Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[CH2:18][CH2:19][CH2:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[N:17]=[C:16]2[CH2:18][CH2:19][CH2:20][C:15]2=[CH:14][CH:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2ccc3c(n2)CCC3)c(C(N)=O)nn1
Temperature: 120 °C
Yield: 73.6 %

Procedure:
A solution of 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxamide (375 mg, 1.29 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (555 mg, 2.59 mmol) in N-methyl-2-pyrrolidinone (3 mL) was treated with tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (555 mg, 2.59 mmol), The reaction mixture was heated at 120° C. for 72 h, then cooled to room temperature, concentrated under high vacuum and the residue obtained was purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 5% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 20 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (444 mg, 73%) as a light brown foam. 1H NMR (CHLOROFORM-d) δ: 11.30 (s, 1H), 8.19 (s, 1H), 8.06 (d, J=3.4 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 6.75-7.10 (m, 1H), 6.61 (d, J=8.3 Hz, 1H), 5.77-6.14 (m, 2H), 3.99 (m, 1H), 3.55-3.74 (m, 1H), 2.67-3.05 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H), 1.18-2.01 (m, 17H); LC-MS 468.2 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH2:29][CH3:30])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH2:29][CH3:30])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2CC)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-ethyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 2N sodium hydroxide solution.
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]3[S:17][C:16]([O:18][CH:19]=[C:20]4[O:24]C(C)(C)N(C(C)(C)C)[CH2:21]4)=[N:15][CH:14]=3)=[O:12])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[Na+]>C(OCC)(=O)C>[C:1]([CH2:21][CH:20]([OH:24])[CH2:19][O:18][C:16]1[S:17][C:13]([C:11]([NH:10][CH2:9][CH2:8][CH:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH2:2][CH2:3]3)=[O:12])=[CH:14][N:15]=1)([CH3:7])([CH3:6])[CH3:2]
Reactant: CC(C)(C)N1CC(=COc2ncc(C(=O)NCCC3C4CCC3CC4)s2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(O)COc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reaction time: 0.5 h

Procedure:
This example illustrates methods of converting the compounds of formula III into the compounds of formula II of the invention. In this example 1 g. of 5-(5-[2-(bicyclo[2.2.1]-hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)methylene-N-t-butyl-2,2-dimethyloxazolidine is dissolved in 50 ml. of ethyl acetate and this solution is treated with aqueous 5% sodium hydroxide (20 ml.) at 20° C. The mixture is allowed to stand for 0.5 hours, washed three times with water, dried over magnesium sulfate and then evaporated to dryness affording 1-t-butyl-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)-propan-2-ol.
Reaction SMILES: [OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C[O-].[Na+].[CH3:24]N(C=O)C.COS(OC)(=O)=O>O>[OH:1][C@@H:2]([C:6]([O:19][CH3:20])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH3:24])=[O:4]
Reactant: CN(C)C=O
Reactant: COC(c1ccccc1)(c1ccccc1)[C@H](O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@H](O)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were introduced with 10.8 g (200 mmol) of sodium methoxide into 300 ml of DMF. 21 ml (210 mmol) of dimethylsulfate were added dropwise to this suspension over 15 minutes, during which the temperature rises to 50° C. and the suspension becomes mobile. The mixture was stirred overnight and then added to 1.5 l of water and ice. The aqueous phase was extracted twice with 500 ml of ether, and the ether phase was in turn washed with 200 ml of water twice. The organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off. 55.8 g of an oil were isolated and were immediately processed further.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][C@@H:14]2[CH3:32])=[O:12])[CH:7]=1.[CH3:33][N:34](C)C=O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:32][C@H:14]1[CH2:15][N:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:17][CH2:18][N:13]1[C:11]([C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:33]#[N:34])[CH:3]=[N:4][C:5]=12)=[O:12]
Reactant: CN(C)C=O
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(Br)cnc12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(C#N)cnc12
Temperature: 95 °C

