Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]([C:13]2[C:14](=O)[O:15][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[N:20]([CH3:32])[CH:19]=2)=[CH:3]1.CO.C[Si](C)(C)[NH:39][Si](C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[C:4]([C:13]2[C:14](=[O:15])[NH:39][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:25]=3)[N:20]([CH3:32])[CH:19]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)OC2=O)c2ccc(C#N)cc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCCC5)ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-Methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-furan-3-yl]-1H-indole-6-carbonitrile (0.16 g, 0.36 mmol) was dissolved in dry DMF (5 mL, dried over 3A° molecular sieves) in a 50 mL round bottom flask. To this was added methanol (0.1 mL) and 1,1,1,3,3,3 hexamethyldisilazane (0.9 mL). The purple solution was stirred at room temperature overnight. Methanol (0.03 mL) and 1,1,1,3,3,3 hexamethyldisilazane (0.27 mL) were added and stirred for 3 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine. The aqueous layer was back extracted with ethyl acetate (2×50 mL). The combined organic extracts were diluted with an equal volume of hexanes, dried (MgSO4), and passed over a pad of silica gel. The silica gel was washed a with 1:1 ethyl acetate/hexanes (150 mL), and the filtrate was concentrated. Chromatography of the residue over silica gel using 25%-40% EtOAc/hexanes gave 1-methyl-3-[4-(1-methyl-6-pyrrolidin-1-yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl]-1H-indole-6-carbonitrile (71 mg, 44%) as a purple solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1.C(N(CC)CC)C.[C@@H:31]12[C:38](=[O:39])[O:37][C:35](=[O:36])[C@@H:32]1[CH2:33][CH2:34]2>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][C:38]([CH:31]2[CH2:34][CH2:33][CH:32]2[C:35]([OH:37])=[O:36])=[O:39])[CH2:18]1
Reactant: Cc1cccc(-c2nc(COCC3CCCC(N)C3)c(C)o2)c1
Reactant: O=C1OC(=O)[C@@H]2CC[C@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(COCC3CCCC(NC(=O)C4CCC4C(=O)O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
50 mg of 3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexylamine were dissolved in 0.97 ml of DMF, and 32 mg of triethylamine were added. 22 mg of cis-cyclobutane-1,2-dicarboxylic anhydride were then added, and the solution was stirred at RT overnight. The solution was purified directly by HPLC, which gave 36 mg of 2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexylcarbamoyl]cyclobutanecarboxylic acid. C25H32N2O5 (440.54), MS (ESI): 441 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28](OCC)=[O:29])[C:10]1=[O:33].[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[O:34]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:29])[C:10]1=[O:33]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1, 1-dioxido-2-isothiazolidinyl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1 H), 8.58 (s, 1 H), 7.86 (s, 1 H), 7.24 (m, 2 H), 7.01 (t, J=8.6 Hz, 2 H), 4.42 (t, J=7.0 Hz, 2 H), 4.12 (s, 2 H), 3.65 (m, 2 H), 3.59 (m, 2 H), 3.42 (s, 3 H), 3.36 (t, J=6.9 Hz, 2 H), 3.26 (t, J=6.7 Hz, 2 H), 3.07 (t, J=7.5 Hz, 2 H), 2.24 (m, 2 H); HRMS C24H27FN4O6S (M+H)+ calcd 519.1635, found 519.1718.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][Si](C=[N+]=[N-])(C)C>C1COCC1.C(OCC)(=O)C>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-2-nitro-benzoic acid (1 g, 5.4 mmol in 5 mL THF, was added (trimethylsilyl)diazomethane (2 M in ether, 11 ml, 22 mmol) at 0° C. The reaction mixture was warmed to room temperature under argon and stirred for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-30% EtOAc/hexane) to give 5-fluoro-2-nitro-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:19]Br>BrBr.O1CCOCC1>[Br:19][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(NS(=O)(=O)NC(C)(C)C)cc1
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)Nc1ccc(C(=O)CBr)cc1

Procedure:
A few drops of bromine (from a total of 10.3 g., 0.064 mole) is added to N-(4-acetylphenyl)-N'-tert.-butylsulfamide (17.3 g., 0.064 mole) in dioxane (200 ml.) solution at 15° C. and the solution is stirred until the color is discharged. The remainder of the bromine is added during 5 min. and the solution is stirred for an additional 10 min. thereafter. The solution is concentrated in vacuo and the residue triturated with isopropyl ether to give 20.7 g. (92%) of intermediate, recrystallized from isopropanol, m.p. 160.5°-161° C. (dec.)
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([CH2:25][C:26]([CH2:29][CH2:30]I)([F:28])[F:27])([C:9]([C:12]([C:15]([C:18]([C:21]([F:24])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]>>[C:6]([CH2:25][C:26]([CH2:29][CH2:30][OH:2])([F:28])[F:27])([C:9]([C:12]([C:15]([C:18]([C:21]([F:24])([F:23])[F:22])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Ethylene (15 g) was introduced to an autoclave charged with C6F13CH2CF2I (170 g) and d-(+)-limonene (1 g), and then the reactor was heated at 240° C. for 12 h. Product was isolated by vacuum distillation to provide C6F13CH2CF2CH2CH2I. Fuming sulfuric acid (129 mL) was added slowly to C6F13CH2CF2CH2CH2I (112 g). The mixture was stirred at 60° C. for 1.5 h. Then the reaction was quenched with ice-cold 1.5 wt % aqueous Na2SO3 and heated at 95° C. for 0.5 h. The bottom layer was separated and washed with 10% sodium acetate aqueous solution and distilled to provide C6F13CH2CF2CH2CH2OH.: mp 38° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH:33]=O)=[CH:24]2>C1COCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH:33]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:24]2
Reactant: COc1cc2cc(C=O)ccc2c(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Reaction time: 0.5 h

