Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction solution was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249-250° C.; 1H-NMR (DMSO-d6) δ 10.21 (s, 1H, D2O exchangeable), 7.90-7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H]+, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:14][NH2:15]>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:14][NH2:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(Cl)c(C(=O)NN)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carboxylic acid (4.0 g, 19.6 mmol) and 1,1-carbonyl diimidazole (6.35 g, 39.2 mmol) were dissolved in 80 mL THF and stirred at room temperature. After 3 h, the solution was cooled in an ice bath and hydrazine hydrate (1.90 mL, 39.2 mmol) was added in one quick portion. The solution was allowed to stir for 5 h, gradually warming to room temperature. The reaction mixture was diluted with excess H2O and extracted with EtOAc several times. These organics were combined and washed with 2 N HCl. The combined aqueous layers were then basified carefully with 5 N NaOH, and extracted once again with EtOAc. This second set of organic layers was combined, dried over magnesium sulfate and concentrated under vacuum to give 2.46 g (58% yield) of product as a white solid. MS (M+H)+ 219.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]3)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:30][NH2:31]>>[CH3:1][O:2][C:3]1[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH:31][CH3:30])=[O:28])[CH2:22]3)(=[O:19])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC(C(=O)O)C2)c1
Product: CNC(=O)C1CCCN(S(=O)(=O)c2cccc(C(=O)Nc3ncccc3OC)c2)C1

Procedure:
The entitled compound was produced according to the method of Example 57 but using the compound obtained in Example 56 and methylamine as the starting materials.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].S([O-])([O-])(=O)=O.[Nd+3:12].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Nd+3]>>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Nd+3:12].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Nd+3:12]
Reactant: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Nd+3]
Product: O=C([O-])C(=O)[O-]

Procedure:
Subsequently, oxalic acid ((COOH)2) is added to neodymium sulfate taken out from the reaction tank (not shown) to produce neodymium oxalate (Nd2(COO)3) that is a Nd oxalic acid salt.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][P:41](=[O:44])([O-:43])[O-:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](Br)(C)C>C(#N)C>[CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][P:41](=[O:42])([OH:43])[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])([O-])C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: c1ccncc1
Product: O=P(O)(O)C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.6 g, 0.89 mmol, 1.0 equiv) in dry acetonitrile (60 mL) was added pyridine (1.1 mL, 10.2 mmol, 11.5 equiv) at 0° C. under argon atmosphere. TMSBr (2.5 mL, 17.7 mmol, 20 equiv) dissolved in dry acetonitrile (25 mL) was added dropwise to the reaction mixture at 0° C. which was stirred for 10 minutes and then warmed to room temperature and stirred for 3 hours. The volatiles were removed in vacuo (bath temperature <15° C.) to give an oil. Ice cold water (20 mL) was added, and the organic material was extracted into DCM (2×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (bath temp <15° C.) to give ((((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonic acid as a pale green solid (0.50 g). The material thus obtained was used without further purification. ESI (M+1) m/z: 619.0; calc for C35H39O8P 618.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]1=[O:19]>C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][C:7]1=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(Cl)c2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of tert-butyl 4-(3-chloro-4-fluorobenzyl)-3-oxopiperazine-1-carboxylate (3.3 g, 9.63 mmol) in ethyl acetate (150 mL), anhydrous hydrogen chloride gas was bubbled for ten minutes. The resultant solution was stirred at 0° C. for 1 hour, and concentrated under vacuum. The residue was treated with chloroform saturated with ammonia gas. The resultant white suspension was stirred at room temperature for 15 minutes and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residue was redissolved in benzene, filtered, and concentrated under vacuum to provide the title piperazinone as pale yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:25]=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH3-]C#N.[Na+]>CC(O)=O.CO>[CH2:8]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH2:25][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCCCC(CNc2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Aniline (0.126 mL, 1.38 mmol) was added to a solution of 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.300 g, 1.15 mmol) in 5% HOAc in MeOH (11.5 mL). The reaction was stirred for approx. 20 minutes, then NaBH3CN (0.2164 g, 3.44 mmol) was slowly added and the reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and EtOAc and a few drops of 10% NaOH were added. The organic was washed with saturated NaCl (aq), dried with Na2SO4, concentrated in vacuo, to give crude 3-phenylaminomethyl-azepane-1-carboxylic acid benzyl ester (148). Compound 148 was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:28]#[N:29])([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:28]#[N:29])([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:10]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 94 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)=O)[CH:10]=1)[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]3[N:17]4[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:16]4=[CH:15][N:14]=3)[CH:10]=1)[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:6]=[CH:5]2
Reactant: COC(=O)c1ccnc(CNC(=O)Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2c(Cc3cc(Cl)cc4cnn(CC(C)C)c34)ncc2c1
Temperature: 90 °C
Reaction time: 22.5 h
Yield: 52.7 %

