Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[C:8]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:7]=2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[C:4]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[N:5][C:6]4[C:11]([C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[C:8]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:7]=4)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.713 g, 1.42 mmol) and 1,4′-bipiperidine (0.311 g, 1.846 mmol) in acetonitrile (25 mL) was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, and the mixture was extracted with methylene chloride (three time). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-10% MeOH with 0.1% NH3/CH2Cl2) to give methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.730 g, 87% yield). MS (m/z) 590.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35]C(=O)C)=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.CCCCCC>CO.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 1 h

Procedure:
To a stirred suspension of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate, (Preparation 1, 1 g) in methanol (25 ml) was added a solution of concentrated hydrochloric acid (2 ml) in methanol (25 ml). After 5 days the reaction mixture was diluted with dichloromethane (150 ml), washed with water (3×100 ml), filtered through cotton wool and evaporated to dryness to give a yellow, oily solid. This residue was partially dissolved in dichloromethane (25 ml) and hexane (50 ml) was slowly added. After 1 hour, the suspension was filtered to give the product as an off-white solid (900 mg).
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21](CCCCCCC(F)(F)C(F)(F)F)[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:69])([C:65]([F:68])([F:67])[F:66])[CH2:48][CH2:49][CH2:50][CH2:51]C(CCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:69])[C:65]([F:66])([F:67])[F:68])[C:22]([OH:24])=[O:23])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1.[CH3:22]I>CS(C)=O>[Br:3][C:4]1[C:9]([N:10]([CH3:22])[C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)c(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.3 g of a 50% dispersion in mineral oil) was added to dimethylsulfoxide (10 ml) and warmed to 50° C. After cooling the mixture to room temperature. N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.0 g) was added and the resulting solution was stirred for 10 min. Methyl iodide (0.4 ml) was then added and the mixture was stirred for 30 min. The reaction mixture was quenched by the addition of water (10 ml) and ethyl acetate (100 ml) was then added. The organic phase was washed with water (4×100 ml), dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride followed by methylene chloride/ethanol, 98:2) to give 1.9 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [OH-].[Li+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.C1COCC1.O.Cl>CS(C)=O>[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Lithium hydroxide (hydrated) (0.59 g, 14.1 mmol) was added to a solution of methyl 4-(2-morpholinoethoxy)benzoate 193 (1.25 g, 4.7 mmol) in a 1:1 mixture of THF-water (20 mL). The reaction mixture was stirred at rt overnight then acidified with 1N HCl to pH 2, solvent was evaporated and the residue was lyophilized to provide crude 194 (1.66 g, >>100% Yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.88 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.53 (m, 2H), 3.89 (m, 4H), 3.53 (m, 2H), 3.26 to 3.14 (m, 4H). MS: 251.12 (calc), 252.1 (obs).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.S(=O)(=O)(O)O.[C:19](=O)([O-])[O-].[K+].[K+]>O>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(F)nc1F

Procedure:
In a round bottom flask, 2,6-difluoro-nicotinic acid (51, 5.60 g, 35.2 mmol), 60.0 mL of methanol and sulfuric acid (1.0 mL, 19.0 mmol) are combined and heated to reflux overnight. The reaction is poured into water, adjusted to pH around 9 with 1M aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a yellow oil (52, 3.5 g).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:30]([CH:31]=O)=[CH:29][C:12]3[C:13]([C:16]4[S:17][CH:18]=[C:19]([C:21]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[O:22])[N:20]=4)=[N:14][O:15][C:11]=3[C:10]=2[F:33])[CH2:3]1.[NH:34]1[C:41](=[O:42])[CH2:40][C:38](=[O:39])[NH:37][C:35]1=[O:36]>CC(O)C>[F:33][C:10]1[C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])[N:20]=3)[C:12]=2[CH:29]=[C:30]2[C:9]=1[N:4]1[CH2:3][C@@H:2]([CH3:1])[O:7][C@@H:6]([CH3:8])[C@@H:5]1[C:40]1([C:38](=[O:39])[NH:37][C:35](=[O:36])[NH:34][C:41]1=[O:42])[CH2:31]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4nc(C(=O)N5CCOCC5)cs4)noc3c2F)C[C@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(-c5nc(C(=O)N6CCOCC6)cs5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 85 °C

