Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1C
Reaction time: 1 h
Yield: 78 %

Procedure:
In a cylindrical quartz tube was placed 4-fluoro-2-methyl-benzoic acid (1.5 g, 9.7 mmol) in MeOH (15 ml) and 2 drops of H2SO4 conc. were added. The tube was introduced into a Smith Creator® Personal chemistry microwave reactor. Microwave irradiation was carried out at 130° C. for 1 h until HPLC revealed the disappearance of the starting-material. The mixture was allowed to cool down and the solvent was removed under reduced pressure. The crude was diluted with DCM and washed with NaHCO3 sat. The organic phase was dried over anhydrous Na2SO4 and concentration of the solution gave the final compound (1.3 g, 78%) as colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[F:17][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[C:7]([F:17])[CH:8]=1)#[N:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)c1nc(N=CN(C)C)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
To a solution of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (3.0 g, 14 mmol) in dry CH3CN (139 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [SELECTFLUOR™] (5.4 g, 15 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours under N2, then concentrated. The residue was diluted with ethyl acetate (100 mL), washed with water (5×40 mL) and brine, dried over MgSO4, and concentrated. The oily residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate=3/1) to give the title compound as colorless crystals (0.63 g, 19%). 1H-NMR (300 MHz, CDCl3) δ ppm: 1.26 (d, J=7.0 Hz, 6H), 3.15 (s, 3H), 3.16 (s, 3H), 3.29 (septet-d, J=7.0, 1.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 8.55 (s, 1H). MS ESI+ m/z: 235 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].[OH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[O:7].[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23](Cl)=[C:24]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:36])[CH2:31][CH2:30]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[N:22][C:23]([NH:4][CH:2]([CH3:3])[CH3:1])=[C:24]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:36])[CH2:31][CH2:30]3)[N:25]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:6]([OH:7])([C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: CC(C)N
Reactant: O=C(c1cc(Cl)ccc1F)C1CCN(c2nc3c(nc2Cl)CN(Cc2ccccc2)CC3)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CCN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
A mixture of propan-2-amine (31.5 μL, 0.366 mmol), (1-(6-benzyl-3-chloro-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone TFA salt (112.4 mg, 0.183 mmol), sodium tert-butoxide (35.2 mg, 0.366 mmol), BINAP (17.1 mg, 0.027 mmol) and Pd2(dba)3 (8.4 mg, 9.16 μmol) in toluene (611 μL) was heated at 100° C. for 16 h. The mixture was purified by HPLC Method A to afford (1-(6-benzyl-3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)(5-chloro-2-fluorophenyl)methanone as its TFA salt (41.7 mg, 35.8%) as a yellow film. ESI-MS m/z [M+H]+ 522.4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]=1[C:38](O)=[O:39]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[CH:37][C:28]=4[O:27][CH3:26])=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc2ccccc2c1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)ccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methoxynaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [CH:1]1([C:6]2[S:15][C:14]3[NH:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[NH:10][C:9](=S)[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O(C)S(C(F)(F)F)(=O)=O.[CH3:30][O:31][CH2:32][CH2:33][C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][NH:35]1.N1C=CC=CC=1>ClCCl>[CH3:30][O:31][CH2:32][CH2:33][C@@H:34]1[NH:35][CH2:36][CH2:37][N:38]([C:9]2[C:8]3[N:7]=[C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[S:15][C:14]=3[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)[CH2:39]1
Reactant: COCC[C@H]1CNCCN1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C4CCCC4)nc32)CCN1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
Combine 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triazabenzo[f]azulene-10-thione (0.529 g, 1.75 mmol) and methyl triflate (0.24 mL, 2.11 mmol) in dichloromethane (3 mL) at 0° C. Stir the mixture at 0° C. for 15 minutes and warm to room temperature overnight. Evaporate the mixture, combine the residue with (S)-2-(2-methoxyethyl)piperazine (0.253 g, 1.75 mmol) and pyridine (3 mL) and heat at reflux overnight. Evaporate the mixture, then dilute with methanol and apply to a 10 g SCX column. Wash with methanol, then elute with a step gradient starting with dichloromethane going to 10% 2N ammonia-methanol in dichloromethane followed by 100% 2N ammonia-methanol to obtain the desired coupled product. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane, to give (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-cyclopentyl 4H-3-thia-1,4,9-triazabenzo[f]azulene (0.378 g, 0.918 mmol, 52%) as a yellow amorphous solid: mass spectrum (APCI): m/z=412.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](=[N:19]/[H])/[NH:17][OH:18])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36](OCC)=O>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[N:19]=[C:36]([C:32]4[S:31][CH:35]=[CH:34][N:33]=4)[O:18][N:17]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Reactant: CCOC(=O)c1nccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3nccs3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 170 °C