Procedure:
A solution/suspension of compound 59 (0.184 g, 0.44 mmol) in toluene was treated with phosphorus oxychloride (1 ml) and stirred at 90° C. under a nitrogen atmosphere for 22.5 h. The mixture was cooled and treated with water (20 ml) then neutralised by addition of solid sodium hydrogen carbonate. The mixture was then extracted with ethyl acetate (2×25 ml) and the organics separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient to give the title compound as a yellow oil (0.092 g, 52%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>C(#N)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#CCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-iodo phenol (700 mg, 3.1 mmol) in acetonitrile (7 ml) was added K2CO3 (1.31 g, 9.5 mmol), followed by bromo acetonitrile (410 mg, 3.4 mmol) at 20-35° C. and the reaction mixture was stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 20-35° C., diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 15% ethyl acetate/hexane as an eluent to get the desired compound as a pale yellow liquid (400 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (dt, J=5.4, 2.9 Hz, 2H), 6.79-6.77 (m, 2H), 4.74 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:15])[CH2:14][S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: Sc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Reaction time: 2 h

Procedure:
To (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (3.00 g) in methanol (100 ml) were added thiophenol (1.5 ml) and triethylamine (2.0 ml), followed by 2 hour' stirring under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 4.14 g of (2S)-1-(t-butoxycarbonyl)-2-[1-hydroxy-2-(phenylthio)ethyl]pyrrolidine.
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:13]CCC.IC>C1COCC1>[CH3:13][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCOS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4 mmol) in THF (8 mL) at about −78° C., n-BuLi (1.6 M in hexanes, 5.26 mL, 8.42 mmol) and iodomethane (0.684 mL, 10.9 mmol) were added simultaneously and the resulting mixture was stirred at about −78° C. for about 2 h and then at ambient temperature for about 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (7 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (15 mL) and the combined organic extracts were dried over anhydrous MgSO4 and concd under reduced pressure. The residue was subjected to silica gel column chromatography (5 to 25% EtOAc in heptane over 30 min) to yield butyl 1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a colorless oil. 1H NMR (DMSO-d6) δ 4.17 (t, 2H), 1.62 (m, 2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)=[C:6]([Cl:28])[CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([NH:11][C:7]3[C:6]([Cl:28])=[CH:5][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:9][C:8]=3[Cl:10])[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]=2[CH:23]=1
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[(4-acetyl-2,6-dichlorophenyl)amino]-9-bromobenzo[c]-2,6-naphthyridin-1(2H)-one (Examples 94 and 95, Step 2) (109 mg, 0.23 mmol) in THF (3 mL) at −10° C. under nitrogen atmosphere was added methyl magnesium bromide (0.61 mL, 3.0 M in THF/toluene). The reaction mixture was stirred for 1 h keeping temperature between −5° C.-0° C. After allowing to warm to room temperature, the solution was quenched with water and diluted with 1:3 iPrOH/CHCl3 and neutralized with sat. NaHCO3. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane to afford the title compound.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.[Cl-].[NH4+]>O1CCCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:14][CH2:15][C:16]([OH:19])([CH3:1])[CH2:17][CH2:18]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
Methyl lithium (1.6M in diethyl ether, 4.89 mL, 7.82 mmol) was added dropwise to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-indoline]-2′,4-dione (preparation 21a, 1.00 g, 3.40 mmol) in tetrahydrofuran (30 mL) at −78° C. The mixture was warmed to 0° C. over 3 hours and stirred at room temperature for additional 4.5 hours. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give a mixture of isomers of the title compound. Purification of the residue by flash chromatography (97:3 dichloromethane/methanol) gave the two pure isomers of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.CC(=O)OCC>CN1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: Fc1cc2[nH]nc(Br)c2cc1F
Reactant: O=C([O-])[O-]
Agent: CN1CCCC1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1nc(Br)c2cc(F)c(F)cc21

