Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11]>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[S:5][C:6]=1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 80.5 %

Procedure:
1.50 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-pentan-1-ol were dissolved in 30 ml dichloromethane. 5.46 g manganese(IV)oxide (activated on charcoal) were added and the resulting mixture was heated under reflux for 2.5 hours. The cooled reaction mixture was filtered through a pad of celite. The filtrate was evaporated in vacuo to obtain 1.2 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-pentan-1-one as an oil.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.O.[OH-].[Na+]>C(O)(=O)C.[Zn]>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[O:6][CH:2]=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)oc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2coc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
To a solution of 3-[5-Bromo-4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.06 g, 0.13 mmol) in the 5 ml of acetic acid was added 50 mg of Zn dust. Reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.02 g, 40%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 3.77 (s, 3H), 5.36 (s, 2H), 6.99 (d, J=8.40 Hz, 2H), 7.12 (m, 1H), 7.37 (m, 1H), 7.71 (d, J=8.40 Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H) and 8.56 (s, 1H). MS ES+ (361.24), HPLC (method I) Rt=15.41 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].N1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:16]([C:5]1([CH2:4][CH2:3][CH:2]=[CH2:1])[CH2:13][C:11](=[O:12])[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10]1)[CH2:17][CH:18]=[CH2:19]
Reactant: C1CCNC1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: Cc1ccccc1
Product: C=CCCC1(CCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Yield: 208.4 %

Procedure:
A mixture of 719 mg (5.21 mmol) of the title product of Example 63, 970 mg (5.00 mmol) of 2,4-dihydroxy-3-propylacetophenone, 360 mg (5.00 mmol) of pyrrolidine, and 5.5 ml of toluene containing 2.0 g of 3A molecular sieves was stirred at reflux for six hours, then kept overnight at room temperature. The solution was then decanted from the sieves, and the sieves were washed with methylene chloride. The solvent was then removed under reduced pressure. Chromatography of the residue over silica gel, using 14:5:1 methylene chloride:hexane:ethylacetate as eluent, gave the title compound (439 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1.O>CN(C=O)C>[F:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][NH:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C@@H:10]3[CH2:14][CH2:13][N:12]([C:15]4[C:16]5[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=5[N:18]=[CH:19][N:20]=4)[CH2:11]3)=[N:4][CH:5]=2)=[CH:41][CH:42]=1
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(NCc2ccc(F)cc2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of (R)—N2-methyl-N2-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridine-2,5-diamine (0.20 mmol) in DMF (5 mL) were added K2CO3 (0.24 mmol) and 1-Chloromethyl-4-fluoro-benzene (0.24 mmol) at room temperature. The mixture was stirred at 80° C. for 18 hours, poured into water and extracted with EtOAc. The organic layer was washed with water and brine sequentially, then concentrated. The residue was purified by preparative TLC to give the title compound in 30% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-])=O)[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Pt]=O>[NH2:17][C:14]1[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[C:11]2[CH:10]([CH2:24][Cl:25])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(N)c1ccccc21
Yield: 90.7 %

Procedure:
A solution of 13 (200 mg, 0.55 mmol) in THF (15 mL) was hydrogenated over PtO2 at 55 psi for 1.5 h. The catalyst was removed, the solvent was evaporated, and the resulting solid was triturated with petroleum ether to give 5-amino-3-(tert-butyloxycarbonyl)-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indole (166 mg, 90%), mp >200° C. 1H NMR [(CD3)2SO] δ 8.01 (d, J=8.4 Hz, 1 H, H-6), 7.64 (d, J=8.3 Hz, 1 H, H-9), 7.45-7.25 (underlying br s, 1 H, H-4), 7.40 (t, J=7.4 Hz, 1 H, H-8), 7.20 (t, J=7.4 Hz, 1 H, H-7), 7.91 (s, 2 H, NH2), 4.11-3.87 (m, 4 H, H-1,2, CHHCl), 3.66 (dd, J=10.5, 8.3 Hz, 1 H, CHHCl), 1.53 (s, 9 H, C(CH3)3).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:19](=[O:20])[C:18]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:16]([O:15][CH3:14])[CH:17]=2)=[CH:22][CH:23]=1)#[N:10]
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1OC
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)cc1OC
Reaction time: 8 h

