Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH:35][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (229 mg, 0.8 mmol) and 4-aminoisophthalic acid dimethyl ester (301 mg, 1.4 mmol) were dissolved in DMF (5 mL), and EDCHCl (140 mg, 0.75 mmol), HOAt (163 mg, 1.2 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The mixture was stirred overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-isophthalic acid dimethyl ester as a white solid (281 mg, 76.3% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([CH3:21])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:10].[CH3:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>C(O)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH:8]([CH3:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)=[O:10])[CH2:30][CH2:29]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(C(=O)C(C)Br)cc1OC
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C(C)N2CCC(Cc3ccc(C)cc3)CC2)cc1OC

Procedure:
5.4 g (0.05 mol) of sodium carbonate are added to a mixture of 13.65 g (0.05 mol) of 2-bromo-3',4'-dimethoxypropiophenone and 9.46 g (0.05 mol) of 4-(4-methylbenzyl)-piperidine in 50 ml of ethanol and the mixture is heated under reflux for 3 hours. It is then evaporated to dryness and the residue is passed through a column of silica using acetone as the eluant. This gives an oil, which is used as such.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][C:19]=4[NH:24][C:25](=[O:27])[CH3:26])[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)Nc1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:39])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:39][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Product: CN(C)Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(4-dimethylaminomethyl-phenyl)2H-pyrazol-3-ylamine. Title compound: ES-MS: 506.49 [M-H]+; RTT=1.30 min (HPLC System 3).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (2.8 g) in anhydrous tetrahydrofuran (400 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (3.0 g). After stirring at room temperature for 45 minutes a solution of 1-bromomethyl-4-chlorobenzene (4.3 g) in tetrahydrofuran (100 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and then the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and methyl tert-butyl ether (4:1 by volume) to afford title compound. 4.8 g.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C:11]([N:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])[CH3:18])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:19]([N:17]([CH3:18])[C:11]([CH3:16])([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:9][OH:8])=[O:33])=[O:20])=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CNC(=O)C(C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)C(C)(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 47.6 %

Procedure:
10% Pd—C (36 mg) was added to a methanol (3.0 mL) solution of N-(benzyloxy)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N′,2-dimethylpropanediamide (0.10 g) as obtained in Example 12-(3), and the mixture was stirred in a hydrogen atmosphere for 4 hours at room temperature. The reaction mixture was filtered through Celite, and the solvent was distilled off. The residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=14/1) to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′,2-dimethylpropanediamide (Compound 324, yellow solid) (38 mg, 48%).
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[C:6]([Cl:16])=[CH:7][C:8]([F:15])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH3:26].C(N(CC)CC)C>O>[Br:4][C:5]1[C:6]([Cl:16])=[CH:7][C:8]([F:15])=[C:9]([S:11]([N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH3:26])(=[O:13])=[O:12])[CH:10]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CNc1ccccc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of DCM (36 mL) containing 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (5.5 g, 17.9 mmol) was added (2-methoxy-phenyl)-methyl-amine (2.6 g, 18.8 mmol) and triethylamine (7.1 mL, 53.7 mmol). The mixture was stirred for 16 hrs. 100 mL of DCM and 100 mL of water were added. The organic layer was separated, washed with water (2×50 mL) and dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (9/1 to 5/1) yielded 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzenesulfonamide as a white solid (4.5 g). MS: 408.0 (M+H)+; tR=8.83 min (method 2). NMR (CDCl3), δ, 7.925 (1H, d, J=6.9 Hz), 7.257-7.367 (3H, m), 6.959 (1H, m), 6.831 (1H, d, m), 3.490 (3H, s), 3.339 (3H, d, J=2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[F:14][CH:15]([F:19])[C:16](O)=O>O>[F:14][CH:15]([F:19])[C:16]1[NH:8][C:7]2[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[N:1]=1
Reactant: O=C(O)C(F)F
Reactant: COc1cc([N+](=O)[O-])cc(N)c1N
Solvent: O
Product: COc1cc([N+](=O)[O-])cc2[nH]c(C(F)F)nc12
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 2,3-diamino-5-nitroanisole (Horner et al., Annalen 1953, 579, 212) (1.10 g, 6 mmol) and difluoroacetic acid (2.31 g, 24 mmol) in polyphosphoric acid (PPA) (50 g) was heated at 130° C. in an oil bath for 1 hr. The hot solution was poured into water, and the pH was adjusted to neutral with cooling to give 2-(difluoromethyl)-4-methoxy-6-nitro-1H-benzimidazole (1.33 g, 91%): mp (EtOH/H2O) 192-194° C.; 1H NMR (DMSO-d6) 814.18 (br, exchangeable with D2O, 1H), 8.18 (br, 1H), 7.65 (dd, J=1.4 Hz, 1H), 7.30 (t, JHF=52.9 Hz, 1H), 4.07 (s, 3H); Anal. Calcd. for C9H7F2N3O3: C, 44.45; H, 2.9; N, 17.3. Found: C, 44.75; H, 3.0; N, 17.3%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Cl)[Cl:31]>>[ClH:31].[NH2:1][C@@H:2]([CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:23]([OH:25])=[O:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(CCCCCCCSC[C@H](N)CC(=O)OC)C(=O)OC(C)(C)C
Reactant: ClCCl
Product: COC(=O)CC(CCCCCCCSC[C@H](N)CC(=O)OC)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl (2R)-2-amino-12-t-butoxycarbonyl-4-thia-1,13-tridecanedicarboxylate (3.39 g, 8.36 mmol) is dissolved in methylene chloride (50 ml) and hydrogen chloride gas is bubbled through the solution for 5 minutes. The reaction mixture is stirred for 2 hours at room temperature. The solvent is evaporated to give dimethyl (2R)-2-amino-12-carboxy-4-thia-1,13-tridecanedicarboxylate hydrochloride as an oil.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[C:7]1([C:13]([O:15][CH3:16])=[O:14])[C:11](=[O:12])[CH:10]=[CH:9][S:8]1.S(=O)(=O)(O)O>C(O)(=O)C>[OH:12][C:11]1[CH:10]=[C:9]([S:2]([CH3:1])(=[O:4])=[O:3])[S:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CS(=O)[O-]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1sc(S(C)(=O)=O)cc1O
Reaction time: 24 h

