Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]>CO>[F:3][C:4]1[CH:5]=[C:6]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methanol (322.2 g) and 30% sodium hydroxide aqueous solution (65.5 g, 1.8 molar equivalents) were added to a solution of ethyl (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylate (48.2 wt % toluene solution, net 61.22 g, 270.6 mmol). The mixture was heated at 65° C. with stirring for 2 hours. The resultant mixture was concentrated under reduced pressure, then toluene and water were added to the concentrate. The mixture was acidified with 35% hydrochloric acid. The organic layer was separated and concentrated under reduced pressure. (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid was obtained as resultant concentrate (net 52.55 g, yield: 98%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(OC)(O[CH3:18])(=O)=O>[OH-].[Na+]>[CH3:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
In 1.5 l of a 1.5N aqueous sodium hydroxide solution was dissolved 170 g of p-hydroxybiphenyl, and 254 g of dimethyl sulfate was dropped into the content while the temperature of the content was maintained at 55° C. Reaction was carried out with stirring at 70° C. for 30 minutes. The reaction product was recovered by filtration and dried under a reduced pressure. Recrystallization of the product from ethanol yielded 150 g of 4-methylbiphenyl (melting point=75°-76° C.).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O.[K+].[Br-]>>[CH3:25][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 7.66 (d, 1H, J=3.2 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.43 (d, 1H, J=5.0 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.08 (dd, 1H, J=5.0, 3.2 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.80 (d, 2H, J=8.4 Hz), 4.16 (t, 2H, J=6.2 Hz), 3.28 and 3.16 (d of Abq, 2H, J=13.8 Hz), 3.00 (t, 2H, J=6.2 Hz), 2.37 (s, 3H), 1.49 (s, 3H). IR (KBr) 3420, 3000, 1714, 1614, 1513, 1327 cm−1. HRMS (ES+) m/z exact mass calcd for C27H25NO5F3S 532.1406, found 532.1412.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[CH2:13]([O:15][C:16](=[O:20])[C:17](Cl)=[O:18])[CH3:14]>C(Cl)Cl.O>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:17](=[O:18])[C:16]([O:15][CH2:13][CH3:14])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(O)CN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
To a stirred solution of 1-amino-propan-2-ol (15.0 g, 199.7 mmol) in DCM (150.0 mL), is added triethylamine (43.30 mL, 299.56 mmol) at 0° C. Chloro-oxo-acetic acid ethyl ester (22.35 mL, 199.7 mmol) is added dropwise to the reaction mixture at 0° C. and the reaction mixture is stirred for 16 hours at room temperature. The mixture is diluted with water (100 mL) at 0° C., extracted with DCM (2×100 mL), washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (3.0:7.0) to give the title compound as a pale yellow gel (10.7 g, 31.0%). ESI/MS m/z 176.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([C:15]2[N:16]=[N:17][N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:14])=[C:11]([N+:36]([O-])=O)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC1C=CC(C(C2N(CC3C=CC(OC)=CC=3)N=NC=2C(OCC)=O)=O)=C([N+]([O-])=O)C=1)=O)(C)(C)C>C(OCC)(=O)C.[Pd]>[NH2:36][C:11]1[CH:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:35]=[CH:34][C:12]=1[C:13]([C:15]1[N:16]=[N:17][N:18]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:14]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Agent: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2N)nnn1Cc1ccc(OC)cc1
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of the 1:1 mixture (872 mg) of ethyl 4-(4-t-butoxycarbonylamino-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate and ethyl 5-(4-t-butoxycarbonylamino-2-nitrobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate, prepared in the step (b), in ethyl acetate (20 ml) was added 10% palladium on carbon (30 mg). The mixture was stirred under a hydrogen atmosphere overnight and filtered. The filtrate was concentrated under reduced pressure, and the resulting oil was purified by column chromatography on silica gel (toluene:ethyl acetate=2:1) to give ethyl 4-(2-amino-4-t-butoxycarbonylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (c-1: less polar component (LP)) (217 mg) and a mixture (219 mg) of the compound c-1 and ethyl 5-(2-amino-4-t-butoxycarbonylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (c-2: more polar component (MP)) (219 mg). c-1 (LP):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(=O)=O>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
293 mg 6-Formyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester (see example 119) is dissolved in 52 mL dichloromethane. 635 □L N-methylpiperazine and then 2.6 mL acetic acid are added. 656 mg sodium triacetoxyborohydride is added in several portions over 3 hours. Sat. aq. NaHCO3-solution is added and the reaction mixture is stirred until the CO2-evolution stopped. The reaction mixture is diluted with dichloromethane, the aq. phase washed with dichloromethane, the combined org. phases dried (MgSO4) and concentrated in vacuo. 344 mg (100%) crude product is obtained, which is directly used in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=O)#[N:2].[Cl-].ClC1N(C)CC[NH+]1C.ClCCl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=2)([NH2:35])[C@@H:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[NH:34][C@@H:32]([CH3:33])[C:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)([C:36]3[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:35]=2)[CH:9]=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Agent: CN1CC[NH+](C)C1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
3-Cyanobenzoic acid (84 mg), triethylamine (159 μL) and. 2-chloro-1,3-dimethylimidazolinium chloride—dichloromethane 25% solution (212 μL) were added to a solution of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (100 mg) described in Reference Example 5-1 in chloroform (3 mL) in this order at 0° C. Then temperature of the mixture was raised to room temperature, and the mixture was stirred for 15 minutes. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained crude product was stirred at 130° C. for 15 hours. The obtained oil was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1) to give the objective compound (140 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:51][C@@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][C@@H:52]1[CH2:56][CH2:55][N:54]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:27])[CH2:53]1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CC[C@@H](O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (55 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (R)-3-hydroxypyrrolidine (26 mg, 0.30 mmol) and N,N-diisopropylethylamine (53 μL, 0.30 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-60% MeCN/water[10 mM Et2NH]) and then silica gel column (0-20% MeOH/CH2Cl2) to afford a white foam.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1nccc2c1c(Nc1ccccc1)nn2C1CCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) obtained in Step C of Example 12 in toluene (3 ml) were added aniline (0.075 mL), tris(dibenzylideneacetone)dipalladium (25.1 mg), 2-dicyclohexyl phosphino-2′,4′,6′-triisopropylbiphenyl (26.1 mg) and sodium tert-butoxide (132 mg), and the mixture was stirred under microwave irradiation at 100° C. for 1 hr. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound (9.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl benzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ4.54 (2H, s), 6.68 (1H, d, JH,H=11.94), 7.12-7.58 (9H aromatic+1H ethylenic).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([O-:11])([O-])=[O:9].[Na+].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:11])=[O:9]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1
Yield: 99.9 %

