Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][C:40]=1[C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=1>>[CH3:57][O:56][C:50]1[CH:49]=[C:48]([C:40]2[NH:41][C:42]3[C:47]([C:39]=2[CH2:38][CH2:37][NH:36][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:53]=[CH:52][C:51]=1[O:54][CH3:55]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
To a stirred solution of 4-nitrophenylacetic acid (100 mg in 2.5 mL N,N-dimethylformamide) was added 1-hydroxybenzotriazole (90 mg) and the mixture cooled to 0° C. After 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg) was added. The mixture was warmed to room temperature and 3-(2-aminoethyl)-2-(3,4-dimethoxyphenyl)indole (316 mg) was added. After 17 hours the reaction was quenched by the addition of water and extracted with ethyl acetate. The organic portion was washed with water, 0.5M sodium bisulfate and brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (116 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=3)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ncccc2F)cc1
Product: C[Si](C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3F)cc2)cc1
Yield: 80.23 %

Procedure:
The synthesis method of compound A-08 is similar to example 9. Just R1 and R3 of Scheme 2 are, respectively, F and p-SiMe3. namely: compound 6 is 4-trimethylsilyl aniline (compound 6a 35 mg); compound 10 is 4-(3-fluoro-pyridine-2-yl)benzoic acid (compound 10c); compound 12 is compound A-08 (62 mg, yield 80.23%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[C:23]2[C:28]([C:29]=1[O:30][CH2:31][O:32][CH3:33])=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc2c(/C=C(\C)C(=O)OCC)cc(OC)c(OCOC)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:11]2)(=O)=O)C=CC=CC=1.C1(S(N2C=C(C#CCCCC)C(C3C=NC=CC=3)=N2)(=O)=O)C=CC=CC=1.C(C1C(C2CN(C)CCC=2)=NNC=1)#CCCCC>>[C:20]1([CH2:19][CH2:18][CH2:17][C:16]#[C:15][C:13]2[C:12]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:11][NH:10][CH:14]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(C#CCCCc2ccccc2)c(-c2cccnc2)n1
Agent: CCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Agent: CCCCC#Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Product: C(#Cc1c[nH]nc1-c1cccnc1)CCCc1ccccc1

Procedure:
Compound 43D was converted to the title compound 44D, using the methodology described for the conversion of 43A to 44A (see Scheme 9). Yield: 86% (oil). 1H-NMR (400 MHz, CDCl3): δ 9.25 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.35 (dt, J=8 Hz, 2 Hz, 1H), 7.74 (s, 1H), 7.40-7.17 (m, 6H), 2.77 ((t, J=7 Hz, 2H), 2.44 ((t, J=7 Hz, 2H), 1.99-1.89 (m, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:9])[CH3:8].Cl>CO.O>[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([O:14][CH3:1])=[O:13])(=[O:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=C(NC(C)=O)C(=O)O)cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)NC(C)=O

Procedure:
This compound was prepared from the product of Example 2 by treatment with sodium carbonate in methanol by a modification of the procedure of Saxena et al (supra). Alternatively, it could be made by esterification of α-acetylamino-3,4-dimethoxycinnamic acid. Thus, 9.62 g of the acid was heated under reflux for 19 hours in 100 mL of methanol containing 1 mL of concentrated hydrochloric acid. After diluting with 500 mL of water, the solution was basified with a 10% aqueous solution of sodium carbonate to a pH of 8-9. The resultant solids were collected by filtration, washed with 3×50 mL of water and dried at the pump. The crude product was further purified by column chromatography on silica gel, eluting with a gradient of methylene chloride/methanol (99:1 thru 96:2). After stripping the solvent from the appropriate fractions, and drying at the pump 2.07 g (21%) of the title compound were obtained; 1HNMR (CDCL3) 7.42 (s, 1H), 7.10 (d, J= 8.5 Hz, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.17 (s, 3H); MP 198°-200° C. Anal. calcd for C14H17NO5 : C, 60.2; H, 6.14; N, 5.02. Found: C, 60.42; H, 5.78; N, 4.53.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH2:10].ClCCl.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:18]2[C:17]3[C:22](=[C:23]([Cl:25])[CH:24]=[C:15]([Cl:14])[CH:16]=3)[CH2:21][N:20]([CH3:26])[CH2:19]2)[CH:28]=1)(=[O:35])=[O:34]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: NCCOCCOCCN
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1

