Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[O:13][C@H:12]([CH3:19])[CH2:11]2>O1CCOCC1>[CH3:19][C@@H:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH:3]=[O:2])[CH:9]=2)[C:14](=[O:18])[O:13]1
Reactant: C[C@@H]1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(CC=O)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1:1 solution of dioxane:3 N HCl was added to a flask containing (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one (780 mg, 3.2 mmol). The reaction was then stirred at room temperature overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated to afford (R)-2-(3-methyl-1-oxoisochroman-6-yl)acetaldehyde which was used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].S(=O)(=O)(O)O.CN(C=O)C>CCOC(C)=O>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 153.2 g (600 mmol) of (1R,2S)-1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (commercially available from Synthetech Oregon, USA) in 80 mL of EtOAc was dosed to a solution of 65.1 g (630 mmol) of sulfuric acid in 480 mL of EtOAc at 20-25° C. The reaction mixture was stirred for 60 min at 42-48° C. After complete conversion the reaction mixture was cooled to 18-22° C. Then 127.5 g (1260 mmol) of TEA was dosed at 20-30° C. Finally 100 mL of DMF was added. The reaction mixture was used in the next step immediately after preparation.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[OH:6][C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:11][CH2:10][C:9](=[O:20])[C:8]=1[C:21](=[O:24])[CH2:22][CH3:23]>C(Cl)(Cl)Cl>[OH:6][C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=2)[CH2:11][CH2:10][C:9](=[O:20])[C:8]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(=O)C1=C(O)C(c2ccc(C)cc2)CCC1=O
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(O)C(c2ccc(C)c(S(=O)(=O)Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulphonic acid (20 ml) was added dropwise to an ice-cold solution of 3-hydroxy-2-propionyl-4-(4-methylphenyl)cyclohex-2-ene-1-one (3.25 g) in chloroform (40 ml). After stirring at room temperature for 4 hours, the mixture was carefully poured onto ice. The chloroform layer was separated and the aqueous phase extracted with more chloroform. The combined extracts were dried over magnesium sulphate, filtered and the chloroform evaporated in vacuo to give 3-hydroxy-2-propionyl-4-(3-chlorosulphonyl-4-methylphenyl)cyclohex-2-ene-1-one (4.4 g). Water (50 ml) was added to the latter, followed by dimethylamine (2 g) and the solution stirred at room temperature for 1/2 hour. The solution was acidified with dilute hydrochloric acid, and extracted with dichloromethane. After drying over magnesium sulphate, the dichloromethane was evaporated in vacuo to give a pale yellow oil. Purification on a silica gel column using chloroform as eluant gave the title compound (4.0 g) as a white solid of m.p. 95°-97° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH3:7].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][CH2:2][C:3]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(C(=O)CCl)cc1
Temperature: 60 °C

Procedure:
23.5 mmol of chloroacetyl chloride and, in portions, 18.1 mmol of acetanilide, are added slowly, under an argon atmosphere, to 108 mmol of aluminium chloride in 90 ml of 1,2-dichloroethane. The reaction mixture is heated at 60° C. for 2 hours and then cooled with an ice bath. After slow hydrolysis using ice, and filtration, the precipitate obtained is washed with ethyl ether and dried. The expected product so obtained is used in the following without being purified.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O=S(Cl)[Cl:18]>CN(C=O)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc2c(O)ncnc2cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Yield: 94.4 %

