Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][C:37](=O)[CH2:36]1)=[O:34])[CH3:31]>C(O)(=O)C.C1COCC1>[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][CH:37]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:36]1)=[O:34])[CH3:31]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)C1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
Dibenzyl amine (0.150 g, 0.77 mmol) and sodium triacetoxyborohydride (0.300 g, 1.4 mmol) were added to a solution of 3-oxo-cyclobutanecarboxylic acid ethyl ester (0.100 g, 0.700 mmol) and acetic acid/THF (10%, 4.4 mL), stirred at room temperature for 72 hours and concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with water, saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo to give crude product. Purification by flash chromatography (silica, 1:9-3:7 EtOAc:hexanes) provided the title compound (0.180 g, 73% yield, 10:1 cis:trans ratio) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].[Na]>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccccn2)C1
Yield: 11.7 %

Procedure:
The title compound was prepared according to General Method 3. 8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 4) (220 mg, 1 mmol), 2-vinylpyridine (1 ml, 18 mmol), sodium (20 mg, 0.87 g atom) and CuSO4 (20 mg, catalytic) in ethanol (5 mL) at 150° C. for 16 h (overnight) to obtain 38 mg of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol, 5 mL) followed by purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([CH3:36])=[N:32][O:33][C:34]=4[CH3:35])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].C(OCC)(=O)C>C(O)C.C1COCC1>[CH3:36][C:31]1[C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(C)noc4C)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(-c2nc(CCOc3ccc(OC(C)(C)C(=O)O)cc3)c(C)o2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Under nitrogen, 2-[4-(2-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-5-methyloxazol-4-yl}-ethoxy)-phenoxy]-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product in 86% yield. Rf=0.10 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.02 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz 2H), 4.17 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.77 (s, 3H), 1.50 (s, 6H); MS (EI) 499.2 (M+Na)+, 477.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH:5]=1)[C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Chloro-O-anisic acid (187 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 5-chloro-2-methoxybenzoyl chloride.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.[NH4+].[Cl-]>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:25][CH3:26])[CH:12]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dihydrochloride (0.108 g, 0.25 mmol), cyclopropanecarboxylic acid (0.02 mL, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.073 g, 0.38 mmol), 1-hydroxybenzotriazole hydrate (0.051 g, 0.38 mmol), and triethylamine (0.16 mL, 1.14 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature for 45 minutes. The mixture was diluted with aqueous NH4Cl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give (5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]2=[O:28])[CH2:26]1)=[O:11]
Reactant: Cc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2-methylphenyl)acetic acid (1.05 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 2 cm, height 16 cm), eluting with ethyl acetate and collecting 45 cc fractions. Fractions 2 to 4 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of acetonitrile (8 cc) and isopropyl ether (7.5 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2-methylphenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (1.25 g) melting at 196° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CN(C)CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)CCn1ccc2cc(N)ccc21
Temperature: 25 °C
Yield: 54.7 %

Procedure:
A suspension of compound 91 (250 mg, 1.07 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.33 mL, 10.7 mmol) and the resulting mixture was refluxed for 20 min. The dark green reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 92(119 mg, 55%) as a yellow oil. 1H NMR (CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.67 (dd, J=2.1, 8.7 Hz, 1H), 6.30 (d, J=3.0 Hz, 1H), 4.17 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.29 (s, 6H); ESI-MS (m/z, %): 204 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:25])([F:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[C:5]([F:25])([F:24])[CH2:6][N:7]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
To a solution of 18 g (0.046 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]-2,2-difluoro-propionic acid ethyl ester (IV-246) in 100 mL of acetic acid was added 15.5 g (0.191 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was washed with 50 mL of hexanes-EtOAc (90:10) and then air dried to give 10.5 g of 2-chloro-9-cyclohexyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-246).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: CC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Sc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
6-Amino-9-benzyl-2-(isopropylthio)purine (60 mg, 0.20 mmol) and bromine (0.4 ml) were dissolved in 85 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (20 mg, yield 26%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[OH:28][CH2:29][C@H:30]1[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:30]([CH2:29][OH:28])[CH2:31][CH2:32][C:33]4=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 63.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and (S)-5-hydroxymethylpyrrolidin-2-one (428 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.05 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Product: CCOC(=O)Cc1ccc(OCC2CC2)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and (bromomethyl)cyclopropane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.NN>C(O)(C)C.[Ni]>[CH:12]1[C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][NH2:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CC(C)O
Product: NCc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 32.1 %

