Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[N:26][C:27]([Cl:33])=[C:28]([CH:32]=1)[C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([NH:14][C:29]([C:28]2[C:27]([Cl:33])=[N:26][CH:25]=[C:24]([F:23])[CH:32]=2)=[O:30])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
(4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (80:20 syn:anti, 4.49 g, 20.9 mmol) was dissolved in dimethylformamide (100 ml) and triethylamine (8.34 ml, 59.8 mmol) was added followed by 5-fluoro-2-chloronicotinic acid (3.5 g, 19.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 21.9 mmol) and 1-hydroxybenzotriazole (2.96 g, 21.9 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (50 ml) and ethyl acetate (100 ml) and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic extracts were concentrated under reduced pressure, re-dissolved in dichloromethane (100 ml), washed with water (50 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (2:3 changing to 1:1, by volume) to give {cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (5.44 g) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C:18]3[CH:30]=[CH:29][O:28][C:19]=3[CH:20]=[N:21]2)=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C:18]3[CH:30]=[CH:29][O:28][C:19]=3[CH:20]=[N:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1ncc1occc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ncc1occc12
Temperature: 70 °C
Yield: 24.5 %

Procedure:
A solution of 2-bromo-4-fluorobenzenesulfonyl chloride (0.57 g) in pyridine (10 mL) was heated to 70° C. and a solution of methyl 7-amino-furo[2,3-c]quinoline-6-carboxylate (Intermediate 16, 0.33 g) in pyridine (10 mL) was added. The mixture was stirred and heated at 70° C. for 4 hours. Further 2-bromo-4-fluorobenzenesulfonyl chloride (0.57 g) was added and the mixture was stirred and heated at 70° C. overnight. After cooling, the mixture was filtered and the solid was washed with methanol. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 15-60%. The product was triturated with diethyl ether and the solid was collected by filtration to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-furo[2,3-c]quinoline-6-carboxylate (0.16 g) as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCOCC1
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 17.8 %

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Compound 15) (0.97 g) in 33 mL dry dimethylacetamide was stirred under nitrogen while adding 60% sodium hydride (0.22 g). After 30 minutes tetrahydropyran-4-yl tosylate (1.0 g) was added and the mixture heated at 105° C. for 4 hours then 135° C. for 3.5 hours. Evaporation in vacuo and treating with water gave pale brown solid which was collected and washed well with water then dried in air. Flash chromatography in 19:1 ethyl acetate:triethylamine afforded 0.22 g (18%) of 3-(4-phenoxyphenyl)-1-(tetrahydropyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine m.p. 187-187.5° C. Calculated for C22H21N5O2 C, 68.2; H, 5.4; N, 18.1; Found C, 68.1; H, 5.5; N, 18.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.ClC1[N:15]=[CH:14][C:13]([CH3:16])=CN=1>>[NH:15]1[CH2:14][CH:13]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[CH2:16]1
Reactant: Cc1cnc(Cl)nc1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(C2CNC2)n1

Procedure:
Compound P17 was prepared according to the general procedure for the synthesis of P12 described in Preparation 51, except that 2-chloro-4-methylpyrimidine (the synthesis of 2-chloro-4-methylpyrimidine is described by D. B. Harden & M. J. Mokrosz, J. Organic Chem., 1998, 53, 4137-4140) was used instead of 2-chloro-5-methylpyrimidine, to provide P17. Yield: 647 mg, 4.34 mmol, 87%. 1H NMR (400 MHz, CD3OD) δ 2.52 (s, 3H), 4.0 (m, 2H), 4.12 (m, 2H), 4.18 (m, 1H), 7.23 (d, J=5.4 Hz, 1H), 8.59 (d, J=5.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.CNC.CN(C)[P:18](N(C)C)N(C)C>>[N:1]12[P:18]3[N:9]([CH2:8][CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH2:12]2
Reactant: C1CNCCCNCCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Product: C1CN2CCCN3CCCN(C1)P23
Yield: 75.8 %

Procedure:
A mixture of 4.20 g of 1,5,9-triazacyclododecane and 4.00 g of hexamethylphosphorous triamide is heated at 100° C for about six hours, by which time evolution of dimethylamine is complete. Distillation under reduced pressure gives 3.70 g (76%) of 1,5,9-triaza-13-phosphatricyclo-[7.3.1.05,13 ]tridecane as a clear, colorless liquid which boils at 104°-135° C at 0.60 mm. The product solidifies at room temperature. Its infrared absorption spectrum (neat) shows absorptions at 3.5, 6.85, 7.01, 7.52, 7.73, 8.00, 8.27, 8.66, 8.90, 9.02, 9.36, 9.56, 10.27, 10.89, 11.42, 11.73, 11.97 and 14.7 μ. The mass spectrum shows an M+ ion at 199; measured mass, 199.1264; calc'd, 199.1238.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH:31][C:32]([OH:34])=[O:33])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:35]([O-])(O)=O.[Na+]>>[CH3:35][O:33][C:32](=[O:34])[CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(c1cc(-c2cccc(-c3cccc(C=CC(=O)O)c3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCc1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-3-yl}-acrylic acid methyl ester (1.0 eq.) from EXAMPLE 11, Step 2, in Tol (0.1M) at was added benzenesulfonyl hydrazide (3.8 eq.). The mixture was stirred at 100° C. for 12 h, cooled to rt, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 8.5:1.5) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]CCCCCC)=[CH:16][CH:15]=2)[S:5][C:6]=1[C:7](=[N:9][NH:10][C:11](=[NH:13])[NH2:12])[CH3:8].CO>O>[CH3:1][C:2]1[N:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH3:22])=[CH:18][CH:19]=2)[S:5][C:6]=1[C:7](=[N:9][NH:10][C:11](=[NH:12])[NH2:13])[CH3:8]
Reactant: CCCCCCCCCc1ccc(-c2nc(C)c(C(C)=NNC(=N)N)s2)cc1
Solvent: O
Solvent: CO
Product: CCCc1ccc(-c2nc(C)c(C(C)=NNC(=N)N)s2)cc1

