Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:12]([CH2:23]O)=[CH:11]2>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:12]([CH2:23][Cl:3])=[CH:11]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1F
Solvent: ClCCl
Product: Fc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (0.850 mL, 11.6 mmol) was added to a stirring solution of (8-chloro-2-(2-fluorophenyl)quinolin-3-yl)methanol (0.670 g, 2.33 mmol) in CH2Cl2. The reaction mixture was stirred at room temperature. After 2.5 h, the crude product was purified by column chromatography on a 40 g Redi-Sep™ column using 0% to 100% gradient of CH2Cl2-MeOH—NH4OH (89:9:1) in CH2Cl2 to give 8-chloro-3-(chloromethyl)-2-(2-fluorophenyl)quinoline: LC-MS (ESI) m/z 306.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: CNc1ccccc1
Product: COC(=S)c1cc(N(C)c2ccccc2)c(C)s1
Yield: 22.2 %

Procedure:
A stirred suspension of 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate and 72 μL (0.487 mmol, 1.3 eq) of N-methylaniline (Aldrich Chemical Co., Milwaukee, Wis.) was treated in a manner similar to Example 245, step (a) to give 23 mg of the title compound (21%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz) δ7.61 (s, 1H), 7.26-6.68 (m, 5H), 3.89 (s, 3H), 3.25 (s, 3H), 2.50 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C14H15NO2S2, 294.1 (M+H), found 294.3.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:9]3[C:10]([NH2:17])=[N:11][CH:12]=[C:13]([N+:15]#[C-:16])[CH:14]=3)=[CH:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.C(OCC)(=O)C>[NH2:17][C:10]1[C:9]([C:7]2[S:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=4)=[O:29])=[CH:3][C:4]=3[CH:8]=2)=[CH:14][C:13]([N+:15]#[C-:16])=[CH:12][N:11]=1
Reactant: [C-]#[N+]c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: [C-]#[N+]c1cnc(N)c(-c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirring mixture of 3-(5-aminobenzo[b]thiophen-2-yl)-5-isocyanopyridin-2-amine (1.064 g, 4 mmol, 1 eq) in anhydrous tetrahydrofuran (25 mL) under nitrogen atmosphere was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (904 mg, 1 eq) and the reaction mixture was stirred at room temperature for three hours. The reaction was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure to lesser amount, to which was added a small amount of EtOAc-Hex (2:1). Upon a filtration, 1-(2-(2-amino-5-isocyanopyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was obtained as white solid in the amount of 1.37 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].[CH3:34]OC(OC)OC>>[CH2:1]([O:3][C:4]([C:6]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:26][CH:34]=[N:28][N:27]=3)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(C(=O)NN)cc2)nc1
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(-c3nnco3)cc2)nc1
Yield: 97.4 %

Procedure:
A mixture of affording 1-[6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g, 0.44 mmol), trimethylorthoformate (0.1 mL, 0.91 mmol) and 1 mL of xylenes was refluxed for 24 hours. The mixture was concentrated in vacuo, affording 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g) as a colorless syrup. MS (APCl, m/z): 467.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH2:13]=[O:14]>CN(C)C=O>[OH:14][CH2:13][NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][N:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C=O
Reactant: NC(=O)c1ccnc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=C(NCO)c1ccnc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
0.8 g. of 2-nitroisonicotinamide and 2 ml. of 37% formalin were stirred in 2 ml. of dimethylformamide at 110° C for 2 hours. After cooling, to this solution was added ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated yielding crystals. The crystals obtained were recrystallized from ethyl acetate to give 0.6 g. of pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]([CH3:12])[CH3:10])[CH:7]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc(CO)ccn1
Temperature: 200 °C
Yield: 94 %

Procedure:
A mixture of 2-chloro-4-hydroxymethylpyridine (1.0 g, 7 mmol), (prepared as described for the starting material in Example 58), and dimethylamine (30 ml of a 30% solution in ethanol) was heated in a Carius tube for 16 hours at 200° C. The mixture was allowed to cool and the mixture partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-hydroxymethyl-2-(dimethylamino)pyridine (1 g, 94%) as a yellow oil.
Reaction SMILES: [CH:1]([C@:4]1([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2].C=O.[BH3-][C:36]#N.[Na+]>CO>[CH:1]([C@:4]1([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][N:24]=3)[CH2:21][CH2:22]2)=[O:16])[CH2:8][CH2:7][C@@H:6]([N:9]([CH3:36])[CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC2CCOC2)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N(C)C2CCOC2)C1

