Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[CH2:12]([O:14][C:15]([CH2:17][C:18](=N)[O:19][CH2:20][CH3:21])=[O:16])[CH3:13]>C(O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:18]([O:19][CH2:20][CH3:21])[CH2:17][C:15]([O:14][CH2:12][CH3:13])=[O:16]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=Nc1ccc(F)c(F)c1F)OCC
Temperature: 20 °C
Reaction time: 48 h
Yield: 105.5 %

Procedure:
2,3,4-Trifluoroaniline (58.8 g) is added in a single portion with stirring to a solution of 2-ethoxycarbonyl-1-ethoxyethylideneamine hydrochloride (90 g) in ethanol (820 cc). After 48 hours' stirring at a temperature in the region of 20° C., the suspension obtained is filtered; the filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50° C. The oily residue is taken up with water (250 cc). The mixture obtained is extracted with ethyl ether (3×200 cc). The combined organic extracts are washed with water (4×150 cc), dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at approximately 30° C. 2,3,4-Trifluoro-N-[1-ethoxy-2-(ethoxycarbonyl)ethylidene]aniline (122 g) is obtained in the form of a yellow oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 97.8 %

Procedure:
To a solution of 21.58 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 325 ml of ethyl alcohol is added 2.15 g of 10% Pd/C and 5.16 g of hydrazine followed by stirring and heating under reflux for 15 hours. The room temperature reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 19.2 g of the desired product as a tan solid. The solid is purified by flash chromatography using 7:1 ethyl acetate-hexane to give 17.97 g of the desired product, m.p. 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[Cl:30])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: ClCc1ccccc1Cl
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in dry dimethylformamide (20 ml) are added potassium carbonate (0.35 g) and 2-chlorobenzyl chloride (0.32 ml), and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove the solvent. The residue is recrystallized from acetone/diethyl ether to give 7-chloro-1-[3-methoxy-4-(2-chlorobenzyloxy)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.76 g) as white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[CH:7][N:8]([C:20]=2[N:21]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:12]([O:13][CH3:14])[C@@:10]1([CH3:19])[OH:11].[CH3:23]I>>[CH3:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[N:6]=[CH:7][N:8]([C:20]=2[N:21]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:12]([O:13][CH3:14])[C@@:10]1([CH3:19])[OH:11]
Reactant: CI
Reactant: CO[C@@H]1[C@@H](CO)O[C@@H](n2cnc3c(N)nc(C)nc32)[C@]1(C)O
Product: CNc1nc(C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC)[C@@]1(C)O

Procedure:
Compound 63 was methylated by methyl iodide and then rearranged to give 2,N6,2',3'-O-tetramethyladenosine (Compound 64).
Reaction SMILES: COC[N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[C:23]4[C:18](=[N:19][CH:20]=[N:21][C:22]=4[S:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:17]=[CH:16]3)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:33]=[CH:34][CH:35]=[N:36][C:5]1=2.B(Br)(Br)Br.O>ClCCl>[N:36]1[C:5]2[NH:4][C:9]3[CH:10]=[C:11]([CH2:14][N:15]4[C:23]5[C:18](=[N:19][CH:20]=[N:21][C:22]=5[S:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:17]=[CH:16]4)[CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[N:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCCSc1ncnc2ncn(Cc3ccc4c(c3)N(COC)c3nccnc3S4)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCCSc1ncnc2ncn(Cc3ccc4c(c3)Nc3nccnc3S4)c12
Yield: 42.6 %