Procedure:
A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1.5 ml) was treated with a 21% solution of NaOEt in EtOH (50 μl, 0.13 mmol) and ethyl 1,3-thiazole-2-carboxylate (18 mg, 0.11 mmol). The mixture was heated in the microwave at 170° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (13 mg, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A stirred suspension of ethyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (Intermediate 47-1, 9.31 g, 25.5 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.73 g, 56.1 mmol) in toluene (127 mL) was heated at reflux for 3 h. The mixture was cooled to rt and the precipitate was collected by filtration, washed with toluene and water, and air dried. The solid was suspended in methanol and the precipitate was collected by filtration, washed with methanol and air dried to provide ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (7.68 g). The filtrate was concentrated and the residue was suspended in methanol. The precipitate was collected by filtration, washed with methanol and air dried to provide additional product (0.60 g) for a total of 8.28 g (90%). 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H) 8.69 (d, J=8.57 Hz, 1H) 8.51 (d, J=1.10 Hz, 1H) 8.26 (br. s., 1H) 7.93 (d, J=8.13 Hz, 1H) 7.87 (dd, J=8.57, 1.54 Hz, 1H) 7.63 (br. s., 1H) 7.50 (d, J=8.13 Hz, 1H) 4.37 (q, J=7.03 Hz, 2H) 1.37 (t, J=7.14 Hz, 3H). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: COc1ccc(CC2NC(=O)OC2c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Yield: 86.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(methyloxy)phenyl)methyl)-1,3-oxazolidin-2-one (12.8 g, 42.5 mmol) in ethanol (200 ml) was added 8N aqueous sodium hydroxide solution (26.6 ml, 210 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (10.08 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A 0° C. solution of 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.191 g, 0.608 mmol) in THF (3 mL) and MeOH (3 mL) was treated with NH4Cl (1.3 g, 24.31 mmol) followed by the slow addition of zinc dust (0.397 g, 6.08 mmol), the mixture allowed to warm to RT and stirred for 2 h. The mixture was treated with THF, the solids removed via filtration through diatomaceous earth, washed well with THF, the filtrate treated with EtOAc, washed with 1:1 brine/satd. NaHCO3, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (164 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J=5.8 Hz, 1H), 8.28 (s, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.29 (dd, J=8.9, 3.0 Hz, 1H), 6.67 (dd, J=5.8, 2.4 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.03 (s, 2H), 2.64 (s, 3H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:25])[C:6]1=[O:29]
Reactant: NCCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.56 (1H, br), 8.16 (1H, br s), 7.26 (3H, m), 7.10 (2H, t, J=8.8 Hz), 4.93 (2H, s), 4.50 (1H, br t), 3.99 (2H, s), 4.43 (2H, m), 3.27 (2H, m), 3.08 (3H, s), 2.78 (3H, s), 1.58 (2H, m, J=6 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1903.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=1)=O.[BH4-].[Na+]>C(O)C.CO>[C:12]([O:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cccc(OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)Oc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.32 g (11.1 mmol) of the ester from step C in 25 ml of ethanol is reduced by portion wise addition of 2.09 g (55.4 mmol) of sodium borohydride. HPLC analysis after stirring at r.t. for 12 hours shows complete reaction. The mixture is diluted with methanol and extracted with ethyl acetate/water to yield a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][CH2:34][C:35]([NH2:37])=[O:36])(OC(C)(C)C)=O.Cl.O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:33][CH2:34][C:35]([NH2:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: NCC(N)=O

