Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].S(=O)(=O)(O)O.O.[Br:18]([O-])(=O)=O.[K+]>C(O)(=O)C>[Br:18][C:6]1[C:5]([CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-nitro-m-xylene (0.96 g, 6.4 mmol) in acetic acid (8 mL) and sulfuric acid (4 g) and Water (4 mL) was added potassium bromate (1.18 g, 7 mmol) portion-wise over 20 minutes. The mixture was allowed to stir 72 hours at room temperature. The desired product was recovered together with starting material after partition between water, and ethyl acetate (2×) washing with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, decanted and upon concentration under reduced pressure yielded the desired 2-bromo-1,3-dimethyl-4-nitrobenzene and starting material as an oily solid. The crude mixture was carried on to step two without further purification.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6].Cl>C1COCC1.O>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
18.5 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150 mg (0.26 mmol) of methyl 4-[(4E)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]-phenyl}pent-4-en-1-yl]benzoate in 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C. for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and concentrated. The residue obtained is purified directly by preparative HPLC. This gives 104 mg (content 97%, 0.18 mmol, 71% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:29])(=[O:28])[CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][S:24]4(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 3.5 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and [1,2]thiazetidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (7 mg) was obtained.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[C:19]2[N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:16]([CH2:29][CH2:30][O:31][CH3:32])[C:15]=2[C:14]([O:33][CH3:34])=[CH:13][C:12]=1[CH2:35][O:36]S(C)(=O)=O>CN(C=O)C>[Br:10][C:11]1[C:19]2[N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:16]([CH2:29][CH2:30][O:31][CH3:32])[C:15]=2[C:14]([O:33][CH3:34])=[CH:13][C:12]=1[CH2:35][O:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COc3ccccc3)cc(OC)c21
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a cooled solution (ice bath) of phenol (7.2 mg, 0.077 mmol) in 1 ml DMF, NaH (3.1 mg, 0.077 mmol, 60% in mineral oil) is added and the reaction is warmed to RT. Methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester (30 mg, 0.059 mmol) is added and the reaction mixture is heated to 60° C. for 1 h. After that the reaction mixture is extracted with sat. NaHCO3-solution and diethyl ether. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 28 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=O)=[CH:5]1>>[CH2:1]([NH:3][CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH3:2]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCN
Product: CCNCc1c[nH]c2ccccc12

Procedure:
prepared by reaction of ethylamine with 1H-indole-3-carbaldehyde
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][OH:39])[CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][OH:39])[CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: OCC1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCCC(CO)C5)c4)cc23)CC1
Yield: 16.9 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 3-piperidinylmethanol (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (10.2 mg, 17%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=[O:23])[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.CO>O1CCOCC1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:21](=[O:23])[CH2:22][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH2:17][C:18]([OH:20])=[O:19]
Reactant: Nc1ccccc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
The solution of commercial 1,2-phenylenediamine (1.08 g) and 3-(4-chlorophenyl)glutaric anhydride (2.25 g) in 1,4-dioxane (7 ml) was stirred at rt for 10 min. A voluminous precipitate is formed which is kept at rt for further 50 min. The thick slurry is heated to reflux with methanol, cooled to rt, isolated by suction filtration, and washed with methanol. After drying in vacuo N-(2-aminophenyl)-3-(4-chlorophenyl)glutaramic acid (2.1 g) is obtained as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: Cc1ccc(Cn2cnc(NC(=O)c3cccnc3)c2C(N)=O)cc1
Yield: 61 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.61 g (6.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 87 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.43 g of 1-(4-methylbenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:7])[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCCc1ccnc(C(N)=O)c1N
Solvent: c1ccncc1
Product: CCCc1ccnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
2-Ethoxybenzoyl chloride (2.96 g, 0.016 mol) was added dropwise to a stirred solution of 3-amino-4-n-propylpyridine-2-carboxamide (Preparation 6; 1.43 g, 0.008 mol) in pyridine (40 ml) at 0° C. The mixture was stirred at ambient temperature for 4 hours and then the solvent evaporated under vacuum. The residue was dissolved in dichloromethane (100 ml), the solution washed with saturated aqueous sodium carbonate solution (100 ml) and the aqueous phase then washed with dichloromethane (2×25 ml). The combined organic extracts were dried (MgSO4) and evaporated under vacuum, then the residue purified by chromatography on silica gel (15 g), using a methanol in dichloromethane elution gradient (0-3% methanol), followed by crystallization from ethyl acetate to give the product as a light brown solid (1.36 g, 60%), 129-131° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([C:13]3([CH3:21])[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:22])[C:8]=12)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([C:13]3([CH3:21])[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:22])[C:8]=12
Reactant: CC1(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(N2C(=O)c3csc(N)c3C2=O)CCC(=O)NC1=O
Yield: 53.2 %

