Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][CH:35](O)[CH3:36])[CH:30]=[CH:31][CH:32]=1.[Br:40]Br>C(Cl)Cl.CCCCCC>[Br:40][CH:35]([CH3:36])[CH2:34][CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:39])([F:38])[F:25])[CH:28]=1
Reactant: CC(O)CCc1cccc(C(F)(F)F)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(Br)CCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
750 mg (11.0 mmol) of imidazole and 2.88 g (11.0 mmol) of triphenylphosphine were added to a solution of 2.0 g (9.2 mmol) of 4-(3-(trifluoromethyl)phenyl)butan-2-ol in DCM (10 ml). 570 μl (11.0 mmol) of bromine were added dropwise at 0° C., and stirring was carried out for 1 h at RT. The mixture was then concentrated in vacuo. CC (hexane) of the residue yielded 2.0 g (7.1 mmol, 78%) of 1-(3-bromobutyl)-3-(trifluoromethyl)benzene.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)=[O:4].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.O>C(#N)C>[O:4]=[C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: O=C1CCN(C(=O)CCl)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(=O)CC2)CC1
Yield: 67.8 %

Procedure:
1-(2-Chloroacetyl)piperidin-4-one (5.17 g, 29.4 mmol) was dissolved in acetonitrile (50 ml). To this solution, tert-butyl piperazine-1-carboxylate (5.48 g, 29.4 mmol) and N-ethyldiisopropylamine (6.2 ml, 35.3 mmol) were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was allowed to return to room temperature, to which water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-[2-oxo-2-(4-oxopiperidin-1-yl)ethyl]piperazine-1-carboxylate (6.49 g, yield 68%) as a pale yellow crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
To a suspension of ethyl 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (EXAMPLE 1) (95 mg) in ethanol (3 mL) was added 1 mL of 3N NaOH and the mixture heated at reflux for 6 h, after which time mixture was cooled to rt and acidified with 3N HCl to pH=3. The resulting off-white solid was collected by filtration to yield 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid. LC-MS (ES+): m/z 306/308 (1/1) [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=7.18 (d, J=1.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H), 8.69 (s, 1H), 12.15 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]=O)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.CO>[CH2:29]([NH:36][CH2:27][CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1cc(CCNCc2ccccc2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 72 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetaldehyde (44 mg, 0.113 mmol) was dissolved in chloroform (1.1 mL) before it was stirred at ambient temperature with benzylamine (62 μl, 0.57 mmol) and PTSA (1 mg) for 16 h. Methanol (1.1 mL) and sodium cyanoborohydride (7.1 mg, 0.113 mmol) were then added and allowed to stir in the reaction mixture over 3 d. The reaction mixture was diluted with DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after flash chromatography. MS (ESI) m/z: Calculated: 479.2; Observed: 480.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([C:14]#[N:15])[C:5](=O)[N:6]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH:7]=1.[OH2:17].[NH2:18][NH2:19].C(=O)([O-])O.[Na+]>C(O)C>[NH2:15][C:14]1[C:4]2[C:5](=[O:17])[N:6]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH:7]=[C:2]([Br:1])[C:3]=2[NH:19][N:18]=1
Reactant: CC(C)C(C)n1cc(Br)c(Cl)c(C#N)c1=O
Reactant: O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-4-chloro-1-(3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (386 mg) in ethanol (6.0 mL) was added hydrazine monohydrate (0.094 mL) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (332 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=1.[C:17]([CH:20]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:21](OCC)=[O:22])(=O)[CH3:18]>CC1C=CC=CC=1C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[OH:22][C:21]1[N:13]2[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[CH:1]=3)[CH:15]=[C:14]2[N:16]=[C:17]([CH3:18])[C:20]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: CCOC(=O)C(CC(=O)OC)C(C)=O
Reactant: Nc1cc(-c2ccc3c(c2)CCCC3)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
A suspension of 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6 g, 28.1 mmol), 1-ethyl 4-methyl 2-acetylsuccinate (24.52 mL, 141 mmol) and Ts-OH.H2O (0.096 g, 0.506 mmol) in o-xylene (200 mL) was heated at 150° C. (oil bath temp) for 16 h. (Note: mixture became homogeneous and in about 15 min slowly yellow solid started crashing out of the reaction.) Then, the reaction mixture was cooled, diluted with hexanes (300 mL), filtered, washed with hexanes and dried to afford methyl 2-(7-hydroxy-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.4 g, 23.90 mmol, 85% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.78-7.62 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 3.64 (s, 3H), 3.58 (s, 2H), 2.82-2.77 (m, 4H), 2.33 (s, 3H), 1.78 (t, J=3.0 Hz, 4H). LCMS (M+H)=352.3.
Reaction SMILES: Cl.Cl.[N:3]1[C:11]2[CH2:10][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[NH:8][CH2:7][C:6]=2[NH:5][CH:4]=1.C(N(CC)CC)C.[Se](=O)=O.CCOCC>C(Cl)(Cl)(Cl)Cl>[N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[N:8]=[CH:7][C:6]=2[NH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1Cc2nc[nH]c2CN1
Agent: Cl
Agent: O=[Se]=O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2nc[nH]c2cn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Methyl (6S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate dihydrochloride (156.5 g, 0.62 mol), triethylamine (445.0 g, 4.4 mol, 7.0 mol eqv.), selenium dioxide (158.2 g, 1.43 mol, 2.3 mol eqv.), and polyphosphatesilyl ether (PPSE) (15.0 g) were added to CCl4 (1.5 L). The mixture was refluxed for 6 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was suspended in methanol (1.5 L), and triethylamine was added to adjust to pH 8. The brown solid was filtered and washed well with methanol. This brown solid (117.0 g) was recrystallized from hot DMF (2 L, 140° C.). The solution was filtered hot to remove black side products. Upon cooling to room temperature, the desired product crystallized out as a yellow solid (51.3 g, 47% yield, 95% pure). 1H NMR (DMSO-d6): δ 13.20 (br s, 1H), 9.02 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 3.89 (s, 3H); LCMS: Rt=1.33 min, and M+1=178.1 u/e.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:33])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH:21]=1>>[F:33][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: CS(=O)(=O)c1cc(F)ccc1-c1cc(Br)ccc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4S(C)(=O)=O)c3)cnc2c1F
Yield: 33 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 5′-bromo-4,2′-difluoro-2-methanesulfonylbiphenyl as described in Example 6 to give 3-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine as an off-white solid (149 mg, 33%): δH (400 MHz, d6-DMSO) 1.57 (6H, s), 3.11 (3H, s), 5.54 (1H, s), 7.20 (1H, t, J 7), 7.49 (1H, t, J 9), 7.65-7.79 (5H, m), 7.96 (1H, dd, J 9 and 3), 8.40 (1H, d, J 7); m/z (ES+) 461 [MH+].
Reaction SMILES: C(O)(=O)C.[N+]([O-])(O)=O.[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:10][CH3:11].[Br:21]Br>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[Br:21])[CH2:10][CH3:11]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: BrBr
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCc1ccc(C(=O)O)cc1Br
Reaction time: 3 h