Procedure:
To a mixture of 6-bromo-3-[((2S)-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinyl)carbonyl]pyrazolo[1,5-a]pyrimidine (may be prepared as described in Example 12) (300 mg, 0.564 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (39.1 mg, 0.070 mmol) under argon in dry N,N-dimethylformamide (6 mL) was added zinc cyanide (86 mg, 0.733 mmol) followed by tris(dibenzylideneacetone)dipalladium(0) (32.0 mg, 0.035 mmol) and the mixture heated to 95° C. for 2 h. The mixture was partitioned between ethyl acetate (30 mL) and aqueous sodium bicarbonate (20 mL). The organic phase was washed with further sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. Half the crude material was purified by MDAP and the solvent evaporated to give the title compound (67 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1>>[CH3:8][N:9]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1)[C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6]
Reactant: O=C(Cl)C1CCC1
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CN(C(=O)C1CCC1)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from cyclobutane carbonyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 378/380 (MH+); HPLC Rf: 4.71 min.; HPLC purity 98%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.Cl.[CH3:29][N:30]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:44]5[CH2:43][CH2:42][CH:41]([N:30]([CH3:29])[C:31](=[O:40])[O:32][CH2:33][C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH2:46][CH2:45]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: Cl
Product: CCOc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 77 %

Procedure:
The same reaction procedure as in Example 27 was performed, except that the compound obtained in Example 85 was used in place of the compound obtained in Example 26, and benzyl methyl(4-piperidinyl)carbamate hydrochloride was used in place of N-methylpiperazine. In this manner, 234 mg (77%) of the captioned compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=NO)[C:6](=[O:13])[NH:7]2.[OH:17]C1C(O)=C(O)C2C(=CC=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:16])=[C:5]([OH:17])[C:6]([OH:13])=[N:7]2
Reactant: Oc1nc2ccccc2c(O)c1O
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Product: Oc1nc2cc(Cl)cc(Cl)c2c(O)c1O

Procedure:
Compound 11b was prepared from 10b similar to 11a. mp 270°-273° C. 1H NMR (DMSO-d6), 7.257 (s, 2) 9.306 (mb, 1), 9.998 (s, 1), 11.919 (s, 1).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([C:14](O)=[O:15])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([CH2:14][OH:15])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:25]
Reactant: O=C(O)c1cccc2c(=O)c(CBr)c(-c3ccccc3)oc12
Reactant: CNC
Product: CN(C)Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O

Procedure:
Ethyl ester of 3-bromomethylflavone-8-carboxylic acid was reacted with dimethylamine in a conventional manner and the resultant product was reduced to give 3-dimethylaminomethylflavone-8-methanol.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH:14]=O.S([O-])([O-])(=O)=O.[Mg+2].CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCCCC1
Reactant: COC(C=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCCCN1CCCCC1)OC
Yield: 0 %

Procedure:
To a solution of 1-piperidinepropylamine (3.00 g, 21.1 mmol) in MeOH (60 mL) were added dimethoxyacetaldehyde (45% solution in TBME, 6.5 mL, 25 mmol) magnesium sulfate (22.8 g, 190 mmol), AcOH (5.07 g, 84.4 mmol), and sodium cyanoborohydride (1.99 g, 31.6 mmol) at 0° C. The ice bath was removed, then after 18 h the reaction mixture was partitioned between sat. aq. sodium hyrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (2.08 mg, 43%). Colorless liquid, 231.2 (M+H)+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4]=O.[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1>Cl.C1(C)C=CC=CC=1>[CH3:4][C:3]1[CH:2]=[CH:1][C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=2)[N:6]=1
Reactant: C/C=C/C=O
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(CC(=O)O)cc2n1
Yield: 12 %