Procedure:
0.323 g of 1-nitro-5-(3-methyl-2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetone, and a solution obtained by dissolving 0.783 g Na2S2O4 in 100 mL of water was added. The reaction mixture was refluxed for 2 h, cooled, and 100 mL of water were added. The aqueous phase was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. The remaining residue was purified on silica gel column chromatography to obtain a solid (0.156 g). MS (m/z): 292 (M−1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (9.48 mmol, 2.05 g) in a biphasic mixture of DCM (10 mL) and saturated sodium bicarbonate (10 mL) at 0° C. was added benzyl chloroformate (2.0 mL) drop-wise and continued stirring at 0-5° C. for 1 h. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 50% ethyl acetate in hexanes to provide (±)-trans-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: S(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[S-2:39].[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C@H:12]12[CH2:13][C@H:14]([N:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:16]1)[CH2:27][S:39]2
Reactant: [S-2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H]2C[C@H]1CS2
Temperature: 110 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
(2S,4R)-benzyl 4-(tosyloxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (10 g, 17.87 mmol) and sodium sulfide (1.125 mL, 26.8 mmol) were combined in DMSO (80 mL) in a 150 mL medium pressure flask. The reaction mixture was purged with N2 (g) and the resulting slurry was heated to 110° C. under a N2 (g) atmosphere. The reaction became deep blue immediately. After 17 h, the resulting black reaction mixture was cooled to rt, diluted with 1:1 EtOAc:Et2O (150 mL) and washed with H2O (100 mL). The aqueous layer was extracted with 1:1 EtOAc:Et2O (100 mL). The combined organic layer was washed with 1N HCl (100 mL), brine, dried over MgSO4, filtered and concentrated to give dark red viscous oil. The crude material was loaded onto a silica gel column (60 g) and eluted with 3:1 hex:EtOAc to give (1S,4S)-benzyl 2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate (2.7 g, 61% yield) as red viscous oil. LC/MS: m/e 250.0 (M+H)+, 2.22 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.31 (m, 5H), 5.18-5.06 (m, 2H), 4.79-4.65 (m, 1H), 3.64 (d, J=7.8 Hz, 2H), 3.59 (br. s., 1H), 3.22-3.04 (m, 1H), 3.04-2.96 (m, 1H), 2.16 (t, J=10.0 Hz, 1H), 1.88 (d, J=10.3 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH:22]12[CH2:27][CH:26]1[CH2:25][N:24]([C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH2:23]2>>[CH:26]12[CH2:27][CH:22]1[CH2:23][N:24]([C:28]1[N:33]=[CH:32][C:31]([NH:34][C:11]([C:9]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=4)[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:13])=[CH:30][CH:29]=1)[CH2:25]2
Reactant: Nc1ccc(N2CC3CC3C2)nc1
Reactant: O=C(O)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC3CC3C2)nc1)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Yield: 67.6 %

Procedure:
According to a method similar to that described in Stage 12.3, starting from 0.45 g (1.56 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in the preceding stage, and 0.3 g (1.71 mmol) of 6-(3-azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine, prepared in Stage 21.2, we obtain 0.47 g of the expected product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][OH:17])=[NH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:18][C:19](=[O:24])[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].N1C=CC=[CH:28][CH:27]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]([O:20][C:19](=[O:24])[NH:18][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:27]([CH3:28])[O:17][N:16]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:25])[CH2:6]1)[CH3:22]
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: c1ccncc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3noc(C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (130 mg, 0.373 mmol) in toluene (2 mL) and pyridine (2 mL) was added acetyl chloride (a solution 0.34 mL of acetyl chloride in 5 mL of toluene was made and 0.52 mL was used, 0.485 mmol) dropwise and the resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture was then warmed to 110° C. and stirred at this temperature for 16 h then cooled to room temperature. Most of the solvents were removed in vacuo and the residue was partitioned between AcOEt and water (acidified to pH 1 with a 2N HCl aqueous solution). The two layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (120 mg, 0.322 mmol, 86% yield) as a white foam. LCMS (method A): Retention time 0.94 min, [M+H]+=373.05
Reaction SMILES: CS(C)=[O:3].[Cl:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](=[O:13])[CH2:11]Br)=[CH:8][CH:7]=1>O>[Cl:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([CH:11]=[O:3])=[O:13])=[CH:8][CH:7]=1
Reactant: CS(C)=O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: O
Product: O=CC(=O)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Dimethyl sulfoxide (60 ml) solution of 4-chlorophenacylbromide (11.11 g, 65.9 mmol) and water (1.7 ml) were stirred. The solution was extracted with ethyl acetate 3 times and washed with water twice and brine and then dried over sodium sulfate. After removal of the solvent, the residue was washed with hexane-ethyl acetate and dried to give 4-chlorophenylglyoxal (4.43 g, 50%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:29]=[CH:28][C:12]3[N:13]=[C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[O:15][C:11]=3[CH:10]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[C:34]([F:41])[CH:33]=1>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:29]=[CH:28][C:12]3[N:13]=[C:14]([CH:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]4)[O:15][C:11]=3[CH:10]=2)=[CH:33][C:34]=1[F:41])(=[O:37])[NH2:38]
Reactant: CC(C)OC(=O)N1CCC(c2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3o2)CC1
Reactant: NC(=O)c1ccc(Br)cc1F
Product: CC(C)OC(=O)N1CCC(c2nc3ccc(-c4ccc(C(N)=O)c(F)c4)cc3o2)CC1
Yield: 14.9 %