Procedure:
To 15 ml of a solution of 0.109 g of ethyl 4-[7-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)purin-6-ylthio]butanoate in dichloromethane was added in a nitrogen atmosphere 0.84 ml of a 1 M solution of boron tribromide in dichloromethane and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was distributed into dichloromethane and water. The organic layer was extracted and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallized from diethyl ether to thereby give 40 mg of the title compound as yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[O:27][CH3:28])=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)=[CH:18][CH:17]=2)=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: CCOC(=O)c1csc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2nc(C(=O)O)cs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid ethyl ester (2.38 g, 5.870 mmol) in THF (40 mL) was treated with a solution of lithium hydroxide monohydrate (2.6 g, 61.96 mmol) in water (40 mL) at room temperature and stirred at 60° C. for 2 h. The mixture was cooled, diluted with water (75 mL), acidified with aq. 3N HCl and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried (MgSO4), filtered and concentrated to 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid (2.13 g, 96.1%) as a pale yellow solid. LC-MS (ES) calculated for C18H13F2NO4S, 377.37; found m/z 378 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[C:33]1([C@@H:39](O)[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][C@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: C[C@H](O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@@H](C(=O)O[C@@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 74.7 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of (S)-(−)-1-phenylethanol (0.23 g, 1.8 mmol) and 0.10 mL of pyridine (96 mg, 1.2 mmol) in dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.46 g (75% yield) of the title compound (35a) as a colorless oil. Rf=0.54 (EtOAc/Hex=1:2). 1H NMR (400 MHz, CDCl3): δ=1.03 (s, 3H), 1.06 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 2.24-2.30 (m, 2H), 3.18-3.23 (m, 2H), 3.63-3.66 (m, 2H), 3.81-3.82 (m, 4H), 3.95 (d, J=9.6 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.26 (d, J=11.6 Hz, 1H), 4.51 (d, J=10.8 Hz, 1H), 6.01 (q, J=6.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.35-7.39 (m, 5H) ppm. D.e.>98% (by 1H NMR-spectroscopy, 400 MHz, CDCl3). MS (ESI) m/z 535.18 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[S:32]([NH2:35])(=[O:34])=[O:33]>O1CCCC1>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][C:6]1[CH:15]=[C:2]([CH:30]([OH:31])[C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:26]=2)[CH:3]=[CH:4][C:5]=1[O:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Reactant: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane (2 g, 6.32 mmol) dissolved in tetrahydrofuran (25 mL) at −78° C. under nitrogen is dropwisely added 1.7 M of tert-butyllithium (8.06 mL, 12.6 mmol). The reaction mixture is stirred at −78° C. for 5 minutes. Then, the solution of 2-chloro-5-formyl-benzenesulfonamide (0.462 g, 2.11 mmol) in tetrahydrofuran (5 mL) is added slowly. The reaction mixture is warmed up to room temperature and stirred for 24 h. The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.57 g (59%) of the title compound as a brown oil. 1H NMR (CDCl3): δ 8.00 (m, 1H), 7.40 (m, 2H), 6.70 (d, 3H), 5.70 (s, 1H), 5.00 (m, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[CH:18]=1)=[O:4].[OH-].[Li+]>>[CH3:13][S:10]([C@H:8]1[CH2:7][N:6]([C:14]2[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=[C:17]([CH3:19])[CH:18]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(C)(=O)=O)C[C@H]2C(=O)O)n(CC(F)(F)F)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound which was used in the next step without further purification. MS (ESI): m/z=356.3 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:3]([C:5]2[N:6]=[C:7]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:8]3[C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
7-Bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (20 mg, 0.07 mmol) and p-fluorobenzylamine (19 uL, 0.17 mmol) in dry methanol (4 mL) was heated to reflux with stirring. Reaction progress was monitored by HPLC. After 6 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was triturated with diethyl ether (2 mL) and the precipitate collected by filtration and washed with diethyl ether (10 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid 4-fluoro-benzylamide (24 mg, 92%) as a yellow brown solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cccn3nc(Cl)nc23)C1

