Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1
Reactant: ICC1CCC(OC2CCCCO2)C1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid methyl ester (prepared as in Example 1, 1.42 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.15 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (2.21 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride 3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (2.12 g, 81.6%) as a clear oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+Na)+ 423.1106. found 423.1093.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>CO.C(Cl)(Cl)Cl>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-propylphenyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHCl3 a brown solid (76.1 mg) which was further purified using preparative HPLC to give the pure sulfonamide as a tan colored oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[N-:8]=[N+:9]=[N-:10].[Na+]>O>[N:8]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOCCCl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCOCCO
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 2-(2-chloro-ethoxy)-ethanol (15 g, 0.12 mol) and sodium azide (15.7 g, 2 equiv.) in H2O (50 ml) was heated at 90° C. for 16 h. The reaction mixture was cooled down to RT then extracted with CH2Cl2 (6×50 ml). The combined organic layers were dried over MgSO4 and filtrated. The solvents were removed under reduced pressure to give azide 2 as a colorless liquid (15 g, 95%). 1H and 13C NMR spectra matched the literature data (Cheng, H. et al. J. Med. Chem. 2005, 48, 645-653).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[N:30]([CH3:29])[CH:31]=[CH:32]3)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc3c(ccn3C)c2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (202 mg, 0.5 mmol), 1-methylindole-5-boronic acid (131 mg, 0.75 mmol), copper (II) acetate (138 mg, 0.75 mmol), triethylamine (0.35 mL, 2.5 mmol) and freshly activated 4A molecular sieves (1 g) in DCM (10 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through Celite, washed with DCM (2×10 mL), the DCM removed in vacuo and the residual oil partitioned between ethyl acetate (25 mL) and water (25 mL). The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate solution, brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in iso-hexane, to give the desired compound (128 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O1CCCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:35])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(NC(=O)c3ccc(OC)cc3)c2)cnc1N
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (20 mg, 0.07 mmol) and triethylamine (160 mg, 0.16 mmol) in tetrahydrofuran (1 mL) was added p-anisoyl chloride (20 mg, 0.12 mmol) slowly at room temperature. The mixture was allowed to stir overnight. The reaction was quenched with water (10 mL) at 0° C. and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (30 mL), saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated at reduced pressure to afford 3-amino-N-methyl-6-[3-({[4-(methyloxy)phenyl]carbonyl}amino)phenyl]pyrazine-2-carboxamide (13 mg, 48% yield) as yellow solid. 1H NMR (400 MHz, d6-DMSO): 10.10 (s, 1H), 8.85 (s, 2H), 8.30 (s, 1H), 8.02 (d, 2H), 7.90 (m, 2H), 7.40 (m, 1H), 7.02 (d, 2H), 3.80 (s, 3H), 2.82 (br s, 3H); MS (EI) for C20H19N5O3: 378 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH3:28][C:7]1[CH:8]=[C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (340 mg, 0.76 mmol) in DMF (10 mL) was added pyrrolidine (433 mg, 6.08 mmol). Then, the reaction mixture was stirred at room temperature for 16 hours. Then, water was added and the solids were filtered. The solids were washed with water and dried to give the title compound as a white solid. Yield: 307 mg (92%). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.87 (s, 2H), 6.71 (d, J=2.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 5H), 2.59 (t, J=6.8 Hz, 2H), 2.42 (m, 4H), 2.26 (s, 6H), 1.89 (m, 2H), 1.67 (m, 4H). MS (ES) m/z: 438.16 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[CH:12]2)=[N:9][CH:10]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([Br:1])[CH2:12]2)=[N:9][CH:10]=1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1ccc(C(F)(F)F)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C(C(F)(F)F)N(Br)CN1c1ccc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
Bromine (0.15 ml) was added in one portion to a suspension of 1-(5-trifluoromethyl-2-pyridyl)-4-trifluoromethylpyrimidin-6-one (compound No. 2 in Table I) (0.5 g) and sodium acetate trihydrate (1.1 g) in acetic acid (4.8 ml). After stirring for 16 hours, the solvent, was removed under reduced pressure, and the residue was poured into water and aqueous sodium bicarbonate solution. Rigourous extraction into diethylether followed by drying over magnesium sulphate and removal of the solvent under reduced pressure, gave 1-(5-trifluoromethyl-2-pyridyl)-3-bromo-4-trifluoromethylpyrimidin-6-one as a pale yellow solid (m.p. 142-143° C.). The compound showed (CDC13) 8.90 (1H,s), 8.80 (1H,s), 8.2 (1H,dg), 8.16 (1H,d).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37]>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:37][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:7]4[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: COc1ccc(Oc2ccc3c(C(=O)Cl)cccc3c2)cn1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(Cl)c4)cccc3c2)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(6-methoxypyridin-3-yloxy)-1-naphthoyl chloride hydrochloride salt (225 mg, 0.64 mmol) and DIPEA (0.22 mL, 1.285 mmol) in DCM (5 mL) at RT was added 3-chloro-4-fluoroaniline (93.5 mg, 0.64 mmol). After stirring for 16 h, the reaction mixture was directly purified by silica gel chromatography (elution hexanes/EtOAC:85/15 to 35/65) to give the title compound as a tan solid. MS (ESI, pos. ion) m/z: 423.1 (M+1). Mass Calc'd for C23H16ClFN2O3: 422.84.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17](OC)=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][OH:24].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([NH:23][OH:24])=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NO)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.22 g, 0.73 mmol) in methanol (10 mL) were added hydroxylamine (2 mL, 30.3 mmol, 50% in water) and sodium hydroxide (2.0 mL. 2.0 mmol, 1 N aqueous solution). The resulting solution was stirred for 16 h at ambient temperature. After addition of 1N hydrochloric acid (2.0 mL. 2.0 mmol) the product precipitated out. It was collected by filtration, washed with water and ethyl acetate, and dried in vacuo to provide the title compound as a solid (0.18 g, 82% yield). 1H NMR (DMSO-d6) δ: 13.19 (s, 1H), 11.41 (s, 1H), 9.17 (s, 1H), 8.39 (s, 1H), 7.71 (d, 1H, 7.34 (t, 2H, 7.16 (t, 2H) 6.68 (d, 1H), 5.54 (s, 2H). LCMS (APCI, M+H+): 302.1. HRMS calcd for C15H12FN3O3 (M+H) 302.0936, found 302.0935. HPLC: 100% purity.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH:8]1[CH2:9][CH:10]([CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(CN2CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CCN(CC2CNC2)CC1
Yield: 100 %