Procedure:
To a 50-mL 3-necked round-bottom flask was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (3.2 g, 21.59 mmol, 21.09 equiv) and dichloromethane (DCM; 20 mL). This was followed by the addition of a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (Intermediate 1.6) (400 mg, 1.02 mmol, 1.00 equiv) in DMF (5 mL) dropwise with stirring. The resulting solution was stirred for 5 h at which time it was diluted with 100 mL of ethyl acetate. The resulting mixture was washed successively with 2×10 mL of water and 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (58%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][OH:11].C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH3:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[CH2:10][O:11][CH2:22][O:23][CH3:24]
Reactant: OC/C=C/c1ccccc1Cl
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC/C=C/c1ccccc1Cl
Temperature: 0 °C
Yield: 92.2 %

Procedure:
To a 250 ml round-bottomed flask, (E)-3-(2-chlorophenyl)prop-2-en-1-ol (2.96 g, 17.5 mmol, Preparation example 1) and Dichloromethane (17.5 ml) were added and the reaction mixture was cooled to 0° C. Diisopropylethylamine (6.1 ml, 35.1 mmol) was added and stirred at 0° C. Methyl chloromethyl ether (2.77 ml, 35.1 mmol) was added dropwise and stirred for overnight. The reaction mixture was quenched with 1N NaOH solution, extracted by dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated under vacuum. The crude compound was purified by a silica gel column to produce the title compound (3.43 g, 85˜95%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.ClC1C(Cl)=CC=CC=1C[NH:15][CH:16]1[CH2:18][CH2:17]1>>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH:16]1[CH2:18][CH2:17]1
Reactant: Cc1cccc(C=O)c1C
Reactant: Clc1cccc(CNC2CC2)c1Cl
Product: Cc1cccc(CNC2CC2)c1C

Procedure:
1B was synthesized from 2,3-dimethylbenzaldehyde (5.0 g, 37.3 mmol) using the procedure described for 1A. Yield: 6.0 g (92%) as light yellow oil. ESI-MS:m/z 176.3 (M+H)+, HPLC retention time: T=1.340 min (FAST-2).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][Br:15])[N:3]=1.[CH3:16][NH2:17]>C(O)C>[BrH:15].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][NH:17][CH3:16])[N:3]=1
Reactant: Cc1nn(CCBr)c(=O)c2ccccc12
Reactant: CN
Solvent: CCO
Product: Br
Product: CNCCn1nc(C)c2ccccc2c1=O

Procedure:
2-(4-Methyl-2H-phthalazin-1-on-2-yl)ethyl bromide (6.1 g) and methylamine (20 ml of 30% ethanolic methylamine) in ethanol (150 ml) were heated in a bomb at 100° for 2 hours. The solvent was removed and the residue triturated with ethyl acetate to give a yellow solid, which was recrystallised from ethanol to afford the title compound, yield 5.03 g, m.p. 219°-221°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].N12CCN(CC1)CC2.[C:18]([O:22]CC)(=[O:21])[C:19]#[CH:20].CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9]/[CH:20]=[CH:19]/[C:18]([OH:22])=[O:21]
Reactant: Cc1cccc(C)c1O
Reactant: C#CC(=O)OCC
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cccc(C)c1O/C=C/C(=O)O

