Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.CCN(CC)CC.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH:34]([NH:37][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])([CH3:36])[CH3:35]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A mixture of 74 mg (0.18 mmol) 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride, 73 mg (0.72 mmol) NEt3 and 14.8 mg (0.252 mmol) isopropylamine in 2 mL CH2Cl2 was stirred for 16 h at 50° C. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 12.5 mg (16%) of the title compound. MS (ESI): 436.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:34])[C@H:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:28][C@H:27]([C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
N-(tert-Butoxycarbonyl)-D-leucine (230 mg, 1.0 mmol) and benzyl-3-tert-butyl-L-alaninate hydrochloride (300 mg, 1.10 mmol) (John X. He, Wayne L. Cody, Annette M. Doherty, J. Org. Chem., 1995, 60, 8262-8266) are reacted by general procedure 6. The crude product is purified (workup method 2) by preparative HPLC (method 16), resulting in 362 mg (80% of theory) of product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(C)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 5-methoxy-2-methylaniline (33 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (45 mg, 60%). 1H NMR (CDCl3): 8.78–8.77 (m, 1H), 8.44 (d, J=8.1 Hz, 1H), 7.81–7.75 (m, 1H), 7.34–7.30 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.7 Hz, 2H), 6.72 (dd, J=2.7, 8.7 Hz, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:38].S>C(O)C>[C:1]1([C:7]2[S:38][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
A 1-liter stirred autoclave was charged with 55.6 g (0.150 mole) of 1,2-diphenyl-4-p-t-butylphenylbutane-1,4-dione, 100 ml of xylene, 33.3 g (0.075 mole) of phosphorus pentasulfide and 130 g of hydrogen sulfide. The reactor was cooled and vented. The residue was stirred with 150 ml of absolute ethanol. Filtration gave a first crop of 18 g (32.6%) m.p. 108°-112° C. Chilling the filtrate and refiltering gave a second crop of 24 g (43.4%) m.p. 102°-105° C. The two crops were combined for recrystallization from a mixture of 50 ml of dioxane and 100 ml of absolute ehtanol. The pure product (31.3 g, 56.6%) had a m.p. of 117°-119° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: CC(=O)OCC(C)(C)CBr
Product: COC(=O)c1cc(OCC(C)(C)COC(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 1.79 g) was reacted with 3-bromo-2,2-dimethylpropyl acetate, worked up and purified analogously to O2.85. 1.01 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][O:19][Si:20]([CH:21]([CH3:22])[CH3:23])([CH:27]([CH3:28])[CH3:29])[CH:24]([CH3:26])[CH3:25])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[O:9][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCc1ccc(C(O)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCc1ccc(C(O[Si](C(C)C)(C(C)C)C(C)C)c2cc(Br)ccc2CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
Step 4) To a solution of (5-bromo-2-((triisopropylsilyloxy)methyl)phenyl)(4-ethylphenyl)methanol (4.76 mmol) and 2,6-lutidine (1.6 mL, 13.51 mmol) in dichloromethane (30.0 mL) was slowly added TIPSOTf (1.8 mL, 6.75 mmol) at 0° C., and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was quenched with CH3OH, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide the title compound (2.94 g, 97% 2-step) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:11]([CH3:17])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([C:33]([CH3:36])([CH3:35])[CH3:34])[S:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(O)(=O)C>O>[CH:14]1([CH2:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29]4[CH:28]=[CH:27][C:26]([S:23](=[O:24])(=[O:25])[N:22]([CH2:21][CH2:20][O:19][CH3:18])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:31][CH:30]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[CH3:17])[CH2:15][CH2:16]1
Reactant: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(I)cc1
Reactant: Cc1ncc(-c2ccnc(N)n2)n1CC1CC1
Solvent: CC(=O)O
Solvent: O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC3CC3)n2)cc1
Yield: 32.2 %

Procedure:
2-Amino-4-(1-cyclopropylmethyl-2-methylimidazol-5-yl)pyrimidine (Method 54; 2 g, 8.73 mmol) was treated with N-(2-methoxyethyl)-N-(t-butyl)-4-iodobenzenesulphonamide (Method 77; 3.82 g, 9.61 mmol) under the conditions described in Example 22. The reaction was quenched by the addition of acetic acid (250 μl, 4.37 mmol), the mixture was poured into water and extracted with EtOAc. The extracts were combined, washed with water and then brine, dried and the solvent removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (97:3) to give the title compound (1.4 g, 32%) as a pale yellow foam. NMR: 0.01 (m, 2H) 0.18 (m, 2H) 1.90 (m, H) 2.26 (s, 3H) 3.15 (s, 3H) 3.37 (m, 4H) 4.42 (d, 2H) 7.08 (d, H) 7.52 (s, H) 7.58 (d, 2H) 7.75 (d, 2H) 8.30 (d, H) 9.75 (s, H); m/z 499.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].[OH-].[Na+]>CS(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.2 %