Procedure:
Sodium methane sulphinate (16 mmol) was added to a solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one in acetic acid (20 ml) containing sulphuric acid (1.3 ml). After standing for 24 hours the precipitate was filtered, m.p. 138°-140° C. (acetic acid).
Reaction SMILES: C1C[O:4]CC1.[Cl:6][C:7]1[C:8]2[N:9]([C:13]([CH:16]3[CH2:19][C:18](=[CH2:20])[CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1.C[N+]1([O-])CCOCC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:35]>>[Cl:6][C:7]1[C:8]2[N:9]([C:13]([CH:16]3[CH2:19][C:18]([CH2:20][OH:4])([OH:35])[CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: C1CCOC1
Reactant: C=C1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: OCC1(O)CC(c2ncc3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a THF solution (170 mL) of 8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (3.1 g, 14 mmol), water (18 mL), 50% N-methylmorpholine-N-oxide in water (3.2 mL) and potassium osmate, dehydrate (200 mg, 0.70 mmol) were added and the reaction was allowed to stir at rt for 4 h. Sodium sulfite (8.0 g, 70.0 mmol) was added to the reaction mixture and allowed to stir for 30 min at which point the reaction was concentrated in vacuo. The crude product was extracted from the aqueous with EtOAc. The organics were washed with brine and the combined aqueous washes were back extracted with EtOAc (5×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compounds as a sticky tan/off-white solid; MS (ES+): m/z 254.17 (100) [MH+], HPLC: tR=1.95 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2].[Na+].C1(S([O-])=O)C=CC=CC=1.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12](/[CH:15]=[CH:16]/[CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2]
Reactant: CC=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C/C1CCC2c3ccc(OCC)c(F)c3OC2C1
Reaction time: 1 h

Procedure:
6.0 g (about 21.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl-1,2,3,4,4a,9b-hexahydrodibenzofuran (see 1.9) are refluxed in 60 ml of toluene together with 1.15 g (7.0 mmol) of benzene-sulfinic acid sodium salt and 21.4 ml of 1 N hydrochloric acid. After 1 h, the mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Repeated recrystallisation from isopropanol gives (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-((E)-propenyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 145° C.).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:24])=[C:16]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[S:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].ClC(OC(Cl)C)=O>ClC(Cl)C.C(Cl)Cl.CO>[Cl:24][C:15]1[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[S:17][C:16]=1[C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)C(=O)c1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1sc2c(c1Cl)CCNCC2
Temperature: 22 °C