Procedure:
To a solution of N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydrofuran-3-amine (160 mg) in 5mL of methanol was added a solution of formaldehyde (10 equiv) followed by NaCNBH3 (3 equiv). Once the reaction was complete, the volatiles were removed and the residue taken in ethyl acetate. The ethyl acetate layer was washed with aqueous NaOH (2.5N). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography to give the title compound (126 mg). MS calculated for C24H35F3N4O2: (M+H) 469.2712; found 469.2817.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:36]=[O:37].CCN(CC)CC>C(Cl)Cl>[CH2:38]([NH:35][C:36](=[O:37])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: O=C=NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (150 mg, 0.33 mmol) and 1-(isocyanatomethyl)benzene (162 μL, 1.32 mmol,) in CH2Cl2 (2 mL) was added Et3N (1.38 mL, 9.9 mmol). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The residue was triturated using MeOH and drops of CH2Cl2 to afford tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (100 mg, 52%)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][C:4]1[S:11][C:10]2[CH:9]=[N:8][NH:7][C:6]=2[CH:5]=1.[I:13]I.[OH-].[K+].S(=O)(O)[O-].[Na+]>CN(C)C=O.O>[I:13][C:9]1[C:10]2[S:11][C:4]([CH2:3][N:2]([CH3:12])[CH3:1])=[CH:5][C:6]=2[NH:7][N:8]=1
Reactant: II
Reactant: CN(C)Cc1cc2[nH]ncc2s1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1cc2[nH]nc(I)c2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.4 %

Procedure:
To dimethyl-(1H-thieno[3,2-c]pyrazol-5-ylmethyl)-amine [1 g, 5.51 mmol, Intermediate (5)] in solution in dimethylformamide (10 mL) is added iodine (2.1 g, 8.3 mmol) and potassium hydroxide (0.930 g, 16.5 mmol). The dark solution is stirred at room temperature for 5 hours. Sodium bisulfite (1.5 g) in solution in water is added. The resulting suspension is extracted twice with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is chromatographed through silica gel (ethyl acetate-1.0M ammonia in methanol, 90:10 as eluant) to produce (3-iodo-1H-thieno[3,2-c]pyrazol-5-ylmethyl)-dimethyl-amine [0.87 g, 51%, Intermediate (6)] as a beige powder. LC/MS: RT=1.20 minutes, 307.98 m/e (M+H).
Reaction SMILES: CC(C)C[N:4]1[C:8]2=[C:9]3[N:19]=[CH:18][N:17]=[C:10]3[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[N:7]2N=N1.[H][H]>[Pt]=O.FC(F)(F)C(O)=O.Cl>[CH3:10][CH:11]([CH3:12])[CH2:16][N:17]1[C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[N:7]=[C:8]([NH2:4])[C:9]=2[N:19]=[CH:18]1
Reactant: CC(C)Cn1nnn2c3ncccc3c3ncnc-3c12
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCCN3