Procedure:
7-fluoro-6-nitroquinazolin-4-ol (15 g, 0.072 mol) was added to 150 ml SOCl2 and 10 drops of DMF was added. The solution was heated to reflux for 4 hours which become a clear solution, then the SOCl2 was removed under reduce pressure to give 4-chloro-7-fluoro-6-nitroquinazoline as yellow powder 15.4 g (94.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1nccs1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1nccs1
Yield: 87.8 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.60 mmol) to give 185 mg of the title compound (88%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.20 (s, 1H), 12.07 (s, 1H), 7.47 (d, 2H, J=3.6 Hz), 7.23 (d, 1H, J=3.6 Hz), 7.22 (bs, 1H), 7.17 (bs, 1H), 5.17~5.28 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.64~2.89 (m, 3H), 2.06 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:35]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[C:36]1B(O)O)=O)(C)(C)C>>[C:40]([C:39]1[NH:35][C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:37][CH:38]=1)#[N:41]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford an off-white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=458.1[M+H]+, m/z=456.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, J=6.48, 3.06 Hz, 1H) 1.82-1.92 (m, 1H) 2.95 (d, J=11.49 Hz, 1H) 3.26 (dd, J=11.74, 4.65 Hz, 1H) 3.31-3.34 (m, 1H) 3.40-3.50 (m, 1H) 4.19-4.28 (m, 1H) 4.88 (d, J=3.42 Hz, 1H) 6.31 (dd, J=3.67, 2.20 Hz, 1H) 7.01 (dd, J=3.67, 2.20 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.82-7.89 (m, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.45 Hz, 1H) 10.16 (s, 1H) 12.59 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]1[C:17]([C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25])=[CH:20][CH:19]=2)=[N:16][N:15]=[N:14]1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:28]=[CH:29][C:18]([C:17]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: NNC(=O)COc1ccc(-c2nnn[nH]2)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccc(-c2nnn[nH]2)cc1)NN=C1C(=O)Nc2ccc(Br)cc21
Temperature: 100 °C
Yield: 68 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 40 mg of the title compound (68%) as a orange Solid in 94.9% purity by HPLC (Rt: 3.34, gradient of 8 mini, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.Br[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:2]1([CH3:1])[CH2:6][C:5]2[C:7]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)c2c1CC(C)(C)O2
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c3c2CC(C)(C)O3)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A solution (30 ml) of Compound 144a obtained in Step A in DMF was added to a mixture of methyl 4-bromobenzoate (1.67 g), palladium acetate (0.18 g), sodium carbonate (2.10 g), and dimethylformamide (DMF) (70 ml), followed by stirring at 80° C. for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20) to give Compound 144 (1.35 g, 55.6%) as colorless crystals.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:10]([CH3:17])[CH2:11][C:12](OCC)=[O:13]>C(O)C>[CH3:17][C:10]1[CH:11]=[C:12]([OH:13])[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(O)n(-c2ccccn2)n1

Procedure:
In a 1.0-liter egg plant-type flask, an ethanol solution (300 mL) of 2-hydrazinopyridine (16.3 g, 0.15 mol) and ethyl 3-oxobutanoate (20.5 g, 0.16 mol) was stirred overnight with heating under reflux. Ethanol was removed from the reaction solution under reduced pressure to obtain the title compound as a brown oily crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]2[C:11]=1[C:12](=[O:26])[NH:13][C:14]2=[O:25])([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C(C)=CC(C)=CC=1C>[O:26]=[C:12]1[C:11]2[C:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:18]=3[CH:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]=2[C:14](=[O:25])[NH:13]1
Reactant: O=C1NC(=O)c2c(-c3ccccc3[N+](=O)[O-])ccc(-c3ccccc3)c21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccccc3c21

Procedure:
3.5 g (10.2 mmole) 1,3-dihydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole and 9.5 g (36.2 mmole) triphenylphosphine are heated under reflux for 16 hours in 100 ml 2,4,6-collidine. The solvent is distilled off in a vacuum and the residue chromatographed on silica gel with toluene/ethyl acetate 3:1. The fraction with the Rf 0.3 is isolated and recrystallized from cyclohexane/acetone. One obtains 1,2,3,6-tetrahydro-1,3-dioxo-4-phenylpyrrolo[3,4-c]carbazole in the form of yellow crystals of the mp 262°-264° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].Br[C:40]1[CH:41]=C2C(=C[CH:48]=1)C(=O)N(C1(C(OC)=O)CCCC1)C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:16][N:8]1[C@@H:3]([C:2]1[CH:38]=[CH:41][CH:40]=[CH:48][CH:1]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Reactant: COC(=O)C1(N2Cc3cc(Br)ccc3C2=O)CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](c1ccccc1)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 372 was prepared analogous to compound of example 360 by reaction of the compound of example 371, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=[C:26]=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:27]
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C=Nc1ccccc1-c1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1-c1ccccc1
Yield: 64 %

