Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:36])[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH2:31]([O:30][C:29](=[O:36])[NH:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:18]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCOC(=O)Cl
Reactant: Cc1ncoc1C(=NOCc1csc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1nc(CON=C(c2ccccc2)c2ocnc2C)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (95 mg, 0.3 mmol) in dichloromethane (2 mL) were added pyridine (36 mg, 0.45 mmol) and after 15 min stirring pentyl carbonochloridoate (91 mg, 0.6 mmol). After stirring at room temperature for 4 h the mixture was passed through a cartridge filled with basic alumina and 1 g silica. After rinsing with dichloromethane the final compound was eluted with heptane/ethylacetate (1/1) to afford after purification on silica pentyl {4-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy) methyl]-1,3-thiazol-2-yl}carbamate (60 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[CH:8]2)=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O1CCOCC1>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(F)cc1)cn2C
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 1-methyl-1H-indole-5-carboxylic acid methyl ester (0.17 g, 0.9 mmol), prepared using procedures as described in Example 1, Ag2O (0.22 g, 0.95 mmol), 4-fluoro-benzyl bromide (0.18 g, 0.95 mmol) and dioxane (4 mL) were heated to reflux for 16 hr, then more 4-fluoro-benzyl bromide (90 mg, 0.5 mmol) was added and the solution was heated at reflux an additional 4 hr. After cooling to room temperature, the reaction mixture was diluted with ether (60 mL), washed with aq. NH4Cl (50 mL) and then brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:3) to provide 3-(4-fluoro-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid methyl ester (58 mg, 22% yield).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5](C=CC=C2CCNC(C2CC2)=O)=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[C:28]2[CH2:31][CH2:32][NH:33][C:34]([CH:36]2[CH2:39][CH2:38][CH2:37]2)=[O:35])=[CH:23][CH:22]=1>>[CH:2]1[CH2:11][CH2:10][CH2:5][CH:4]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[C:28]3[CH2:31][CH2:32][NH:33][C:34]([CH:36]3[CH2:39][CH2:38][CH2:37]3)=[O:35])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: O=C(NCCc1cccc2ccc(O)cc12)C1CCC1
Reactant: O=C(NCCc1cccc2ccc(O)cc12)C1CC1
Product: O=C(NCCc1cccc2ccc(OC3C=CCCC3)cc12)C1CCC1

Procedure:
Using the procedure described in Example 25, but replacing the compound obtained in Example 24 by the compound obtained in Example 41, N-{2-[7-(cyclohexen-3-yl)oxy-1-naphthyl]ethyl}cyclobutanecarboxamide is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[C:4]([F:24])[N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([NH:32][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[C:4]([F:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(F)c2)cc1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(NCc3ccccc3)c2)cc1
Temperature: 130 °C

