Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=2.[H][H].O1CCOCC1.O.[OH-].[Na+]>CO>[NH2:12][C:9]1[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:18][CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (0.1233 g) was dissolved in methanol (5 mL). To this solution was added 4N hydrogen dioxane (2 mL), stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a gum. To this material was added water (3 mL) to give a solution, which was then neutralised (to pH 7) using 2N sodium hydroxide. This gave a white solid which was filtered under suction and then washed with a few drops of methanol. The solid was then air-dried under suction before being dried in under vacuo at 50° C. for 2 hours. This gave the title compound as a white solid (86 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28](=[O:29])[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)=[O:32]
Reactant: COC(=O)C1(C)CCN(c2ccc(N)cn2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(N2CCC(C)(C(=O)OC)CC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of methyl 1-(5-aminopyridin-2-yl)-4-methylpiperidine-4-carboxylate (2.96 g, 11.89 mmol) in DCM (100 mL) was added triethylamine (2.2 mL, 15.84 mmol) followed by methyl chlorooxoacetate (1.6 mL, 17.15 mmol) and the reaction mixture was allowed to stir at ambient temperature for 1.5 hrs. The reaction mixture was washed with brine (2×100 mL), the aqueous layer was re extracted with DCM (50 mL) and the organic washings were combined, dried and concentrated to leave the title compound as a brown gum (3.98 g, 11.89 mmol, 100%). 1H NMR (CDCl3) δ 1.72-1.82 (m, 2H), 1.96-2.02 (m, 2H), 2.52-2.59 (m, 1H), 2.95-3.03 (m, 2H), 3.70 (s, 3H), 3.97 (s, 3H), 4.16-4.22 (m, 2H), 6.67 (d, 1H), 7.93 (d, 1H), 8.28 (s, 1H), 8.66 (s, 1H); MS m/e MH+ 336.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:36][N:37](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:36]#[N:37])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(Cl)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-chloro-6-(m-tolylamino)pyrimidine-5-carboxylate (399.7 mg, 0.816 mmol), tetrakis(triphenylphosphine)palladium(0) (96.3 mg, 0.083 mmol), and zinc cyanide (53.2 mg, 0.453 mmol) in DMF (5 mL) was stirred at 120° C. for 1 h under microwave irradiation. Water (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic layers were washed with saturated aq NaHCO3 (50 mL), water (50 mL), and brine (50 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a colorless oil (315.0 mg, 80%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.77 (m, 15H), 2.36-2.39 (m, 3H), 3.00-3.21 (m, 2H), 3.49-3.69 (m, 1H), 3.97 (s, 3H), 4.49-5.10 (m, 3H), 6.96-7.02 (m, 1H), 7.24-7.41 (m, 3H), 10.14-10.45 (m, 1H). [M+H] calc'd for C25H33N6O4, 481; found, 481.
Reaction SMILES: [N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][C:4]([C:12](OCC)=[O:13])([C:7](OCC)=[O:8])[CH2:3][CH2:2]1.C1COCC1.[Li+].[BH4-]>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:4]1([CH2:12][OH:13])[CH2:5][CH2:6][N:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 1-tert-butyl 4,4-diethyl piperidine-1,4,4-tricarboxylate (2.00 g, 6.07 mmol) in 1:1 THF:toluene (50 mL) was added LiBH4 (15.18 mL, 30.4 mmol, 2.0 M in THF). The reaction was stirred at 60° C. for 18 h. It was then quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography (15-100% EtOAc/hexanes) to give tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 3.66 (d, J=5.0 Hz, 4H), 3.41-3.37 (m, 4H), 2.29 (t, J=5.1 Hz, 2H), 1.47-1.45 (m, 4H), 1.45 (s, 9H). MS: cal'd 268 (MNa+), exp 268 (MNa+).
Reaction SMILES: Br.S1C=CC=C1C(O)=O.[Br:10][CH2:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[S:17][C:18]=1[CH3:19])=O.[C:26]1([NH:32][C:33]([NH2:35])=[S:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[BrH:10].[CH3:19][C:18]1[S:17][C:16]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:15][C:14]=1[C:12]1[N:35]=[C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:34][CH:11]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Agent: Br
Agent: O=C(O)c1cccs1
Product: Cc1sc(C(=O)OC(C)C)cc1-c1csc(Nc2ccccc2)n1
Yield: 86.7 %

