Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][SH:35]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: CN(C)CCS
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: Cl
Product: COc1nc(SCCN(C)C)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.3 g) and 2-(dimethylamino)ethanthiol hydrochloride (0.2 g). Yield 0.25 g.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[F:31][C:32]([F:44])([F:43])[S:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1.CO.ClCCl>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([S:33][C:32]([F:43])([F:31])[F:44])=[CH:35][CH:36]=3)=[O:42])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)Nc3ccc(SC(F)(F)F)cc3)cc2)cc1)C(=O)O
Yield: 57 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; (0.547 mmole) was dissolved in tetrahydrofuran (5 ml). Sodium hydrogencarbonate (0.051 g; 0.607 mmole) was added and the mixture was stirred for a little while. 4-(Trifluoromethylthio)phenyl isocyanate (0.126 g; 0.575 mmole) was added. The reaction mixture was stirred at room temperature for 6 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of residue on silica gel (isolute, SI) using dichloromethane, methanol:dichloromethane (1:99) and then methanol:dichloromethane (2:98) as eluants gave 0.17 g (57% yield) of (S)-2-ethoxy-3-[4-(2-{4-[({4-[(trifluoromethyl)sulfanyl]anilino}carbonyl)amino]phenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH3:20])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)C.[OH-].[K+].CO>O>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH:7]=[C:6]([CH:5]([CH3:20])[C:4]([OH:21])=[O:3])[CH:18]=[CH:17][C:16]2=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(O)cc12
Yield: 48.5 %

Procedure:
A mixture consisting of 6-hydroxy-a-methyl carbazole-2-acetic acid ethyl ester (5.0 g, 0.021 mol), potassium hydroxide (5.0 g, 0.089 mol), methanol (300 mL), and water (20 mL) is refluxed for 15 hours. The reaction mixture is cooled concentrated and acidified with a 1:1 solution of concentrated HCl and water to pH 1. The aqueous layer is extracted with ether (4×300 mL), washed with water (200 mL), brine (200 mL), dried over MgSO4, filtered and concentrated to give 2.6 g of product as a foam.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:26])[C:11]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)([NH2:18])C1C=CC=CC=1)[CH2:2]2.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>C(#N)C>[Br-:27].[O:30]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:26])[CH:11]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][C:24]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18])[CH2:2]2
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(C(N)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1ccc(C(N)C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c(-c2ccccc2)c1
Product: [Br-]
Temperature: 100 °C
Yield: 117.3 %

Procedure:
To a solution of 4-methyl-phenyl-amino-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (C245) (63.5 mg, 0.18 mmol) in acetonitrile (5 mL), is added 2-bromo-1-phenyl-ethanone (36 mg, 0.18 mmol) and the mixture was heated at 100° C. for 1 hour in a MW oven (UPLC-MS monitoring: complete conversion). Solvent is evaporated and the resulting crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a white solid (58 mg, 32% yield, bromide salt, mixture of diastereoisomers).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])=[CH2:20].[H-].[Na+]>C1(C)C=CC=CC=1>[F:16][C:14]([F:17])([F:15])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=1)[C:3]([CH:23]1[CH2:24][CH2:25][N:21]([CH:19]=[CH2:20])[C:22]1=[O:26])=[O:18]
Reactant: C=CN1CCCC1=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CN1CCC(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Reaction time: 12 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)-benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil. A solution of 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodium hydride (60% suspension in mineral oil—0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 hrs, then it was partitioned between saturated ammonium chloride solution and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (1.6 g) as a beige oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH:15]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14])([CH3:17])[CH3:16]
Reactant: Brc1nccs1
Reactant: CC(C)c1ccc(N)cc1O
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.40 mL, 4.48 mmol), 5-amino-2-isopropylphenol (339 mg, 2.24 mmol) and 37% HCl solution (0.37 mL, 4.48 mmol) in 10% aqueous EtOH solution (10 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69% yield (360 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]([NH2:20])=[O:19])=[N:14][C:13]=3[N:21]=2)=[CH:5][CH:4]=1)=O.[Cl-].[O:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:32][NH3+:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.CN(C=O)C.O>[O:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:32][NH:33][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]([NH2:20])=[O:19])=[N:14][C:13]=3[N:21]=2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: [NH3+]CCC(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NC(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(CNCCC(=O)c4ccccc4)cc3)nc2n1
Reaction time: 0.5 h

