Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=CC=1OCCC.Cl.Cl.COC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.[CH2:57]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[C:66]([O:69][CH2:70][CH3:71])[C:67]=1[F:68])[CH:63]=O)[CH3:58]>>[CH2:57]([O:59][C:60]1[CH:61]=[C:62]([CH:65]=[C:66]([O:69][CH2:70][CH3:71])[C:67]=1[F:68])[CH2:63][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH3:58]
Reactant: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)ccc1OC
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(N)=O)cn3)CC2)cc(OCC)c1F

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide (example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3,5-diethoxy-4-fluoro-benzaldehyde (intermediate E5) in a yield of 2.3 mg (3%). MS (ISP): 485.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][C:15]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:14]2>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][C:15]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:14]2
Reactant: O=c1ccn2cc(C#Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Product: O=c1ccn2cc(CCc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F

Procedure:
A solution of 1-(2,6-difluorophenyl)-7-[(2,4-difluorophenyl)ethynyl]-2H-quinolizin-2-one in methanol was added a catalytic amount of Pd/C under hydrogen atmosphere (1 atm) for 1 hour. The mixture was filtered through celite and the filtrate was concentrated. The crude material was purified by silica gel (100% ethyl acetate) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#N)=[CH:3][CH:2]=1.C(O)=[O:18]>[Ni]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:18])=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(OCc2ccncc2)c1
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1cccc(OCc2ccncc2)c1
Yield: 37 %

Procedure:
A mixture of 3-(4-pyridinylmethoxy)benzonitrile (2.5 g, 0.012 mol) in 75% formic acid (35 ml) was treated with raney nickel (2 g) and heated to reflux for 4 hours. The reaction mixture was filtered through SUPERCELL®, the filtrate was brought to a pH of 8-9 with 5N NaOH, extracted with EtOAc (3×150 ml) and the combined organic layers were dried over MgSO4, filtered and stripped. The residue was purified by column chromatography on silica gel eluting with EtOAc (100%) to afford 0.94 g (37%) of 3-(4-pyridinylmethoxy)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2c1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.CN(OC)[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21].[Cl-].[NH4+]>C1COCC1>[CH2:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:23][CH2:24]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1-Bromo-4-trifluoromethoxybenzene (5.3 g, 22.0 mmol) was dissolved in dry THF (70 ml) under a nitrogen atmosphere, and this solution was cooled to −60° C. n-Butyllithium (1.6 M) hexane solution (15 ml, 24.0 mmol) was added dropwise to the solution, and the mixture was allowed to reach a temperature of −30° C. and stirred for 1 hour. This mixture was cooled to −60° C. again, to which a solution of 1-benzylpiperidine-4-carboxylic acid N-methyl-N-methoxyamide (4.1 g, 15.6 mmol) prepared in Reference Example 147 in THF (10 ml) was added dropwise, and the mixture was stirred for 1 hour and then at 0° C. for 3 hours. The reaction mixture was poured into saturated ammonium chloride aqueous solution, and extracted with diethyl ether. The extract was washed with water and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 1-benzyl-4-(4-trifluoromethoxybenzoyl)piperidine (4.8 g, yield 85%) as a pale yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:35]([C:38]4C=CC(C)=CC=4)(=[O:37])=[O:36])[CH2:31][CH2:30]3)[N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7]>>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:31][CH2:30]3)[N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: CS(=O)(=O)Cl
Product: CCOc1ccc(C2=NN(C3CCN(S(C)(=O)=O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from methanesulfonylchloride and starting compound A2 as described for compound 1. Crystallisation from methanol/water. M. p. 99-102° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][NH:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH2:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:18]([N:16]3[CH2:17][CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:7])[CH2:9][CH2:10]4)[CH2:15]3)=[O:19])[CH:21]=2)[CH2:26]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc2c(c1)CCN(Cc1ccccc1)C2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH2Cl2 and H2O, and pH of the water layer was adjusted to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H+) 502.0.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
Compound 2007 (0.0527 g, 0.079 mmol) in anhydrous THF (4 ml) under Ar was treated with tetrabutylammonium fluoride (TBAF) (0.237 ml, 1 M in THF, 0.237 mmol). The solution was stirred until no starting material remained by TLC. The solvent was removed in vacuo, the residue taken up in 5 ml CH2Cl2, washed with 5 ml aqueous saturated NaHCO3 solution, and the aqueous layer was extracted 2× with 5 ml CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 8:1 hexanes:EtOAc) gave compound 2008 (0.0395 g, 90%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar—H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.58 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.315 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.90 (m, 1H, THP OCH2), 3.62-3.58 (m, 3H, C-24 H & THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 0.92 (d, J=6.6 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3600, 2900 cm−1; MS (CI/isobutane) m/z 554 (M+1, 2%), 361 (M+1-THP-HOBn, 42%), 343 (M+1-THP-HPBn, H2O, 100%); m.p. 52-56° C.; Anal. calcd. for C36H56O4: C=78.21; H=10.21. Found: C=77.93; H=10.39.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:41](OC)[CH2:42][NH2:43]>C(Cl)Cl>[CH2:1]([N:4]1[CH:41]=[CH:42][N:43]=[C:5]1[C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCn1ccnc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of N-allyl-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxamide (150 mg, 0.406 mmol) in DCM (2.64 mL) was added phosphorus pentachloride (101 mg, 0.485 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.0154 mL, 0.0614 mmol) and the mixture was heated to 60° C. for 1.5 h. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (0.486 mL, 4.46 mmol) was added. The resulting mixture was heated at 60° C. for 2 h. The mixture was cooled to room temperature, diluted with DCM (10 mL), washed with water (2×2 mL) and brine (2 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DCM (3.0 mL) and 4 M hydrochloric acid in 1,4-dioxane (0.608 mL, 2.43 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL) and saturated sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→5/95) to give 99 mg of the title compound (62% yield). LC/MS (FA) ES+ 393. 1H NMR (300 MHz, CDCl3) δ: 8.72-8.70 (m, 2H), 7.80-7.72 (m, 2H), 7.26 (m, 1H), 7.22-7.14 (m, 4H), 7.06 (m, 1H), 5.84-5.71 (m, 1H), 5.23-5.19 (m, 1H), 5.01-4.96 (m, 1H), 4.38-4.34 (m, 2H), 4.20 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:23][C@H:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:25][CH3:26])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:23][C@H:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][CH3:26])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:40](=[O:42])[CH3:41])=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)C(=O)OC)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)c1ccccc1
Reaction time: 2.5 h

