Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.C(N(CC)CC)C>C(O)(C)C>[C:1]([N:5]1[CH2:9][CH:8]([OH:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)N1CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of tert-butylamine (10 mmol) in isopropylalcohol (20 mL) was added dropwise epichlorohydrine (10 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was re-dissolved in acetonitrile (20 mL) and triethylamine (20 mmol) was added. The mixture was heated at 100° C. for 24 h, cooled to rt and filtered. The filtrate was concentrated providing 1-tert-butyl-azetidin-3-ol (1.1 g). MS (ESI): mass calcd. for C7H15NO, 129.1; m/z found, 130.1 [M+H]+. 1H NMR (CDCl3): 6.15-5.70 (br s, 1H), 4.84-4.72 (m, 1H), 4.24-4.12 (m, 2H), 4.03-3.87 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(=O)oc1CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 2.0 g of 4-chlorobenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.9 g of the captioned compound as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.O>CC(O)(C)C>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Solvent: CC(C)(C)O
Solvent: O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 2.5 °C

Procedure:
A mixture of piperazine (10.2 g, 0.118 mmol) and 3-chloro-1,2-benzisothiazole (4.0 g, 0.024 mmol) in t-BuOH (4 mL) was refluxed overnight. The reaction mixture was poured into water (100 mL) and extracted with toluene (200 mL). The organic phase was dried over MgSO4 and evaporated until about 20 mL remained, under vacuum. The resulting suspension was cooled at 0-5° C. overnight. The precipitate was filtered and dried under vacuum to provide 3-(piperazin-1-yl)benzo[d]isothiazole as an intermediate (3.36 g, 15.4 mmol, 65%).
Reaction SMILES: [CH3:1][O:2]CCOC.[O:7]1[C:11]2[CH:12]=[C:13]([S:16]([CH:19]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=3[F:38])[C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:26]([NH2:28])=[O:27])=[N:24][CH:25]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1.C=O.[OH-].[Na+]>O>[O:7]1[C:11]2[CH:12]=[C:13]([S:16]([CH:19]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=3[F:38])[C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:26]([NH:28][CH2:1][OH:2])=[O:27])=[N:24][CH:25]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1
Reactant: COCCOC
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc2ccoc2c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a 1,2-dimethoxyethane solution (5 ml) of 5-[(1-benzofuran-6-ylsulfonyl)(2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (210 mg, 0.457 mmol), an aqueous solution of formaldehyde (37%, 0.111 ml) and 1 N aqueous sodium hydroxide (0.023 ml) were added, and the mixture was stirred for 4 hours at room temperature. An aqueous solution of formaldehyde (37%, 0.111 ml) and 1 N aqueous sodium hydroxide (0.023 ml) were added to the reaction mixture, and the mixture was stirred for 5 hours at room temperature. An aqueous solution of formaldehyde (37%, 0.111 ml) was further added, and then the mixture was stirred for 18 hours at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and then was washed with water and saturated brine. The mixture was dried over magnesium sulfate and concentrated, and the resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated. The resulting solid was recrystallized from 2-propanol to obtain the title compound (138 mg, 0.273 mmol, 60%) as a white solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2ncn(CC(=O)O)c2n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Sodium (2 g 87 mmol) was dissolved in benzyl alcohol (20 mL) and heated to 130° C. for 2 h. After cooling to 0° C., a solution of 2-amino-6-chloro-9-carboxymethylpurine (4.05 g, 18 mmol) in DMF (85 mL) was slowly added, and the resulting suspension stirred overnight at 20° C. Sodium hydroxide solution (1N, 100 mL) was added and the clear solution was washed with ethyl acetate (3×100 mL). The water phase was then acidified to a pH of 3 with 4N hydrochloric acid. The precipitate was taken up in ethyl acetate (200 mL,), and the water phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride solution (2×75 mL), dried with anhydrous sodium sulfate, and evaporated to dryness, in vacuo. The residue was recrystallized from ethanol (300 mL). Yield, after drying in vacuo, over sicapent: 2.76 g (52%). M.p. 159°-65° C. Anal. (calc.; found): C(56.18; 55.97), H(4.38; 4.32), N(23.4; 23.10). 1H-NMR (DMSO-d6) δ:4.82 (s, 2H); 5.51 (s, 2H); 6.45 (s, 2H); 7.45 (m, 5H); 7.82 (s, 1H).
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[CH3:15][C:14]([CH3:18])=[CH:13][C:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:11]
Reactant: CON(C)C(=O)c1cccnc1