Procedure:
In a sealed-tube was combined 3-(2,6-difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (Example 44, 35 mg, 0.11 mmol) and benzylamine (3.0 mL, 2.9 g, 27 mmol), and the reaction was placed in a preheated oil bath at 130° C. The reaction was stirred at 130° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube was transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 18 mg (0.04 mmol, 36%). 1H NMR (d6-acetone) δ 8.67(d, 1H, J=6.8 Hz), 7.71(dd, 2H, J=5.6, 8.8 Hz), 7.59(d, 1H J=8.8 Hz), 7.30–7.45(m, 6H), 7.24(t, 2H, J=8.8 Hz), 7.05(t, 1H, J=6.8 Hz) 6.73(br t, 1H, J=6.0 Hz), 6.46(s, 1H), 6.09(s, 1H), 4.59(d, 2H, J=6.0 Hz). MS (ES+ve): 413.1 (100, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16](=[O:17])[C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=23)[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][O:11][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 3-[3-chloro-4-(2-hydroxyethoxy)-5-methoxy-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (160 mg, 0.40 mmol) in DCM (10 mL) and DIPEA (0.11 mL, 0.64 mmol) is added methane sulfonylchloride (0.04 mL, 0.48 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2-chloro-6-methoxy-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-ethyl ester (183 mg) as a yellow oil; LC-MS: tR=1.15 min, [M+1]+=515.15.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:24]1[CH:25]=[C:26]2[C@@:37]3([CH2:41][O:40][C:39]([NH2:42])=[N:38]3)[C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:43]#[C:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:35]=3)[O:30][C:27]2=[CH:28][CH:29]=1)(=O)=O.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:42][C:39]1[O:40][CH2:41][C@:37]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:43]#[C:44][C:45]([CH3:46])([CH3:47])[CH3:48])[CH:35]=3)[O:30][C:27]3[C:26]2=[CH:25][C:24]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=2)[C:1]#[N:2])=[CH:29][CH:28]=3)[N:38]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncc(C#N)c3)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with 5-cyanopyridin-3-ylboronic acid (0.030 g, 0.206 mmol), palladiumtetrakis (10.80 mg, 9.35 μmol), potassium carbonate (0.129 g, 0.935 mmol), and (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.090 g, 0.187 mmol) was treated with 1 mL of dioxane followed by 0.4 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-5-(2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)nicotinonitrile.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([O:20][C:21](=[O:23])[CH3:22])[CH2:8][NH:7]1.CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>ClCCl>[CH2:34]([O:33][C:31]([N:7]1[CH2:8][C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CN[C@@H]1c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CN(C(=O)OCc2ccccc2)[C@@H]1c1ccco1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
To the solution of the product of Example 37 (189 mg, 0.58 mmol) in dichloromethane (2.5 mL) was added Et3N (0.10 mL, 0.72 mmol), and the mixture was cooled to 0° C. CbzCl (0.11 mL, 0.73 mmol) was added dropwise, and the solution was warmed up room temperature for 2 h. The reaction was quenched with aqueous NaCl, extracted with dichloromethane several times. The combined organic layer was dried over MgSO4. After the removal of volatiles, the residue was chromatographed on silica gel using hexanes-EtOAc (3:1) and hexanes-EtOAc (1:1) to yield pure product (138 mg) and starting material (5.81) (75 mg), 86% yield based on the consumed (5.81). Contain two rotamers at rt. 1H NMR (360 MHz, MeOD-d4) δ 7.55-7.48 (m, 1H), 7.38-7.21 (m, 5H), 6.50-6.33 (m, 2H), 5.90 (d, J2,3=5.7 Hz, 0.5H, H2), 5.87 (d, J2,3=5.7 Hz, 0.5H, H2), 5.76 (t, J4,3=J4,5=9.6 Hz, 0.5H, H4), 5.74 (t, J4,3=J4,5=9.6 Hz, 0.5H, H4), 4.99 (ddd, J5,6b=10.9 Hz, J5,4=9.6 Hz, J5,6a=5.6 Hz, H5), 4.39 (dd, J6a,6b=13.0 Hz, J6a,5=5.6 Hz, 0.5H, H6a), 4.35 (dd, J6a,6b=13.0 Hz, J6a,5=5.6 Hz, 0.5H, H6a), 3.07 (dd, J6b,6a=13.0 Hz, J6b,5=10.9 Hz, 0.5H, H6b) 2.97 (dd, J6b,6a=13.0 Hz, J6b,5=10.9 Hz, 0.5H, H6b), 2.00 (s, 3H), 1.99 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: C([C:3]1[C:4](CC)=[C:5]([C:14]([CH3:21])([C:18]([O-:20])=[O:19])C([O-])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])C.[OH-].[K+].[CH3:26][CH2:27]O>>[C:11]([CH2:10][CH2:9][C:8]1[CH:3]=[CH:4][C:5]([CH:14]([CH3:21])[C:18]([O:20][CH2:26][CH3:27])=[O:19])=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CCc1c(CCC(=O)O)ccc(C(C)(C(=O)[O-])C(=O)[O-])c1CC
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(C)c1ccc(CCC(=O)O)cc1

Procedure:
The tricarboxylic ester of Example 6 (35 g, 0.1 mol) in EtOH (400 ml) was stirred at room temperature with a solution of KOH (13.2 g of 85%, 0.2 mol) in EtOH (100 ml) for 96 hours. The mixture was evaporated to dryness. The solid foam was broken up, treated with Et2O (200 ml) and filtered. The residue was dissolved in H2O (100 ml), acidified with 5 N HCl to give an oil which was extracted with Et2O. The Et2O was dried (Na2SO4) filtered and evaporated to give an oily solid. The solid was shaken with a mixture of CHCl3 -light petroleum (b.p. 40°-60° C.) (100 ml of 50:50), filtered, the residue washed with the same solvent mixture (100 ml) and the filtrate evaporated to leave an oil which was distilled to give the title product, b.p. 175°-7° C./0.25 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)CBr)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]2[N:6]([CH:10]=[CH:11][N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cc1F
Reactant: CCOC(CBr)OCC
Product: Fc1cc(Br)cn2ccnc12
Yield: 88.9 %