Procedure:
To a solution of (S)-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (120 mg) in DCM (3 mL) was added pyridine at 0° C. To this mixture was added acetic anhydride. The mixture was stirred for 2-3 h. After completion of the reaction, the mixture was diluted with DCM (20 mL) and was washed with water, 1N HCl and brine solution. The organic layer was dried and concentrated to get the desired product as a white solid (110 mg). LCMS (m/z): 491.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)[CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15](C(OCC3C=CC=CC=3)=O)[CH2:16]2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:37][CH:36]=1)#[N:39]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CN(C(=O)OCc3ccccc3)CC(C1)O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CNCC(C1)O2
Yield: 73.5 %

Procedure:
A solution of benzyl 7-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (ix) above; 2.55 g, 4.7 mmol) in 95% ethanol (50 mL) was hydrogenated over 5% Pd/C (0.8 g) at 30 kPa. When the quantity of hydrogen calculated for complete reaction had been consumed, the reaction was stopped. The mixture was filtered through Celite®, and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography on silica, eluting with CHCl3:ammoniacal methanol (95:5), to yield the title compound 1.39 g (75%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([S:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:38]([Cl:49])[CH:37]=1>C1COCC1.CN(C=O)C>[Cl:49][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[S:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2c1
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Dissolved 314 mg (3.72 mmol) 2-butynoic acid in 40 ml THF under N2. Chilled to 0° and added 409 μl (3.72 mmol) N-methylmorpholine and 485 μl (3.72 mmol) isobutyl chloroformate and stirred for 10 minutes. Added dropwise a solution that was prepared by dissolving 1.00 g (2.48 mmol) 6-amino-4-[(3-chloro-4-thiophenoxyphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF and adding 20 ml THF. Stirred mixture for minutes at 0° and 25° C. overnight. To drive reaction to completion, added 1.24 mmol of the mixed anhydride (104 mg acid, 136 μl NMM, and 161 μl isobutyl chloroformate) in 15 ml THF. Stirred overnight. Stripped solvent, dried in vacuo. Recrystallized from ethyl acetate, dried in vacuo, giving 284 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=469.2, 471.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C@H:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[NH:21]C(=O)OC(C)(C)C)=[O:15])[CH2:10][C:9]2([CH3:30])[CH3:29])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:1].[NH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([CH3:30])([CH3:29])[CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CN(C(=O)[C@@H]2CCC[C@@H]2N)CCN1c1ccc(Cl)cc1

