Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Br.Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C1COCC1.ClCCl.O>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:12][CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[CH:23][CH:24]=1
Reactant: BrCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OCc2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of N-Boc-azetidin-3-ol (500 mg, 2.89 mmol) in THF (10 mL) was cooled to 0° C. t-BuOK (1M in THF, 11.6 mL) was added dropwise and the reaction mixture was stirred at room temperature for 0.25 h then cooled to 0° C. A solution of 4-bromomethylpyridine hydrobromide (2.19 g, 8.67 mmol) in dichloromethane (5 mL) stirred with DIPEA (4 mL, 24 mmol) for 0.5 h was then added. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The organics were separated from the aqueous layer and combined, dried over Na2SO4 and concentrated to dryness. The crude mixture was purified by column chromatography (eluent: Pentane/EtOAc, 1/1 to 7/3) to give the title product (313 mg, 41%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A solution of indoline 1 (2.0 g, 16.78 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.68 g, 18.46 mmol) in dry 1,2-dichloroethane (30 mL) was treated with acetic acid (2.4 mL, 42.00 mmol) followed by NaBH(OAc)3 (5.34 g, 25.2 mmol) at 0° C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1 N NaOH solution (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 2 (5.0 g, 99%) as a syrup. 1H NMR (CDCl3) δ 7.05 (t, 2H, J=7.8 Hz), 6.62 (t, 1H, J=7.2 Hz), 6.43 (d, 11, J=7.5 Hz), 4.25-4.20 (m, 2H), 3.55-3.46 (m, 2H), 3.35 (t, 2H, J=8.4 Hz), 2.95 (t, 2H, J=8.4 Hz), 2.77 (t, 2H, J=12.3 Hz), 1.81-1.77 (m, 2H), 1.63-1.51 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %) 303 (MH+, 5), 247 (100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][N+:21]([O-])=O)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:20][NH2:21])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C[N+](=O)[O-])c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(CN)c2cccnc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-Nitro-1-pyridin-3-yl-ethyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.92 g, 7.17 mmol) in MeOH (60 ml) was added nickel chloride hexahydrate (1.70 g, 7.17 mmol) and the mixture was cooled in an ice bath. Sodium borohydride (1.08 g, 28.7 mmol) was portionwise added over 30 minutes and the resulting suspension was stirred for further 30 minutes at 0° C. The reaction was quenched with saturated NH4Cl solution (30 ml) and MeOH was removed in vacuo. The aqueous residue was extracted with EtOAc (2×50 ml) and DCM (2×50 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:11][C:12]1[C:13]([CH3:18])=[N:14][NH:15][C:16]=1[CH3:17]>CN(C)C=O>[C:3]([N:15]1[C:16]([CH3:17])=[C:12]([O:11][C:10]2[CH:19]=[C:20]([Cl:22])[CH:21]=[C:8]([Cl:7])[CH:9]=2)[C:13]([CH3:18])=[N:14]1)(=[O:5])[CH3:4]
Reactant: CC(=O)Cl
Reactant: Cc1n[nH]c(C)c1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1nc(C)c(Oc2cc(Cl)cc(Cl)c2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 684 mg, 17.1 mmol) was added to a stirred solution of acetyl chloride (1.21 ml, 17.1 mmol) and the pyrazole of Example 53 (4.00 g, 15.6 mmol) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour and then quenched by the addition of water (100 ml). The aqueous extracted was with ether (2×50 ml). The combined organic phases were washed with water (30 ml) and brine (30 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ether (90:10, by volume) to provide the title compound (3.0 g) as a white solid, m.p. <60° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](Br)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[NH:37][C:36]([C@@H:38]4[CH2:42][CH2:41][CH2:40][N:39]4[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:35][CH:34]=3)=[CH:29][CH:28]=2)O1.C([O-])(O)=O.[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>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[NH:37][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)nn(C(=O)OC(C)(C)C)c4c3)cc2)[nH]1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
A mixture of tert-butyl 3-amino-6-bromo-1H-indazole-1-carboxylate (1.17 g, 3.73 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.62 g, 3.68 mmol), NaHCO3 (0.96 g, 11 mmol) and Pd(PPh3)4 (212 mg, 0.184 mmol) was degassed and then heated at 80° C. After heating for 24 h the reaction mixture was poured into EtOAc/H2O (500/100 mL) and the mixture was shaken and the layers separated. The aq phase was extracted once more with EtOAc and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and concentrated in vacuo. The residue was purified by BIOTAGE® (40+M, TLC 2:1 EtOAc:hex) affording a light yellow foam (807.8 mg) which was repurified by BIOTAGE® (TLC 6:3.5:0.5 hex:EtOAc:MeOH) to give the title compound as a light yellow solid (413.9 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.86-12.22 (m, 1H), 8.20 (s, 1H), 7.85-7.92 (m, 3H), 7.75-7.76 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.53-7.62 (m, 2H), 6.35 (s, 2H), 4.75-4.86 (m, 1H), 3.49-3.58 (m, 1H), 3.35-3.39 (m, 1H), 2.10-2.26 (m, 1H), 1.80-2.01 (m, 3H), 1.60 (s, 9H), 1.40 and 1.15 (s, 9H, rotamers). LCMS: Anal. Calcd. for C30H36N6O4: 544; found: 545 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].C(OC(=O)[CH:17]([C:25]#[N:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[K+]>O.CCOCC.C(O)C>[C:19]1([C:18]2[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:1][C:17]=2[C:25]#[N:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C#N)Cc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: N#Cc1[nH]c2ccccc2c1-c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 4.08 g. (0.044 mol) of aniline in 18 ml. of concentrated hydrochloric acid and 50 ml. of water was maintained below 5° while a solution of 3.00 g. (0.043 mol) of sodium nitrite in 10 ml. of water was added. This solution was then added to a mixture of 8.30 g. (0.041 mol) of α-cyanobenzenepropanoic acid ethyl ester, 50 ml. of ethanol, 100 ml. of water, and 18 ml. of 50% potassium hydroxide solution maintained below 0°. After stirring for an additional 20 minutes the reaction was diluted with water and shaken with ether. Some insoluble solid was removed by filtration and the ether layer was concentrated. The residue was heated on the steam bath for 4 hours with 60 ml. of acetic acid and 60 ml. of concentrated hydrochloric acid. The cooled reaction was diluted with water and extracted with dichloromethane. The extracts were dried, filtered over some silica gel and concentrated. Recrystallization of the residue from dichloromethane-hexane gave 3-phenylindole-2-carbonitrile as tan crystals, m.p. 137°-142°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C:13]#[N:14].C(=O)(O)[O-].[Na+].[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:13]#[N:14])[C:4]=1[CH3:12]
Reactant: Cc1cc2ccccc2c(O)c1C#N
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)c(O)c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-hydroxy-3-methyl-2-naphthonitrile (1.065 g, 5.8 mmol) was dissolved CHCl3 (24 mL) and combined with sodium bicarbonate (952 mg, 11.3 mmol) and bromine (330 μL, 6.43 mmol) and allowed to stir at room temperature overnight. The reaction was quenched by adding 10 mL of 10% sodium thiosulfate and the mixture stirred until decolorization was maximal. The solids were removed by filtration as crude product (1.47 g, 97% yield.) 1H-NMR: (300 MHz, DMSO-d6): δ 8.334 (d, J=8.0 Hz, 1H); 8.166 (d, J=8.4 Hz, 1H); 7.81-7.77 (m, 1H); 7.65-7.61 (m, 1H); 2.65 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S.CI.[N:30]1C=CC=CC=1>CCN(CC)CC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[NH:30])[NH2:25])=[CH:22][CH:23]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Agent: S
Solvent: CI
Solvent: CCN(CC)CC
Product: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reaction time: 16 h

Procedure:
A solution of 4-(4-cyanobenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.4 g, 6.87 mmol) in 30 mL of pyridine and 3 ml of Et3N is saturated with H2S. The resulting mixture is sealed and stirred for 16 hours. After this time, the solution is concentrated. The residue is dissolved in 30 mL of acetone and methyl iodide (19.4 g, 137 mmol) is added. The solution is refluxed for 2 hours. After this time, the solution is concentrated. The residue is dissolved in MeOH (40 mL) and NH4OAc (5.0 g, 65 mol) is added. The solution is reluxed for 3 hours. After this time, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of CH3CN to 60% CH3CN/H2O(0.1%TFA). The appropriate collected fractions are lyophilized to give the product as a white foam. MS (FAB) m/z 367, (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][OH:23])=[CH:18][N:17]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].CCN(CC)CC.[CH:43]([N:46]=[C:47]=[O:48])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][O:23][C:47](=[O:48])[NH:46][CH:43]([CH3:45])[CH3:44])=[CH:18][N:17]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:14]2=[CH:15][N:16]=1)[CH3:10]
Reactant: CC(C)N=C=O
Reactant: CCCC(CO)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(COC(=O)NC(C)C)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentan-1-ol (100 mg, 0.20 mmol) in DCM (3 mL), DMAP (1 mg), Et3N (60 μL, 0.42 mmol), and isopropyl isocyanate (30 μL, 0.3 mmol) are added, and the mixture is stirred for 18 h at room temperature. All volatiles are removed under reduced pressure, and the product is purified by chromatography on silica gel (EtOAc-hexane, 2:1) to afford isopropyl-carbamic acid 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentyl ester as colorless oil: LCMS m/z 554.18 (2.71 min).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:32][O:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:32][O:31][CH2:30]3)[CH2:25][CH2:24]2)=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(F)c1C1CCN(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cncc(F)c1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-[1-(oxetan-3-yl)-4-piperidyl]-3-pyridyl]carbamate (174 mg, 0.4951 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature for 4 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo to give 5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a yellow oil (109 mg, 88% Yield). MS (ES+) 252.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12

Procedure:
32 g of methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate were heated under reflux for 16 hours in 350 ml of carbon tetrachloride with 16 g of N-bromosuccinimide in the presence of 280 mg of dibenzoyl peroxide. The mixture is left to cool and 24.3 ml of triethylamine were added thereto. The mixture was then again heated under reflux for 3 hours. After cooling, the mixture was treated with about 900 ml of methylene chloride, and the organic phase was washed once with 550 ml of 1N hydrochloric acid and thereafter dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel and was recrystallized from ethyl acetate. There was obtained methyl 10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate as yellow crystals of m.p. 169°-170°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][N:29]=[C:30]=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:30]([NH:29][CH2:28][C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])=[O:31])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Nc1ccc(Br)c2cnccc12