Procedure:
A. Spitzer and R. Stewart, J. Org. Chem., 1974, 39, 3936 disclose nitrating aromatics in the presence of a trifluoroacetic acid medium. In one example benzene and sodium nitrate were reacted together in a 1:1 molar ratio at room temperature to form nitrobenzene in a 99.9% yield. In another example sodium nitrite was reacted with benzene in the same 1:1 molar concentration and at the same temperature as the nitrate example, however, nitrobenzene yield was only about 3%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:7][NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([I:18])=[CH:11][N:10]=1)[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:7][NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([I:18])=[CH:11][N:10]=1)[CH3:2]
Reactant: CCOc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(OC)nc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(OC)nc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a stirred suspension of N-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine (4.34 g, 8.09 mmol) in acetic acid (25 mL) was added iron powder (2.26 g, 40.46 mmol). The reaction mixture was heated to 90° C. After 15 min, the reaction mixture became a gray-brown suspension. The mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL). The mixture was filtered through Celite with the aid of additional ethyl acetate (50 mL). The filtrate was washed with water (2×50 mL) and then with 1N sodium hydroxide solution (3×50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 3.99 g (97%) of N2-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine as a tan solid.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>O>[N:7]1[CH:8]=[CH:9][N:10]=[CH:11][C:6]=1[CH2:5][NH:4][C:15](=[O:16])[CH2:14][CH2:13][Cl:12]
Reactant: O=C(Cl)CCCl
Reactant: NCc1cnccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCl)NCc1cnccn1
Yield: 56.7 %

Procedure:
To an aqueous solution of sodium hydroxide (2.31 g) in water (30 ml) was added 2-aminomethylpyrazine hydrochloride (7.0 g) under ice cooling, to which 3-chloropropionylchloride (5.05 g) and solution of sodium hydroxide (2.31 g) in water (30 ml) were simultaneously added dropwise over 30 minutes under stirring. The mixture was stirred for 1 hour at room temperature, followed by extraction with ethyl acetate-THF (1:1, 100 ml×2). The aqueous layer was subjected to salting out with sodium chloride, followed by extraction with ethyl acetate-THF (1:1, 100 ml×2). The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure. The concentrate was subjected to column chromatography [carrier: silica gel, 200 g; developing agent: ethyl acetate→ethyl acetate-ethanol (4:1)]. The eluent was concentrated and the resulting solid was washed with hexane to give the title compound (4.50 g) as colorless solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[CH2:24]([O:26][C:27](=[O:36])[CH:28](Br)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25]
Reactant: CCOC(=O)C(Br)C1CCCCC1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Yield: 75.9 %