Procedure:
A solution of the product from step (h) (assumed 0.35 mmol) in anhydrous dichloroethane (2 ml) was cooled to 0° C., treated with K2CO3 (˜50 mg) and 1-chloroethyl chloroformate (0.38 ml, 3.5 mmol). The reaction was allowed to warmed to 22° C. for 18 hours. The reaction diluted with CH2Cl2 (50 ml) and washed with sat. NaHCO3 (2×50 ml), brine (50 ml), dried (MgSO4) and solvent evaporated in vacuo providing an oily residue, which was dissolved in anhydrous MeOH (10 ml) and refluxed for 1.5 hours. The MeOH was evaporated in vacuo to give the crude product. A portion of the crude was purified by preparative HPLC-MS to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.25 (br s, 1 H); 3.05-3.19 (m, 8 H); 1.34 (s, 9 H); MS: ESI (positive): 272, 274 (M+H).
Reaction SMILES: C(NCC1SC(C2C=[C:12]3[C:16](=[C:17](C(N)=O)C=2)[NH:15]C=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:33]([C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)=O.C(N)(C)C.[BH3-]C#N.[Na+]>>[CH3:12][CH:16]([NH:15][CH2:33][C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)[CH3:17]
Reactant: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)N
Product: CC(C)NCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 74 mg of the title compound (37%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)(C)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1]/[C:11](=[CH:10]\[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13])#[N:5]
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#Cc1ccccc1N
Solvent: CC(C)(C)O
Product: COC(=O)/C=C(\Nc1ccccc1C#N)C(=O)OC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A solution of 2-aminobenzonitrile (5.00 g, 42.3 mM) and dimethyl acetylenedicarboxylate (6.42 g, 45.2 mM) in t-butanol (70.5 mL) was refluxed under a nitrogen atmosphere for 12 hr. After cooling the reaction mixture to room temperature, a precipitate formed and was collected by filtration. The material was washed with cold methanol and air dried to give a yellow solid (4.88 g). Recrystallization of this solid from methanol provided the title compound (4.39 g, 39.9%) as yellow crystals, mp 116.5°-117.5° C.; MS(CI): 261 (M+H). Analysis for C13H12N2O4 : Calculated: C, 60.00; H, 4.65; N, 10.76 Found: C, 60.03; H, 4.67; N, 10.84
Reaction SMILES: O[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CN(C)C1CCCCC1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH2:28]>C1(C)C=CC=CC=1>[C:18]([O:26][CH:4]1[CH2:5][C:6](=[O:7])[NH:2][C:3]1=[O:8])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Reactant: O
Solvent: CN(C)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)OC1CC(=O)NC1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
115.1 g (1 mol) of N-hydroxysuccinimide are introduced into 600 ml of toluene in a round-bottom flask, and 127.3 g (1 mol) of dimethylcyclohexylamine are added. At 60° C., 162.5 g (1 mol) of octanoyl chloride in 180 ml of toluene are added dropwise. The reaction mixture is stirred at 60° C. for 5 hours. Subsequently water is added and the organic phase is washed with water, concentrated hydrochloric acid, water and sodium bicarbonate solution in this order. The organic phase is dried over sodium sulfate, filtered and concentrated. The crystallized residue is dried at 40° C./100 mbar. 219 g (90%) of octanoyloxysuccinimide are obtained with a purity of 99.5%.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH2:18][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: NCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea with excess ethylenediamine at room temperature afforded the title compound m.p. 164°-167° (from acetonitrile-ethanol). (Found: C, 46.9; H, 6.5; N, 35.1; S, 11.1%. C11H19N7S requires: C, 47.0; H, 6.8; N, 34.8; S, 11.4%).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1)([CH3:5])[CH3:4].Br[CH2:30][C:31]([N:33]1[CH2:39][CH:38]2[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]2)[CH2:34]1)=[O:32]>CN(C)C=O>[CH:38]12[CH2:40][CH2:41][CH:35]([CH2:36][CH2:37]1)[CH2:34][N:33]([C:31]([CH2:30][N:10]1[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]([CH:3]([CH3:5])[CH3:4])=[N:7][CH:8]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:20])[C:9]1=[O:17])=[O:32])[CH2:39]2
Reactant: Cc1cccc(NC(=O)NC2N=C(C(C)C)c3ccccc3NC2=O)c1
Reactant: O=C(CBr)N1CC2CCC(CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2N=C(C(C)C)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a suspension of sodium hydride (0.030 g of a 65% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added gradually N-[(3RS)-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.250 g) at 5˜10° C. in an ice-bath for 30 minutes. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. To the above mixture was added dropwise a solution of N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (0.200 g) in dry N,N-dimethylformamide (5 ml) for 10 minutes and stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate (100 ml) and a saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was separated, washed with a brine (50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give a crude product. The product was purified by column chromatography on silica gel with a mixture of chloroform and ethyl acetate (10:1) as an eluent. The fractions containing the desired compound were combined and evaporated in vacuo to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-isopropyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.160 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=[CH:12]1.[Cl:32]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:32][C:12]1[O:11][C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
LiHMDS (1.06 M in THF, 9.54 mL, 10.00 mmol) was added to a solution of tert-butyl 2-(oxazol-5-yl)-1H-indole-1-carboxylate 20 (2.37 g, 8.34 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (2.96 g, 12.50 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC: H2O (50 mL: 15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (2.64 g, 99% yield) as white solid. MS (ES) m/z 319 (M+H+).