Procedure:
Eight-hundred milligrams of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-glycineamide were dissolved in 3 ml of dichloromethane, and 3 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 2 hours. Thirty milliliters of diethyl ether were added thereto, and the resulting mixture was filtered. The thus-obtained powder was hot-washed with a mixture of chloroform, isopropanol and toluene at a ratio by of 6:8:20 to produce 483 mg (1.11 mmols) of the final compound in a yield of 65%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([CH3:15])[O:12][C:11]=2[CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[CH3:16][C:11]1[O:12][C:13]([CH3:15])=[CH:14][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[N:7]=1
Reactant: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1
Reactant: Nc1cccc(O)c1
Product: Cc1cc(CNc2nc(Nc3cccc(O)c3)ncc2F)c(C)o1
Yield: 51 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: CC(CC(N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)=O.[C:14](#[N:18])[CH2:15][C:16]#N>>[CH:14]1[C:15]2[C:8](=[CH:9][CH:10]=[CH:11][CH:16]=2)[CH:13]=[CH:12][N:18]=1
Reactant: N#CCC#N
Reactant: CC(=O)CC(=O)Nc1ccccc1
Product: c1ccc2cnccc2c1
Yield: 85 %

Procedure:
The procedure of Reference Example 5 was repeated except that 0.04 mole of acetoacetic anilide (Reference Example 8) or 0.04 mole of malononitrile (Reference Example 9) was employed instead of acetylacetone to give a corresponding isoquinoline derivative with yield of 85%, 65%, respectively. The structures of the obtained isoquinoline derivatives were identified by means of elementary analysis, IR spectrum and 1H-NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCO
Product: O=C1CCc2cc(NCC(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-quinolin-2-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 197-200° C. (ethyl alcohol)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1>>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: NCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Yield: 59.1 %

Procedure:
Using the general method of Example 89 Part A, 3-aminopropan-1-ol (9.52 mL, 124 mmol) was reacted with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) to provide 17.35 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][NH:10][C:11]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[C:7]([O:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][NH:10][C:11]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[C:7]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1

Procedure:
A solution of the 2-[4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.2 g, 0.32 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2 h. The mixture was poured into ice, then taken to basic pH with 5 N aqueous sodium hydroxide, and extracted with dichloromethane. The organic layer was separated, and the aqueous layer was thoroughly extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a yellow oily residue which was purified on a silica gel chromatotron plate. Elution with 9:1 dichloromethane-2 N ammonia in methanol provided the title compound as a clear oil which foamed up under vacuum (0.15 mg, 87%). Recrystallization of the oil from ethyl acetate-hexanes provided analytically pure product (0.09 mg) as a yellow-white crystalline solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[F:18].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1.O>O1CCCC1.C([Mg]Cl)CCC>[F:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=1[CH:25]([C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[OH:26]
Reactant: Fc1ccc(OC(F)(F)F)cc1Br
Reactant: O=Cc1ccncc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccncc1)c1cc(OC(F)(F)F)ccc1F
Temperature: 25 °C

Procedure:
To a solution in tetrahydrofuran (3 mL) at 0° C. of 2.3M n-butyllithium in hexanes (0.95 mL) and 2M n-butylmagnesium chloride in tetrahydrofuran (0.55 mL) is added a solution of 2-bromo-1-fluoro-4-trifluoromethoxybenzene in tetrahydrofuran (4 mL). After stirring at 0° C. for 20 minutes 4-pyridinecarboxaldehyde (193 μL) is added and the mixture stirred at room temperature for one night. After hydrolysis with water, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient heptane/ethyl acetate from 2/1 to 1/1) to give pure (2-fluoro-5-trifluoromethoxyphenyl)pyridin-4-ylmethanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1>N.CO.[Ni]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CCN(c3ccc(C#N)cc3)[C@H]2C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1C[C@H]2CCN(c3ccc(CN)cc3)[C@H]2C1

Procedure:
The product of Example 68 (676 mg, 3.0 mmole) in 50 mL of 20% ammonia in methanol was stirred in the presence of 6.8 g Raney-Nickel under an atmosphere of hydrogen at 60 psi at room temperature for 4 hours. Catalyst was removed by filtration through CELITE® and the filtrate concentrated under reduced pressure. The resulting oil was purified by flash chromatography (eluting with a mixture of 5% basic methanol in dichloromethane) to provide the titled compound. 1H NMR (CDCl3) δ ppm 7.17 (d, J=8.82 Hz, 2H) 6.55 (d, J=8.48 Hz, 2H) 4.07-4.16 (m, 1H) 3.77 (s, 2H) 3.45-3.59 (m, 1H) 3.16-3.28 (m, 1H) 2.88-3.04 (m, 1H) 2.63-2.74 (m, 2H) 2.53-2.63 (m, 2H) 2.34 (s, 3H) 2.08-2.23 (m, 1H) 1.86-2.05 (m, 1H); MS (M+H)+=232.