Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C29H28ClFN7O4S (M+H)+: m/z=624.0.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[O:4][CH:5]([CH:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[OH:20])[NH:13][CH:12]=2)[CH3:10])[C:6](=[O:8])[N:7]=1.[CH3:22]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:21][N:2]([CH3:1])[C:3]1[O:4][CH:5]([CH:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:22])[NH:13][CH:12]=2)[CH3:10])[C:6](=[O:8])[N:7]=1
Reactant: CC(c1c[nH]c2cccc(O)c12)C1OC(N(C)C)=NC1=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc2[nH]cc(C(C)C3OC(N(C)C)=NC3=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-dimethylamino-5-[1-(4-hydroxyindol-3-yl)ethyl]2-oxazolin-4-one (120 mg) was dissolved into dimethylformamide (3 ml). Potassium carbonate (115 mg) and indomethane (156 l) were added. The mixture was stirred for 3 hours at room temperature and additional indomethane (78 μl) was added. The mixture was stirred for 36 hours at room temperature. To the reaction mixture was added water and the whole was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the ethyl acetate solution gave a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided 2-dimethylamino-5-[1-(4-methoxyindol-3-yl)ethyl]-2-oxazolin-4-one (54 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][C:15]([NH:17][CH3:18])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][NH:17][CH3:18])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(CCC(=O)NC)cc1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(CCCNC)cc1OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 0.26 g of 3-(3,4-diethoxy-phenyl)-N-methyl-propionamide in 5 mL THF was added 1.4 mL of a LiAlH4 solution (2.3M in THF) at 0° C. The reaction mixture was stirred for 1 h at rt and for 2 h at 60° C. At rt, a 1M NaOH solution was added dropwise. The resulting mixture was filtrated over a pad of celite, washed with THF and the filtrate concentrated in vacuo. Purification by CC with EtOAc-MeOH (7:3) yielded 0.13 g of [3-(3,4-diethoxy-phenyl)-propyl]-methyl-amine as yellow oil.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2OCC[O:10]2)[N:4]=1>C(O)=O>[F:14][CH:2]([F:1])[C:3]1[N:4]=[C:5]([CH:9]=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)c1cccc(C2OCCO2)n1
Solvent: O=CO
Product: O=Cc1cccc(C(F)F)n1
Temperature: 60 °C
Yield: 53 %

Procedure:
To a solution of 2-(difluoromethyl)-6-(1,3-dioxolan-2-yl)pyridine (0.5 g, 2.4 mmol) was added 85% formic acid (5 mL). The reaction mixture was warmed to 60° C. for 1.5 h. The mixture was then concentrated under reduced pressure, diluted with ice cold water, neutralized with aqueous sodium hydroxide (4N) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated and purified via flash chromatography to afford 6-(difluoromethyl)picolinaldehyde (0.2 g, 51%). MS (ES+) (M+H) 158.16; LCMS retention time: 5.28 min (Method H).
Reaction SMILES: [OH-].[K+].[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([O:9]CC)=[O:8]>C(O)C>[OH:3][CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]#[C:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCC(O)C#CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(O)C#CC(=O)O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of potassium hydroxide (885 mg, 15.8 mmol) in 95% ethanol (35 ml) was added to ethyl 4-hydroxytridec-2-ynoate (2.68 g, 10.5 mmol) in the same solvent (5 ml) at 0°. After stirring at room temperature for 9 hours, most of the solvent was removed and water (20 ml) was added. The mixture was extracted thoroughy with dichloromethane (discarded), acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate. Evaporation of the dried (magnesium sulphate) ethyl acetate extracts gave an off-white solid, which on recrystallization from petroleum ether (at -78°) gave the title acid as colorless prisms: mp 65°-6°.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH2:9][C:10]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(NC(C)C)(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:13]([C:10]1([CH2:9][C@H:4]([CH2:5][C:6]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:8])[C:3]([OH:2])=[O:20])[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1(Cc2ccccc2)CC1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-2-(1-Benzyl-cyclopropylmethyl)-succinic acid 1-methyl ester (2.453 g, 8.88 mmol), di-isopropyl amine (1.1 eq, 9.76 mmol, 1.26 g) and morpholine (1.5 eq., 13.3 mmol, 1.16 g) in dry dichloromethane under N2 was added PyBOP (1.1 eq., 9.76 mmol, 5.08 g). The mixture was stirred at room temperature for 5 hr, and concentrated in vacuum. The residue was dissolved in ethyl acetate (150 mL) and washed with water (100 mL), NH4Cl (100 mL), NaHCO3 (2×100 mL), then water (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuum. The residue was purified over 120 g silica gel, eluted with ethyl acetate:heptane (1:1.5, 1:1, to 2:1) to afford the desired compound contaminated with PyBOP residues. A solution of the mixture in ether containing ethyl acetate (250 mL total) was washed with dilute HCl (150 mL), water (150 mL) dilute NaOH (150 mL) then water (150 mL). The organic layer was dried (MgSO4) and concentrated in vacuum to afford (R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid methyl ester as a white solid (2.292 g, 74.7% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO.O>[N:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:20][CH:21]=1
Reactant: Sc1ccncc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCc2cc(OCCCCSc3ccncc3)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.0 gm of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril were added to a solution of 1.3 gm of 4-mercapto-pyridine and 2.3 gm of a 30% sodium methylate solution in 15 ml of methanol, and the mixture was stirred for 14 hours at room temperature. Subsequently, the reaction solution was diluted with 20 ml of water and the resulting precipitate was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCBr
Yield: 81.6 %

