Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:41])[CH2:38][CH2:39][CH3:40]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:41])[CH2:38][CH2:39][CH3:40]
Reactant: CCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 88 mg (1 mmole) of n-butanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 186 mg (Yield: 52%) of the title compound having the following structure as a red oil.
Reaction SMILES: [CH3:1][CH:2]([CH:25]([CH3:28])[CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:24])=[CH:11][N:12]3[C:19](=[O:20])[C:18]([C:21](O)=[O:22])=[CH:17][N:16]=[C:13]32)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[C:42]1([CH:48]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][NH2:57])[CH2:51][CH2:50]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:58]1([CH:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:49]2[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][NH:57][C:21]([C:18]3[C:19](=[O:20])[N:12]4[CH:11]=[C:10]([CH3:24])[C:9]5[C:14]([C:13]4=[N:16][CH:17]=3)=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH:25]([CH3:28])[CH2:26][CH3:27])=[CH:7][CH:8]=5)=[O:22])[CH2:53][CH2:54]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)O)cnc3c2c1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)NCCN4CCN(C(c5ccccc5)c5ccccc5)CC4)cnc3c2c1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirred mixture containing 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (455 mg), triethylamine (0.174 ml) and dry dichloromethane (70 ml) was added slowly ethyl chloroformate (0.12 ml) at 0° C. under an inert atmosphere. After being stirred for 2 hours, a solution of 2-(4-diphenylmethyl-1-piperazinyl)-ethylamine (359 mg) in dry dichloromethane (10 ml) was added dropwise to the reaction mixture at 5° C. After stirring was continued for 12 hours at room temperature, the mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel with chloroform-methanol. The eluate was concentrated in vacuo to give residue, which was recrystallized from chloroform-ether to give N-[2-(4-diphenylmethylpiperazin-1-yl)ethyl]-7-methyl-10-(2,3-dimethylpentanoylamino)-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxamide (0.59 g).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][N:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][N:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NN4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-amino 4-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.05 (m, 8H) 2.22 (br. s., 3H) 2.42 (m, 4H) 2.93 (t, J=4.55 Hz, 4H) 3.28 (br. s., 3H) 3.72 (m, 2H) 3.93 (br. s., 3H) 4.87 (m, 1H) 5.39 (d, 2H) 5.99 (m, 1H) 7.43 (br. s, 2H) 7.82 (s, 1H) 8.12 (br. s., 1H) 8.32 (d, J=8.0 Hz, 1H) 9.36 (s, 1H). Melting point: 253-263° C. [M+H] calculated for C28H37FN8O3, 553. found 553.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O>>[CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:18])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc2ccccc2c1Cl

Procedure:
Using the procedure of Step F of Example 1, 1.2 g of the product of Step B and 10 ml of phosphorous oxychloride were reacted to obtain after chromatography on silica (eluant:hexane-ethyl acetate (6.4)), 1.16 g of the desired product melting at <50° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)C.[OH-].[Na+].Cl>CCO.CCOC(C)=O>[CH2:17]([O:16][C:14]([N:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CN(CCc1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reaction time: 8 h

Procedure:
The crude material from step (a) (165 mmol, ˜47 g) was dissolved in EtOH (700 mL) and treated with 600 mL of 1 M NaOH. After stirring overnight, the reaction was acidified with concentrated HCl to pH-1. The crude reaction was diluted with EtOAc (400 mL) and washed with water. The water was back-extracted with EtOAc. The combined organic extracts were washed with water (2×) and dried over MgSO4. Concentration and evaporation from toluene (2×) gave the sub-title product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:13]I>CO.C(OCC)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cn1ncc2ccc(Br)cc21

Procedure:
6-Bromoindazole (400 mg) was dissolved in methanol (10 mL). To this solution, potassium hydroxide (450 mg) was added followed by methyl iodide (0.50 mL) and the mixture was refluxed for 2.5 h. The reaction was cooled, diluted with diethyl ether, washed with water, brine, dried and concentrated. The product 6-bromo-1-methylindazole (160 mg) was separated from its isomer by Combiflash.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:21]=[C:20](Cl)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[N:13]=3)[CH2:9][CH2:8][CH2:7][C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:21]=[C:20]([NH:27][CH2:26][CH2:25][NH2:28])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[N:13]=3)[CH2:9][CH2:8][CH2:7][C:6]=2[CH:24]=1
Reactant: Clc1ccc2nc(N3CCCc4cc(Br)ccc4C3)cc(Cl)c2c1
Reactant: NCCN
Product: NCCNc1cc(N2CCCc3cc(Br)ccc3C2)nc2ccc(Cl)cc12
Temperature: 160 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
The mixture of 7-bromo-2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (200 mg, 0.47 mmol) and ethane-1,2-diamine (0.5 mL) was heated with stirring in a 5 mL microwave process vial for 2 hours at 160° C. under microwave irradiation. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 38 mg of product (yield was 18%). MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J=2.4 Hz, 1 H), 7.49 (d, J=8.8 Hz, 1 H), 7.41 (m, 1 H), 7.35 (m, 1 H), 7.31 (m, 2 H), 5.99 (s, 1 H), 4.80 (s, 2 H), 4.13 (m, 2 H), 3.40 (m, 2 H), 3.00 (m, 4 H), 1.90 (m, 2 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Na+].[Na+].C(OCCO)C.[OH:29][S:30]([OH:33])(=[O:32])=[O:31]>CC(O)C>[S:30]([OH:33])([OH:32])(=[O:31])=[O:29].[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([CH3:11])[CH:4]=1
Reactant: C1CCNC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCCO
Solvent: CC(C)O
Product: Cc1cc(N)ccc1N1CCCC1