Procedure:
3-Piperidin-1-ylmethylazetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.70 mmol) was treated with a solution of TFA:DCM (1:1 v/v, 5 mL) and the resultant solution stirred at room temperature for 1 h. The solution was concentrated in vacuo afford 1-azetidin-3-ylmethylpiperidine (INTERMEDIATE III.1) (190 mg, 0.70 mmol, 100%) as the trifluoroacetic acid salt which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:9][C:8]=2[CH:15]=1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)O[C@@H](CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 90 °C
Yield: 30.8 %

Procedure:
(S)-2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (11.5 g, 49.8 mmole), 7-(3-bromopropoxy)coumarin (14.2 g, 50.0 mmole), and diisopropylethylamine (12 ml, 68.9 mmole) were combined in 350 ml of DMF and heated at 90° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. Upon addition of an equal volume of saturated aqueous sodium bicarbonate, a white solid precipitated. This was filtered and redissolved in 550 ml of warm methanol and 35 ml of 4N isopropanolic HCl was added. The solution was boiled on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.54 g of the title compound precipitated as a white solid, monohydrochloride, quarter hydrate, m.p. 225°-227° C. Subsequent crops yielded as additional 6.1 g of product.
Reaction SMILES: O[C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:31][NH2:32]>ClCCl>[NH:31]([C@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1)[NH2:32]
Reactant: O=C(N[C@H]1C[C@@H](O)C1)OCc1ccccc1
Reactant: NN
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NN[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 80 °C