Procedure:
20.0g (93.5 mmoles) of 2-chloromethylquinoline hydrochloride, 11.6 g (93.5 mmoles) of 3-hydroxybenzyl alcohol and 7.48 g (186.42 mmoles) of powdered sodium hydroxide are combined in 56 ml of dimethylsulfoxide. After stirring room temperature for 24 hours the mixture is poured into ice-water and the resulting solid is collected and dried to give 25.6 g of 3-(2-quinolinylmethyloxy)benzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[CH:7][C:6]=2[CH:12]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][C:6]=2[CH:7]=1
Reactant: OCc1cc2cc(F)ccc2o1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Fc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Compound 14 (150 mg, 0.90 mmol) was dissolved in toluene (10 mL) and the solution was cooled to 0° C. PBr3 (102 μL, 1.08 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 15 (150 mg, 72%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.43 (1H, d, J=7.60 Hz, H-7), 7.21 (1H, t, J=8.10, H-4), 7.06 (1H, t, J=8.90, H-4), 6.75 (1H, s, H-3), 4.60 (2H, s, 2-CH2). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 113.08 (C-7), 112.08 (C-6), 106.87 (C-4), 106.34 (C-3), 60.42 (CH2—Br).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.Br[CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:11]
Reactant: N#Cc1cccc2[nH]ncc12
Reactant: CCOC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Reaction time: 7 h
Yield: 37 %

Procedure:
1H-Indazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd.) (500 mg, 3.49 mmol), ethyl 3-bromo-2,2-dimethylpropanoate (D98) (803 mg, 3.84 mmol) and Cs2CO3 (1.36 g, 4.19 mmol) in dry DMF (3 ml) was heated to 80° C. overnight and then for a further 7 hours. The reaction mixture was then partitioned between EtOAc and H2O. The two layers were separated and the organic phase was washed with more H2O, brine, dried and concentrated a yellow oil. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (356 mg, 37%) as a crystalline material. MS (ES) C15H17N3O2 requires 271, found 272 [M+H]+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][OH:16].Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:20]=1[O:21][CH2:22][C:23]#[N:24]>>[CH3:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:20]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: OCCCOCc1ccc2ccccc2n1
Reactant: Cc1cccc(CBr)c1OCC#N
Product: Cc1cccc(COCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 377 (M+H)+. Prepared from 3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE 34a) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:19]=[CH:20][C:21]([NH:22][S:2]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (4.0 g, 16.08 mmol) in N,N-dimethylacetamide (20 mL) was added 4-(trifluoromethyl)aniline (10.37 g, 64.3 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 2.5 hours, and then it was diluted with ethyl acetate (130 mL). The organic solution was washed with 1 N HCl (2×60 mL) and saturated NaCl (60 mL). The organic layer was concentrated, ethanol (40 mL) was added, and the mixture was concentrated to give ethyl 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoate.
Reaction SMILES: [O:1]1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]1[C:3]([O:5]C)=[O:4].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][CH:2]([CH:7]([OH:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([OH:5])=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC1OC1C(=O)OC
Product: CCCCCCCCCCCCCCCC(O)C(NCc1ccccc1)C(=O)O
Yield: 68 %

Procedure:
For preparation of racemic dihydrosphingosines, K. Sisido, et al., report in J. Org. Chem., Vol. 29, No. 9, pp. 2783-2784 (1964) a process comprising, for example, reacting methyl trans-2-octadecenoate with perbenzoic acid in chloroform to obtain methyl 2,3-epoxyoctadecanoate having formula (V'): ##STR3## whose planar structure is the same as that of the compound represented by formula (V) hereinafter described, hydrolyzing the ester (V'), cyclizing the resulting acid by reaction with benzylamine to obtain 2-benzylamino-3-hydroxyoctadecanoic acid (cyclization yield: 68%), converting the acid to a methyl ester, and reducing the ester in an ether solvent with lithium aluminum hydride (LiAlH4) (reduction yield: 71%). Reduction of such a carboxylic acid as 2-benzylamino-3-hydroxyoctadecanoic acid to an alcohol has generally been carried out by once esterifying the carboxylic acid and using LiAlH4 as a reducing agent as in the above report. However, LiAlH4 is a reagent unsuitable to industrial use because it is not only expensive but difficult to handle on account of reactivity with moisture in air.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH2:20])=[O:19]>CC(C)=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH2:20])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC(=O)c1cccn1N
Solvent: CC(C)=O