Procedure:
(E)-3-(2,6-dimethylphenoxy)acrylic acid 30a was prepared by the general method of Fan, et al. ((2006 Synthesis 2286): ethyl (E/Z)-3-(2,6-dimethylphenoxy)acrylate: 2,6-Dimethylphenol (1.5 g, 12.3 mmol) and 1,4-diazabicyclo[2.2.2]octane (100 mg, 0.9 mmol) and 2 mL of methylene chloride were combined with magnetic stirring. Ethyl propiolate (1.2 mL, 12.6 mmol) in 3 mL of methylene chloride was added drop wise over 5-10 minutes. Thin-layer chromatography of the reaction mixture (silica gel, hexane) showed the formation of two products. The reaction mixture was diluted with ˜70 mL of ethyl acetate and extracted with 10% potassium hydroxide, and then with saturated sodium chloride solution. The mixture was then extracted with 10% hydrochloric acid solution and then again with saturated sodium chloride solution. The ethyl acetate extract was dried with anhydrous magnesium sulfate, filtered, and evaporated to dryness to afford 2.9 g (100%) of product. A sample of this material (1.0 g) was purified by normal-phase chromatography (COMBIFLASH) to afford 650 mg of ethyl (E)-3-(2,6-dimethylphenoxy)acrylate [1H NMR (400 MHz, CDCl3): 1.24 (t, 3H, J=7.2 Hz), 2.17 (s, 6H), 4.13 (q, 2H, J=7.2 Hz), 5.00 (d, 1H, J=12.4 Hz), 7.04 (m, 3H), 7.74 (d, 1H, J=12.4 Hz], and 300 mg of the ethyl (Z)-3-(2,6-dimethylphenoxy)acrylate [1H NMR (400 MHz, CDCl3): 1.31 (t, 3H, J=7.2 Hz), 2.24 (s, 6H), 4.23 (q, 2H, J=7.2 Hz), 5.02 (d, 1H, J=6.8 Hz), 6.46 (d, 1H, J=6.8 Hz), 7.02 (m, 3H)]. (E)-3-(2,6-Dimethylphenoxy)acrylic acid 30a. Three hundred milligrams of ethyl (E)-3-(2,6-dimethylphenoxy)acrylate was combined with 0.5 g of KOH in 10 mL of a 20:80 mixture of water/ethanol and heated at reflux for 2.5 hours. The progress of the reaction was monitored by thin-layer chromatography (silica gel, hexane/ethyl acetate, 95:5). When the reaction had gone to completion, the reaction mixture was removed from heat and the ethanol was removed under reduced pressure. The reaction mixture was acidified with 5% hydrochloric acid solution and extracted with three 30-mL portions of ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solid that formed was titrated with hexane and collected by vacuum filtration to afford 100 mg of (E)-3-(2,6-dimethylphenoxy)acrylic acid 30a. NMR (400 MHz, CDCl3): 2.17 (s, 6H), 5.00 (d, 1H, J=12.4 Hz), 7.05 (s, 3H), 7.80 (d, 1H, J=12.4 Hz), 11.0 (br s, 1H). MS (ESI): 215 [M+Na]+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]([C:22]#[C:23][Si](C)(C)C)=[CH:14][CH:13]=2)=[C:8]([CH3:28])[C:7]=1[CH:29]1[C:42]2[C:41](=[O:43])[CH2:40][C:39]([CH3:45])([CH3:44])[CH2:38][C:37]=2[O:36][C:35]2[CH2:34][C:33]([CH3:47])([CH3:46])[CH2:32][C:31](=[O:48])[C:30]1=2.Cl>C1COCC1.O>[C:22]([C:15]1[C:16]([C:18]([OH:20])=[O:19])=[N:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[C:7]([CH:29]3[C:30]4[C:31](=[O:48])[CH2:32][C:33]([CH3:46])([CH3:47])[CH2:34][C:35]=4[O:36][C:37]4[CH2:38][C:39]([CH3:44])([CH3:45])[CH2:40][C:41](=[O:43])[C:42]3=4)[C:8]=2[CH3:28])=[CH:13][CH:14]=1)#[CH:23]
Reactant: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Reaction time: 17 h
Yield: 89.6 %