Reactant: CC(C)=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CC(=O)c1cccnc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of N-methoxy-N-methylnicotinamide (500 mg, 3.0 mmol) in anhydrous THF (3.5 mL) under nitrogen at −78° C. add 2-methyl propenyl magnesium bromide (12 mL, 6.0 mmol, 0.5 M in THF) dropwise. After one hour at −78° C., allow to reach room temperature. After 2 h, add saturated aqueous ammonium chloride. (10 mL) and water (2 mL). Extract with ethyl acetate three times, dry the combined organic phases with anhydrous sodium sulfate and concentrate to obtain 442 mg (91%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[OH:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Yield: 49.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.7 g of 4-methoxyphenyl isocyanate, 4.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.1 g of triethylamine and 50 ml of methylene chloride, to give 1.4 g (25% of theory) of N-(4-methoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 236°-238° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1>[CH3:19][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-nitro-2-phenyl-1H-indole (106 mg, 0.44 mmol) and 18-Crown-6 (130 mg, 0.49 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was added potassium tert-butoxide (55 mg, 0.49 mmol) followed by methyl iodide (31 μL, 0.49 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 110 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C(O)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc2c(c(=O)[nH]1)CCCC2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
8.45 g (53 mmol) of 3-methyl-2H-isoquinolin-1-one are dissolved in 80 ml of glacial acetic acid and, after addition of 168 mg (0.74 mmol) of platinum(IV) oxide, hydrogenated under 5 bar at RT for 8 h. The suspension is filtered and concentrated and the residue is recrystallized from methanol. 7.15 g (83%) of a colorless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=O.[C:16]([NH2:19])(=S)[CH3:17]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:19][C:16]([CH3:17])=[N:9][N:8]=2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(N)=S
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: COc1cc(-c2nnc(C)[nH]2)ccc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
The mixture consisting of 590 mg g of 3-methoxy-4-nitrobenzoic hydrazide, 6 ml of pyridine and 210 mg of thioacetamide was heated to 95° C. for 2 hours. After cooling, the volatile fractions were removed under reduced pressure at 40° C. and the residue was subjected to column chromatography purification (silica gel, solvent: 95:5 dichloromethane:methanol)
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].C1COCC1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][C:28]3[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:24]2)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([O:27][C:28]3[C:29]4=[N:34][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:30]4[CH:31]=[CH:32][CH:33]=3)=[CH:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ccc(Oc3cccnc3N)cc2c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ccc(OC3=CC=CN4CCS(=O)(=O)N=C34)cc2c1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a mixture of sodium hydride (60%, 375 mg), 2-chloroethanesulfonyl chloride (612 mg) and dehydrated THF (15 mL) was added a mixture of 3-[(7-methoxynaphthalen-2-yl)oxy]pyridin-2-amine (500 mg) and dehydrated THF (15 mL) at room temperature. The reaction mixture was stirred for 2 hr, water was added, and THF was evaporated under reduced pressure. The resulting precipitate was washed with water and diisopropyl ether to give the title compound (348 mg) as a pale-brown solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a pale-brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>CN(C=O)C>[CH2:16]([N:15]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:3]=2)=[CH:12][CH:13]=[N:14]1)[CH3:17]
Reactant: Sc1ccccn1
Reactant: CCn1nccc1Oc1cc(Br)cnc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reaction time: 1 h
Yield: 93.3 %

Procedure:
5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g, 55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF (160 ml), and pyridine-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml) was added dropwise over 30 minutes. The mixture was agitated for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified over silica gel (20-35% ethyl acetate/hexanes) to afford 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6 g, 93% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)[N:8]2C2CCCCO2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)[NH:8]2)=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:3]=1
Reactant: OC1(c2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)COC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OC1(c2nc3c(N4CCOCC4)nc(Cl)nc3[nH]2)COC1
Temperature: 50 °C
Yield: 85.5 %