Procedure:
Benzyl (cis-3-hydroxycyclobutyl)carbamate (intermediate 47, 3.26 g, 14.73 mmol) was suspended in a mixture of diisopropylethylamine (4 ml, 23.00 mmol) and dichloromethane (100 mL) and cooled in an acetone/ice bath under nitrogen. Methanesulfonyl chloride (1.3 ml, 16.80 mmol) was added slowly and the solution stirred for minutes. The reaction was partitioned between water (200 mL), saturated ammonium chloride (50 mL) and dichloromethane (100 mL). The aqueous was extracted with additional dichloromethane (100 mL) and the organic layers combined. They were dried with magnesium sulfate and evaporated to dryness under reduced pressure using a 40° C. water bath. The crude solid mesylate was suspended in ethanol (10 mL) and treated with hydrazine (anhydrous, 4 ml, 127 mmol). The slurry was heated at 80° C. As the mixture warmed it became homogeneous. After 2 hours additional hydrazine (2 mL) was added and the flask was fitted with a reflux condenser. The bath temperature was raised to 95° C. After an additional 3 hours the solution was evaporated to dryness under reduced pressure to give benzyl (trans-3-hydrazinylcyclobutyl)carbamate as a thick white oil. It was further dried under high vacuum at 50° C. for 20 minutes then used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH2:12])[CH:3]=1.[C:13](Cl)([CH3:15])=[O:14]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C:13](=[O:14])[CH3:15])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCc1nc(N)cc(N)c1C#N
Solvent: c1ccncc1
Product: CCc1nc(NC(C)=O)cc(N)c1C#N
Yield: 68 %

Procedure:
The 4,6-diamino nicotinonitrile from Example 101A (35 mg, 0.22 mmol) was dissolved in 0.5 mL of anhydrous pyridine. AcCl was then dropped in until the TLC shows the starting material was completely consumed (appr. 150 μL of AcCl used). Water was then added, the light-yellow precipitate was collected through filtration and dried in vacuum oven to provide the titled compound (30 mg, 68% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.39 (s, 1H), 6.82 (s, 2H), 2.66 (q, J=7.5 Hz, 2H), 2.06 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). MS (ESI) m/e 205 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: NCc1ccncc1
Product: c1cc(CNCc2ccncc2)ccn1