Procedure:
Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 5 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water and sodium bicarbonate. The resulting precipitate was isolated by filtration. The solid was dissolved in 1N hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with 10% methanol in ethyl acetate. The eluant was concentrated under vacuum and the residue was recrystallized from methanol/water to provide 0.9 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine as a solid, m.p. 231-233° C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55; Found: %C, 62.99; %H, 7.74; %N, 28.33.
Reaction SMILES: C([O-])(O)=O.[Na+].[Na+].[I-].Br[C:9]1[S:13][C:12]([Cl:14])=[CH:11][CH:10]=1.[CH2:15]([OH:18])[CH:16]=[CH2:17]>CN(P(N(C)C)(N(C)C)=O)C.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:14][C:12]1[S:13][C:9]([CH2:17][CH2:16][CH:15]=[O:18])=[CH:10][CH:11]=1
Reactant: Clc1ccc(Br)s1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=CCCc1ccc(Cl)s1
Temperature: 90 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
To a mixture of Pd(OAc)2 (0.12 g, 0.53 mmol), NaHCO3 (0.52 g, 6.19 mmol) and NaI (0.28 g, 1.87 mmol) in 5 mL of HMPA is added 5-bromo-2-chloro-thiophene (1.00 g, 5.06 mmol) and allyl alcohol (1.03 mL, 15.2 mmol). The mixture is heated to 90° C. and stirred for 16 hours. The reaction mixture is cooled to room temperature, diluted with Et2O and washed with water. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by flash column chromatography eluting with a gradient of 10% Et2O/hexanes to 20% Et2O/hexanes to provide the product (0.18 g, 1.03 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ9.81 (s, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 3.07 (t, 2H), 2.81 (t, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:9]O)[S:7][CH:8]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:35]I>C1(C)C=CC=CC=1>[I:35][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH:2]([CH3:3])[CH3:1])[N:5]=1
Reactant: CC(C)c1csc(CO)n1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1csc(CI)n1
Temperature: 10 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
A mixture composed of 2.5 g of 4-(1-methylethyl)thiazole methanol, 6.3 g of triphenylphosphine, 2.2 g of imidazole and 100 ml of toluene was warmed until all of the solids dissolved. This solution was cooled to 10° C. and 6.1 g of iodine was added. After 2 hr, the mixture was washed with an excess of sodium thiosulfate solution. The aqueous layer was back extracted with ethyl ether and the combined organic layers were washed with brine and then dried (MgSO4). Removal of the solvents in vacuo yielded 5.0 g of 2-iodomethyl-4-(1-methylethyl)thiazole as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]#[N:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([C:29]#[N:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNC(C#N)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C#N)C1

Procedure:
Intermediate 1 was coupled with 3-cyano-piperazine-1-carboxylic acid tert-butyl ester (generated according to literature procedure (ref 3)) following procedure B. LC-MS showed the product had the expected M+H+ of 414.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:41]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:41].[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:24][CH2:25]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)(1-{2-[7-(methyloxy)-2-oxo-1(2H)-quinolinyl]ethyl}-4-piperidinyl)carbamate (92 mg) in chloroform (1.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml) and the reaction stirred at rt for 1 h. More 4N HCl in 1,4-dioxane (0.5 ml) was added and the reaction stirred at rt for 0.5 h then the solvents removed. The residue was dissolved in MeOH (25 ml) and treated with Amberlyst A21 basic resin until the pH was 6. The residue was filtered off and the solvent removed; the residue was subjected to column chromatography on silica gel eluting with 0-20% methanol-DCM to afford the free base of the title compound (67 mg, 89%).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=3)[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.[NH2:47][C:48]1[NH:52][N:51]=[N:50][N:49]=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([C:14]2[N:18]([CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:47][C:48]4[NH:52][N:51]=[N:50][N:49]=4)=[O:26])=[CH:22][N:21]=3)[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)[CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)[C@H]1CC[C@@H](NC(=O)c2cc(-c3ccc(Cl)c(Cl)c3)nn2Cc2ccc(C(=O)O)cn2)CC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@@H](NC(=O)c2cc(-c3ccc(Cl)c(Cl)c3)nn2Cc2ccc(C(=O)Nc3nnn[nH]3)cn2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from example 8 step H (65 mg, 0.122 mmol) in DMF (2 mL) was added HOAt (25 mg, 0.184 mmol), amino tetrazole(32 mg, 0.36 mmol), DIEA (64 μL, 0.37 mmol) and EDC (36 mg, 0.184 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was diluted with ethyl acetate and washed with 1N HCl and saturated NaCl solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on the Gilson reverse phase HPLC to give the title compound. 1H NMR (DMSO, 500 MHz): 9.12 (s, 1H), 8.4 (dd, J=2.0, 9.1 Hz, 2H), 8.18 (d, J=6.6 Hz, 1H), 8.03 (d, J=1.9 Hz, 1H), 7.83 (dd, J=1.9, 8.3 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 5.91 (s, 2H), 3.96 (bm, 1H), 1.83 (d, J=12.3 Hz, 2H), 1.48 (m, 3H), 1.28 (m, 2H), 0.98 (m, 1H), 0.82 (s, 9H). LC-MS=2.71 min; (M+H)=596.2.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[CH:16]=[C:15]([CH3:27])[N:14]=2)=[O:12])=[N:6]1)(=O)[NH2:2].O=P(Cl)(Cl)Cl>>[C:1]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[CH:16]=[C:15]([CH3:27])[N:14]=2)=[O:12])=[N:6]1)#[N:2]
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ccn(CC(N)=O)n2)n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ccn(CC#N)n2)n1

