oxychloride (0.72 mL, 7.71 mmol) at room temperature. The mixture was heated at 80° C. and stirred for 3 h. The resulting mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carbonitrile (35 mg, 14.9%) as a white solid: LC/MS m/e calcd for C22H23N3O2S [M+H]+ 394.51, observed 393.8; 1H NMR (400 MHz, CD3OD) δ ppm 8.42 (s, 1H), 8.26 (d, J=1.5 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 6.54 (s, 1H), 4.34 (t, J=8.0 Hz, 1H), 3.32-3.32 (m, 1H), 3.31 (s, 8H), 3.09 (s, 2H), 2.24-2.32 (m, 1H), 2.10-2.18 (m, 1H), 1.60-1.87 (m, 3H), 1.44-1.55 (m, 1H), 1.17-1.32 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][CH2:12][C:11]1[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:10]=1[C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1C=O
Product: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CNCc1ccccc1

Procedure:
2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzaldehyde and benzylamine were reacted as described in Example 17, Step 1 to provide benzyl-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-])=O.[BH4-].[K+].[H][H]>CO.Cl[Cu]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: [H][H]
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C

Procedure:
To a suspension of 6-nitro-2H-1,4-benzoxazin-3(4H)-one 1 (0.5 g, 0.0026 mol) and CuCl (0.77 g, 0.0078 mol) in anhydrous methanol (25 mL), stirred at 25° C. was added potassium borohydride (0.98 g, 0.018 mol) in portions (exothermic with evolution of hydrogen gas). The reaction mixture was stirred at 25° C. for 30 min. The black precipitate formed was filtered and washed with methanol. The combined filtrate and washings was evaporated to give 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one which was purified by silica gel column chromatography using ethyl acetate. Brown solid (0.29 g, 67%). 1H NMR (400 MHz, CDCl3): δ 4.34 (s, 2H); 4.81 (s, 2H); 6.09 (dd, J=2.8, 8.4 Hz, 1H); 6.14 (d, J=2.8 Hz, 1H); 6.59 (d, J=8.4 Hz, 1H); 10.44 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH:31]([F:33])[F:32])[C:25]3=[N:24][CH:23]=2)=[N:5][C:6]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=[O:16])[CH3:11])=[N:7][CH:8]=1)#[N:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:3]1[C:4]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH:31]([F:32])[F:33])[C:25]3=[N:24][CH:23]=2)=[N:5][C:6]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[CH3:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cccc(C(C)Nc2ncc(C#N)c(-c3cnc4c(C(F)F)cccn34)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
370 mg of the methyl 3-[1-({5-cyano-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amino)ethyl]benzoate [100-3] was suspended in a mixture solvent of 6 mL of methanol and 6 mL of tetrahydrofuran, then 4.15 mL of 1N aqueous solution of sodium hydroxide was added, and stirred at 50° C. for 30 minutes. Under an ice-cold condition, 825 μL of 5N hydrochloric acid was added, then the reaction solution was neutralized and concentrated under reduced pressure. The obtained residue was purified by preparative reversed phase liquid chromatography, and 216 mg of 3-[1-({5-cyano-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amino)ethyl] benzoic acid [100-4] was obtained as a pale yellow solid.