Procedure:
Isopropyl 5-methyl-4-[2-phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide: Isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (64 mg, 0.21 mmol) was allowed to react with phenylthiourea (32.1 mg) as described in Example 154, step (a) to give 80 mg (87% yield) of isopropyl 5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C18H18N2O2S2, 358.5 (M+H), found 359.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:13]
Reactant: CCOC=O
Reactant: NCc1nc2ccccc2o1
Product: O=CNCc1nc2ccccc2o1

Procedure:
A mixture of 4.29 g (28.9 mmol) of 2-(aminomethyl)benzoxazole (PREPARATION 6) and 20 ml of ethyl formate is heated at 80° for 2 hr, after which the excess ethyl formate is removed under reduced pressure. The residue is chromatographed on silica gel (350 ml) eluting with methanol/dichloromethane (2/98), the appropriate fractions are pooled and concentrated to give the product, which is crystallized from dichloromethane/hexane to give the title compound, mp 98°-99°; MS (m/z) at 176; IR 1655, 1621, 1519, 1241, 750 cm-1 ; NMR (CDCl3) 4.81, 6.45, 7.36, 7.53, 7.70, 8.39 δ.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C@H:30]([NH:40][CH3:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C@H:30]([N:40]([CH3:41])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.72 g, 2.53 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.78 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.06 g (74%) of the title product as colorless foam. ES-MS m/e: 567.3 (M+H+).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[N:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C1COCC1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][CH:7]=[N:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cccc2ncccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=P(Cl)(Cl)Oc1cccc2ncccc12
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (0.385 mL, 4.14 mmol.) and quinolin-5-ol (Aldrich, 600 mg, 4.14 mmol.) were stirred in anhydrous THF (25 mL). Anhydrous triethylamine was added (0.576 mL, 4.14 mmol.) at −78° C. and the solution was allowed to warm to room temperature. The reaction mixture was monitored by 31PNMR for completion of phosphorus oxychloride (about 30 min) and this mixture was used directly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][CH:13]([C:15]([OH:17])=[O:16])[NH2:14])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:28]([O:32][C:33](ON=C(C1C=CC=CC=1)C#N)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>O.O1CCOCC1>[C:28]([O:32][C:33]([NH:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]1[CH:18]=[CH:19][CH:20]=[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH:10]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: NC(Cc1cccc(Oc2ccc(Br)cn2)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccc(Br)cn2)c1)C(=O)O

Procedure:
The compound (VII) (4.20 g) obtained above was suspended in water (40 ml) and 1,4-dioxane (10 ml) and triethylamine (6.0 ml) was further added. To this solution, a solution of 2-t-butoxycarbonyloxyimino-2-phenylacetnitrile (VIII) (3.06 g) in 1,4-dioxane (20 ml) was added at once at room temperature. The mixture was allowed to react at room temperature for 3 hours. Water (40 ml) and ethyl acetate (30 ml) were added to remove the unreacted compound (VIII). The aqueous layer was made weak acidic with citric acid. The separated oily product was extracted with ethyl acetate, followed by washing with water and drying. After distilling off the solvent in vacuo, the desired compound (I) (5.04 g), which was confirmed by NMR and IR analyses, was obtained in the amorphous state.
Reaction SMILES: ClCCl.C(O)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[NH:15]1[CH2:16][CH2:17][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(SC3CCNCC3)ccc12
Reaction time: 2 h