Procedure:
To a solution of 4-(4-cyanophenyl) dibenzofuran (20 g, 0.074 mol) in isopropylalcohol (1.5 L) was added Raney-Nickel (10 g) with stirring. The reaction mixture was heated to reflux, treated with hydrazine hydrate (100 mL) and refluxed for 6 h. The reaction mixture was cooled, filtered through celite and washed with isopropylalcohol. The filtrate was concentrated and crude purified by column chromatography over silica gel (CHCl3/MeOH; 9:1) to give the title compound as a solid (6.5 g, 32%). 1H NMR (THF-d8, 300 MHz) δ 7.30-8.30 (m, 13H), 3.98 (s, 2H)
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:16])([CH3:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].N([O-])=[O:22].[Na+]>OS(O)(=O)=O>[OH:22][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:16])([CH3:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: O=N[O-]
Reactant: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of N-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (1.6 g, 5.7 mmol) in H2SO4 (15%, 6 mL) was added NaNO2 at 0-5° C. The mixture was stirred at this temperature for 20 min and then poured into ice water. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100:1) to give N-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide (0.7 g, 38%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH2:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22])[CH3:11]>CO.C(O)(=O)C>[CH2:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2])[CH3:11]
Reactant: CCn1c(NN)nc2ccccc21
Reactant: CC(=O)c1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: CCn1c(NN=C(C)c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-acetyl pyridine (0.62 g, 5.11 mmol) and 1-ethyl-2-hydrazinobenzimidazole (0.90 g, 5.11 mmol) in 20 ml of methanol is stirred at room temperature for 24 hours after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.99 g (70% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[NH:39][N:38]=[C:37]([CH:40]3[CH2:42][CH2:41]3)[CH:36]=2)[CH:31]=[CH:30][N:29]=1>CC(O)C>[CH:40]1([C:37]2[NH:38][N:39]=[C:35]([NH:34][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:33]=3)[CH:36]=2)[CH2:42][CH2:41]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2ncn(C3CCCCO3)c2c1
Yield: 29.4 %

Procedure:
A mixture of 58 (200 mg, 0.87 mmol), DIPEA (335 mg, 2.61 mmol) and 53 (203 mg, 0.87 mmol) in IPA (3 mL) was irradiated in a microwave reactor at 120° C. for 2 h. The solvent was removed under reduced pressure to afford 110 mg (30%) of crude N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (60) as brown solid, which was used in the step without further purification: MS (ESI) m/z=431.7 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCCCC3)n2)cc1
Yield: 81.4 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (100 mg, 0.46 mmol) was acylated in CH2Cl2 using cyclohexane carbonyl chloride (85 μL, 0.57 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 123 mgs cyclohexanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(CO)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(N)ncc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1cnc(N)cc1C

Procedure:
A mixture of 2-amino-5-carboxy-4-methylpyridine (100 mg, 0.657 mmol) in 7:3 benzene-methanol (4 mL) was treated with (trimethylsilyl)diazomethane (2M solution in hexanes, 0.33 mL, 0.66 mmol). The mixture was evaporated and the residue chromatographed on silica gel eluting with 25% acetone/hexane to afford pure title compound; yield 88 mg (81%).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:33][CH:32]=[CH:31][C:18]=3[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:33][CH:32]=[CH:31][C:18]=3[NH:19][N:20]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N3CCN(Cc4ccccc4)CC3)c3sccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of KOH(s) (56.09 g, 2.66 mol) in methyl alcohol (1.33 L) is added 3-(4-benzyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-thieno[3,2-c]pyrazole (241 g, 0.532 mol). The mixture is heated at reflux for 1.25 hours, cooled to room temperature and evaporated. The residue is taked up in EtOAc (1 L) washed with water (2 L), dried (MgSO4) filtered and evaporated. The residue was recrystallized from EtOAc/Heptane yielding 129 g (81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:25]=2[C:36]=1[CH3:37].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:31][CH2:32][N:33]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:34][CH2:35]3)[C:25]=2[C:36]=1[CH3:37]
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Cc1c(Cl)ccc2[nH]c(=O)n(C3CCNCC3)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1c(Cl)ccc2[nH]c(=O)n(C3CCN(CCCC(c4ccc(F)cc4)c4ccc(F)cc4)CC3)c12
Temperature: 25 °C

Procedure:
A mixture of 3.5 parts of 1,1-bis(4-fluorophenyl)-4-chlorobutane, 3.65 parts of 6-chloro-1,3-dihydro-7-methyl-1-(4-piperidinyl)- 2H-benzimidazol-2-one, 2.65 parts of sodium carbonate, 0.1 parts of potassium iodide and 100 parts of 4-methyl-2-pentanone is stirred and refluxed for 36 hours. After cooling to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in methylbenzene. The aqueous- and methylbenzene phases are decanted and discarded. From the sticky residual salt, the free base is liberated in the conventional manner and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 6-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-7-methyl-2H-benzimidazol-2-one; mp. 171.9° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15]OCC)[S:11][C:10]1=[S:19])([OH:7])=[O:6]>C(O)C>[CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][N:9]1[C:13](=[O:14])[C:12](=[CH:15][NH:4][CH2:3][CH2:1][OH:2])[S:11][C:10]1=[S:19])([OH:7])=[O:6]
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Solvent: CCO
Solvent: NCCO
Product: O=C(O)CN1C(=O)C(=CNCCO)SC1=S
Reaction time: 1 h

Procedure:
0.62 Gram of monoethanolamine was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5ethoxymethylidenerhodanine and 10 ml of ethanol. The reaction was carried out at a temperature of 50° to 60° C. for 1 hour. The formed precipitate was separated by filtration and recrystallized from a mixture of methanol and ether (7/3 by volume) to give 0.85 g of 3-carboxymethyl-5-hydroxyethylaminomethylidenerhodanine ethanolamine salt in the form of light brown crystal (yield: 53.1 %).