Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(N(CC)CC)C.[K+].[Br-]>CC#N>[F:25][C:22]1[CH:21]=[CH:20][C:19]([S:18][CH2:17][CH2:16][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[CH2:13][CH2:12]2)=[CH:24][CH:23]=1
Reactant: Fc1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc(SCCCN2CCN(c3ncc(F)cn3)CC2)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(5-fluoro-2-pyrimidinyl)piperazine (1.58 g, 8.67 mmol), 1-bromo-3-(4-fluorophenylthio)propane (2.16 g, 8.67 mmol), triethylamine (1.33 mL, 9.53 mmol) and KI (1.58 g, 9.52 mmol) in MeCN (45 mL) was refluxed under N2 atm. for 18 h, then cooled at 23° C. and concentrated under reduced pressure. The residue was solubilized in EtOAc (400 mL) and the resulting organic solution was washed with water (2×40 mL), dried (MgSO4) and concentrated to dryness. The crude material (3.0 g) was purified on a silica gel pad (3.4×8.5 cm) using a mixture of 50%-100% EtOAc in hexane. Appropriate fractions were combined and concentrated leaving 2.64 g (87%) mp 68°-70° C. Recrystallization from EtOH afforded an analytical sample, mp 70°-1° C.; 1H NMR (CDCl3, 200 MHz) δ: 1.6-1.9 (m, 2H), 2.2-2.7 (m, 6H), 2.92 (t, J=7 Hz, 2H), 3.6-3.9 (m, 4H), 6.9-7.1 (m, 2H), 7.3-7.5 (m, 2H), 8.17 (s, 2H); IR (KBr) ν: 1609, 1552, 1500, 1490 cm-1 ;
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.55 g (99%) of N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 243-245° C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.64; H, 3.43; N, 12.64; S, 7.37.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].[CH3:14][S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16].C(N(CC)CC)C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[C:19]#[N:20])=[C:3]1[Cl:13]
Reactant: CS(=O)(=O)CC#N
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(Cl)c(C=C(C#N)S(C)(=O)=O)c2ccccc21
Reaction time: 144 h

Procedure:
To 550 mg of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 25 ml of THF, was added 730 mg of methylsulfonylacetonitril and 1.2 g of triethylamine. After 24 hours another 300 mg of methylsulfonylacetonitril was added, and the mixture was stirred for 6 days. The precipitate was collected by filtration to give (3a). Yield 630 mg of (3a), m.p. 180° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[N+:22]([O-])([OH:24])=[O:23]>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=C(N1CC(CCl)c2c1ccc1cc([N+](=O)[O-])ccc21)C(F)(F)F
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A stirred solution of 108 (5.24 g, 16.7 mmol) in dry CH2Cl2 (70 mL) was treated dropwise at 10° C. with fuming HNO3 (2.0 mL, 48 mmol) and then warmed to room temperature for 5 min. The mixture was diluted with CH2Cl2 (100 mL) and the resulting solution was washed with water, dried, filtered through a column of silica gel, then concentrated to 25 mL and diluted with EtOAc (25 mL). Following refrigeration the precipitate was collected and washed with EtOAc to give 1-(chloromethyl)-3-(trifluoroacetyl)-7-nitro-1,2-dihydro-3H-benzo[e]indole (131) (2.31 g, 39%) as a pale yellow solid: mp (CH2Cl2/iPr2O) 213-214° C.; 1H NMR [(CD3)2SO] δ 9.06 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.1 Hz, 1H), 8.33-8.25 (m, 2H) 4.67-4.51 (m, 2H), 4.46 (br d, J=10.6 Hz, 1H), 4.17 (dd, J=11.3, 3.0 Hz, 1H), 4.07 (dd, J=11.3, 5.5 Hz, 1H). Anal. (C15H10ClF3N2O3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[S:24][C:25]([CH2:28][NH2:29])=[CH:26][N:27]=1>C(#N)C>[Cl:22][C:23]1[S:24][C:25]([CH2:28][NH:29][C:9]([NH:8][CH2:7][C:4]2[S:3][C:2]([Cl:1])=[N:6][CH:5]=2)=[N:12][N+:13]([O-:15])=[O:14])=[CH:26][N:27]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: NCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C(NCc1cnc(Cl)s1)NCc1cnc(Cl)s1
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a mixture of 1 g N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea, 560 mg potassium carbonate, 400 mg cuprous chloride and 12 ml acetonitrile was added 610 mg of 2-chloro-5-(aminomethyl)thiazole and the mixture was stirred for 1 hour under reflux. Thereafter, the reaction mixture was concentrated, then water was added to the resultant solids, followed by stirring thoroughly. Thereafter, the solids were collected by filtration and purified by column chromatography [eluent: dichloromethane-methanol (10:1)] to afford 191 mg of N,N'-bis(2-chloro-5-thiazolylmethyl)-N"-nitroguanidine (compound No.39) as a white powder, mp 217-218° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][OH:22])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:40][O-].[Na+].CO>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[CH2:21][O:22][CH3:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[O-]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of the product from Example 127 (32 mg, 0.064 mmol) in anhydrous CH2Cl2 (1 ml) was added thionyl chloride (23 μL, 0.32 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was partitioned between saturated aq. NaHCO3 (5 ml) and CH2Cl2 (5 ml) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (1 ml), and a solution of 25% NaOMe in MeOH (58 μL, 0.254 mmol) was added. The resulting mixture was stirred at 50° C. for 2 h. The mixture was partitioned between 1 N aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (15 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H) 9.86 (s, 1H) 7.62-7.87 (m, 3H) 7.12-7.39 (m, 5H) 5.66 (d, J=7.72 Hz, 1H) 4.58 (s, 2H) 3.78 (s, 3H) 3.35 (s, 3H) 3.00 (s, 3H) 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39](Br)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:25]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:45]3[C:40]([CH:41]=[CH:42][CH:43]=[CH:44]3)=[C:39]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=3)[C:38]=2[CH3:47])=[O:36])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Temperature: 90 °C
Yield: 65.9 %