Procedure:
The title compound, was prepared by treatment of 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid (1-carbamoylmethyl-1H-pyrazol-3-yl)-amide with POCl3 in accordance with the general method of example 163, step 2 to yield the final compound as a white solid, MS (ISP): m/e=354.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[C:13]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=O)[CH:9]1[CH2:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6]2)=[O:4].O.[NH2:30][NH2:31]>CO>[CH3:1][O:2][C:3]([C:5]12[C:13]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[N:30][NH2:31])[CH:9]1[CH2:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6]2)=[O:4]
Reactant: NN
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2(C)c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2(C)c1ccccc1
Yield: 90 %

Procedure:
A solution of 3 g (7.95 mmol) of methyl(3aRS,4SR,7aRS)-2-benzyl-4-methyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate and of 1.55 cm3 (31.8 mmol) of hydrazine hydrate in 30 cm3 of methanol was brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in dichloromethane, washed with three times 30 cm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 2.8 g (89%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono4-methyl-4-phenyloctahydroisoindole-3a-carboxylate were thus obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[Cl:19][C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1>N1C=CC=CC=1.CN(C=O)C>[ClH:19].[F:27][C:26]([F:29])([F:28])[C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH2:4][CH2:3]2)[N:25]=1
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(N2CCC(Oc3ccc4cnccc4c3)CC2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
75 mg of 6-(Piperidine-4-yloxy)-isoquinoline-Hydrochloride (124) are dissolved in 5 mL of dry pyridine and 5 mL of DMF. 55 mg 2-Chlor-4-trifluoromethyl-pyrimidine are added and the solution is stirred at 60° C. for 3 hours. The solvents are removed in vacuo and the residue is taken up in brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCl salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield: 29 mg. Rt=1.69 min (Method #2). Detected mass: 375.1 (M+H+).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:8]([O:10][C:11](Cl)=O)[CH3:9]>ClCCl>[O:10]1[C:11]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:9]=[C:8]1[C:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH:3]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C1=CNCCC1
Solvent: ClCCl
Product: C1=C(c2cc3ccccc3o2)CCNC1
Temperature: 25 °C

Procedure:
To a solution of the foregoing tetrahydropyridine (1.1 g, 3.8 mmol) in dichloromethane (50 ml) at 0° C. was added 1-chloroethylchloroformate (493 μl, 4.6 mmol), keeping the temperature below 0° C. The reaction was allowed to warm to room temperature over 1 hr, after which the solvent was evaporated. Methanol (50 ml) was added to the residue and the mixture heated under reflux for 2 hrs. The solvent was removed by evaporation, and the residue chromatographed on silica, eluting with dichloromethane/methanol/ammonia (90:10:1), to yield the title compound as a buff solid (600 mg, 79%); δH (CDCl3) 2.44-2.48 (2H, m, tetrahydropyridinyl CH2), 3.14 (2H, t, J 5.8 Hz, tetrahydropyridinyl CH2), 3.60-3.63 (2H, m, tetrahydropyridinyl CH2), 6.54-6.58 (2H, m, CH=CR, 3'-H), 7.16-7.26 (2H, m, 5'-H, 6'-H), 7.42 (1H, d, J 7.8 Hz, 7'-H), and 7.50 (1H, d, J 7.2 Hz, 4'-H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C>[Si:28]([O:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: COC(=O)C1CC(O)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (4.00 g, 15.4 mmol) in dichloromethane (40 mL) was subsequently added imidazole (1.26 g, 18.5 mmol), DMAP (0.38 g, 3.1 mmol), and TBDMS-Cl (2.79 g, 18.5 mmol). The reaction was stirred at room temperature for 40 h. The mixture was washed with HCl solution (1N), saturated sodium bicarbonate, and brine sequentially and dried over anhydrous sodium sulfate, filtrated, and concentrated to give the title compound. MS (m/z): 274 (M-Boc+H)+.