Procedure:
Crotonic aldehyde (33.0 mL, 0.40 mol) was added to 3-aminophenylacetic acid (30.0 g, 0.20 mmol) in concentrated hydrochloric acid (400 mL) and toluene (100 mL) at 110° C. The mixture was heated at 1100 for 90 minutes. The aqueous layer was separated, washed with diethyl ether (350 mL) then neutralised with aqueous ammonia. The aqueous solution was washed with chloroform (3×500 mL) and the organic phase was evaporated in vacuo. The solid residue was refluxed with chloroform (900 mL) and methanol (100 mL) then the solution was decanted and purified by column chromatography on silica gel (gradient of chloroform:MeOH 9:1 to 4:1) to afford a mixture of isomeric acids. This was purified by fractional crystallisation using isopropanol to afford the title compound as a white solid in 12% yield, 4.90 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15]C)=[C:10]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]2)=[O:18])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([OH:15])=[C:10]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]2)=[O:18])[CH:9]=1
Reactant: C=CC(=O)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c(Cl)cc2OC)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To a solution of 1-(4-(2′,6-Dichloro-4-methoxy-[1,1′-biphenyl]-3-carbonyl)piperazin-1-yl)prop-2-en-1-one (200 mg, 0.48 mmol) in DCM (15 mL) at −60° C., BBr3 (0.6 g, 2.4 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 1 h. The mixture was poured into ice-water, basified with saturated NaHCO3 solution to adjust the pH to 8-9, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1) to afford the desired product (10 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.6 (s, 1H), 7.57-7.33 (m, 5H), 7.12 (s, 1H), 7.05 (s, 1H), 6.80 (m, 1H), 6.15-6.11 (dd, J=2, 16.8 Hz, 1H), 5.72-5.70 (m, 1H), 3.6 (m, 8H). ESI-MS m/z: 405.3[M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[H-].[Na+].[C:31](OC)(=O)[CH3:32]>C1COCC1>[CH:25]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]4[N:28]=[C:31]([CH3:32])[O:1][N:2]=4)=[CH:5][CH:6]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:24][CH2:23]1)([CH3:26])[CH3:27]
Reactant: COC(C)=O
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=N)NO)cc3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(O[C@H]3CC[C@H](C(=O)N4CCN(C(C)C)CC4)CC3)cc2)no1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 0.1 g (0.26 mmol) of trans-N-Hydroxy-4-[4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzamidine and 0.24 g of molecular sieves 4A in 3 ml THF, 17 mg (0.39 mmol, 55% purity) of sodium hydride was added and the mixture was stirred at 60° C. for 45 min. After cooling down, 0.1 ml (1.45 mmol) of methyl acetate was dropwised to the mixture and the mixture was refluxed for 5 hr. After that, 56 mg (1.28 mmol, 55% purity) of sodium hydride and 1 ml (14.5 mmol) of methyl acetate were added to the mixture. The mixture was refluxed for 16 hr. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel eluting with dichloromethane and methanol=from 98:2 to 19:1, after that, purified with cyclohexane and ethyl acetate=from 3:1 to 2:1. The combined product fractions were evaporated to dryness to yield 0.022 g (20% yields) of the titled compound. MS (m/e): 413.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27]Br>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([CH2:27][CH:23]2[CH2:24][CH2:25][CH2:26][O:22]2)[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Reactant: BrCC1CCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cccc(C23CCCC2CN(CC2CCCO2)CC3)c1
Temperature: 25 °C