Procedure:
tert-Butyl (1S,2S)-2-(4-(4-chlorophenyl)-3,3-dimethylpiperazine-1-carbonyl)cyclopentylcarbamate was dissolved in 4N HCl in dioxane to provide, after concentrating and drying, ((1R,2S)-2-aminocyclopentyl)(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)methanone hydrochloride.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[N:13]([O-])=O.[Na+].CC([O-])=O.[K+]>O.C1OCCOCCOCCOCCOCCOC1.C(Cl)Cl>[NH:2]1[C:3]2[C:8](=[CH:7][CH:6]=[C:5]([C:10](=[O:12])[CH3:11])[CH:4]=2)[CH:9]=[N:13]1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(C)c(N)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
Concentrated HCl (2 mL) was added to a mixture of 1-(3-amino-4-methylphenyl)ethanone (8.4 mmol) and NaBF4 (1.2 g, 11 mmol) in H2O (10 mL) and the solution was cooled to 0° C. A solution of NaNO2 (0.58 g, 8.4 mmol) in H2O (1.5 mL) was added dropwise and the mixture was stirred at 0° C. for 30 min. The solid that formed was collected by filtration and washed with H2O (5 mL) followed by Et2O (5 mL) and dried under a reduced pressure. CH2Cl2 (20 mL), KOAc (0.91 g, 9.3 mmol) and 18-crown-6 (50 mg, 0.2 mmol) was added to the solid and the mixture was stirred at room temperature for 4 h. H2O (20 mL) was added and the layers were separated. The organic layer was dried (MgSO4) and the solvent removed at reduced pressure to afford 1-(1H-indazol-6-yl)ethanone (0.52 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CN1CCc2ccc(O)cc2C1=O
Reactant: ClCCCCBr
Product: CN1CCc2ccc(OCCCCCl)cc2C1=O

Procedure:
By a similar method as in Reference Example 9,7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one in the form of a brown oil was prepared from 7-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one using 1-bromo-4-chlorobutane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[C@H:29]12[CH2:35][C@H:32]([NH:33][CH2:34]1)[CH2:31][O:30]2.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:33]4[CH2:34][C@H:29]5[CH2:35][C@@H:32]4[CH2:31][O:30]5)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2C[C@H]3C[C@@H]2CO3)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 53.1 %

Procedure:
A mixture of 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 335 μmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (136 mg, 1.00 mmol), propylphosphonic anhydride (50% in ethyl acetate, 493 μl, 837 μmol) and N,N-diisopropylethylamine (398 μl, 2.34 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carbonyl)-2H-pyrazole-3-carboxylic acid (2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (79 mg, 53.1%) as a white solid. mp: 272-273° C., MS: m/z=445.1 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:17]([CH2:18][CH3:19])[N:16]=[N:15][C:8]=2[C:9]([NH:13][NH2:14])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH3:20][C:21]([CH3:23])=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:17]([CH2:18][CH3:19])[N:16]=[N:15][C:8]=2[C:9]([NH:13][N:14]=[C:21]([CH3:23])[CH3:20])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1c(C)nc(NN)c2nnn(CC)c12
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc(NN=C(C)C)c2nnn(CC)c12
Reaction time: 8 h
Yield: 95 %

Procedure:
2.6 g. of 1-ethyl-4-hydrazino-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester (0.01 mol.) are dissolved in 10 ml. of acetone. One drop of acetic acid is added and the mixture is allowed to stand overnight. The excess acetone is distilled off in vacuo and the residue is recrystallized from petroleum ether to obtain 1-ethyl-6-methyl-4-[2-(1-methylethylidene)hydrazino]-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester in 95% yield, m.p. 68°-72°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19]C1C=C(NC2C=CC=CC=2)C=CC=1.N1C=CC=CC=1C=O>>[F:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Nc2ccccc2)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Fc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-fluorophenylaniline (33.3 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-fluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][NH:10][CH3:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:10]([CH3:11])[CH3:9])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC
Product: CN(C)S(=O)(=O)CCCCl

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and dimethylamine. High vacuum drying gave the title compound (2.1 g, 100%): 1H NMR (DMSO-d6) δ: 2.06-2.11 (2H, m), 2.75 (6H, s), 3.10-3.15 (2H, m), 3.72 (2H, t).