Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH:12][C:13](=[O:16])[O:14][CH3:15].[C:17](Cl)([Cl:19])=[O:18]>C1(C2C=CC=CC=2)C=CC=CC=1.CO.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:12]([C:6]1[C:5]([CH3:4])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:11])[C:13](=[O:16])[O:14][CH3:15])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Nc1c(C)cccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CO
Product: COC(=O)N(C(=O)Cl)c1c(C)cccc1C
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of toluene (150 mL), biphenyl (0.2 g) and sodium methoxide in methanol (23.76 g, 0.11 mol, 25% by weight) was heated at reflux, and the methanol-toluene azeotrope was removed. The mixture was allowed to cool to 80° C., and toluene (80 mL) was added. To the resulting mixture was added in five portions methyl (2,6-dimethylphenyl)carbamate (17.9 g, 0.1 mol). The methanol formed in the reaction was removed as the above azeotrope. When most of the methanol had been removed, ethylene glycol dimethyl ether (8 mL) was added, and the mixture was distilled until the head temperature reached 110° C. The mixture was allowed to cool to 25° C., and ethylene glycol dimethyl ether (3 mL) was added. The mixture was then added to phosgene in toluene (22.5 g, 0.56 mol, 25% by weight). When the addition was complete, excess phosgene was removed by distillation. The mixture was allowed to cool to 25° C., and then washed with sodium bicarbonate solution (40 mL, saturated). The organic layer was dried and the volatiles removed by evaporation to give 17.21 g (64.5%) of the title compound as a solid. An analytical sample was prepared by column chromatography on silica gel using 1:3 ethyl acetate-hexanes as the eluent.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([O:28][CH:29]([F:31])[F:30])=[C:23]([F:32])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([F:32])[C:24]([O:28][CH:29]([F:31])[F:30])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc(F)c1OC(F)F
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3cc(F)c(OC(F)F)c(F)c3)cc2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,5-difluoro-4-difluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-3,5-difluoro-4-difluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.6 g of the trans isomer (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:10]1([CH3:25])[CH:15]=[CH:14][C:13]([S:16]([O:19][CH2:20][C:21]2([CH3:24])[CH2:23][O:22]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(#N)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C:21]([OH:22])([CH3:23])[CH2:20][O:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:25])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 70.4 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1 g, 6.78 mmol), 2-methyloxiran-2-ylmethyl paratoluenesulfonate (2.46 g, 10.15 mmol), benzyl(triethyl) ammonium chloride (1.50 mg, 0.66 mmol) and acetonitrile (10 ml) were stirred under reflux for 8 hours. The reaction mixture was allowed to return to room temperature, diluted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution twice, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=6/1) to afford 2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (1.86 g, yield 70%) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=3)[CH2:19][N:20]3[C:25](=[O:26])[CH:24]=[CH:23][C:22]([C:27]4[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=4)[C:30]#[N:31])=[N:21]3)=[N:14][CH:15]=2)[CH2:4][CH2:3]1.[C:38](O)([CH3:41])([CH3:40])[CH3:39].C(O)=[O:44]>ClCCl>[C:38]([NH:31][C:30](=[O:44])[C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:22]2[CH:23]=[CH:24][C:25](=[O:26])[N:20]([CH2:19][C:18]3[CH:35]=[CH:36][CH:37]=[C:16]([C:13]4[N:14]=[CH:15][C:10]([O:9][CH2:8][CH:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:11][N:12]=4)[CH:17]=3)[N:21]=2)[CH:28]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: O=CO
Reactant: CC(C)(C)O
Reactant: CN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Solvent: ClCCl
Product: CN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C(=O)NC(C)(C)C)c5)ccc4=O)c3)nc2)CC1

Procedure:
3.3 g (3.8 mmol) of 3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (“C27a”) are dissolved in 10 ml of formic acid and 2.8 g of tert-butanol and stirred at 90° C. for 16 h. The reaction mixture is diluted with dichloromethane, washed with 2×50 ml of water, dried and evaporated. The residue is recrystallised from isopropanol. ESI: 567 (M+H);
Reaction SMILES: [ClH:1].N[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:25])[C:12]3[C:17]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:16][N:15]([CH3:24])[C:13]=3[N:14]=2)=[C:5]([O:26][CH3:27])[CH:4]=1.N([O-])=O.[Na+].[S:32](=[O:34])=[O:33]>O.[Cu](Cl)Cl.C(O)(=O)C>[CH:18]1([C:17]2[C:12]3[C:11](=[O:25])[NH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:32]([Cl:1])(=[O:34])=[O:33])=[CH:4][C:5]=4[O:26][CH3:27])=[N:14][C:13]=3[N:15]([CH3:24])[N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a 2.5 ml concentrated hydrochloric acid/8.5 ml acetic acid mixed solution of 750 mg (2.12 mmol) of the compound obtained in Example 44, a solution of 220 mg (3.2 mmol) of sodium nitrite in 1.5 ml of water was added with ice cooling. The mixture was stirred for 30 minutes at the same temperature. To the resulting solution, 87 mg (0.65 mmol) of copper dichloride and 4.5 ml of a 22% acetic acid solution of sulfur dioxide were added, and the mixture was stirred at room temperature for 6 hours. Then, water was added to the reaction mixture, and precipitated solids were collected by filtration. The collected solids were dissolved in dichloromethane again, and the solution was washed with water and a saturated aqueous solution of sodium chloride. The washed solution was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ether was added to the residue, and the cake was collected by filtration to obtain 673 mg (73%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C[O:39]CC1>>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:11]2[C:2]([Cl:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:12][CH3:13])=[CH:6][CH:5]=3)([OH:39])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1ccc2nc(Cl)c(C3(O)CCN(Cc4ccccc4)CC3)cc2c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere 5.0 g (25 mmol) 2-chloro-6-methoxyquinoline in a small amount of THF were added dropwise at −78° C. to 14 mL (28 mmol) of a 2 M lithium diisopropylamide solution (in THF) in 50 mL THF. Then the mixture was stirred for 1.5 h at −78° C. and 4.5 mL (25 mmol) N-benzylpiperidone was added dropwise. The mixture was stirred for a further 15 min with cooling before slowly being heated to RT. The reaction mixture was stirred overnight, evaporated down and purified by flash chromatography on aluminium oxide. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59]([CH:61]([CH2:65][OH:66])[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59]([CH:61]([CH2:65][OH:66])[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reactant: O=C(O)C(CO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S/C=C\c2cccnc2)CS[C@@H]2C(NC(=O)C(CO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1.50 g) and 2-(2-tritylaminothiazol-4-yl)-3-hydroxypropionic acid (1.42 g) in tetrahydrofuran was added N,N'-dicyclohexyl-carbodiimide (925 mg) under ice-cooling. The resultant mixture was stirred for 1 hour at the same temperature and stirred for 2 hours at ambient temperature. The resultant precipitate was filtered off. To the filtrate was added ethyl acetate (100 ml) and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (120 g) and eluted with a mixture of ethyl acetate and diisopropyl ether (3:1). The fractions containing the object compound were combined and concentrated in vacuo to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-3-hydroxypropionamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (1.10 g).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH:23]([SH:26])[CH2:24][CH3:25].O>C(#N)C>[CH3:22][CH:23]([S:26][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH3:25]
Reactant: CCC(C)S
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Yield: 74.9 %

Procedure:
2-Nitro-4-trifluoromethylbenzonitrile (10.8 g) and potassium carbonate (8.3 g) were heated to reflux in acetonitrile. A solution of 1-methylpropanethiol (5 g) in acetonitrile was added. The resultant suspension was heated at reflux for 4.5 hours. After cooling water was added and the mixture extracted with ethyl acetate. The organic extracts were washed with water. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ethyl acetate in cyclohexane to give 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (9.7 g) as a yellow oil, NMR (CDCl3) 1.0(t,3H), 1.2(d,3H), 1.5(m,2H), 3.4(m,1H), 7.3(m,1H), 7.6(m,2H).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[CH:15]=CC=C[CH:11]=1>>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:10]([CH3:15])[CH3:11])([CH3:9])[CH3:8]
Reactant: c1ccccc1
Solvent: CC(C)c1ccccc1
Product: CC(C)c1ccccc1C(C)C

Procedure:
feeding the bottoms product from step (b) to a cumene column to obtain a cumene product stream essentially free of diisopropylbenzene and heavier benzene alkylates, and a bottoms stream comprising diisopropylbenzene and heavier benzene alkylates;
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].I[CH2:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3([CH3:49])[CH2:48][O:47][CH2:46]3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CC1(CI)COC1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC1(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)COC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS(m/e): 367.3 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[NH2:39][OH:40].ClCCl.C(O)C>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:39][OH:40])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Reactant: NO
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(CNc2ccc(C(=N)NO)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Yield: 27 %

Procedure:
Prepared analogously to Example 96 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulphonylaminocarbonyl)-ethyl]-amide and hydroxylamine. Yield: 27% of theory, C26H28N8O5S (564.6) Rf value: 0.75 (silica gel; dichloromethane/ethanol=7:3+1% glacial acetic acid) ##EQU137##
Reaction SMILES: [OH-].[K+].Cl.[NH2:4]O.[CH3:6][O:7][N:8]=[C:9]([CH:29]=[C:30]([CH3:32])[CH3:31])[C:10](=[N:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:22][O:23][CH2:24][C:25]([O:27][CH3:28])=O)[CH3:11].[C:33](=[O:36])([O-])[O-].[K+].[K+].BrCCBr>CO>[CH3:6][O:7][N:8]=[C:9]([CH:29]=[C:30]([CH3:32])[CH3:31])[C:10](=[N:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[N:22][O:23][CH2:24][C:25]1[O:27][CH2:28][CH2:33][O:36][N:4]=1)[CH3:11]
Reactant: CON=C(C=C(C)C)C(C)=NOCc1ccccc1C=NOCC(=O)OC
Reactant: O=C([O-])[O-]
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: BrCCBr
Product: CON=C(C=C(C)C)C(C)=NOCc1ccccc1C=NOCC1=NOCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3.3 g (59 mmol) of potassium hydroxide in 20 ml of methanol was added to a solution of 1.75 g (25 mmol) of hydroxylamine hydrochloride in 20 ml of methanol. The mixture was stirred at room temperature for 5 minutes, 4.5 g (12 mmol) of 5-methylhex-4-ene-2,3-dione 2-(O-(2-(methoxycarbonylmethoxyiminomethyl)benzyl)oxime) 3-(O-methyloxime) were then added and the mixture was stirred at 40° C. for 1 h. 1.8 g (13 mmol) of potassium carbonate and 5.1 ml (59 mmol) of 1,2-dibromoethane were subsequently added. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure, and the residue was purified by chromatography. This gave 0.6 g of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1)=[O:22]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
1-(4-Piperidyl)indol-2-one (53 mg, 0.245 mmole), 2,4-dimethoxybenzoyl chloride (54 mg, 0.27 mmole), and 38 mL (0.27 mmole) triethylamine were mixed in 4 ml of chloroform at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and then at 23° C. for 15 minutes during which time the pH was adjusted to 7.5 with triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative thick layer chromatography (CHCl3 --CH3OH--NH4OH; 95:5:0.5) to yield 42 mg of the title compound: m.p. 88°-93° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:33][C:34]([F:39])([F:38])[C:35]([O-:37])=[O:36].[C:40]([C:43]1[C:44]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)=[N:45][N:46]([C:48]2([CH2:54][C:55]#[N:56])[CH2:53][CH2:52][NH2+:51][CH2:50][CH2:49]2)[CH:47]=1)(=[O:42])[NH2:41].CCN(C(C)C)C(C)C>CN(C=O)C>[C:35]([OH:37])([C:34]([F:39])([F:38])[F:33])=[O:36].[C:55]([CH2:54][C:48]1([N:46]2[CH:47]=[C:43]([C:40]([NH2:41])=[O:42])[C:44]([NH:57][C:58]3[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=3)=[N:45]2)[CH2:53][CH2:52][N:51]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:50][CH2:49]1)#[N:56]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(O)CC(F)(F)F