Procedure:
Starting with 0.381 g (1.03 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 2.13 g (8.26 mmol) of 1,7-dibromoheptane, the title compound was obtained as a colorless oil, in 81.6% yield, using the procedure of example 21.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21](Cl)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:30]4[N:29]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:36]=3)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2ncccn2)c1
Reactant: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 95 °C

Procedure:
To a mixture of (R)-benzyl-1-((6-chloro-5-cyanopyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate (80 mg, 0.20 mmol) in Dioxane (2 mL) was added 3-(pyrimidin-2-yl)aniline (41 mg, 0.24 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), BINAP (25 mg, 0.04 mmol) and K2CO3 (83 mg, 0.6 mmol). After heating at 95° C. for 2 h, the mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to give (R)-benzyl-1-((5-cyano-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sulfur trioxide pyridine complex (800 mg, 5.0 mmol) was added to a solution of 3-[5-methyl-3-(1-naphthalenylsulfonyloxy)phenoxy]propanol (600 mg, 1.6 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (60 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (540 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 9.76 (s, 1H), 8.80 (d, J=8.6 Hz, 1H), 8.14 (d, J=7.7 Hz, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.35 (s, 1H), 6.20 (s, 1H), 4.02 (t, J=6.1 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H), 2.15 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:36]=[CH:35][C:14]([O:15][C:16]2[C:21]([C:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:24][CH:23]=[C:22]([C:21]2[C:16]([O:15][C:14]3[CH:35]=[CH:36][C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCNC1

Procedure:
Tert-butyl 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (501.9 mg) was taken up in DCM and TFA was added. Upon completion, the solvent was evaporated. The residue was taken up in DCM and loaded onto an Agilent SCX cartridge. The impurities were washed from the cartridge with DCM and MeOH. N-(4-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine was filtered from cartridge using 2.0M ammonia in MeOH. MS (ESI, pos. ion) m/z: 401.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH2:34][O:35][CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:33][CH2:34][O:35][CH3:36])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]([NH2:21])=[O:20])[CH3:2]
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCOC)c(OC)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.22 g, 0.65 mmol), DMF (15 ml), Cs2CO3 (0.64 g, 1.98 mmol), and 2-bromoethylmethylether was stirred at 100° C. for 2 h. The reactionmixture was evaporated and chromatographed on furnishing the title compound (0.045 g, 18%.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:7]=1[CH:8](OC)[O:9]2.[Br-].[Br:27][C:28]1[S:32][C:31]([Zn+])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:27][C:28]1[S:32][C:31]([CH:8]2[C:7]3[CH:16]=[C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:19][C:6]=3[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[O:3][CH:2]([F:25])[F:1])[O:9]2)=[CH:30][CH:29]=1
Reactant: COC1Oc2cccc(OC(F)F)c2-c2ccc(NS(C)(=O)=O)cc21
Reactant: [Zn+]c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(c1ccc(Br)s1)Oc1cccc(OC(F)F)c1-2
Reaction time: 0.08 h

Procedure:
A solution of Example 96C (50 mg, 0.13 mmol) in dichloromethane (20 ml) at −20° C. was treated with borontrifluoridediethyletherate (184 mg, 1.3 mmol) dropwise, stirred for 5 minutes, treated with 5-bromo-2-thienylzincbromide (7.8 ml of 0.5M solution in THF, 3.9 mmol) dropwise over 2 minutes, stirred for 15 minutes, treated with saturated NaHCO3 solution (15ml), extracted with dichloromethane. The extract was concentrated and the concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product. MS (ESI(−)Q1MS) m/z 500 and 502 (M−H)−; 1H NMR (400 MHz, CD3OD) δ 8.29 (d, J=9 Hz, 1H), 7.32 (dd, J=9 Hz, 2 Hz, 1H), 7.21(t, J=9 Hz, 1H), 7.16 (d, J=2 Hz, 1H), 6.88 (t, J=74 Hz, 1H), 6.84-6.89 (m, 3H), 6.59 (dd, J=4 Hz, 1Hz, 1H), 6.39 (s, 1H), 3.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[OH-].[Na+]>Cl.O1CCOCC1.O>[CH3:1][O:2][CH:3]1[CH:8]([NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC1CNCCC1NC(=O)c1ccccc1