Procedure:
In this Example, reductive amination of 4-pyridine-carboxaldehyde (2) with 4-(aminomethyl)pyridine (1) was carried out using a one-pot two-step protocol to produce bis((pyridin-4-yl)methyl)amine (4). Time-resolved mass spectra of the aldehyde-amine condensation step and the imine reduction step are shown in FIG. 16. Ions were identified according to their m/z values and confirmed by tandem mass experiment. Reactant 1 was first injected into the methanol reaction solvent. Ions of protonated 1 at m/z 109 were detected at 0.4 min later, on the heels of which the protonated dimer at m/z 217 appeared and reached its steady state within 4.8 s. (FIG. 16 panels A-B) After reactant 2 was injected into the reaction solution and the protonated methanol adduct ions of the monomer and dimer of 2 at m/z 140 and 279 showed up. The ions of the intermediate (pyridin-4-yl)-N-((pyridin-4-yl)methylene)methanamine (3) at m/z 198 and 230 formed quickly and the intensity increased sharply (FIG. 16 panel C). The intensity of ions of 1 decreased but the ions did not disappear, which corresponded to the fact that this is an equilibrium reaction (FIG. 16 panel D). About 50 min later, sodium borohydride solution was injected into the system. The sodiated adduct ions of product 4 at m/z 222 started to appear, while the intermediate ions of 3 decreased a lot (FIG. 16 panel E). Ten minutes later, the peak of the product 4 was reaching its highest intensity (FIG. 16 panel F). The selected ion chronogram shows dynamic changing of ions corresponding to the precursor 1, intermediate 3 and product 4 (FIG. 17). The kinetic process of reductive amination can be clearly seen. The first condensation step of this reaction happened very fast; once 2 was added to the solution of 1, it took less than 1 min for the reaction to reach equilibrium. The intermediate 3 was generated simultaneously with the decrease of 1. The second reduction step was not as fast as the first step. With the reduction of intermediate 3, the first step was driven to the right. Thus ions of 1 were depleted. Altogether, it took around 10 min for the product 4 to reach its highest intensity. The total monitoring time was 90 min without any clogging in the fused-silica capillary using high concentrations of reaction solution that are representative of those of industrial interest.
Reaction SMILES: CCOC1N(CC2C=CC(C3C=CC=CC=3C3N=NNN=3)=CC=2)C2[C:10]([C:31]([O:33][CH:34]([O:36]C(OC3CCCCC3)=O)[CH3:35])=O)=[CH:9][CH:8]=CC=2N=1.[CH2:46](Cl)Cl>>[C:34]([O:33][CH2:31][CH2:10][CH:9]([CH3:8])[CH3:46])(=[O:36])[CH3:35]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: ClCCl
Product: CC(=O)OCCC(C)C

Procedure:
Candesartan cilexetil Form I (C) (2.5 g) was dissolved in DCM (3.5 ml) at about 25° C. to form a solution, and isoamyl acetate (35 ml) was added dropwise. The solution was cooled in an ice bath and stirred for about 3 hours to obtain a precipitate. The precipitate was collected by filtration and dried under reduced pressure (30 mbar) at 50° C. for about 7.5 hours to obtain Form XIII.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23].C(=O)=O>CN(C)C=O>[C:21]([O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cccc(-c2ccccc2)c1
Reaction time: 2 h

Procedure:
Into a 200 mL four-neck flask equipped with a stirrer, a thermometer, and a cooling tube, 20.0 g of 3-(bromomethyl)biphenyl, 39.3 g of anhydrous dimethylformamide, 13.4 g of anhydrous potassium carbonate, and 6.2 mg of methoquinone were charged, and acrylic acid was added thereto at room temperature. After the completion of foaming of carbon dioxide, the mixture was heated to a reaction temperature of 90° C. and a reaction was caused to proceed for two hours. The temperature was decreased to room temperature, and then dilution with 120 mL of water, extraction with 100 g of toluene, and washing with water were performed. The resultant crude reaction product was purified with a silica gel column to obtain 16.1 g of meta-phenylbenzyl acrylate. The obtained meta-phenylbenzyl acrylate was a colorless, transparent liquid at ordinary temperature and had a refractive index of 1.5888 and a viscosity of 24 mPa·s at 25° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])(=O)[CH3:2].Cl>C(O)C>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][N:16]1[C:6]2[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=[CH:15][C:5]=2[N:4]=[C:1]1[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(NCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1

Procedure:
A mixture of 250 g of ethyl 4-(acetylamino)-3-((2,4-dichlorobenzyl)amino)benzoate, 68.4 g of concentrated hydrochloric acid, and 1197 g of ethanol was refluxed for 2 hours, to give 1-(2,4-dichlorobenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole. To this reaction solution, a solution consisting of 105 g of sodium hydroxide and 1000 g of water was added, and the reaction solution was refluxed for 2 hours. The reaction solution was cooled, and was neutralized with the slow addition of 193.3 g of concentrated hydrochloric acid. The crystals precipitated were separated through filtration, were washed with 900 ml of a mixed solution of ethanol and water at a ratio of 2:1, and were dried to give 214 g of the title compound.