Procedure:
3-(2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)oxetan-3-ol (1.8 g, 0.0045 mol) in MeOH (50 mL) was treated with cat. amount of p-toluenesulfonic acid (78 mg, 0.00044 mol). The reaction mixture was heated to 50° C. overnight and was then concentrated under reduce pressure. The residue was partitioned between water and EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to dryness to give 3-(2-chloro-6-morpholino-9H-purin-8-yl)oxetan-3-ol (1.2 g, 84% yield). LC/MS (ESI+): m/z 312 (M+H)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:42]([CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:43])[NH2:44]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C(Cc1ccccc1)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylalaninamide (38 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 40 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (246 mg, 2.00 mmol), 2,4,5-trichloropyrimidine (367 mg, 2.00 mmol, 1 equiv.) and Na2CO3 (233 mg, 2.20 mmol, 1.1 equiv.) in EtOH (10 mL) was heated at 40° C. for 16 h. The crude reaction mixture was diluted with EtOAc and sequentially washed with: water (3×) and saturated aqueous NaCl (1×). The resulting EtOAc layer was dried over Na2SO4 and then concentrated in vacuo, providing 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 270.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C@@H:17]1[C:30]([O:32]C)=[O:31].[OH-]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C@@H:17]1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@H]1CN(CCCc2cccs2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of 0.37 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)propyl]piperidine-3-carboxylate in 6 cm3 of dioxane, to which dioxane had been added 1.6 cm3 of N aqueous hydroxide, was stirred at a temperature in the region of 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 45° C., the residue obtained was taken up in 20 cm3 of water and then the aqueous phase was washed with 20 cm3 of ethyl ether. After separating the ether by settling, the aqueous phase was neutralized with 1.6 cm3 of N hydrochloric acid and then extracted with 2 times 30 cm3 of ethyl acetate. The combined extracts were dried over magnesium sulfate. The organic solution, after filtration, was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.21 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1 -[3-(thien-2- yl)propyl]piperidine-3-carboxylic acid was obtained in the form of a foam with a beige color which melts at approximately 60° C. with softening.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1-c1ccccc1
Temperature: 70 °C

Procedure:
6-Cyano-biphenyl-4-carboxylic acid methyl ester from step 2 (1.4 g, 5.9 mmol) was dissolved in THF (24 ml). LiBH4 in THF (2 M, 5.9 ml, 11.8 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[S:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][C:10]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCSc2ccc(N)cc2C1
Product: COCCN1CCSc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2C1
Yield: 26.8 %

Procedure:
Following the procedure of 512f, 8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00029 mol) and N-[(1S,2R)-2-(2,5-dichoro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.099 g, 0.00029 mol) were reacted. Purification was carried out by SiO2 prep plate chromatography giving N-((1R,2R)-2-{5-chloro-2-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino]pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (0.042 g, 28%) as a grey solid. MP: 140-3° C.; 1H-NMR (DMSO-d6) 9.28 (s, 1H), 7.95 (s, 1H), 7.60-5 (s, 1H), 7.58 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 4.01 (s, 2H), 3.80-90 (m, 1H), 3.36-45 (m, 4H), 3.21 (m, 4H), 2.93 (s, 2H), 2.67 (s, 2H), 2.0010 (m, 2H), 1.65-80 (m, 2H), 1.20-45 (m, 4H); LC/MS (ESI+): 541 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]([I:13])=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(I)c1N

Procedure:
Methyl 2-amino-5-fluorobenzoate (1.0 eq, 8.47 g, 0.051 mol) was reacted with N-Iodo succinimide (1.03 eq, 11.6 g, 0.0515 mol) in acetic acid (100 ml) at room temperature for 20 minutes. The solvent was removed in vacuo. A K2CO3 aqueous solution was added and the compound extracted with ethylacetate. The organic layer was washed with 1M sodium thiosulfate, water and then brine. After drying over Na2SO4, and evaporation of the solvent, methyl 2-amino-5-fluoro-3-iodobenzoate was isolated as a purple solid (14.21 g, 96% yield). 1H NMR (CDCl3, 400 MHz) δ 3.8 (s, 3H), 6.3 (br s, 2H), 7.6 (m, 2H) ppm.