Procedure:
A mixture of 6-mercapto-2H-isoquinolin-1-one (50 mg, 0.28 mmol), 4-methane-sulphonyloxy-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.42 mmol) and K2CO3 (64 mg, 0.46 mmol) in N, N-dimethylformamide (1.5 ml) was heated at 50° C. then left at ambient temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the mixture which was extracted with ethyl acetate (x 3). The combined organics were dried (Na2SO4) and concentrated in vacuo to give a residue. Flash chromatography of the residue using ethyl acetate:heptane (1:9 to 99:1) gave 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester (15 mg). A dichloromethane:trifluoroacetic acetic acid solution (7:3, 5 ml) was added to the 4-(1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl)piperidine-1-carboxylic acid tert-butyl ester and the mixture stirred for 2 h, then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford crude 6-(piperidin-4-ylsulfanyl)-2H-isoquinolin-1-one, which was purified by prep-HPLC (2 mg), El-MS: m/z=261.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1)=[O:11]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH2:11][C:12]#[N:13].Cl>CN(C)C=O.O>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[CH:11]([C:12]#[N:13])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)Br
Reactant: COc1ccc(Cl)cc1CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(C#N)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (2.4 g) in dimethylformamide (100 ml) was added a solution of 2-bromopropane and 2-methoxy-5-chlorobenzyl cyanide (18.2 g) in dry dimethylformamide (50 ml), keeping the temperature at 20°-30° C. The mixture was then stirred for 30 minutes, water was added cautiously, and the mixture was then poured into ice-water. Hydrochloric acid was then added and the mixture was extracted with dichloromethane, washed with water then with sodium chloride solution, then dried over magnesium sulphate, filtered, and the solvent was then removed to give 25 g of a brown oil. Distillation gave the title product (15 g) as a colourless oil, bp 180° C./20 mm Hg.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:30]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nsc(N2CCC(Nc3nc4c(Br)cccn4n3)CC2)n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)ccc5Cl)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 66c employing (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine and 2-chloro-5-(trifluoromethyl)-phenyl boronic acid. The title compound was obtained as light yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.C(#N)C.C[O:31][CH2:32][CH2:33][NH2:34].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15]([CH:12]1[CH2:11][CH2:10][N:9]([C:4]2[N:3]=[C:2]([NH:34][CH2:33][CH2:32][OH:31])[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: Cc1nc(Cl)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Reactant: COCCN
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NCCO)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
To a 10 mL reaction vial was added the 1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (50 mg, 0.121 mmol) and acetonitrile (0.754 mL) to give a white suspension. Then, [2-(methyloxy)ethyl]amine (0.105 mL, 1.206 mmol) and DIEA (0.063 mL, 0.362 mmol) were added. The reaction was heated for 1 h at 80° C. The reaction mixture was diluted with DMSO and purified by preparative HPLC to provide N-[(2,4-dichlorophenyl)methyl]-1-{4-[(2-hydroxyethyl)amino]-6-methyl-1,3,5-triazin-2-yl}-4-piperidinecarboxamide (46 mg, 0.078 mmol, 65%) as a white solid. MS (ES) m/e 439, 441 [M+H]+. 1H NMR (400 MHz, DMSO-D6) 8.5 (bs, 1H), □ 8.3 (bs, 1H), 7.7 (s, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 4.7 (m, 2H), 4.3 (m, 2H), 3.8-3.3 (3H under H2O peak), 3.1 (m, 4H), 2.6 (m, 1H), 2.3 (s, 3H), 1.8 (m, 2H), 1.5 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[C:4](C)[CH:3]=1.BrC1C=CC(CCO)=C([F:22])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:10])=[C:4]([F:22])[CH:3]=1
Reactant: OCCc1ccc(Br)cc1F
Reactant: Cc1cc(Br)ccc1CCI
Product: Fc1cc(Br)ccc1CCI
Yield: 95.7 %

Procedure:
The title compound was synthesized according to the same general procedure described for the synthesis of 4-bromo-1-(2-iodo-ethyl)-2-methyl-benzene in Preparation #2, Step 1, except that 2-(4-bromo-2-fluoro-phenyl)-ethanol was used instead of 2-(4-bromo-2-methylphenyl)ethanol to yield the title compound as a clear oil (5.75 g, 95.7%) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.13-3.24 (m, 2H) 3.26-3.44 (m, 2H) 7.06-7.14 (m, 1H) 7.21-7.24 (m, 1H) 7.26-7.31 (m, 1H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36](=[N:38]O)[NH2:37]>>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36]1[N:38]=[C:25]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:26][N:37]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1
Reactant: NC(=NO)c1c(F)cccc1F
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1

