Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH:6]1[O:21][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]1[CH3:22])[NH:14][C:13](=[O:19])[C:12]([CH3:20])=[CH:11]3)[CH3:5])=[N+]=[N-].[H][H]>CO.O1CCCC1.CN(C)C=O.[Pd]>[NH2:1][CH:4]([CH:6]1[O:21][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]1[CH3:22])[NH:14][C:13](=[O:19])[C:12]([CH3:20])=[CH:11]3)[CH3:5]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N=[N+]=[N-])O3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N)O3
Yield: 65.6 %

Procedure:
The compound obtained in Example 290 (2.08 g, 7.0 mmol) was dissolved in a mixture of methanol (30 ml), tetrahydrofuran (30 ml) and dimethylformamide (30 ml). To the obtained solution, 10% palladium-on-carbon (0.70 g) was added, and allowed to react at ambient temperature for 4 hours in the stream of hydrogen gas. The insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (benzene:methanol=2:1) to obtain 1.25 g of the title compound as a colorless solid (66.0%, mp.: 195°-207° C.)
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:19])[CH:13](C)[C:14]([CH2:16]Br)=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:20][C:21]([NH2:23])=[S:22].[CH2:24](O)C>>[NH2:20][C:21]1[S:22][CH2:24][C:16](=[CH:14][CH2:13][C:12](=[O:19])[N:4]([C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[CH:1]([CH3:2])[CH3:3])[N:23]=1
Reactant: NC(N)=S
Reactant: CC(C(=O)CBr)C(=O)N(c1ccc(Cl)cc1)C(C)C
Reactant: CCO
Product: CC(C)N(C(=O)CC=C1CSC(N)=N1)c1ccc(Cl)cc1

Procedure:
A solution containing 43.3 g (0.13 mole) of N-isopropyl-4'-chloro-4-bromo-2-methylacetoacetanilide, 10.2 g (0.14 mole) of thiourea and 300 ml of ethanol was refluxed for two hours. A portion of the ethanol was evaporated and water was added. The reaction solution was made basic with ammonium hydroxide. After drying, the white solid weighed 33 g (78%), M.P. 145°-47°. N.M.R. (dimethyl-d6 sulfoxide, CDCl3) ∂0.9-1.3 (CH3, 9 protons), 3.1-3.4 (CH), 4.6-5.1 (CH, isopropyl), 5.9 (hetero-aromatic), 6.5 (NH2), 7.0-7.5 (aromatic).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[I:14]I>C1COCC1>[F:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:14]
Reactant: II
Reactant: Nc1ncccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1nccc(I)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-fluoropyridine (1.0 g, 8.9 mmol) in anhydrous THF (40 ml) was treated dropwise at −78° C. with n-butyllithium (1.6 M in hexanes, 13.9 ml, 22.3 mmol). Following the addition, the mixture was stirred at −78° C. for 1 h, then a solution of iodine (10.2 g, 40.1 mmol) in THF (20 ml) was added. The mixture was extracted with ethyl acetate, and the organic extracts were washed with sodium thiosulfate, sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (8:1 to 2:1 hexanes/ethyl acetate eluant) to provide the title compound. MS m/z 238.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nnc(N2CCC(Nc3ncn(Cc4cccc(Cl)c4)n3)CC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (91 mg, 0.5 mmol) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine (104 mg, 0.5 mmol) in dry toluene (8 mL) and acetic acid (0.4 mL) was heated under reflux at a Dean-Stark trap for 12 hours. The reaction mixture was cooled to room temperature, ethanol (5 mL) was added, followed by sodium borohydride (19 mg, 0.5 mmol) and stirred at room temperature overnight. The reaction mixture was extracted with water and ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (91 mg, 49%).
Reaction SMILES: BrCCOCCO[C:8]1[CH:17]=[C:16]2[C:11]([C:12](N([Cl:28])C3C=CC=CC=3F)(OC)[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>CN1CCNCC1>[ClH:28].[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:17]=2)[CH:12]=[N:13][CH:14]=1
Reactant: COC1(N(Cl)c2ccccc2F)NC=Nc2cc(OCCOCCBr)ccc21
Agent: CN1CCNCC1
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 100 °C
Yield: 101.3 %