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1Cl)Nc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 mL, 1:4) was treated with 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to provide the title compound. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O.HCl+0.25EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:13]([C@H:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:14]
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: CN
Solvent: CC(=O)OC(C)=O
Product: CNC(=O)[C@@H]1CC[C@H](C(=O)O)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
Cis-N-benzylpyrrolidine-2,5-dicarboxylic acid (41.3 g, 0.166 mole) and acetic anhydride (206.5 ml) were heated carefully together to 100°C; the solid gradually dissolved, and the mixture assumed a dark brown color. In typical experiments, solution was complete in 10-30 minutes, depending on the state of subdivision of the starting material. Heating time was minimized. Just before the last solid dissolved, the excess acetic anhydride was removed in vacuo, and the brown oily residue of crude cis-N-benzylpyrrolidine-2,5-dicarboxylic acid anhydride was taken up in 400 ml benzene. Anhydrous methylamine (0.33 mole as 9.9% solution in benzene) was added in two portions, and the mixture was heated on the steam bath for 45 minutes. After cooling, the crude cis-5-(N-methylcarbamyl)-1-benzylpyrrolidine-2-carboxylic acid (35.8 g) was collected by filtration, washed with benzene and recrystallized from ethanol. Yield: 31.4 g (72%), melting point 190°-192°C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])=[CH:4][CH:3]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[O:6][C:5]1[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH3:17]
Reactant: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reactant: C=COC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
trans-2-(4-Bromophenoxy)cyclohexanol (5.305 g, 19.56 mmol) was dissolved in ethyl acetate (196 mL) and treated with vinyl acetate (3.37 g, 39.1 mmol), followed by lipase enzyme from Candida antarctica (Novozyme 435, Sigma L4777, lipase immobilized on acrylic resin, 5.3 g). The reaction was capped and stirred for 18 hours, then filtered through Celite® and rinsed with ethyl acetate (500 mL). Concentration of the filtrate in vacuo provided a pale yellow oil, which was purified via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to afford (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate, the less polar product, as a colorless oil. Yield: 2.047 g, 6.54 mmol, 33%. Data for (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate: 1H NMR (400 MHz, CDCl3) δ 1.32-1.59 (m, 4H), 1.71-1.80 (m, 2H), 1.95 (s, 3H), 2.02-2.14 (m, 2H), 4.17 (ddd, J=9.6, 8.1, 4.4 Hz, 1H), 4.96 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H). Enantiomeric alcohol (1S,2S)-2-(4-bromophenoxy)cyclohexanol, the more polar product, was obtained as a white solid (3.57 g). Data for (1S,2S)-2-(4-bromophenoxy)cyclohexanol: 1H NMR (400 MHz, CDCl3) δ 1.26-1.46 (m, 4H), 1.74-1.79 (m, 2H), 2.08-2.15 (m, 2H), 2.50 (br s, 1H), 3.72 (ddd, J=10.6, 8.5, 4.6 Hz, 1H), 3.96 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H). The absolute configurations of these compounds were assigned on the basis of an X-ray crystal structure of the enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide (see step 7 below).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Br[C:18]1[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CC(C)CSc1ccc(B(O)O)cc1C#N
Reactant: COC(=O)c1ccc(Br)s1
Product: CC(C)CSc1ccc(-c2ccc(C(=O)O)s2)cc1C#N

Procedure:
Using [3-cyano-4-(isobutylthio)phenyl]boronic acid and methyl 5-bromothiophene-2-carboxylate, 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was obtained in accordance with the method of Example 2. Then, 333 mg of the resulting 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was suspended into 10 ml of ethanol, and 1.05 ml of a 1 M aqueous sodium hydroxide solution was added to the suspension, followed by stirring at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, the residue was suspended into 2-propanol, and the precipitate was collected by filtration to obtain 256 mg of sodium 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+]>CN(C)C=O>[OH:14][CH:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:25][C:26]([OH:28])=[O:27])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH:15]([CH3:17])[CH3:16])[CH3:1]
Reactant: CCOC(=O)CBr
Reactant: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
(1-Hydroxy-2-isopropyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2-methyl-2-isopropyl-6,7-dichloro-1,5-indandiol (8.3 g., .03 mole); potassium carbonate (7.2 g.); ethyl bromoacetate (6.2 ml.); and dimethylformamide (70 ml.); and hydrolyzing the resultant ester with aqueous sodium hydroxide in accordance with Example 4, Step F, gives (1-hydroxy-2-isopropyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.