Procedure:
55% Sodium hydride (241 mg) was suspended in THF (2.5 mL) at −10° C. under an argon atmosphere, a solution of ethyl diethylphosphonoacetate (1.23 g) in THF (5 mL) was added dropwise to the suspension, and the mixture was stirred for 30 minutes. A solution of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.23 g) in THF (10 mL) was then added dropwise, and the mixture was stirred for 30 minutes at −10° C. and 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH2:35])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH:35][C:8](=[O:9])[C:7]3[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=3)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.9 %

Procedure:
Using the general method of Example 92, 3,5-di-(1,1 dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248–250° C. Analysis: Calculated for C30H40N6O2: % C, 69.74; % H, 7.80; % N, 16.27; Found: % C, 69.65% H, 7.69; % N, 16.42. HRMS (EI) calcd for C30H40N6O2 (M+) 516.3212 found 516.3226.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[CH3:4][Si:3]([CH2:2][NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Solvent: CC#N
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of chloromethyltrimethylsilane (1.34 kg, 10.96 mol) in acetonitrile (17.0 L) is added benzylamine (2.34 kg, 21.92 mol) and the reaction mixture is heated at reflux for 16 h. The reaction mixture is cooled to room temperature and the precipitate of benzylamine hydrochloride is removed by filtration. The filtrate is concentrated under vacuum to about 5 L and then diluted with water (5 L). The reaction mixture is extracted with hexane (2×5 L). The organic extracts are combined and washed with brine (5 L) and dried over MgSO4. The filtrate is concentrated under vacuum to give 1.77 kg (83%) of N-(trimethylsilylmethyl)benzylamine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])[O:6][CH:7]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[F:31][C:27]1[CH:26]=[C:25]2[C:30]([C:22]([C:19]3[N:20]=[C:21]4[C:13]([C:11]([NH:10][C@@H:8]([C:5]5[O:6][CH:7]=[C:3]([CH2:2][O:1][S:49]([CH3:48])(=[O:51])=[O:50])[N:4]=5)[CH3:9])=[O:12])=[CH:14][N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:38])[CH3:40])[C:16]4=[N:17][CH:18]=3)=[N:23][N:24]2[CH3:32])=[CH:29][CH:28]=1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 2 h
Yield: 114.2 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-hydroxymethyl-oxazol-2-yl)-ethyl]-amide (115 mg, 0.20 mmol) was dissolved in dichloromethane (1 ml). The solution was cooled to 0° C. and triethylamine (0.04 ml, 0.29 mmol) and methanesulfonyl chloride (19 μl, 0.24 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford 147 mg of methanesulfonic acid 2-((R)-1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-oxazol-4-ylmethyl ester as a yellow foam which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:28]=[O:29].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:33][C:32]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[CH2:24][N:12]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)COc1ccc(C=O)cc1CCl
Reactant: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C=O)cc1CN(CCc1ccccc1)c1nc(-c2ccccc2)cs1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
To a solution of 4-phenyl-N-(2-phenylethyl)-1,3-thiazole-2-amine (0.95 g, 3.40 mmol) in N,N-dimethylformamide (7 mL) was added sodium hydride (60% in oil, 0.14 g, 3.40 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 5 min. Then, 3-(chloromethyl)-4-isobutoxybenzaldehyde (0.70 g, 3.09 mmol) and sodium iodide (0.51 g, 3.40 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give the title compound (1.43 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: CCOCC.[CH:6]1([Mg]Cl)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:24]2[NH:33][C:32](=[O:34])[C:31]3[C:26](=[CH:27][C:28]([F:36])=[C:29](Br)[CH:30]=3)[N:25]=2)[CH:23]=1)=[O:18])[CH3:15].Cl>[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO.C1COCC1>[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:24]2[NH:33][C:32](=[O:34])[C:31]3[C:26](=[CH:27][C:28]([F:36])=[C:29]([CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[CH:30]=3)[N:25]=2)[CH:23]=1)=[O:18])[CH3:15]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Br)cc3c(=O)[nH]2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(F)c(C4CCCCC4)cc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To THF (5 mL), a 1M solution of ZnCl2 in ether (5.00 mL, 5.00 mmol) was added followed by a 2M solution of cyclohexyl magnesium chloride in ether (2.50 mL, 5.00 mmol). The reaction mixture was stirred overnight at room temperature and the stirring was stopped until all of the precipitate settled to the bottom of the flask. In a different flask, THF (4 mL) was added to a mixture of palladium acetate (11.8 mg, 0.053 mmol), Ru-Phos (48.9 mg, 0.105 mmol) and 1-(6-bromo-7-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.200 g, 0.525 mmol) and purged with nitrogen for 5 minutes. Then, a solution of cyclohexyl zinc chloride prepared as described above (5.25 mL, 2.62 mmol) was added and the mixture stirred for 18 h. The crude reaction mixture was poured into EtOH (10 mL) and acidified with 6 M aq. HCl (1 mL) slowly. The precipitated product was collected by filtration, triturated with EtOH and filtered again to provide the titled compound (0.110 g, 54%). MS (ESI/Cl): mass calcd. for C20H21FN4O3, 384.2; m/z found, 385.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 32 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (13 mg, 32%) which was obtained as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [I:1]Cl.[O:3]=[C:4]1[C:13]2[NH:14][CH:15]=[CH:16][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18].C(O)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClCCl.C(#N)C>[I:1][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][C:4](=[O:3])[C:13]3[NH:14][CH:15]=[CH:16][C:12]=3[C:11]=2[CH:10]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Reactant: ClI
Agent: CCC(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Temperature: 45 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
Alternatively, 1.5 mL (1.5 mmol) of a 1M solution of iodine monochloride in dichloromethane is added to a solution of 316 mg (1 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with 1 equivalent of acetic acid and 652 mg (1 mmol) of indium triflate in anhydrous acetonitrile (20 mL). The solution is heated at 45° C. for 3 hours then stirred at room temperature for 20 hours. The solid is filtered, and triturated with acetonitrile and diisopropyl ether to give 368 mg (96%) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[CH2:13][CH3:14].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1.[N:45](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[N:45]=[CH:12]2
Reactant: CCc1c(Br)ccc(NC(C)=O)c1C
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1c(Br)ccc2c1cnn2C(C)=O