Procedure:
A mixture of 7-(2-(2-bromoethoxy)ethoxy)4-(chloro-2-fluoroanilino)4 methoxyquinazoline (150 mg, 0.32 mmol) in 1-methylpiperazine (2 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 80/20). The purified solid product was dissolved in methylene chloride/methanol (III) and 2.9M ethereal hydrogen chloride was added. The volatiles were removed by evaporation and the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)+methoxy-722-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline hydrochloride (54 mg, 28%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].[C:30]1(N)C=CC=C[C:31]=1N>>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:1]=[CH:10][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:31][CH:30]=2)=[CH:4][CH:3]=1)=[O:12]
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1O
Product: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccccc1O
Yield: 39 %

Procedure:
Following the procedure described in Example 22, but substituting carboxylic acid 50h for carboxylic acid 50g and 2-aminophenol for 1,2-phenylenediamine, the title compound 74 was obtained in 39% yield. 1H NMR (CDCl3:CD3OD 5:1): δ 7.99 (d, J=8.4 Hz, 2H), 7.60 (m, 4H), 7.41 (m, 4H), 7.02 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 2.98 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.74 (m, 4H), 1.42 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:21])([F:22])[F:23])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc([N+](=O)[O-])n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98 mmol) and sat. aq NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with DCM, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d, J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:41]#[C:42]Br>C(O)C.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:42](=[NH:41])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: N=C1OC[C@@H]2C[C@H](c3cnc(N)c(-c4ccc(C(=O)N[C@H](CO)c5cccc(Cl)c5)c(F)c4)c3)CN12
Reaction time: 1 h

Procedure:
A room temperature mixture of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (12.5 mg, 0.026 mmol) (Example 7) and cesium carbonate (33.6 mg, 0.103 mmol) in ethanol (0.75 mL) was treated with cyanogen bromide (6.2 μL, 0.031 mmol). After 1 h, the reaction was diluted with water (1.0 mL) and extracted into ethyl acetate (10 mL). The organics were washed with brine (2 mL), then dried over Na2SO4 and concentrate and purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-iminohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide. LCMS (m/z): 510.1, 512.1 (MH+), 0.52 min. 1H NMR (400 MHz, CD3OD) δ ppm 8.63-8.54 (m, 1H), 7.92-7.85 (m, 2H), 7.80 (t, J=7.83 Hz, 1H), 7.40-7.31 (m, 3H), 7.29-7.24 (m, 2H), 7.24-7.16 (m, 1H), 5.14-5.06 (m, 1H), 4.97-4.88 (m, 1H), 4.61-4.49 (m, 2H), 3.88-3.70 (m, 4H), 3.32 (s, 1H), 2.41-2.31 (m, 1H), 2.02-1.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH2:30][OH:31])=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O=C1CCC(=O)N1[O:39][C:40](=O)[CH2:41][C:42]#[N:43].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>O1CCOCC1.C(O)C.C(OC(=O)C)C>[C:42]([CH2:41][C:40]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:27])[CH3:28])[CH:22]=4)[C:17]3=[O:29])[C:11]=2[CH2:30][OH:31])[CH:3]=1)=[O:39])#[N:43]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(N)c(=O)n(C)c3)c1CO)C2=O
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(NC(=O)CC#N)c(=O)n(C)c3)c1CO)C2=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.095 mmol) was placed in a mixture of 1.5 ml dioxane and 0.5 ml of ethanol. To this mixture was added cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester, at first 1 equivalent (17.4 mg, 0.095 mmol), and then over a period of 3 days 5 more equivalents of this reagent at 2-4 hours intervals. During this time the reaction mixture was heated at 50-60° C. After cooling, the reactin mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by Prep TLC with 5% methanol in dichloromethylene to afford 12 mg (26% yield) of 2-Cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-acetamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 77 %

Procedure:
10 g of 2-amino-4,6-dichloropyrimidine are suspended in 100 ml of ethanol. 20.8 g of ethylamine are added as 33% solution in water. The reaction mixture is refluxed for 2 hours and is then evaporated to dryness. The precipitate obtained is taken up in 100 ml of water. After 1 hour's stirring, the mixture is filtered on sintered glass. The precipitate is recrystallized from 25 ml of acetonitrile. 8.10 g of 2-amino-4-ethylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24]([C:28]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][C:13]3[C:22]4[N:21]=[CH:20][C:19](=[O:23])[NH:18][C:17]=4[N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)c2ccccc12
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)c3ccccc23)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly yellow solid (65 mg, 80%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C@@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[N+:22]=[N-:23]
Reactant: CCCC(CCC)COc1cccc(C[C@H](O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCC(CCC)COc1cccc(C[C@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (S)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: C([N:8]1[CH:15]([CH3:16])[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][CH:15]1[CH2:14][CH:13]2[CH:9]([CH2:10][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)[NH:8]1
Reactant: CCOC(=O)N1CC2CC(C)N(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CC(C)NC2C1