Procedure:
Following the General Procedure-3, the titled compound (55 mg) was prepared from Intermediate 16 (360 mg, 0.87 mmol) and 4-bromo-2-fluorobenzamide (190 mg, 0.87 mmol) as an off-white solid. M.P.: 178-181° C. MS (m/z): 425.45 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])OC)([CH3:3])[CH3:2].[ClH:13]>>[CH:1]([Si:4]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])[Cl:13])([CH3:3])[CH3:2]
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: Cl
Product: CC(C)[Si](Cl)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 10 h
Yield: 98.5 %

Procedure:
A 500 ml-capacity, four-necked flask fitted with a stirrer, a thermometer and a Dimroth was charged with 37.7 g (0.2 moles) of triisopropylmethoxysilane. To the flask was then added 150 g of 35% hydrochloric acid, and the resulting mixture was stirred at 20° C. for 10 hours to effect the reaction. The resulting reaction solution was separated into the aqueous layer and the organic layer. The organic layer was distilled to afford 38 g of triisopropylchlorosilane as a fraction boiling at 78° C.-80° C./10 mm Hg (yield; 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.CCCCCC.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:27]=[C:28]([NH:37][C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:39])[S:29][C:30]=1[C:31](=[O:36])N(OC)C.[Cl-].[NH4+]>C1COCC1>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:27]=[C:28]([NH:37][C:38]([C:40]2[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=2)=[O:39])[S:29][C:30]=1[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)=[O:36]
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: COc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
2-Bromo-6-methoxypyridine (0.274 mL, 2.23 mmol) was dissolved in THF (1 mL), and a 1.58 mol/L solution of n-butyllithium in n-hexane (1.42 mL, 2.23 mmol) was added thereto in a stream of argon at −78° C., followed by stirring for 15 minutes at −78° C. A solution of Compound 98 (200 mg, 0.558 mmol) in THF (2 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:9) to afford the entitled Compound 283 (77.0 mg, 34%).
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:7])[Si:3]([Cl:6])([CH3:5])[CH3:4].[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:1][Si:2]([CH3:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[Si:3]([Cl:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)[Si](C)(Cl)Cl
Reactant: [Li]c1ccccc1
Product: C[Si](C)(Cl)[Si](C)(Cl)c1ccccc1
Reaction time: 3 h

Procedure:
1,1,2-trichloro-1,2,2-trimethyl disilane 103.8 g (0.5 mole) and petroleum ether 200 g were placed in the same type of reaction apparatus as used in the above Comparative Example, and an petroleum ether solution of phenyl lithium 42.5 g (0.5 mole) was dropwise added thereto for 3 hours while stirring at the reaction temperature of 25° to 30° C. After the dropwise addition, the stirring was continued for 2 hours at 25° to 30° C. to complete the reaction. In order to identify the reaction product, the product obtained by separating the by-produced lithium salt by filtration was subjected to 1H-NMR spectrum (C6D6) analysis in the same manner as in the above Comparative Example. As this result, it was proved that 1,1-dichloro-1,2,2-trimethyl-2-phenyl disilane was not substantially produced and that 1,2-dichloro-1,2,2-trimethyl-1-phenyl disilane could be produced at a favourable selectivity. The reaction product was then purified by a normal purification method to obtain 1,2-dichloro-1,2,2-trimethyl-1-phenyldisilane 113.4 g at the yield of 91%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=O)[NH:8][C:7]2=[O:17])([O-:3])=[O:2].[CH3:18][N:19](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN>CN(C=O)C>[CH3:18][NH:19][C:14](=[O:16])[CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7](=[O:17])[NH:8]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of crude (5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetic acid (0.14 g) in DMF, was added TBTU (0.20 g), followed by N,N-ethyldiisopropylamine (0.40 mL) and after 10 minutes methylamine (0.32 mL of a 2 M solution) was added. The reaction was stirred overnight and was quenched with 2N HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Flash column chromatography of the residue over silica gel afforded the desired N-methyl-2-(5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetamide (0.040 g) as a yellow solid. MS (ESI−):249.1 ([M−H]−).