Procedure:
To the solution of 75 g (0.28 mol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole in 750 ml N,N-dimethylformamide 116 g (0.33 mol) cesium carbonate and 88 g (0.35 mol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added. The mixture was heated to 100° C. and after stirring for 90 min. another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 6 h another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 22 h (total reaction time) the reaction mixture was cooled to 30° C. and was poured on 1 L ice water and 2 L ethyl acetate. The phases were separated and the aqueous phase extracted with 500 mL ethyl acetate. The combined organic phases were washed three times with 500 ml ice water and once with brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using n-heptane:ethyl acetate (9:1 v/v) as eluant. The product-containing fractions were pooled and the solvent evaporated until a suspension had formed. The suspension was cooled in an ice bath and filtered to give 92 g (75%) of the desired product as colorless solid. MS (ES+): 433 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][CH2:16][NH2:17])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:26])[CH3:25].Cl>O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][CH2:16][NH:17][C:24](=[O:26])[CH3:25])=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCCN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2cccc(CCCNC(C)=O)c2c1
Reaction time: 2 h

Procedure:
After 0.005 mol (equivalent to 1.26 g) of 3-(7-methoxy-1-naphthyl)propylamine hydrochloride has been dissolved in 20 cm3 of water, 0.015 mol of potassium carbonate is added. The amine precipitates. Thereafter, 50 cm3 of chloroform are added and 0.010 mol of acetyl chloride is added dropwise. The medium is left stirring for 2 hours. It is acidified with 2N of hydrochloric acid and then stirred for 15 minutes. The aqueous phase is extracted with 3 times 50 cm3 of chloroform. The organic phases are washed with water, dried over calcium chloride and evaporated. Purification of the products is performed either by recrystallization or by column chromatography.
Reaction SMILES: [N:1]([O-])=O.[Na+].O.S(=O)(=O)(O)O.[CH3:11][S:12]([CH2:14][C:15]1[C:16](=[CH:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:17])=[O:13]>C(O)CC>[CH3:11][S:12]([C:14]1[C:15]2[C:16](=[CH:18][CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[NH:17][N:1]=1)=[O:13]
Reactant: CS(=O)Cc1cc(C(F)(F)F)ccc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CS(=O)c1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/water) solution of 3.7 g. of sodium nitrite predissolved in 20 ml. of water is slowly added 50 ml. of 3N sulfuric acid. To the resulting cooled (ice/water) solution is added dropwise, over a period of 30 minutes, a solution of 12.0 g. of a α-methylsulfinyl-4-trifluoromethyl-o-toluidine predissolved in 200 ml. of 1-propanol, while the temperature is maintained below 10° C. After the reaction mixture is stirred with cooling for an additional 90 minutes, it is allowed to stand overnight at room temperature. The reaction mixture is then nearly concentrated to dryness under vacuum and taken up in 100 ml. of chloroform and 60 ml. of a 15% sodium hydroxide solution. After separation of the phases, the aqueous phase is acidified with concentrated hydrochloric acid and the resulting precipitate filtered off. The acidified aqueous phase is washed three times with chloroform and the combined chloroform extracts are dried over potassium carbonate to a solid. Recrystallization of the crude product from chloroform/hexane yields 3-methylsulfinyl-5-trifluoromethyl indazole, m.p. 168°-170° C.
Reaction SMILES: [BrH:1].[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]O)([CH3:4])[CH3:3]>C(Cl)Cl>[Br:1][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([CH3:4])[CH3:3]
Reactant: Br
Reactant: CC(C)c1ccccc1CO
Solvent: ClCCl
Product: CC(C)c1ccccc1CBr

Procedure:
Add 1.7M tert-BuLi (26 ml, 44 mmol) dropwise, at −78° C. under inert atmosphere, to a solution of 1-Iodo-2-iso-propylbenzene (5 g, 20.3 mmol) in 70 ml of dry THF and stir. After 10 min, add Paraformaldehyde (2 g, 66.7 mmol) in a single portion. Stir the reaction at this temperature for 15 min and then at room temperature for 2 h. Add a saturated aqueous solution of NH4Cl and extract with CH2Cl2 three times. Dry the combined organic extracts over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to afford pure (2-Isopropyl-phenyl)-methanol as pale purple oil. Add aqueous concentrated HBr (15 ml) to a solution of (2-Isopropyl-phenyl)-methanol (1,93 g, 12.85 mmol) in CH2Cl2(15 ml) and stir at room temperature. After 2 h. separate phases and wash the organic one with H2O; dry over Na2SO4 and evaporate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to obtain 1-Bromomethyl-2-isopropyl-benzene as very pale pink light oil. 1H-NMR (CDCl3, 200 MHz): δ 7.33-7.25 (m, 3H), 7.19-7.11 (m, 1H), 4.58 (s, 1H), 3.31 (sep, J=6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H).