Procedure:
To a solution of 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-[4-(morpholin-4-ylcarbonyl)-1,3-thiazol-2-yl]-1,2-benzoxazole-5-carbaldehyde (Intermediate 389, 90 mg, 0.19 mmol) in IPA was added barbituric acid (24 mg, 0.103 mmol) and the mixture heated at 85° C. for 16 hours. Solvents were evaporated and the residue was purified by reverse phase HPLC to give product as solid (as a TFA salt). Yield: 16 mg (14%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Mg].II.C[O:18]B(OC)OC.OO>O1CCCC1.O.C(O)(=O)C>[OH:18][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: COCCOCc1ccc(Br)cc1
Agent: II
Agent: OO
Agent: [Mg]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 139.9 %

Procedure:
2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal of iodine was added and the mixture heated until an exothermic reaction commenced. A solution of the remaining 2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintain the temperature of the reaction mixture at reflux. When the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10° C., dropwise over 45 minutes whilst maintaining the temperature below -5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropwise addition of 30% hydrogen peroxide (11.77 ml) in water (11 ml) whilst maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in ether (100 ml) and extracted into IM aqueous sodium hydroxide (50 ml×3). The aqueous extract was acidified with 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil; NMR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:37][CH3:38])[N:26]=1.C(O)(=O)C>C1COCC1.CO>[Cl:24][C:25]1[N:29]=[CH:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH:34][C:2]3[N:3]=[C:4]([N:18]4[CH2:19][C:20]([F:23])([F:22])[CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:32][C:31]=2[O:37][CH3:38])[N:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Reactant: Fc1ccc(C2CCc3c2nc(Cl)nc3N2CC(F)(F)C2)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N4CC(F)(F)C4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation Ha) (170 mg, 0.500 mmol) and 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (Preparation F) (146 mg, 0.650 mmol) in THF (1498 mL) was added Acetic Acid (1498 mL). The resulting mixture was heated to 100° C. and stirred overnight. The reaction mixture was then concentrated in vacuo. MeOH was added to the residue which resulted in a suspension. This was filtered to give a solid which was taken up in hot MeOH and filtered. The filtrate was then concentrated in vacuo to give N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (racemate) (130 mg, 49.22% yield) as a yellow solid. LC-MS (M+H)+=528.1. 1H NMR (500 MHz, MeOD) δ ppm 8.81 (1H, s), 7.65 (1H, d, J=8.55 Hz), 7.59 (1H, s), 7.29-7.36 (2H, m), 7.11-7.21 (3H, m), 4.87-4.88 (4H, m), 4.47 (1H, s), 3.91 (3H, s), 3.11-3.19 (1H, m), 2.99-3.08 (1H, m), 2.77 (1H, dddd, J=13.47, 8.96, 4.43, 4.27 Hz), 2.13 (1H, dq, J=8.89, 6.70 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:27]([S:29]([CH2:32][CH2:33][NH:34][C@@H:35]([C:37]1[N:46]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[CH:49][CH:48]=2)[C:45](=[O:59])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[CH3:36])(=[O:31])=[O:30])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([S:29]([CH2:32][CH2:33][N:34]([C@@H:35]([C:37]1[N:46]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[CH:51][CH:52]=2)[C:45](=[O:59])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1)[CH3:36])[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)(=[O:30])=[O:31])[CH3:28]
Reactant: CCS(=O)(=O)CCN[C@H](C)c1nc2ccccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@H](C)c1nc2ccccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
4-Fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (64 μL, 0.74 mmol) was added, then after 5 min., N,N-dimethylformamide (5.7 μL, 0.07 mmol) was added. The reaction stirred at 0° C. for 30 min. and room temperature for 1 h. The solution was added slowly to a mixture of 12 (210 mg, 0.43 mmol) and triethylamine (182 μL, 1.30 mmol) in dichloromethane at −78° C. This stirred for 30 min., then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 256 mg of a colorless solid, 11. MS (ESI+): m/z=715.2 [M+H]+. 