Procedure:
To a light brown suspension of 3-bromo-5,6-difluoro-1H-indazole (1.0 g, 4.29 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in N-methylpyrrolidine (20 mL) was added iodomethane (0.81 mL, 12.9 mmol) at room temperature. The resulting dark brown solution was stirred for 15 h at room temperature under nitrogen atmosphere by which time the TLC (2:1, Hex:EA, Rf=0.6, major and 0.4, minor) indicated the presence of the desired compound. The reaction was diluted with water (˜100 mL), the organic compound was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with brine solution. After drying over MgSO4, the filtrate was concentrated to obtain the crude light brown solid which was purified by chromatography using an ISCO (80 g) column eluting with hexanes (1 min), 0-15% EA in hexanes (2 min), 15-40% EA in hexanes (15 min) to obtain 746 mg (70%) of 3-bromo-5,6-difluoro-1-methyl-1H-indazole as a white solid and 186 mg (18%) of 3-bromo-5,6-difluoro-2-methyl-2H-indazole as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[C:15]([CH3:17])[S:14][C:13]=2[CH3:18])=[C:4](Cl)[N:3]=1.Cl.[OH-:21].[Na+]>>[CH3:18][C:13]1[S:14][C:15]([CH3:17])=[CH:16][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:21])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Cc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(C)s1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(Cn2cnc3c(=O)[nH]c(N)nc32)c(C)s1

Procedure:
A mixture of 2-amino-9-[(2,5-dimethyl-3-thienyl)methyl]-6-chloropurine (3.8g, 0.0129 mol) and 2N HCl was heated on a steambath for 3.0 hours and then heated under reflux for another hour. At the end of this time 1N NaOH solution was added to the solution till basic and the mixture was heated for another five minutes. The mixture was then acidified with acetic acid,cooled, and filtered to give 3.6 g, of the product. An analytical sample was obtained by chromatography over silica gel using 10% methanol/chloroform as eluting solvent, mp>300° C. (dec).
Reaction SMILES: [CH3:1][CH:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1)[C:3]([OH:5])=[O:4].P([O-])([O-])([O-])=O.[OH-].[Na+]>>[CH3:1][C@H:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](C(=O)O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Methyl (RS)-(1-tert-Butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (50 g, 0.17 mol) was mixed with Candida Antarctica Lipase (CAL, SP-435, Novo Nordisk, Denmark) (2.5 g) and subsequently added 0.1 M phosphate buffer (pH=7.0) (3 L) under vigorous stirring. The resulting mixture was stirred vigorously at 25° C. for 120 h, and the pH was maintained at 7 by the addition of 0.5 N NaOH. After addition of about 0.45 equivalent of base, filtering off the enzyme stopped the reaction. The enzyme was washed with diethyl ether (1 L), and the pH of the aqueous phase was adjusted to 8. The aqueous phase was extracted with diethyl ether (2×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude methyl (R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid, which was used for the synthesis of (−)-(R)-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-3-yl)acetic acid (see below). The aqueous phase was cooled by addition of ice, and the pH adjusted to 1.5 with 37% HCl (aq). The aqueous phase was extracted with diethyl ether (3×1 L), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give crude title compound (enantiomeric excess was about 80-85%). A number of precipitations from diisopropyl ether gave the title compound: mp 137-138° C.; enantiomeric excess 96.5%; [α]D=+12.8° (c=0.45, methanol). The chiral analysis was performed on a Ultron ES OVM 150×4.6 mm, flow 1.0 ml/min, eluent 25 mM phosphate buffer (pH≅4.6)/methanol/2-propanol/tetrahydrofuran 90/5/5/0.5, T=30° C. Enantiomeric purities expressed as enantiomeric excess (ee) were calculated from peak areas.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)CC[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A solution of 7 (170 mg, 0.28 mmol) in 4 mL toluene was added, by cannula, to a −40° C. mixture of hydrido(triphenylphosphine)copper(I) hexamer (300 mg, 0.15 mmol) in 4 mL toluene, rinsing with 0.5 mL toluene. The temperature was allowed to warm to 0° C. over 1 h and then was allowed to warm to room temperature. After a further 1 h, the reaction was quenched by addition of 15 mL saturated NH4Cl solution. The mixture was extracted with ethyl acetate (3×15 mL) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (8% ethyl acetate/hexanes→10%) gave the title ketone (150 mg, 0.25 mmol, 89%).