Procedure:
3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as pale yellow viscous oil (0.544 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.6 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 4.98 (br s, 1H), 3.65-3.08 (m, 6H), 2.64-2.51 (m, 1H), 2.15-2.05 (m, 1H), 1.80-1.65 (m, 1H), 1.47 (s, 9H). 163 b) 3-({2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.421 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (300.0 mg, 1.568 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (78.0 mg, 0.143 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.284 g, 39%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.5 Hz, 1H), 7.46 (d, J=8.9 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.71 (t, J=7.3 Hz, 1H), 6.59 (s, 1H), 6.35 (d, J=7.7 Hz, 1H), 4.75 (br s, 1H), 3.66-3.05 (m, 10H), 2.63-2.52 (m, 5H), 2.36 (s, 3H), 2.15-2.04 (m, 1H), 1.80-1.65 (m, 1H), 1.46 (s, 9H). MS=507 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH2:3][CH2:4][CH3:5].[CH:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH:16]([NH:19][C:20](=[O:21])[O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])[CH:7]=[CH:8]2)([CH3:18])[CH3:17]
Reactant: CC(C)N=C=O
Reactant: CCCC(C)n1ccc2cc(O)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C)n1ccc2cc(OC(=O)NC(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a stirred solution of 1-(pentan-2-yl)-1H-indol-5-ol (9) (2.60 g, 12.8 mmol) in dichloromethane (CH2Cl2, 40 mL) was added isopropyl isocyanate (10) (i-PrNCO, 1.63 g, 19.3 mmol), followed by triethylamine (NEt3, 0.90 mL). The solution was stirred at room temperature overnight, and then concentrated to dryness in vacuo. The resulting oil was purified by silica gel column chromatography (1:3 ethyl acetate/hexanes) to provide 1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (11) (3.6 g, 98%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.35 (d, J=2.0, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.98 (dd, J=8.5, 2.0, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.86 (d, J=6.5 Hz, 1H), 4.49 (m, 1H), 3.82 (m, 1H), 1.87 (m, 2H), 1.51 (d, J=6.5, 3H), 1.26 (m, 8H), 0.90 (t, J=7.5, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18](O)=[O:19].C[CH2:23][N:24]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN.Cl>CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:24][CH3:23])=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc2nn(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxylic acid (1.0 g, 2.8 mmol) in dry DMF (500 mL) were added EDCI (1.1 g, 6.2 mmol) and HOBT (0.5 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 1 h, and then Et3N (5 mL) and MeNH2.HCl (0.9 g, 14.3 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and 300 mL Na2CO3 (a.q.) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (PE:EA=3:1) to give 6-amino-5-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (0.8 g, yield: 74%). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.55˜7.58 (m, 2H), 7.20˜7.26 (m, 2H), 6.98 (s, 1H), 5.75 (s, 1H), 4.32 (s, 2H), 2.98 (d, J=4.8 Hz, 3H). MS (M+H)+: 363/365.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[N:8]=[C:7]2[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.C(O)C.[C].[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[N:8]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc([N+](=O)[O-])cc1)n2C1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)cc1)n2C1CCCC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
Ethyl 1-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5-carboxylate (12 g) obtained in Example 21 was dissolved in tetrahydrofuran (200 ml) and ethyl alcohol (50 ml), 7.5% palladium carbon (50% wet, 1 g) was added. The mixture was hydrogenated for 1 hr at atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Tetrahydrofuran was added to the residue to allow crystallization and the crystals were collected by filtration to give the title compound (11 g, yield 98%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32](=[O:39])[NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:46][O:47][C:48]([C:50]1[S:54][C:53](B(O)O)=[CH:52][CH:51]=1)=[O:49].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:40])([CH2:14][CH2:15]2)[C@@:12]2([CH3:41])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:42])([CH3:43])[C:7]([C:53]2[S:54][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:51][CH:52]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:39]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)c1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (100 mg, 0.152 mmol), 5-(methoxycarbonyl)thiophen-2-ylboronic acid (36 mg, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.0045 mmol) and sodium carbonate (48 mg, 0.456 mmol) in water (1 mL) and DME (1 mL) was heated up at 90° C. for 2 hours. The reaction mixture was quenched with distilled water, extracted with ethyl acetate (3×5 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a brown oil (60 mg, 32%). LCMS: m/e 647.63 (M−H)−, 2.67 min (method 1).
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](=O)([O-])[O-:15].[K+].[K+].C=O>C(#N)C.O>[OH:15][CH2:14][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]1=[O:13]
Reactant: O=C1CCCCCCCCCCC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCCCCCCCC1CO
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of cyclododecanone (1) (5.0 g, 27.47 mmol, 1 equiv) and potassium carbonate (0.06 g, 0.41 mmol, 0.015 equiv) in acetonitrile (20 mL) and water (2 mL) was added formaldehyde (37% in water) (4.2 mL, 52.20 mmol, 1.9 equiv) at 40° C. dropwise. The reaction was stirred at 40° C. for 4 hours, then cooled to room temperature and extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure. The crude product was purified on an AnaLogix system using a gradient of 0 to 30% ethyl acetate in heptanes to give the desired product as a clear oil, which slowly solidifies to a white solid (2.5 g, 43% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)Cc1cc([N+](=O)[O-])ccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(N)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Methyl 2-methoxycarbonylmethyl-4-nitrobenzoate (1.74 g, 6.87 mmol) was dissolved in a mixed solvent of ethyl acetate and methanol under nitrogen atmosphere, and then 10% palladium ddcarbon (30 w/w %) was added thereto. After replacing nitrogen gas with hydrogen gas, the reaction solution was stirred at room temperature overnight. The palladium catalyst was removed by Celite filtration, followed by washing with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure to give the title compound (1.30 g, 84%).