Procedure:
60 mg (0.16 mmol) of the compound from Example 60A and 42 mg (0.24 mmol) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 53 mg (65% of theory)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36](OC)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1.O>CCOCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]4[C@:34]([C:36]([C:2]5[N:3]=[C:4]([Si:7]([CH3:10])([CH3:9])[CH3:8])[S:5][CH:6]=5)=[O:37])([CH2:35][C:26]=3[CH:25]=[N:24]2)[CH2:33][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH2:30]4)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)c1nc(Br)cs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2csc([Si](C)(C)C)n2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A solution of 4-bromo-2-(trimethylsilyl)thiazole (304 μl, 1.784 mmol) in dry ether (2 mL) was added to a solution of butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dry ether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. then slowly warmed to −50° C. over 2 hours. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foamy solid (76 mg). LCMS (Method F, ES-API): RT 2.65 min, m+H=553.3.
Reaction SMILES: [C:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][S:6][N:5]=1)(=O)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH:22][NH2:23])=[NH:21])[CH:16]=[CH:17][CH:18]=1>>[CH3:2][C:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][S:6][N:5]=1)=[N:23][NH:22][C:20](=[NH:21])[NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: CC(=O)c1nscc1C(=O)O
Reactant: N=C(NN)Nc1cccc(F)c1
Product: CC(=NNC(=N)Nc1cccc(F)c1)c1nscc1C(=O)O

Procedure:
Following the procedure of Example 7, 3-acetyl-4-isothiazole carboxylic acid (2.05 g, 12.0 mmol) and N-(3-fluorophenyl)hydrazinecarboximidamide (3.55 g, 12.0 mmol) are reacted together to give 2-[methyl(4-carboxy-3-isothiazolyl)methylene]-N-(3-fluorophenyl)hydrazinecarboximidamide, (compound 17).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].S([O-])([O-])(=O)=[O:11].[Mg+2].OO.[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>CC(C)=O.C[Re](=O)(=O)=O.C(OCC)(=O)C>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[C:1]([CH2:3][CH2:4][N:5]([CH2:6][CH2:7][C:8]#[N:9])[OH:11])#[N:2]
Reactant: N#CCCNCCC#N
Reactant: O=S(=O)([O-])[O-]
Agent: C[Re](=O)(=O)=O
Agent: O=C(O)C(=O)O
Agent: OO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#CCCN(O)CCC#N
Temperature: 25 °C
Yield: 134.7 %

Procedure:
Bis(2-cyanoethyl)amine (3.0 g, 0.0224 mole) was added with ethyl acetate (15 ml) and anhydrous magnesium sulfate (3 g), and the mixture was stirred at room temperature. A solution of methyltrioxorhenium (0.0183 g, 0.0734 mmole) dissolved in 35% aqueous hydrogen peroxide (2.9 g, 0.029 mole) was added dropwise to the mixture while internal temperature was kept at from 20° C. to 30° C. After the reaction mixture was stirred at room temperature for 1 hour, the magnesium sulfate was removed by filtration, and the filtrate was added with a solution of oxalic acid (2.2 g, 0.224 mole) dissolved in acetone (8 ml). The mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to obtain oxalic acid salt of N,N-bis(2-cyanoethyl)hydroxylamine (4.2 g, yield: 75.0%) having melting point of 129-130° C. Chemical structure of the product was analyzed by 1H-NMR, mass spectrometry and elemental analysis. 1H-NMR (DMSO-D6) σ (ppm) (multiplicity, integrated value): 12.0-9.50 (br, 2H), 2.77 (t, 4H), 2.58 (t, 4H). Elemental analysis, calculated for C8H11N3O5 : C, 41.92; H, 4.84; N, 18.33, found: C, 42.50; H, 4.74; N, 18.38.