Procedure:
A solution of 1.5 g. of 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 15 ml. of N,N-dimethylformamide containing 1.0 g. of sodium bicarbonate and 0.95 g. of 2-tetrahydrofurylmethyl bromide was heated at reflux for four hours. After cooling the reaction mixture to about 25° C., the mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil so formed was dissolved in diethyl ether and added to a solution of hydrogen bromide gas in diethyl ether. The product crystallized out of solution and was collected by filtration to provide 1.0 g. of 4a-(3-hydroxyphenyl)-2-(2-tetrahydrofurylmethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M.P. 190°-192° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[C:21]([CH2:20][Cl:19])([CH3:26])[CH3:25])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Added to a solution of 16.1 g of 3-(trifluoromethyl)-aniline in methylene chloride were 16.7 ml of triethylamine, and 14.2 ml of 3-chloro-2,2-dimethylpropanoyl chloride were added dropwise under chilling with ice water. After stirring the mixture at room temperature for 1 hour, the resulting liquid reaction mixture was washed once each with water and saturated saline and dried on magnesium sulfate. Methylene chloride was distilled off, and the residue was purified by column chromatography on silica gel to obtain 28 g (yield: 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccc(F)c(F)c2)ccn1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccc(F)c(F)c2)ccn1
Yield: 65.6 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 300 mg (0.82 mmol) of 4-(2-aminopyridin-4-yl)-3-(3,4-difluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 24-5) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 198 mg of the title compound as a white powder. (Yield: 66%)
Reaction SMILES: [NH2:1][C@H:2]1[C@@:7]([OH:9])([CH3:8])[C:6]([CH3:11])([CH3:10])[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]=[N:18][N:17]=3)=[CH:15][C:3]1=2.[CH3:29][S:30][C:31](SC)=[N:32][C:33]#[N:34].N1C=CC=CC=1.CO>ClCCl>[C:33]([N:32]=[C:31]([S:30][CH3:29])[NH:1][C@H:2]1[C@@:7]([OH:9])([CH3:8])[C:6]([CH3:10])([CH3:11])[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]=[N:18][N:17]=3)=[CH:15][C:3]1=2)#[N:34]
Reactant: CSC(=NC#N)SC
Reactant: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](N)[C@](C)(O)C(C)(C)O2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](NC(=NC#N)SC)[C@](C)(O)C(C)(C)O2
Temperature: 75 °C

Procedure:
A mixture containing (3S,4R)-4-amino-3,4-dihydro-6-(1-[3-ethoxycarbonylprop-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Preparation 55) (1.2 g), dimethyl N-cyanodithioiminocarbonate (0.7 g) and pyridine (10 ml) was heated at 75° C. for 18 hours then concentrated in vacuo to give a gum which was stirred in dichloromethane containing methanol (2.5%) (20 ml). The resulting solid was filtered off and dried in vacuo to give the title compound, 0.85 g, m.p. 225°-227° C. Found: C,54.13; H,5.91; N,19.81; C22H29N7O4S requires: C,54.20; H,6.00; N,20.11%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([CH2:16][N:17]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([CH2:16][NH2:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC1CCN(C(=O)OC(C)(C)C)CC1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1CN

Procedure:
To a stirred solution of 3-azidomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.74 mmol, 0.2 g) in ethyl acetate (5 mL) was added 10% palladium on carbon (0.1 g, wet), and the resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 1 h. The catalyst was filtered through a pad of celite, washed the celite pad with methanol, and the combined filtrate was concentrated under reduced pressure to provide 3-aminomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:14][C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18](Cl)=[CH:19][CH:20]=1.[OH-].[Na+]>CN(C)C=O>[Cl:14][C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:20]=1
Reactant: Cc1csc(NC(=O)c2nc(Cl)ccc2Cl)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2nc(Oc3ccccc3)ccc2Cl)n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
Phenol (135 mg; 1.43 mmol) and 540 mg (1.66 mol) of cesium carbonate were added to a solution (3 ml) of 84 mg (0.292 mmol) of 3,6-dichloro-N-(4-methyl-thiazole-2-yl)-2-pyridine carboxamide in N,N-dimethylformamide followed by stirring at 120° C. for 24 hours. Aqueous solution (1N) of sodium hydroxide was added to the reaction solution followed by extracting with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, dried and concentrated in vacuo. The resulting residue was purified by a thin-layer silica gel chromatography (hexane:ethyl acetate=4:1) to give 61 mg (yield: 61%) of 3-chloro-6-phenoxy-N-(4-methyl-thiazole-2-yl)-2-pyridine carboxamide as a white solid.