Procedure:
To a mixture of 150 ml of glacial acetic acid, 33 ml of concentrated nitric acid and 25 ml of water, were added 8.2 g (0.05 moles) of parapropyl benzoic acid and 8.8 g (0.055 moles) of bromine. Then, at a temperature of 25° C., and over a period of half an hour, a solution of 8.5 g (0.05 moles) of silver nitrate in 25 cc of water was added. The solution was stirred for three hours, thirty minutes following which the suspended solid was removed by filtration and rinsed until neutral. Thereafter, the acid was dissolved in ethanol. Recrystallization from hexane yielded 4-propyl-3-bromo-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC(OC)=C2C=1C=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Fc1cc(Br)cc2cc[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cc(F)c2[nH]ccc2c1
Yield: 74 %

Procedure:
3-(7-Fluoro-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXXXI (215 mg, 74% yield)was prepared from 5-bromo-7-fluoroindole using the procedure described for 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][C:3]=1[OH:17].Cl.[CH:19](OCC)(OCC)OCC>CO>[CH2:8]([C:7]1[C:2]2[N:1]=[CH:19][O:17][C:3]=2[CH:4]=[CH:5][C:6]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH3:9]
Reactant: CCc1c(NC(=O)C(F)(F)F)ccc(O)c1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CO
Product: CCc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Temperature: 90 °C

Procedure:
A mixture of 2-amino-3-ethyl-4-trifluoroacetamidophenol (18.15 mmol) and concentrated hydrochloric acid (45 mL) in methanol (5.2 mL) is treated with triethyl orthoformate (27.2 mmol). A simple distillation apparatus is attached and the mixture is heated with an oil bath to 90° C. and methanol is distilled from the reaction. The reaction mixture is cooled to room temperature and distributed between ethyl ether (200 mL) and water (20 mL). The ether layer is washed with a 0.1 M aqueous solution of sodium hydroxide (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield 4-ethyl-5-trifluoroacetamidobenzoxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[N:20][N:21]2COCC[Si](C)(C)C)=[CH:17][CH:16]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)n[nH]c3c1)C(=O)N2
Yield: 53.5 %