Procedure:
0.229 g (1.27 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.492 g (2.12 mmol) of potassium phosphate dihydrate and 0.024 g (0.02 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.410 g (1.06 mmol) of methyl 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoate in 8 ml of a DME/H2O (5/1) mixture. The reaction medium is heated at 90° C. for 18 hours. The reaction medium is extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 309 mg of a yellow solid are obtained.
Reaction SMILES: [Na].C(O[C:5](=[O:17])[CH:6]([C:15]#[N:16])[CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])C.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:16][C:15]1[N:21]=[C:19]([SH:20])[N:18]=[C:5]([OH:17])[C:6]=1[CH2:7][CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(Cc1c(N)nc(S)nc1O)OCC
Temperature: 85 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To ethanol (200 ml) was added sodium (2.05 g, 89 mmol) in small portions. The solution was stirred until complete dissolution of the sodium metal. 2-Cyano-4,4-diethoxy-butyric acid ethyl ester (J. Chem. Soc., 1960, 131-138) (9.292 g, 40.5 mmol) was then added as a solution in ethanol (50 ml), followed by addition of thiourea (3.08 g, 40.4 mmol). The solution was heated at 85° C. for 18 hours, and then cooled to room temperature. The solution was concentrated, and saturated aqueous ammonium chloride solution (150 ml) was added. The mixture was stirred at room temperature for 18 hours, after which time the solid was collected by filtration, and washed with water (20 ml) to yield the product (3.376 g, 36%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:10]=[C:9]1[C@H:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([CH2:29][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][O:32][CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:10]=[C:9]1[C@H:21]([NH:26][CH2:27][CH2:29][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][O:32][CH3:33])[C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)cn1Cc1ccccc1
Reactant: COC[C@H](CC=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H](CCN[C@@H](c1nc(-c2cc(F)ccc2F)cn1Cc1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine (1 eq) in dichloromethane was added tert-butyl (S)-1-formyl-3-methoxypropan-2-ylcarbamate (1.5 eq) and acetic acid (1 eq). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (2 eq) was added at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Solvent was concentrated and crude was partitioned between ethyl acetate and satd. sodium bicarbonate. The organic layer was washed with water, brine and dried over sodium sulfate. Purification by silica gel chromatography (25% EtOAc/Hexane) provide pure product as a white foamy solid.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[CH3:1][S:2]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16])=[O:22]
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)C1C(=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.13 h

Procedure:
To a cooled (ice/water) solution of 9.4 g. of 3 -methylthio-5-trifluoromethyl-2-indolinone predissolved in 318 ml. of methylene chloride is added 7.33 g. of m-chloroperoxybenzoic acid in small portions over a period of one minute. The ice/water bath is then removed; and, after eight minutes stirring, the reaction mixture is filtered (after the peracid is dissolved and before the product precipitates). The reaction mixture is stirred for an additional hour during which product precipitates. The product is then collected by filtration. Recrystallization from ethyl acetate/ligroine gives 3-methylsulfinyl- 5-trifluoromethyl-2-indolinone, m.p. 141°-142°C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[NH:18])[NH:16]O)=[CH:11][CH:10]=1)=[O:7])C.C([O-])=O.[NH4+]>C(O)(=O)C>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:19])=[O:3])=[CH:14][CH:13]=1)(=[NH:16])[NH2:18]
Reactant: CCOC(=O)CC(=O)Nc1ccc(C(=N)NO)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(NC(=O)CC(=O)O)cc1
Reaction time: 5 h