Procedure:
Lithium hydroxide monohydrate (303 mg, 7.21 mmol) was added to a solution of the methyl 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-3-[(trimethylsilyl)ethynyl]pyridine-2-carboxylate produced in Example 12-2 (564 mg, 0.90 mmol) in THF (11 ml) and water (5.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 17 hours. Thereafter, a 1 N aqueous solution of hydrochloric acid (7.21 ml) was added to the reaction solution, and water was then added thereto. The solution thus mixed was then extracted with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the solid thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (435 mg, yield: 89%).
Reaction SMILES: CSC.ClN1C(=O)CCC1=O.[OH:12][C@@H:13]1[CH2:17][N:16]([C:18](=[O:28])[C@@H:19]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:20]([CH3:22])[CH3:21])[C@H:15]([C:29]2[NH:30][CH:31]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[CH:46]=[C:45]([C:50]4[NH:54][C:53]([C@@H:55]6[CH2:59][CH2:58][CH2:57][N:56]6[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:52][CH:51]=4)[CH:44]=[CH:43]5)=[CH:36][CH:35]=3)[N:33]=2)[CH2:14]1.C(N(CC)CC)C>ClCCl>[CH3:27][O:26][C:24]([NH:23][C@@H:19]([CH:20]([CH3:22])[CH3:21])[C:18]([N:16]1[CH2:17][C:13](=[O:12])[CH2:14][C@H:15]1[C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[C:42]4[C:47](=[CH:48][CH:49]=3)[CH:46]=[C:45]([C:50]3[NH:54][C:53]([C@@H:55]5[CH2:59][CH2:58][CH2:57][N:56]5[C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])=[N:52][CH:51]=3)[CH:44]=[CH:43]4)=[CH:36][CH:35]=2)[N:33]=1)=[O:28])=[O:25]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CSC
Product: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Dimethyl sulfide (164 μL, 2.23 mmol) was added dropwise to a solution of N-chlorosuccinimide (238 mg, 2.12 mmol) in dichloromethane (10 mL) at 0° C. After 15 minutes the mixture was cooled to −15° C. (ice-salt bath). A solution of (S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (809 mg, 1.06 mmol) in dichloromethane (5 mL) was added dropwise. The temperature was not allowed to go above −10° C. After 2 hours a solution of triethylamine (316 μL, 2.23 mmol) in dichloromethane (2 mL) was added dropwise and the mixture was allowed to warm to room temperature at which point the reaction was complete. The mixture was washed with saturated ammonium chloride (3×10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to yield (S)-tert-butyl 2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (734 mg, 0.96 mmol, 90%).
Reaction SMILES: O.[CH3:2][C:3]1([CH3:25])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[N:17])[CH:12]=3)[C:7]=2[C:6](=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([CH:23]=C)=[CH:22][C:4]1=2.I([O-])(=O)(=O)=[O:27].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH:23]([C:21]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:8]4[C:13](=[CH:12][C:11]([C:16]#[N:17])=[CH:10][CH:9]=4)[NH:14][C:15]=3[C:3]([CH3:2])([CH3:25])[C:4]=2[CH:22]=1)=[O:27]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1(C)c2cc(C=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To the THF (24 ml) and distilled water (6 ml) suspension of 6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-24, 600 mg, 1.920 mmol), t-butanol solution of osmium tetraoxide (192 μl, 0.1 eq.) and sodium meta periodate (821 mg, 2.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. Aqueous solution of sodium thiosulfate (0.3 M) was added to the solution, which was then extracted with an ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (470 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]([S:45](Cl)(=[O:47])=[O:46])([CH3:44])[CH3:43]>C(#N)C>[CH:42]([S:45]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:47])=[O:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 38.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0303 g, 0.0656 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0550 mL, 0.394 mmol) and isopropanesulfonyl chloride (0.0220 mL, 0.197 mmol) to obtain 4-isopropanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0145 g, yield 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH3:17])=[O:15])[C:4]=1[C:5](NC)=[O:6].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:6])[N:16]([CH3:17])[C:14](=[O:15])[NH:13]2
Reactant: CNC(=O)Nc1cccc(OC)c1C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Yield: 96.6 %

Procedure:
A mixture of 2-Methoxy-N-methyl-6-[[(methylamino)carbonyl]amino]benzamide (200 mg, 0.843 mmol), 5% sodium hydroxide solution in water (8 ml) and ethanol (4 ml) was refluxed for 1 h. The solution was allowed to cool and then acidified with acetic acid. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum to afford 168 mg (97%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[CH:11]2)[CH2:3]1.C1(C)C=CC=CC=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=4)[C@@H:8]1[CH2:9][CH:10]=[CH:11]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CC=C3C[C@@H](O)CC[C@]3(C)[C@H]1CC2
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2

Procedure:
250 ml. of a solution of 68 g. of 3β-hydroxy-androsta5,16-diene in 1.25 l. of toluene and 0.5 l. of cyclohexanone was distilled to obtain an anhydrous solution. A solution of 34 g. of aluminum isopropoxide in 170 ml. of dry toluene was added. The mixture was slowly distilled during 30 minutes to remove the acetone formed. After completion of the reaction water was added, and the mixture steam distilled to remove volatile components. the residue was extracted with methyl isobutyl ketone and the extract washed with an aqueous hydrogen chloride solution and water. The solvent was removed by distillation in vacuo and the residue was crystallized from acetone; 38.1 g. of androsta-4,16-dien-3-one were obtained. Recyrstallization from acetone yielded a pure product melting at a 131°-133° C. mol. peak in mass spectrum (m/e): 270. EXAMPLE IV
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:19].[OH-].[Na+].OO>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:19])[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(C)=O
Reactant: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.24 g, 10 mmol) in methanol (25 mL) was added DMSO (1 mL), aqueous 1N NaOH (12 mL, 12 mmol) and H2O2 (4 mL) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.