Procedure:
A solution of (1R*,2S*)-5′-methoxy-2-(3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (10 mg, 0.02 mmol) in THF (2.0 mL) was treated with TBAF (0.10 mL, 1M in THF) and refluxed for 3 h. The reaction was diluted with EtOAc and the organic layer was washed with brine (4×) and then dried over MgSO4. The solvent was removed and the crude product was purified by silica gel chromatography using EtOAc as eluent followed by trituration (EtOAc: Hexanes, 1:1) to give the title compound as a yellow powder (5 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J=2.4 Hz, 1H), 8.14 (dd, J=8.8, 2.4 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.62 (dd, J=8.5, 2.6 Hz, 1H), 5.61 (d, J=2.5, 1H), 4.63 (s, 1H), 3.84 (t, J=4.8 Hz, 4H), 3.58 (t, J=5.0 Hz, 4H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.28-2.25 (m, 1H), 2.21-2.18 (m, 1H); MS ESI 468.3 [M+H]+, calcd for [C27H25N5O3+H]+ 468.20.
Reaction SMILES: [SH:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][S:1][C:2]2[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: NC(=O)c1c(S)nsc1Nc1cccnc1
Reactant: ClCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1cccnc1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Compound 14 (50 mg, 0.14 mmol) is dissolved in DMF (0.15 mL) and Hunig's base is added (0.048 mL, 0.27 mmol) followed by 4-chlorobenzyl chloride (22 mg, 0.14 mmol) at room temperature. The reaction is stirred for 1 hour and then water (0.2 mL) is added and the resulting solids are filtered and washed with water and then methylene chloride to provide 3-(4-Chloro-benzylsuIfanyl)-5-(pyridin-3-ylamino)-isothiazole-4-carboxylic acid amide (25.7 mg, 49%). 1H NMR (d6 DMSO): δ 10.37 (1H, br. s), 8.51 (1H, d, J=2.8 Hz), 8.26 (1H, d, J=4.4 Hz), 7.61–7.64 (1H, m), 7.42 (2H, d, J=8 Hz), 7.38–7.41 (1H, m), 7.33 (2H, J=8 Hz), 4.40 (2H, s). LRMS (M+): 376.9, (M−): 374.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].Cl.[C:39]1([S:45]([CH2:48][CH2:49][NH2:50])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:50][CH2:49][CH2:48][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: NCCS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1)NCCS(=O)(=O)c1ccccc1

Procedure:
Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:32][O:33][C:34]1[C:35]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:44]=2[CH2:53]Br)=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:53][C:44]3[CH:45]=[C:46]([C:49]([F:50])([F:51])[F:52])[CH:47]=[CH:48][C:43]=3[C:35]3[CH:36]=[C:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one) (46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3 mL) was added. NaHMDS (296 μL of a 1M solution in THF, 0.296 mmol) was added and the reaction was stirred for 5 min. At this time, 2′-(bromomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl methyl ether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2 mL). After 30 min, the reaction was quenched with saturated NH4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The organic layer was washed with water (15 mL), and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H), 3.25-3.74 (m, 4H), 2.88 (m, 1H), 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OC([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(#N)C.[I-].[K+]>[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][N:11]([C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2ccccc2[nH]1)[C@@H]1CCCc2cccnc21
Temperature: 50 °C
Reaction time: 22 h
Yield: 111.7 %

Procedure:
To a solution of 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 0.39 mol) and 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (103 g, 0.39 mol) in acetonitrile (780 mL) at room temperature was added diisopropylethylamine (101 mL, 0.58 mol) and potassium iodide (6.4 g, 0.04 mol) and the mixture heated to 50° C. for 3 hours. The mixture was then concentrated under reduced pressure and redissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pH was adjusted to 2 with 6N HCl then the phases were separated. The aqueous layer was washed with methyl t-butyl ether (500 mL). The aqueous phase was stirred for 22 hours, adding 6N HCl as needed to maintain pH=2. The solution was basified to pH 10-11 with 10N NaOH and extracted with toluene (2×1.5 L). The organic phase was washed with 1N NaOH (1×200 mL) and brine (1×200 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione (209 g). 1H NMR (300 MHz, CDCl3, δ ppm) 0.75-1.75 (series of m, 5H), 1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H, J=7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J=17.0 Hz), 4.11 (d, 1H, J=17.0 Hz), 7.10-7.30 (m, 4H), 7.39 (d, 1H, J=7.5 Hz), 7.50-7.55 (m, 1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J=3.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CO.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH2:11][O:10][CH3:9])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: COCCOc1cccc(Br)c1
Yield: 69.2 %

Procedure:
To a solution of 3-bromophenol (0.865 g, 5 mmol) in MeOH (1.5 ml) was added 2-bromoethyl methyl ether (0.56 ml, 6 mmol) followed by K2CO3 (0.68 g, 5 mmol). The mixture was heated using microwave irradiation in a CEM discover microwave synthesizer (50 W) at 100° C. until the reaction was complete. The reaction was diluted with ether and filtered to remove solid which was washed with further ether. Filtrate concentrated under reduced pressure to give (0.8 g) of product.
Reaction SMILES: C[O:2][CH:3]1[CH2:7][N:6](C(O)=O)[CH:5]([C:11]([OH:13])=[O:12])[CH2:4]1.[CH2:14](N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:14][O:13][C:11]([C@H:5]1[CH2:4][C@@H:3]([OH:2])[CH2:7][N:6]1[C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12]
Reactant: COC1CC(C(=O)O)N(C(=O)O)C1
Reactant: CCN(CC)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl3 (100mL) was added triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5 g, 52 mmol). The mixture was stirred at RT for 3d before concentrating and redissolving in EtOAc. The solution was washed sequentially with 10% aq. citric acid, water, and brine before drying over MgSO4 and concentrating under reduced pressure to reveal 2 (20 g, 100%) as a yellow solid.