Procedure:
15.5g (0.1 mole) 2-fluoro-5-nitrotoluene, 25 ml (0.3 mole) pyrrolidine, 11.0 g Na2CO3 were combined with 50 ml 2-ethoxyethanol and refluxed with stirring. When the TLC showed no evidence of starting material (ca. 2 hours), the mixture was poured onto ice. The precipitate was filtered, washed 5 times with cold H2O, and dried on filter paper for 2 hours. The resulting solid was mixed with 125 ml 2-propanol, 10% Pd/C, and hydrogenated at 60 psi on a Parr apparatus. The mixture was filtered through filter-aid and stirred with external cooling in an ice/acetone bath. A cold solution of 10.7 g (0.105 mole) concentrated H2SO4 in 15 ml 2-propanol was added dropwise over 15 minutes. The resultant precipitate was filtered, washed 2 times with 2-propanol and dried in vacuo at 50° C. The final yield was 24.45 g (89%) of a light grey solid. MS (solid probe): m/e 176 (free base).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:16][OH:17]>>[CH3:16][O:17][C:3](=[S:2])[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CSC(=S)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CO
Product: COC(=S)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
14.1 g of N-(4-chlorophenylsulfonyl)-dithiocarbamic acid-S-methyl ester (0.05 mol) are refluxed in 100 ml of methanol, and after about 5 hours the formation of mercaptan has finished. The solvent is distilled off in a rotary evaporator, and the residue is recrystallised from methanol; yield 116 g (87% of theory), m.p. 129°-130° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34]>>[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Product: CC(C)(C)CNc1cccc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)c1

Procedure:
1-[2-[3-(2,2-Dimethyl-propylamino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,2-dimethyl-propylamine following general procedures as described in these Examples. M+H=387.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:21][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a mixture of the product aniline of Example 31 (15 g) and 18 g of anhydrous potassium carbonate suspended in 400 ml of dimethylformamide was added 11 g of methyl iodide in 30 ml of dimethylformamide. After 16 hours the mixture was concentrated to an oily residue which solidified upon trituration with water. The crude solid was purified by chromatography as in Example 34 to give the title compound. Samples prepared by the methods of Examples 34 and 36 were identical.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([F:16])[CH:7]=1.[CH2:17](O)[CH3:18]>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])=[C:8]([F:16])[CH:7]=1
Reactant: Nc1ccc(CC(=O)O)c(F)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(N)cc1F
Temperature: 40 °C

Procedure:
Thionyl chloride (986 mL, 8.51 mol) was added dropwise to a stirred suspension of 2-(4-amino-2-fluorophenyl)acetic acid (960 g, 5.68 mol) in ethanol (10 L) at 0° C. under a nitrogen atmosphere. The reaction mixture was then heated to 40° C. for 48 hours, with the reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was evaporated to dryness and the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L). Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase was basic. The layers were separated and the organic phase washed with saturated sodium hydrogen carbonate solution (4 L), dried over magnesium sulphate and the solvent removed under reduced pressure gave the desired product, ethyl (4-amino-2-fluorophenyl)acetate, as an orange oil (1042 g, 93% yield), that may crystallise upon standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14]CC)=O)=[CH:5]2.[CH3:17][N:18]1C2C(=CC=CC=2)C=C1C(OCC)=O>>[CH3:17][NH:18][C:12]([C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:14]
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1C
Reactant: CCOC(=O)c1cc2ccccc2n1C
Product: CNC(=O)c1cc2cc(F)ccc2n1C
Yield: 68 %

Procedure:
According to the procedure of Preparation 1(b), except substituting ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate for the ethyl 1-methyl-1H-indole-2-carboxylate, the title compound (2.1 g, 68%) was prepared as a white solid: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Clc1ccccc1-c1nc(-c2ccccc2)[nH]c1-c1ccccc1Cl
Product: CCOC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 77.6 %