1H NMR (500 MHz; CDCl3; T=298 K): δ 9.10-8.95 (m, 1H), 8.66-8.58 (m, 1H), 7.78-7.57 (m, 1H), 7.47-7.36 (m, 3H), 7.24 (m, 1H), 7.13 (m, 3H), 5.03 (q, 1H, J=7.4 Hz), 4.43 (quint, 2H, J=8.0 Hz), 3.77 (s, 1H), 3.71 (m, 1H), 3.62-3.49 (m, 2H), 3.23-3.09 (m, 3H), 2.81 (d, 1H, J=12.9 Hz), 2.62-2.41 (m, 1H), 2.14-1.90 (m, 2H), 1.68 (broad s, 2H), 1.64-1.45 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([N:3]2[C:2]([CH3:8])([CH3:1])[CH2:6][O:5][C:4]2=[O:7])[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC1(C)COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 4,4-dimethyloxazolidin-2-one (0.103 g, 0.895 mmol) and 2,4,6-trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3 mL) was treated with NaH (60%, 0.0429 g, 1.07 mmol, 1.2 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided 3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (0.146 g, white solid) in 62.3% yield. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 4.16 (s, 2H), 1.74 (s, 9H); LCMS m/z 261.9 (M+H)+, Rt 0.91 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N[N:31]1[C:39]2[C:34](=[CH:35][CH:36]=C[CH:38]=2)[CH2:33][C:32]1=O>C(N1CCC(=O)CC1)C.CO.C(O)(=O)C>[CH2:39]([N:31]1[CH2:36][CH2:35][CH:34]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH2:33][CH2:32]1)[CH3:38]
Reactant: NN1C(=O)Cc2ccccc21
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCN1CCC(=O)CC1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1CCC(Nc2ccc3c(c2)CC(=O)N3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a 2 L round bottom flask was added 5-aminooxindole (80 g, 0.54 mol), 1,2-dichloroethane (800 ml), 1-ethyl-4-piperidone (80.1 ml, 0.59 mmol) and Glacial acetic acid (80 ml). The mixture was stirred for 30 minutes, cooled under ice/water bath for 30 minutes and then sodium triacetoxyborohydride (160 g, 0.76 mmol) was added in 10 portions over 60 minutes. The mixture was stirred at room temperature 4 hs. TLC showed no trace of amino-oxindole and then Celite (100 g) and MeOH (500 mL) were slowly added. The reaction mixture was filtered and concentrated. The resulting dark oil was acidified with c-HCl (150 mL) and ice (50 g). The reaction mixture was extracted with ethyl acetate (2 L×2) to remove the side product. The aqueous layer was cooled to 0° C., basified with 40% NaOH (ca. 150 mL) and then the solid was formed. After 30 min stirring, the formed solid was filtered and washed with H2O (1 L) and suspended with Acetone (2 L) for 1 h. After filtering, the crude solid was dissolved in CHCl3 (2.5 L), treated with charcoal (50 g) and filtered using Celite. The filterate was concentrated and solidified with ethyl acetate to give the desired product (81 g, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 39.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0306 g, 0.0663 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chlorobenzenesulfonyl chloride (0.0275 mL, 0.195 mmol) to obtain 4-(3-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0168 g, yield 40%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and morpholine (10 μl, 0.11 mmol), and stirred 18 hours at room temperature. The reaction was heated to 50° C. for 8 hours, and then was allowed to stir 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-morpholinoethoxy)benzamide. MS (Q1) 530 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][C:11]3[NH:12][C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[O:5][N:4]=1)[CH3:2].[H-].[Na+].[H][H].Br[CH2:26][CH2:27][CH2:28][Cl:29]>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][N:12]1[C:11]2[CH:10]=[N:9][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=3)=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CCc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Reactant: [H][H]
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c4ccccc4n(CCCCl)c3cn2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 166.6 %

Procedure:
To a solution of Compound 2 (0.73 g, 2.8 mmol) in anhydrous DMF (100 mL), sodium hydride (60% in mineral oil, 0.13 g, 3.3 mmol) was carefully added. The resulting mixture was stirred at room temperature for 30 min, until hydrogen evolution had ceased. The reaction mixture was slowly added to a solution of 1-bromo-3-chloropropane (0.52 g, 3.3 mmol) in anhydrous DMF (150 mL). The resulting mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo to give a yellow solid (1.59 g). The residue was dissolved in acetone, filtered and the filtrate concentrated in vacuo, giving the title compound (1.07 g, 100%). 1H- and 13 C-NMR revealed that the crude product was a mixture of the bromo and chloro isomers in the ratio 70:8. The crude product was used without further purification.