Product: NC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of benzoylisothiocyanate (1.2 mL, 8.8 mmol) in acetone (10 mL) was treated with 1-aminopyrrole-2-carboxamide (1.0 g, 8.0 mmol) at ambient temperature. The resulting suspension was stirred for one hour and then cooled to 0° C. The solid material was collected by vacuum filtration and washed with diethyl ether before drying under high vacuum to afford 1A (2.2 g, 96%). HPLC tR=2.55 min (YMC S5 Combiscreen ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 254 nm). [M+H]+=289.29. 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H), 11.9 (s, 1H), 8.0 (dd, 2H, J=1.2, 7.2 Hz), 7.68 (t, 1H, J=7.6 Hz), 7.55 (m, 3H), 7.03 (s, 1H), 6.92 (br s, 1H), 6.82 (dd, 1H, J=1.6, 4.0 Hz), 6.11 (dd, 1H, J=3.2, 4.0 Hz).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1cccnc1
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1cccnc1
Yield: 41.8 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(3-pyridyl)propionate (4.1 g), benzylamine (3.5 g) and acetonitrile (80 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(3-pyridyl)imidazole-4-carboxylate (2.2 g), melting point 196-197° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[C@H:14]([O:21][CH3:22])[CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23](OCC)(OCC)(OCC)[CH3:24].C(O)(=O)C>>[CH3:22][O:21][C@@H:14]1[CH2:13][C@@H:12]([N:11]2[C:3]3=[C:4]4[S:10][CH:9]=[CH:8][C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[C:23]2[CH3:24])[CH2:17][CH2:16][C@@H:15]1[CH2:18][C:19]#[N:20]
Reactant: CCOC(C)(OCC)OCC
Reactant: CO[C@@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Solvent: CC(=O)O
Product: CO[C@@H]1C[C@@H](n2c(C)nc3cnc4ccsc4c32)CC[C@@H]1CC#N
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
A mixture of {(1R,2R,4S)-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-2-methoxycyclohexyl}acetonitrile (racemic) (45 mg, 0.14 mmol) and triethyl orthoacetate (79 μL, 0.43 mmol) in acetic acid (0.4 mL, 7 mmol) was stirred at 120° C. for 30 min. The solvent was removed, and the residue dissolved in methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (28 mg, 58%). LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.0.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and 5-chloro-indan-2-carbaldehyde. The less polar of the two substances isolated by chromatography gave cis-2-(1-{4-[(5-chloro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C27H34ClN3O (m/e) calcd 451.2390, obsd 452.3 (M+H). 1H-NMR (CD3OD) □ 7.83 (d, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 7.03 (d, 1H), 5.32 (m, 1H), 3.16 (m, 2H), 2.96 (br s, 1H), 2.73-2.85 (m, 7H), 2.43 (s, 3H), 2.00 (m, 2H), 1.72 (s, 6H), 1.68 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH2:34][CH2:33][CH2:32][N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCCCn1ccnc1
Product: Cn1c(=O)c(C(=O)NCCCn2ccnc2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 32.8 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and [3-(1H-imidazol-1-yl)propyl]amine (48 mg, 0.0384 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(1H-imidazol-1-yl)propyl]-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (4 mg, 33% yield), as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.36 (br s, 1 H), 8.59 (s, 1 H), 7.74 (s, 1 H), 7.42 (s, 1 H), 7.18-7.14 (m, 2 H), 7.12 (s, 1 H), 7.05-7.01 (m, 3 H), 4.15 (s, 2 H), 4.11-4.07 (m, 2 H), 3.59 (s, 3 H), 3.51-3.45 (m, 2 H), 2.19-2.12 (m, 2 H); MS m/z 436 (M+1).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33].Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[S:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1ccc(N=C=S)cc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=S)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 3-chloro-4-methylphenyl isothiocyanate (0.26 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. The mixture was stirred at ambient temperature for 3 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-(3-chloro-4-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-thiourea as a white solid (0.52 g, 84% yield); mp 240-242° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.11 (97.48%); 1H NMR (DMSO-d6) δ 1.95-2.06 (m, 1H, CHH), 2.29 (s, 3H, CH3), 2.35-2.47 (m, 1H, CHH), 2.55-2.67 (m, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.32 (d, 1H, CHH), 4.46 (d, 1H, CHH), 4.86 (d, J=5.1 Hz, 2H, CH2 and CHH), 5.11 (dd, 1H, CH), 7.25 (dd, 1H, Ar), 7.28 (d, 1H, Ar), 7.47 (d, 1H, Ar), 7.54 (s, 1H, Ar), 7.61 (s, 1H, Ar), 7.70 (d, 1H, Ar), 8.37 (t, 1H, NH), 9.73 (s, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.96, 22.49, 31.20, 47.13, 51.58, 122.14, 122.88, 123.48, 127.13, 130.39, 130.97, 131.12, 132.67, 138.29, 142.27, 143.32, 167.92, 170.99, 172.86, 181.00; LCMS: MH=457/459; Anal. Calcd for C22H21ClN4O3S: C, 57.83; H, 4.63; N, 12.26. Found: C, 57.57; H, 4.51; N, 12.21.
Reaction SMILES: C(O[C:4]1[CH2:9][O:8][CH:7]([CH3:10])[C:6](=[O:11])[CH:5]=1)C.[NH3:12]>>[NH2:12][C:4]1[CH2:9][O:8][CH:7]([CH3:10])[C:6](=[O:11])[CH:5]=1
Reactant: CCOC1=CC(=O)C(C)OC1
Reactant: N
Product: CC1OCC(N)=CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 88A was treated with ammonia saturated ethanol (60 mL), stirred at ambient temperature for 16 hours and concentrated to provide the title compound (0.98 g).