Procedure:
4,5-Bis(2-chlorophenyl)-2-phenylimidazole (1.7 g) (J. Org. Chem., 1971, 36, 2262) was reacted with ethyl 8-bromooctanoate in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 4,5-bis(2-chloro-phenyl)-1-(7-ethoxycarbonylheptyl)-2-phenylimidazole (1.94 g, 77.6%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24](=[CH2:28])[CH2:25][CH2:26][CH3:27])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:39])[NH:12][CH:11]3[C:24](=[CH2:28])[CH2:25][CH2:26][CH3:27])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=C(CCC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: C=C(CCC)C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.4 g, 3.1 mmol) prepared in example 89d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (1.7 g, 4.25 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a off white solid (Yield 1.2 g, 84%).
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:54]([O:57][CH2:58][CH3:59])(=[O:56])C>>[NH:1]([C:54]([O:57][CH2:58][C:59]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:37]=1)=[O:56])[C@H:2]([C:12]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
6.62 g. (8.7 mmoles) of H-28-31-OtBu are dissolved in 65 ml. of ethyl acetate, and 2.72 g. (8.5 mmoles) of Z-Ala-ONSu are added to the solution. After 5 minutes of stirring, a homogeneous solution is formed. The reaction mixture is stirred for one hour; at that time the product separates from the mixture. The mixture is left to stand overnight, thereafter the product is filtered off and washed with ethyl acetate. The crude product is recrystallized from 65 ml. of ethyl acetate. 6.61 g. (80.7 %) of Z-27-31-OtBu are obtained. M.p.: 193°-195° C, Rf11 = 0.75.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:11]1[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=1)\[CH3:21])[CH3:16]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Cc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(C)nc1
Temperature: 23 °C
Yield: 56.2 %

Procedure:
Potassium t-butoxide (10.4 g, 0.092 mol) was added to a stirred solution of 6-methyl-pyridin-3-ol (5.00 g, 0.046 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 6.80 g, 0.046 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(6-methyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (5.72 g, 56%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].S(=O)(=O)(O)[OH:28]>FC(F)(F)C(O)=O>[CH2:23]([NH:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]([NH2:2])=[O:28])[CH:4]=3)[CH2:8]2)=[O:13])=[CH:16][CH:17]=1)=[O:26])[CH2:24][CH3:25]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(N)=O)cc3C2)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5-cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (30 mg, 0.9 mmol) in sulfuric acid (0.1 mL) and trifluoroacetic acid (0.3 mL) was stirred at room temperature for 16 hours. The reaction was treated with ice and the suspension was stirred for 10 minutes and filtered. The solid collected was washed with water and dried under vacuum; the solid was purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.97-8.00 (bs, 1H), 7.81-7.86 (m, 2H), 7.75-7.79 (m, 2H), 7.63-7.68 (m, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.34-7.39 (bs, 1H), 4.81-4.82 (bs, 4H), 3.16-3.24 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 367 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCBr
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Yield: 36.7 %

Procedure:
Benzyl alcohol (28 mL, 270 mmol) and triethylamine (3.8 mL, 27 mmol) were combined and stirred over an ice bath, under nitrogen (N2). 4-Bromobutyryl chloride (1) (3.1 mL, 27 mmol) was added in a dropwise fashion, then the reaction was stirred an additional 30 minutes. The completed reaction was poured into 250 mL H2O and extracted with Et2O (3×200 mL). The ether extracts were combined, dried over MgSO4, and solvent removed in vacuo. Resulting crude product was purified by column chromatography, eluting with EtOAc/Hex (10/90) to afford 2.55 g (37%) of the desired benzyl 4-bromobutyrate (2a). 1H NMR (200 MHz, CDCl3) d 7.4 (s, 5H), 5.2 (s, 2H), 3.4 (t, 2H), 2.6 (t, 2H), 2.2 (p, 2H); mass spec (DCl, NH3) (M+NH4)+ 275.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[ClH:8].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.[BH4-]>CO>[ClH:8].[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1
Reactant: O=Cc1ncc[nH]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ncc[nH]2)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole-2-carboxaldehyde (2.45 g, 25.5 mmol) is added to a solution of 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride (11.1 g, 24.9 mmol) and triethylamine (5.05 mL, 50.0 mmol) in methanol (500 mL). The mixture is stirred at room temperature for 16 hours. Polymer supported borohydride (Aldrich, borohydride on Ambelite IR-400, 2.5 mmol/g, 10.0 g, 25.0 mmol) is added, the mixture stirred for 2 hours, filtered and concentrated under reduced pressure. The residue is taken up in ethanol (100 mL) and a saturated solution of hydrochloric acid gas in diethyl ether (10 mL) is added. The white precipitate is collected to yield 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-imidazolylmethylamino)-indan-5-yl] amide hydrochloride m.p. 240-242° C. Free base has m.p. 169-170° C.