Procedure:
2-{1-[4-Methyl-2-(4-nonylphenyl)thiazol-5-yl]ethylidenehydrazinecarboximid-amide (1f). Yellow solid (133 mg, 55%): mp 203-206° C. 1H NMR (DMSO-d6) δ 11.32 (brs, 1 H), 7.79 (d, J=8.1 Hz, 2 H), 7.60 (brs, 3 H), 7.28 (d, J=8.1 Hz, 2 H), 2.58 (m, 5 H), 2.41 (s, 3 H), 1.55 (m, 2 H), 1.22 (m, 12 H), 0.82 (t, J=6.9 Hz, 3 H); 13C NMR (DMSO-d6) δ 165.80, 156.87, 153.45, 147.99, 146.28, 131.19, 131.60, 129.44, 126.25, 36.34, 35.29, 31.60, 30.98, 29.28, 29.19, 28.99, 22.42, 18.46, 18.39, 14.27; ESIMS m/z (rel intensity) 400 (MH+, 100); HRESIMS, m/z 400.2540 MH+, calcd for C22H34N5S 400.2535; HPLC purity (methanol:water, 1:1): 95.40%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:2]=1.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH2:14]([O:21][N:22]=[C:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCCC1c1cccnc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(CON=C2CCCC2c2cccnc2)cc1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
A mixture of (±)-2-(3-pyridyl)cyclopentanone (2.0 g) and benzyloxyamine hydrochloride (1.98 g) in anhydrous pyridine was stirred at 60° C. for 4.5 hours. The pyridine was removed in vacuo (40° C., 0.2 mmHg), the residue was dissolved in chloroform (75 ml), washed with water (4×75 ml), dried over magnesium sulphate and evaporated. The residual oil was purified by flash chromatography on silica, eluting with chloroform/methanol (100/1) to give (±)-2-benzyloxyimino -1-(3-pyridyl)cyclopentane (mixture of syn and anti isomers, 1:3), a pale yellow oil (2.91 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:26])[NH:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[O:14])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[CH:23]1([CH2:22][NH:21][C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][O:11][C:9]2[N:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[O:26])[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1.45 g 5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 18 ml THF and 5 ml water were added 2.3 ml aqueous NaOH (2 M) portionwise at 0° C. After 12 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction. Yield: 1.50 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[OH-].[K+].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1.CO>[N+:17]([CH2:20][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:13]=1)[OH:12])([O-:19])=[O:18]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a cooled (0° C.) solution consisting of 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) in THF (5 mL) and NO2CH3 (0.3 mL) and MeOH (2.5 mL) was added KOH (2.5 M, 1.13 mL). The reaction mixture was stirred at 0° C. for 30 min. and then quenched with a saturated NH4Cl solution. The aqueous mixture was extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (257 mg, 60%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[CH3:29]I>C1COCC1>[CH2:11]([O:13][C:14]([C:16]1([CH3:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of NaHMDS (2M in THF, 148 mmol, 74 mL, diluted to 100 mL) is cooled at −78° C. and a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (25.74 g, 100 mmol) in THF (50 mL of solution) is added slowly. The mixture is stirred for 2 h at −78° C. Methyliodide (7.5 mL, 120 mmol) is dissolved in THF (60 mL) and the cold solution of enolate is added. The mixture is stirred at r.t. for 1 h and quenched with HCl (1M, 75 mL) and ether (200 mL). the phases are separated and the organic phase washed with HCl (1M, 2×50 mL) and NaOH (1M, 2×50 mL). The organic phase is dried (Na2SO4), filtered and evaporated to provide the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[S:14]([CH2:24][N+:25]#[C-:26])([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[C-]#N.[Na+]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[O:7][CH:26]=[N:25][C@@H:24]2[S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, 4-chloro-3-(trifluoromethyl)benzaldehyde (0.31 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 404.5 (M+H+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)CCC>>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2ccncc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)pyridine. The title compound (52 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH3:22])[C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:8]([CH2:21][CH3:22])[C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(N(CC)Cc2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)c1cccc(C(=O)O)c1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred solution of ethyl 3-[benzyl(ethyl)amino]-2-methylbenzoate (370 mg, 1.24 mmol) in THF (20 ml) and MeOH (5 ml) was added 2M NaOH (3.11 ml, 6.22 mmol) and the reaction was stirred at 50° C. for 16 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH1 using 1M HCl. The product was extracted into DCM (3×50 ml), washed with brine (20 ml), dried with Na2SO4 concentrated and filtered to afford the title compound as an orange oil (296 mg, 80%) which was used in the next stage without any further purification. LC-MS 91%, m/z=270.0, 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J=7.5 Hz, 1H), 7.34-7.30 (m, 4H), 7.23 (dt, J=15.4, 6.9 Hz, 3H), 4.12 (d, J=13.5 Hz, 2H), 3.04-2.94 (m, 2H), 2.69 (s, 3H), 0.99 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:30][S:31]([O:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform (40.00 mL) and the mixture was cooled to 0° C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0° C. for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:14][N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:6]=3[C:5]=2[N:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[C:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1
Reactant: CCOC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CCc1cnc(SC)nc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1n[nH]c2c1CCc1cnc(SC)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Ethyl 8-(methylsulfanyl)-1-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.0 g, 1.99 mmol) in DCM (20 ml) was treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred at r.t. for 1 hour and the solvent removed in vacuo. The residue was triturated with diethyl ether filtered and dried to provide the title compound 500 mg (96%). LC/MS (254 nm) HPLC method 2 Rt 3.62 min.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33](=[O:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:35]([CH2:34][C:33]([O:32][CH3:31])=[O:39])(=[O:37])=[O:36])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.1 %