Procedure:
A mixture of 7-(4-formylphenyl)-6-phenylpyrido[2,3-d]pyrimidine-2-carboxamide (2-6) (0.033 g, 0.093 mmol), 3-oxo-3-phenylpropan-1-aminium chloride (0.031 g, 0.168 mmol), and TEA (0.023 mL, 0.168 mmol) in 5% CH3COOH in DMF (0.5 mL) was stirred for 4 hr at which point NaBH(OAc)3 (0.039 g, 0.186 mmol) was added. The mixture was stirred for a 30 min. further. 2 drops of water were added and the material was purified by reverse phase HPLC. 1H-NMR (500 MHz, d6-DMSO) δ 9.90 (s, 1H), 8.88 (bs, 2H), 8.79 (s, 1H), 8.43 (s, 1H), 7.99 (d, 3H, J=7.3 Hz), 7.70 (t, 1H, J=7.1 Hz), 7.62-7.53 (m, 3H), 7.50 (d, 2H, J=8.3 Hz), 7.43-7.31 (m, 6H), 4.31-4.34 (m, 2H), 3.50 (t, 2H, J=6.6 Hz), 3.36-3.26 (m, 2H); LRMS, calc'd: 488.1; found 488.1.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Li][CH2:9]CCC.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][C:16]=1[C:23]1[C:32]([CH3:33])=[CH:31][C:30]2[C:29]([CH3:35])([CH3:34])[CH2:28][CH:27](C)[CH:26]([CH3:37])[C:25]=2[CH:24]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:17][C:16]=1[C:23]1[C:32]([CH3:33])=[CH:31][C:30]2[C:29]([CH3:35])([CH3:34])[CH2:28][CH2:27][C:26]([CH3:37])([CH3:9])[C:25]=2[CH:24]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(CBr)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CC2SC(=O)NC2=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl alcohol (195 mg, 0.57 mmol) in acetic acid (glacial, 3 mL) was added HBr (48%, 1 mL) and the resulting mixture heated at reflux for 2 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 200 mg of crude 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide. To a stirred solution of 2,4-thiazolidinedione (133 mg, 1.14 mmol) in anhydrous THF (6 mL) was added, at −78° C. under argon, n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) dropwise. The mixture was maintained at −78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to −78° C., 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide was added in THF (3 mL). After 30 minutes the orange solution was allowed to warm to room temperature. After 1.5 hours, the solution was treated with 2N HCl, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane 2:8) to give 61 mg of 5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl] thiazolidine-2,4-dione (24% for 3 steps from benzaldehyde). 1H NMR (500 MHz; CDCl3): δ1.27 (s, 6 H); 1.26 (s, 6 H); 1.69 (s, 4 H); 2.08 (s, 3 H); 3.12 (dd, J1=14.0 Hz, J2=9.5 Hz, 1 H); 3.50 (dd, J1=14.0 Hz, J2=4.0 Hz, 1 H); 3.76 (s, 3 H); 4.54 (dd, J1=9.5 Hz, J2=4.0 Hz, 1 H); 6.89 (d, J=8.0 Hz, 1 H); 7.03 (d, J=2 Hz, 1 H); 7.07 (s, 1 H); 7.14 (s, 1 H); 7.17 (dd, J1=8.0 Hz, J2=2.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:26]=[CH:25][CH:24]=[CH:23][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[N:6][N:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:22][C@H:9]1[N:8]([C:5]2[C:4]3[CH:23]=[CH:24][CH:25]=[N:26][C:3]=3[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:7][N:6]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ncccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2ncccc12
Yield: 76.6 %