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenylphenylisocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H)+.
Reaction SMILES: FC1C=C2C(=CC=1)NC=C2.C([BH3-])#N.[Na+].C(OC(=O)C)(=O)C.[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23].[N+:35]([O-])([OH:37])=[O:36]>C(O)(=O)C.S(=O)(=O)(O)O>[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([F:34])=[C:31]([N+:35]([O-:37])=[O:36])[CH:32]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2cc(F)ccc21
Agent: Fc1ccc2[nH]ccc2c1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-fluoro-1H-indole (5.0 g, 37 mmols) in acetic acid (300 ml) was added sodium cyanoborohydride (2.79 g, 44 mmols). After stirring overnight at rt, the reaction was concentrated under reduced pressure, redissolved in ethyl acetate (300 ml) and the pH was adjusted to 8 with saturated sodium bicarbonate. The organic layer was separated, filtered through a cotton plug, evaporated, and placed on the high vacuum for one hour prior to the next synthetic step. The crude material was then dissolved in acetic acid (100 ml), followed by the addition of acetic anhydride (3.5 ml, 37 mmols). After heating at 60 C for one hour, the reaction was poured into ice, stirred for one hour, solid was removed by vacuum filtration, rinsed with water and allowed to dry overnight under house vacuum. Next, to a solution of the 1-acetyl-5-fluoro-2,3-dihydro-1H-indole (500 mg, 2.79 mmol) in sulfuric acid (10 ml) at OC was added nitric acid (0.196 ml, 3.07 mmols) by a slow dropwise addition. After stirring 30 min at OC, the reaction was quenched by pouring into ice water. The solids were removed by vacuum filtration, redissolved in dichloromethane (50 ml), adsorbed to silica gel, and purified by LC(25% to 75% ethyl acetate/hexanes). The lower Rf spot was isolated and the structure was determined to be the desired regioisomer by IR profiling. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3 H) 3.25 (t, J=8.63 Hz, 2 H) 4.18 (t, J=8.53 Hz, 2 H) 7.50 (d, J=11.24 Hz, 1 H) 8.64 (d, J=7.22 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:19][S@@](C(C)(C)C)=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>C(Cl)Cl>[NH2:19][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(Br)c1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution of tert-butyl ((S)-2-(3-bromo-5-fluorophenyl)-2-((R)-1,1-dimethylethylsulfinamido)ethyl)carbamate (1.78 g, 4.07 mmol) in DCM (13.57 mL) was added HCl (4M in dioxane) (4.07 mL, 16.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized to pH=7, then extracted by EtOAc to give the desired (S)-tert-butyl (2-amino-2-(3-bromo-5-fluorophenyl)ethyl)carbamate (300 mg) as a free base. LCMS (m/z): 317.1/319.1 (MH+), 0.66 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][N:13]([N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=[C:2]1[CH3:1])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: Cc1nc(-c2cccnc2)cn1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccnc2)cn1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of tert-butyl 2-methyl-4-(pyridin-3-yl)-1H-imidazol-1-ylcarbamate (2.0 g, 7.3 mmol) in dry DMF (15 mL) at 0° C. was added sodium hydride (0.35 g, 8.7 mmol, 60% dispersion in oil). The reaction was stirred at 0° C. for 30 minutes and then methyl iodide (1.55 g, 10.9 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 3 hours before it was warmed to ambient temperature. The reaction was extracted with ethyl acetate (15 mL×2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.18 g, 56.2%) as an orange oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3): δ 8.96 (s, 1H), 8.49 (s, 1H), 8.16-8.13 (m, 1H), 7.38-7.36 (m, 2H), 3.36 (s, 3H), 2.35 (s, 3H), 1.44 (s, 9H); ESIMS m/z 289 [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([O:30]C)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Yield: 77.6 %

Procedure:
A mixture of 330 mg racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (330 mg, 0.55 mmol), NaOH (80 mg, 2 mmol), H2O (5 mL) and methanol (10 mL) was heated at 60° C. for 2 h. Then the methanol was removed in vacuum. The water solution was acidified by concentrated hydrochloric acid to “pH” 2. The white precipitate was collected by filtration to give title compound (Yield: 250 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1>C1COCC1.CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Sodium borohydride (4.5 g, 115. mmol) was added to a solution of methyl 5-methylpicolinate (6.0 g, 39.5 mmol) in THF (60 mL) and methanol (6 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic layer was concentrated under vacuo to afford (5-methylpyridin-2-yl)methanol (3.5 g, 72.9%,) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.5 (s, 1H), 7.7 (d, 1H), 7.15 (d, 1H), 5.0 (s, 3H), 3.4 (s, 3H). MS: [M+H]+: m/z=124.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:9][C:6]1[CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8][CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1ncc(O)cc1CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(OCc2ccccc2)cc1CC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-methoxy-5-neopentylpyridin-3-ol (2.00 g), potassium carbonate (4.25 g) and DMF (20 mL) was added benzyl bromide (2.40 mL) at room temperature, and the mixture was stirred at 50° C. for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:7][S:8](O)(=[O:10])=[O:9]>>[CH3:1][N:2]1[CH:6]=[C:5]([S:8]([Cl:7])(=[O:10])=[O:9])[CH:4]=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1cccn1
Product: Cn1cc(S(=O)(=O)Cl)cn1
Temperature: 0 °C

Procedure:
Add 1-methyl-1H-pyrazole (100 g, 1.18 mol) dropwise to chlorosulfonic acid (325 mL, 4.84 mol) stirring at 0° C. under nitrogen atmosphere. Heat reaction mixture at 110° C. for 3 hr. Cool to room temperature, then pour carefully into crushed ice with stirring. Recover the resulting white solid by vacuum filtration, wash with water, and dry under vacuum. Use the resulting material (72.2 g, 33%) without further purification.