Procedure:
To a solution of 3.72 g of the acetamide prepared in Example 212b in 31.5 ml chloroform were added 4.1 ml of acetic anhydride and 2.85 g of potassium acetate, and 192 mg of 18-crown-6 and 3.4 g of isopentyl nitrite were then added dropwise. The reaction mixture was heated for 20 hours under reflux and after cooling diluted with 200 ml ethyl acetate. The organic phase was washed with 20 ml sodium carbonate solution and once with saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo and the crude product thus obtained purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 3.78 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([OH:18])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:18][CH:9]1[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]12)(=[O:34])[CH3:33]
Reactant: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21
Reaction time: 2 h

Procedure:
To a solution of 0.38 g. of 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide (3/2 hydrate) in 5 ml. of pyridine is added 0.2 ml. of acetic anhydride and the mixture is left to stand at room temperature for 2 hours, followed by addition of water. The precipitated crystals are collected by filtration to yield 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[1,5-a][1,4]-benzodiazepine-2-carboxamide as crystals. This product is identical with the product in Example 1 with respect to melting point and infrared absorption spectrum.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[OH-].[K+].O.BrC[C:18](=O)[C:19]([OH:21])=[O:20].OS([O-])=O.[Na+].Cl>O>[OH:12][C:5]1[CH:6]=[N:7][C:8]2[C:4]([C:18]=1[C:19]([OH:21])=[O:20])=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: O=C(O)C(=O)CBr
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(O)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-iodoindoline-2,3-dione (50 g, 183 mmol) was dissolved in a hot solution containing potassium hydroxide (82 g, 1465 mmol) and water (250 mL). The reaction mixture was in homogeneous solution for 5 min then was precipitated out completely. Enough ethanol (30 ml) was added to redissolve the reaction mixture. After cooled to rt and mechanically stirred, 3-bromo-2-oxopropanoic acid hydrate (47 g, 256 mmol) was added portionwise—tremendous heat was generated (>80° C.). After the addition, the reaction mixture was cooled to rt and continued to stir for 3 days. The reaction mixture was treated with sat. solution of NaHSO3 (sodium bisulfite, 12 g, 115.32 mmol) in order to prevent the development of color in the product. The resulting mixture was then acidified to pH=2 using concentrated HCl. After stirred for 1 h, the yellow ppt. that was formed in the solution mixture was collected by filtration. The solid was washed with water and suspended in water with SO2 bubbling in the solution. After 30 minutes the solid again was separated by filtration. This wet solid was suspended in water, stirred, and dissolved by gradual addition of solid Na2CO3. The solution was treated with a saturated solution of NaHSO3 and filtered. The filtrate was acidified to pH=2 using concentrated HCl. The solid that was formed in the solution mixture was collected by filtration. The solid was washed with water, then resuspended in water, and again filtered. The solid was suspended in EtOH, separated by filtration, and airdried to afford the desired product as a brown solid. MS m/z: 316.2 (M+H). Calc'd. for C10H6INO3—315.06.