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCN(C(=O)CC(F)(F)F)CC1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,3,3-Trifluoropropanoic acid (0.009 mL, 0.1 mmol) and HATU (40 mg, 0.11 mmol) were combined in DMF (0.15 mL) and allowed to stir at ambient temperature for 5 minutes. A solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (30 mg, 0.066 mmol) in DMF (0.10 mL) was then added to the reaction mixture, followed by DIPEA (0.045 mL, 0.26 mmol). The resulting solution was allowed to stir at ambient temperature for 16 hours. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound, Example #35-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C)[C:5](O)=[C:6]([CH:10]=1)[C:7](O)=O.[C:13]([O-:16])([O-])=[O:14].[K+].[K+].[CH3:19]I.[C:21]([O-:24])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:6]([CH3:7])[C:5]([O:24][CH3:21])=[C:4]([CH:3]=1)[C:13]([O:16][CH3:19])=[O:14]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C(=O)O)c1O
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)cc(C)c1OC
Temperature: 58 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 5-bromo-2-hydroxy-3-methyl-benzoic acid (3 g, 12.9 mmol, 1.0 eq) and K2CO3 (5.38 g, 38.9 mmol, 3.0 eq) in acetone (15 mL) was added MeI (5.53 g, 38.9 mmol, 3.0 eq). The mixture was stirred at 58° C. overnight. TLC indicated that the reaction was not completed. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo. The crude solid obtained was dissolved in DMF (20 mL) and Cs2CO3 (6 g, 18.4 mmol, 1.4 eq) added. To the mixture was added MeI (2 mL, 38.95 mmol, 3 eq). The mixture was stirred for 1 h at room temperature, water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (2.6 g, 77%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C1(S(O)(=O)=O)C=CC=CC=1>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 19 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of trimethylsilyl ester of benzenesulfonic acid. 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 54 mg of a trimethylsilyl ester of benzenesulfonic acid were added with a microsyringe. 0.9 mg of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and then placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 27% and a phenethylmethyldichlorosilane yield of 19%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 4.2:1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCO>O>[NH2:6][C:5]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:3][C:2]([F:1])=[CH:8][C:7]=1[NH2:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cc([N+](=O)[O-])c1N
Yield: 50 %

Procedure:
A solution of 4-fluoro-2,6-dinitroaniline (125 mg, 0.62 mmole) in freshly prepared 6% (NH4)2S (5 mL) and EtOH (5 mL) was refluxed for 30 min, diluted with water (10 mL) and kept at 4° C. for several hours. The precipitate was collected and washed with cold water (2×1 mL), affording 53 mg of 1,2-diamino-4-fluoro-6-nitrobenzene (50%) as red crystals. 1H NMR (CDCl3 : δ 3.619 (s, 2H), 5.724 (s, 2H), 6.732 (dd, 1H, J1 =2.4 Hz, J2 =8.4 Hz), 7.403 (dd, 1H, J1 =2.4 Hz, J2 =8.4 Hz).
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]Cl)(=[O:3])[CH3:2].[I-:30].[Na+]>C(C(C)=O)C>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][I:30])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)N(CCCCl)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)N(CCCI)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Yield: 93.2 %

Procedure:
6.31 g (14.9 mmol) of 2-[4-[N-acetyl-N-(3-chloropropyl) amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 50 was dissolved in 240 mL of methyl ethyl ketone, 6.09 g (149 mmol) of sodium iodide was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled to room temperature and filtered. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-chloroform:methanol=50:1) to give 7.17 g of 2-[4-[N-acetyl-N-(3-iodopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 93%).