Procedure:
To a solution of N-[4-(N-hydroxycarbamimidoyl)-phenyl]-malonamic acid ethyl ester (16.9 g, 63.41 mmol) and ammonium formiate (20.0 g, 317.1 mmol) in glacial acetic acid (400 ml) Pd/C, 10% (675 mg) was added. The suspension was stirred for 5 h under reflux. The reaction mixture was filtered through celite and evaporated. The crude product was dissolved in ethanol (400 ml) and treated with an aqueous solution of sodium hydroxide (2 M, 300 ml). The reaction mixture was stirred for 4 h at RT and then hydrochloric acid (2 N) was added (pH=8). The suspension was filtered and the solid was dissolved in ACN/water and acidified with trifluoroacetic acid (pH=1). Lyophilization left the product (9.88 g, 46%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[C:7]([CH3:32])=[C:8]([C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])=[CH:20][CH:21]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[C:7]([CH3:32])=[C:8]([C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])=[CH:20][CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)/C=C/c1ccc(NS(=O)(=O)c2ccccn2)c(C(=O)OCc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccn2)c(C(=O)O)c1C

Procedure:
A solution of Example 214A (131 mg) in methanol (10 mL) was treated with Pd/C (10%, 150 mg) under one atmosphere of hydrogen for 16 hours. Filtration and evaporation of the solvents to provide the desired product. 1H NMR (DMSO-d6) δ 2.20 (s, 3H), 2.54 (t, 2H), 2.80 (t, 2H), 3.57 (s, 3H), 6.90 (d, 1H), 7.10 (d, 1H), 7.66 (m, 1H), 7.87 (d, 1H), 8.04 (q, 1H), 8.73 (d, 1H), 9.70 (s, 1H), 13.20 (br s, 1H); MS (ESI(−)) m/e 377 (M−H)−.
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[I-].[Na+].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Cl)[CH3:26]>C(O)C.O>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:11][CH:10]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH3:26]
Reactant: CC(=O)Nc1ccc(C2C(=O)c3ccccc3C2=O)cc1
Reactant: CCOC(=O)CCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A solution of sodium (0.412 g) in absolute ethanol ((200 mL) was treated with 2-(4-acetylaminophenyl)-indan-1,3-dione (5 g, Reference Example 14) then with sodium iodide (2.69 g) and chloroacetic acid ethyl ester (3.6 mL). The mixture was heated at 100° C. for 20 minutes then poured into water (500 mL) and then extracted with ethyl acetate (500 mL). The organic extract was dried over magnesium sulfate and then evaporated to give the title compound (5.25 g) as a pale coloured solid.
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:57])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:56])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[C:41](\[CH3:55])/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:59])[CH3:58])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CC#N.O>C(Cl)Cl>[Cl:54][C:51]1[CH:50]=[CH:49][C:48]([C:45]2([NH:44][C:42](=[O:43])/[C:41](/[CH3:55])=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:56])([CH2:21][CH2:22]4)[C@@:19]4([CH3:57])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:59])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:60])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)=[CH:53][CH:52]=1
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 0.355 mmol) in DCM (6 mL) was added TFA (3 mL, 0.355 mmol). The reaction mixture was stirred at rt for 2 hr and evaporated in vacuo to afford crude product which was diluted with DCM (30 mL) and washed with water, saturated NaHCO3, water, saturated NH4CI and water. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a residue which was dissolved into MeCN—H2O (1:2, 9 mL) and freeze-dried to give the title compound (150 mg, 0.190 mmol, 53.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.81-11.61 (m, 1H), 8.73-8.51 (m, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.22-7.04 (m, 2H), 6.54 (s, 1H), 4.39 (dd, J=4.9, 11.2 Hz, 1H), 3.23-3.10 (m, 1H), 2.79-0.44 (m, 57H); LC/MS: m/z calculated 787.5. Found 788.3 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][C:29](=[CH2:32])[CH2:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][C:29](=[CH2:28])[CH2:30][NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: C=C(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 130.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), 2-methyl-allylamine (16.4 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (91%) of the title compound as a TFA salt (1.6 H2O, 1.3 TFA, effective MW=586.53). 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.72 (2H, m), 8.13 (4H, m), 7.70 (1H, d, J=7.1), 7.58 (2H, m), 7.41 (2H, m), 7.27 (1H, s), 7.06 (1H, d, J=7.1), 6.91 (1H, t, J=7.5), 4.42 (1H, m), 2.22 (2H, m), 2.08 (2H, m), 1.68 (2H, m). ESIMS (M+H+): 410.1.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 6.0 mmol) in CH2Cl2 (15.0 mL) was added 2-hydroxyisoindoline-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylate as light yellow oil.