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (68 mg, 185 μmol), tetrakis(triphenylphosphine)palladium (11 mg, 9 μmol), phenylboronic acid (34 mg, 277 μmol), and 2 M sodium carbonate (185 μl, 370 μmol) yielded (R)-(3-methyl-4-(8-phenylpyrido[3,2-d]pyridazin-5-yl)piperazin-1-yl)(phenyl)methanone 81 (58 mg, 77% yield) after chromatographic purification. MS 409.2 (calc'd) 410.2 (M+H, found).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][CH:5]([O:4][C:2]([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)=[O:3])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=S1(=O)CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)N1CCS(=O)(=O)CC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1 mL, 9.27 mmol) was reacted with thiomorpholine 1,1-dioxide (1.1638 g, 8.61 mmol) and pyridine (783 mg, 801 μl, 9.9 mmol) in methylene chloride (15 mL) at room temperature for 3 h to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester. A portion of 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-chloro-ethyl ester (577 mg, 1.614 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (150.5 mg, 0.244 mmol) in the presence of cesium carbonate (598.4 mg, 1.84 mmol) in dimethylformamide (7 mL) overnight to give 1,1-dioxo-thiomorpholine-4-carboxylic acid 1-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-ethyl ester as an off-white solid (175.3 mg, 87% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O8S: [(M+H)+]: 821, found: 821
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12](C2C=C(OC)C(Cl)=C(CC3C=CC(OCC)=CC=3)C=2)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:59]([O:62][C:63]1[CH:68]=[C:67](Br)[CH:66]=[C:65]([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:64]=1[Cl:77])[CH:60]=[CH2:61]>>[CH2:59]([O:62][C:63]1[CH:68]=[C:67]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:11]2)[CH:66]=[C:65]([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:64]=1[Cl:77])[CH:60]=[CH2:61]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Reactant: C=CCOc1cc(Br)cc(Cc2ccccc2)c1Cl
Product: C=CCOc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl

Procedure:
Similar procedure with preparation of 76 proceeded except for using compound 168 to obtain the compound 169.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)O)c(-c2cccc(F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(3-fluorophenyl)-1-methylisoquinoline-3-carboxylate (0.423 g, 1.43 mmol) and 3.0 M lithium hydroxide in water (2.39 mL, 7.16 mmol) in tetrahydrofuran (2.4 mL) was stirred at room temperature for 3 hours. After neutralized with 1 N HCl, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting crude acid was used directly in the next step (0.40 g, 99%). LCMS calculated for C17H13FNO2 (M+H)+: m/z=282.1; Found: 282.0.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]#[N:16])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:29]>CO>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:29])[NH2:16])=[N:6]1
Reactant: [NH4+]
Reactant: Cc1ncc2c(C#N)nn(Cc3ccccc3F)c2n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 994 mg (purity 81%, approx. 3.01 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile was dissolved in 15 ml of absolute methanol. 209 mg (3.72 mmol) of sodium methylate was added and it was stirred for 1 h at RT. Then a further 31 mg (0.56 mmol) of sodium methylate was added and it was stirred for 15 min at RT. 871 mg (14.50 mmol) of acetic acid and 489 mg (4.46 mmol) of ammonium chloride were added and the mixture was stirred for 45 min at 45° C. The reaction mixture was concentrated by evaporation, the residue was mixed with 1N sodium hydroxide solution, the precipitate was filtered with suction and dried under high vacuum. 918 mg (purity 91%, 97% of theor.) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)c(F)c1F
Reaction time: 48 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 4-amino-2,3-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,3-difluorophenylacetic acid (200 mg, 42%) as a white solid. 1H-NMR (CDCl3) δ 2.30 (s, 3 H), 3.35 (s, 2 H), 6.98 (m, 1 H), 7.04 (m, 1 H), 7.18 (d, J=7.3 Hz, 2 H), 7.69 (d, J=8.1 Hz, 1 H), 7.90 (m, 1 H); MS (FAB) m/z 321 (M++1).
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[OH:14]>CCO.O>[NH2:6][C:7]1[C:8]2[O:14][C:3](=[S:5])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: S=C=S
Reactant: Nc1cccc(N)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc2[nH]c(=S)oc12
Yield: 49.7 %

Procedure:
A solution of KOH (0.875 g, 15.6 mmol) in EtOH (14.3 mL) and water (2.6 mL) was treated with carbon disulfide (0.828 g, 10.9 mmol), followed by of 2,6-diaminophenol (1.50 g, 12.1 mmol). The mixture was heated at reflux temperature for 3 h, concentrated, neutralized with 1M HCl to pH 7, and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.90 g, 45%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][OH:22])=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+]>CO.ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][OH:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A solution of (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(2-hydroxyethyl)pyrrolidine (5.0 g) and conc. hydrochloric acid (2.53 ml) in methanol (25 ml) was stirred under ice-cooling for 10 minutes and then stirred at ambient temperature for 1 hour. To the reaction mixture cooled at 0° C. was added 28% sodium methoxide in methanol solution (5.84 ml). The resulting precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was dissolved in dichloromethane (15 ml) and the solution was dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was washed with n-hexane and dried in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-hydroxyethyl)pyrrolidine (3.10 g).