Procedure:
To product of example 205 (21.5 mg, 0.05 mmol) in methylene chloride (1 mL) was added chlorosulfonyl-acetic acid methyl ester (35 mg, 0.2 mmol) and triethylamine (30 μl, 0.22 mmol) and the resulting mixture was stirred at room temperature for 3 days. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was chromatographedon silica gel eluting with 199:1 dichloromethane:methanol. The product was dissolved in dichloromethane and added two drops of acetic acid, then stirred at rt for 10 min, washed with water. The organic layer was dried with magnesium sulfate and evaporated in vacuo to give the title compound (2 mg, 7%). 1H NMR (300 MHz, DMSO-d6): δ 0.99 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.65 (s, 3 H) 4.40 (s, 2 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.59 (dd, J=8.82, 2.57 Hz, 1 H) 7.66 (d, J=2.57 Hz, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.73 (s, 1 H) 14.15 (s, 1 H). MS (ESI−) m/z 562 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]1([CH2:23]OOC(=NC(C)C)NC(C)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([O:1][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:7]=1
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Reactant: CC(C)N=C(NC(C)C)OOCc1ccccc1
Solvent: CC#N
Product: COC(=O)c1oc2ccc(OC)cc2c1OCc1ccccc1
Yield: 64 %

Procedure:
A mixture of 8.0 g (0.036 mole) of 3-hydroxy-5-methoxy-2-benzofurancarboxylic acid, methyl ester and 10.0 g (0.043 mole) of O-phenylmethoxy-N,N'-diisopropylisourea (L. J. Mathias, Synthesis, 561 (1979)) in 200 ml of acetonitrile is stirred at reflux under a nitrogen atmosphere for 22 hours. The mixture is cooled and filtered to remove by-product 1,3-diisopropylurea. The insoluble material is washed with hexane and the combined filtrates are evaporated (vacuum). The residue is treated with 250 ml of diethyl ether, and the mixture is again filtered and evaporated. The crude oil residue is chromatographed over silica gel using dichloromethane/hexane (2:1) elution to obtain 7.2 g 64% yield) of the purified 5-methoxy-3-(phenylmethoxy)2-benzofurancarboxylic acid, methyl ester as an oil. The ester is saponified without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Solvent: CCO
Product: CCCN[C@@H]1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Alternatively, to a solution of 160 mg (0.72 mmol) racemic N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) (as the free base) in 1.0 mL EtOH were added a solution of 270 mg (0.72 mmol) of (L)-(−)-O,O-(R,R)-dibenzoyltartaric acid monohydrate in 2.0 mL EtOH and stirred for 10 min at room temperature to get a fine white precipitate, which was filtered, washed with cold ethanol and suspended in 10% (v/v) aqueous KOH. After the extraction of the aqueous layer with methylenehloride for four times the organic layers were dried over Na2SO4, the solvent was evaporated in vacuo to get (R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16](N)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.C(ON=O)CC(C)C.[I:27]CI>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([I:27])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: ICI
Reactant: CSc1nccc(-n2cnc3cc(N)ccc32)n1
Agent: CC(C)CCON=O
Product: CSc1nccc(-n2cnc3cc(I)ccc32)n1
Temperature: 100 °C

Procedure:
2-Methylthio-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 3, 513 mg) was dissolved in diiodomethane (5 mL), isoamylnitrite (0.32 mL) was added and the resulting solution was heated to 100° C. for 30 minutes. Upon cooling to rt, the reaction mixture was directly purified by column chromatography (SiO2, 5% MeOH in CH2Cl2) to yield 342 mg of the title compound. Mass spectrum 371.1 (ESI) (M+).