Procedure:
Prepared from 5-bromo-3-fluoro-pyridin-2-ylamine (example C.29 step 3) (3.1 g, 15.7 mmol) and bromoacetaldehyde diethyl acetal (90%, 4.86 mL, 31.3 mmol) as described in example C.20 step 1. Obtained the title compound as a light brown solid (3.0 g, 89%). MS (ISP) 215.1 [(M+H)+], 217.1 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:27])=[O:26]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3c(Cl)cccc3Cl)n2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide (63 mg) and 2,6-dichlorobenzenesulfonyl chloride (66 mg) as described in the synthetic METHOD B to give a white solid (5.6 mg) with purity >80%: MS (pos) m/z 442.2, 444.4.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:20])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrBr
Reactant: CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
6-Amino-9-benzyl-2-methylthiopurine (100 mg, 0.37 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 3 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 (0.5% methanol/chloroform) to give the subject compound (10 mg, yield 8%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[O:15].[OH-].[K+].O>C(O)C>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14](=[O:15])[CH:13]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COC(OC)C(C)=O
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1

Procedure:
To a solution of 5-formyl-2,2'-bithiophene (4.0 g) in ethanol (120 ml) was added dimethoxymethyl methyl ketone (3 ml). Potassium hydroxide aqueous solution (50%) was added dropwisely into the solution mixture at 16° C. Color changed from yellowish brown into dark green, then dark brown. Yellow solid was formed during the reaction. Water was added. Solid residue was filtered and washed with water, redissolved in acetone and separated by silica gel chromatography eluted with ethyl acetate/n-hexane (1:9). Yellowish crystals 1.88 g were obtained, melting point 74° C.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:19]1([NH:22][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[C:6](=[O:8])[N:7]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC2CC2)S/C1=C\c1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
The suspension of 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (55 mg, 02 mmol, example 14a), cyclopropylamine (23 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1.0 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-cyclopropylamino-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one (40 mg, 71%) as a light yellow solid. LC-MS m/e 285 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]=2[CH3:32])=[O:35])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[O:31][CH:30]([F:29])[F:40])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1OC(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)Oc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-difluoromethoxy-benzaldehyde. MS (ESI) m/z 535.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=23)=[CH:25][CH:24]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(C)n(CC=Cc2ccccc2)c2c(Cl)nncc12
Product: Cc1c(C)n(CC=Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 47.7 %

Procedure:
The title compound (trans) was prepared as pale yellow crystals in 47.7% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazine (trans) and 4-fluorobenzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 69.9 %

Procedure:
A mixture of 2.0 g (11.9 mmol) of 2,5-dihydroxybenzoic acid methyl ester, 4.55 g (13.1 mmol) of 1-bromooctadecane and 1.9 g (13.7 mmol) of potassium carbonate in 50 ml of acetone was stirred at reflux for 24 hours. The solvent was removed at reduced pressure and the residue was treated with water. The product was extracted with ethyl acetate and the dried extract was concentrated to a solid which was recrystallized from ethyl acetate-hexane to give 3.5 g (70% yield, mp 53°-54°) of 2-hydroxy-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccc(Cl)cc3)C2)cc1

Procedure:
4-Chlorobenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 4-chlorobenzyl carbonochloridate (68 mg, 0.22 mmol) according to General Procedure H to give 25 mg (26.6%) of white solid. Anal. Calcd. for C26H31ClN4O2 m/z 466.2, found: 467.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J=8.9 Hz, 2H), 7.30 (s, 4H), 6.98 (d, J=9 Hz, 2H), 4.99 (m, 2H), 3.70 (m, 1H), 3.57 (m, 1H), 3.29 (m, 1H), 2.98 (m, 1H), 2.75 (m, 1H), 2.68 (m, 1H), 2.50 (m, 1H), 2.04 (m, 1H), 1.91 (m, 2H), 1.77 (m, 3H), 1.64 (m, 1H), 1.32 (m, 5H), 1.21 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1Cl)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 195 mg (0.325 mmol) of (2R*,4S*)-2-benzyl-1-(2,4-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 26 mg (0.649 mmol) of sodium hydroxide in 2 ml of methanol and 2 ml of tetrahydrofuran is left to stir at 0° C. for 18 hours. The reaction mixture is then concentrated, taken up in methylene chloride and washed with water and brine. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (800:50:1). The title compound ##STR66## is obtained (157 mg, 96%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =503,505.