Procedure:
32 g (0.11 mol) of ethyl 2-benzyl-3-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 560 ml of ethanol are hydrogenated at 100° C. and 100 bar on 4.5 g of palladium-active carbon. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O.[NH2:24][NH2:25]>O1CCCC1.CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:24][NH2:25])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 4'-methylbiphenyl-2-carboxylic acid (6.4 g) in tetrahydrofuran (50 ml) were added N,N-dimethylformamide (two drops) and oxalyl chloride (4.4 g). The mixture was stirred for 16 hours at room temperature. The solvent was evaporated to dryness under reduced pressure to give an oil, which was added dropwise to a solution of hydrazine monohydrate (7.5 g) in tetrahydrofuran (50 ml) with stirring, followed by stirring for further 6 hours. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel to give crude crystals. Recrystallization from chloroform-isopropyl ether afforded the title compound as colorless needles (4.3 g, 63%), m.p.98-99° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][NH2:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:18]([O:22][C:23]([NH:25][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-oxo-1-piperidinecarboxylate (10.0 g, 42.9 mmol), tert-butyl-1-hydrazinecarboxylate (5.70 g, 42.9 mmol) and sodium triacetoxyborohydride (13.6 g, 64.1 mmol) were stirred together for 4 hours at room temperature in dichloromethane/acetic acid (40 ml, 10% solution). The solvents were evaporated under reduced pressure. The residue was basified with saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a colourless gum, 14.2 g.
Reaction SMILES: [C:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:8]1(C)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=C[CH:20]=1>>[C:10]1([CH3:20])[C:11]([S:14]([O:7][CH2:6][C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=[CH:8][CH:9]=1
Reactant: c1ccncc1
Reactant: OCC1=CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccccc1S(=O)(=O)OCC1=CCCC1
Yield: 89.6 %

Procedure:
A mixture of (cyclopent-1-en-1-yl)methanol (1.96 g, 20 mmol) and para-toluenesulfonylchloride (3.81 g, 20 mmol) were stirred at room temperature for 2 hrs in pyridine (30 ml). After the concentration of pyridine, the reaction residues were extracted with dichloromethane, washed 1N HCl, dried with MgSO4, concentrated and separated by the column chromatography to give the desirable product (4.52 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C@H:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]3[N:51]=[CH:52][N:53]=[C:27]23)[CH2:22][CH2:21]1>C(OCC)(=O)C>[OH:13][C@H:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[O:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][CH:35]=3)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]3[N:51]=[CH:52][N:53]=[C:27]23)[CH2:24][CH2:25]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3CCC[C@@H]3O)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3CCC[C@@H]3O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.22 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[C:9]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[N:10]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(O)ccc23)n[nH]1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(O)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To 2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-ol (50 mg, 0.14 mmol) in 1:3 DMSO/DCM was added Dess-Martin periodinane (81 mg, 0.19 mmol) in one portion. After stirring for 1 h at rt, the solution was cooled to 0° C. and quenched by addition of a 1:1 mixture of 10% sodium thiosulfate pentahydrate and saturated sodium bicarbonate. The resulting dark precipitate was collected and chromatographed on silica eluting with 2 to 10% MeOH/DCM. Trituration of the colored solid with MeOH afforded (4-fluorophenyl)(7-hydroxy-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a white solid (7 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3H), 6.47 (bs, 1H), 7.06 (m, 2H), 7.13 (m, 1H), 7.38 (m, 2H), 8.06 (m, 2H), 8.57 (m, 2H), 10.41 (bs, 1H), 10.60 (bs, 1H), 12.15 (bs, 1H). LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:24]([C:29]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])=[CH:3][C:2]=2[N:1]=1)([CH3:28])([CH3:25])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl (3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate (185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was concentrated. The residue was dissolved in 4 mL of DCE and P2O5 (catalytic) was added and the solution was heated at 125° C. for 1 h using a Personal Chemistry microwave apparatus.