Procedure:
To a solution of 1,1-dimethylethyl 3-(methyloxy)-4-[(phenylcarbonyl)amino]-1-piperidinecarboxylate D20 (4.0 g) in HCl/1,4-dioxane (30 ml) was stirred at room temperature for overnight. The resulting mixture was dissolved in water (50 ml) and basified with sodium hydroxide to pH 10.0 then extracted with DCM (3×100 ml). The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to desired product D21 as an oil in 500 mg. LCMS [MH+] 235@1.17 and 1.19 (isomers) (5 min run)
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([CH3:16])[C:13]=2[OH:15])[CH2:8][CH2:7]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([NH:5][CH:6]1[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([CH3:16])[C:13]=2[OH:15])[CH2:8][CH2:7]1)(=[O:21])=[O:20]
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(c1O)C(NS(C)(=O)=O)CC2
Reaction time: 4 h
Yield: 22.7 %

Procedure:
Into 100 ml of a chloroform solution containing 1.77 g of 1-amino-4,6-dimethyl-7-hydroxyindane and 2 ml of triethylamine was added dropwise 1.72 g of methanesulfonyl chloride at a room temperature, the mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed with a diluted hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, in this order, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was recrystallized from ether-n-hexane to obtain 0.58 g of 1-methanesulfonylamino-4,6-dimethyl-7-hydroxyindane in the form of colorless powdery substance. Melting point: 114°-116° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2 (1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2 (1H)-pyrimidinone.
Reaction SMILES: OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:13][C:14]1([CH3:21])[C@H:19]([OH:20])[C:17](=[O:18])[O:16][CH2:15]1.[OH-].[Na+]>>[CH3:13][C:14]1([CH3:21])[C@@H:19]([OH:20])[C:17](=[O:18])[O:16][CH2:15]1
Reactant: CC1(C)COC(=O)[C@H]1O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC1(C)COC(=O)[C@@H]1O
Temperature: 80 °C

Procedure:
The aqueous phase (21 ml; Na L-pantoate) was adjusted to pH 1 with about 5 ml of 3 M H2SO4, heated at 80° C. for 15 min and mixed with 8 g of anhydrous Na2SO4. The resulting L-pantolactone was analogously extracted 3× with one volume of ethyl acetate, dried with Na2SO4 and evaporated. For recycling to the hydrolysis, the L-pantolactone melt can be racemized by heating after addition of NaOH in the presence of small amounts of Na L-pantoate (180° C., 3 h).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].OC(C(F)(F)F)=O.[O:14]=[C:15]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19].[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Br>CN(C=O)C>[F:38][C:39]([F:48])([F:49])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][N:35]1[CH2:36][CH2:37][N:32]([C:15](=[O:14])[CH2:16][NH:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[O:19])[CH2:33][CH2:34]1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Yield: 55.4 %

Procedure:
K2CO3 (50.5 mg, 0.37 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (80 mg, 0.18 mmol) in DMF (3 mL). 2-Trifluoromethyl benzyl bromide (52.2 mg, 0.22 mmol) was then added, and the resulting mixture was heated to 90° C. overnight. The product was extracted with ethyl acetate and the ethyl acetate layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 48 mg (45.7% yield) of biphenyl-4-carboxylicacid {2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 94.3%, 1H NMR: (CDCl3) δ 7.9 (d, 2H), 7.8-7.7 (d, 1H), 7.7-7.6 (m, 5H), 7.55 (m, 1H), 7.5 (m, 2H), 7.4 (m, 3H), 4.3 (d, 2H), 3.7 (s, 4H), 3.5 (t, 2H), 2.5 (q, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:12])=[CH:8][C:9]=1[CH3:11])[C:4]([OH:6])=[O:5])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 2,4,6-trimethylbenzoic acid (4.6 g, 28 mmol) in 70% HNO3 (85 mL) conc. H2SO4 (5 mL). was added dropwise at RT. The brown reaction mixture was stirred for 1 h, poured into ice-water (500 mL). The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 3-nitro-2,4,6-trimethylbenzoic acid as a yellow solid (6.7 g, 94%).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]=2[C:4](=[O:13])[N:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+].I[CH2:32][CH3:33]>C(#N)C>[CH2:32]([S:1][C:2]1[N:3]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:18][CH:19]=2)[C:4](=[O:13])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1)[CH3:33]
Reactant: CCI
Reactant: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,5,6-tetrahydropyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione (0.1 g) in acetonitrile (2 mL) were added 1M aqueous sodium hydrogen carbonate solution (0.269 mL) and iodoethane (0.109 mL), and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.08 g).