Procedure:
0.68 g (3.45 mmol) of 3-(2-aminoethoxy)benzonitrile monohydrochloride was dissolved in 20 ml of N,N-dimethylformamide (dehydrated). 0.9 g (3.14 mmol) of 4-(3,4-dimethoxybenzoyl)benzoic acid, 0.47 g (3.45 mmol) of 1-hydroxybenzotriazole, 0.48 ml (3.45 mmol) of triethylamine and 0.66 g (3.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[C:17]1[S:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=1.[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([C:17]4[S:18][C:19]([C:22]([F:23])([F:24])[F:25])=[N:20][N:21]=4)[CH:12]=3)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(F)(F)F)s2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-[1,1′-biphenyl]-4-ol (195 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (157 mg) and tributylphosphine (213 mg) in THF (5.0 mL) was added ADDP (226 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (298 mg) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([C:25]3([OH:29])[CH2:28][CH2:27][CH2:26]3)=[N:22][CH:21]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(O)(=O)C>O1CCOCC1>[CH:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]3[CH:14]=[C:15]([C:20]4[S:24][C:23]([C:25]5([OH:29])[CH2:28][CH2:27][CH2:26]5)=[N:22][CH:21]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)[N:7]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1nccc(C2CCC2)n1
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C3CCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
2-Chloro-4-cyclobutylpyrimidine (65 mg, 0.39 mmol), Intermediate 15 (100 mg, 0.39 mmol), and acetic acid (22 μL, 0.39 mmol) were combined in dioxane (1.9 mL) and the mixture was stirred at 120° C. for 3 h. The mixture was cooled to room temperature and directly purified by Combiflash chromatography on silica gel, eluting with ethyl acetate/isohexane to provide 66 mg (0.17 mmol, 44%) of 1-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol. MS ESI: [M+H]+ m/z 393.2. 1H NMR (600 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.33 (d, J=4.8, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.05 (s, 1H), 6.68 (d, J=5.4, 1H), 6.46 (s, 1H), 3.53-3.50 (m, 1H), 2.52-2.46 (m, 2H), 2.33-2.22 (m, 9H), 1.99 (m, 1H), 1.87-1.83 (m, 3H). rhSYK activity=+++
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CO.[CH2:14](Br)[C:15]#[CH:16].C[O-].[Na+]>CCOCC>[CH2:16]([NH:10][S:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:9])=[O:8])[C:15]#[CH:14]
Reactant: O=S(=O)(NO)c1ccccc1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C#CCNS(=O)(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 8.6 g. piloty acid dissolved in 50 ml. methanol, propargyl bromine (6.6 g.) was added. 10.8 g. sodium methoxide (25%) was added slowly dropwise. An exothermic reaction resulted, the temperature was maintained at 30° C. The reaction mixture was stirred for approximately 1 hour at room temperature. The solvent was removed in vacuo. There was obtained a yellow solid. This material was treated with ether and the solid filtered off and dried. There was obtained 3.1 g. of the title compound, a low melting solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1>C1COCC1>[NH2:10][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)c1ccnc(N)c1
Solvent: C1CCOC1
Product: Nc1cc(CO)ccn1
Temperature: -45 °C

Procedure:
2-Amino-isonicotinic acid methyl ester (6.0 g, 39.4 mmol) was dissolved in 80 mL anhydrous THF in a flame dried round bottom flask under nitrogen gas. The solution was cooled to −45° C. and LAH (39.4 mL, 1M in THF) was added slowly. The reaction was allowed to warm to 0° C. and was quenched by the addition of 15 mL of 1M NaOH (aq). The solution was filtered and the solid was washed with THF. The filtrate was concentrated to afford the pure product. 1H NMR (DMSO-d6) δ 7.79 (d, 1H, J=5.2 Hz), 6.41 (s, 1H), 6.38 (d, 1H, J=5.9 Hz), 5.79 (bs, 2H), 5.19 (t, 2H, J=5.7), 4.35 (d, 2H, J=5.6 Hz).
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.O=[C:24]1CCCN(C(OC(C)(C)C)=O)CC1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[NH:5][N:6]=[CH:7]3)[CH2:24][CH2:16]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Product: c1ccc(CN2CCCC(Nc3ccc4[nH]ncc4c3)CC2)cc1

Procedure:
The title compound was prepared by reaction of 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one with tert-butyl 4-oxoazepane-1-carboxylate using the method of Example 3, deprotection using the method of Example 4, reaction with benzaldehyde following the method of Example 8, and final deprotection using the method of Example 9.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[CH:18][CH2:19]Br>C(COC)OC>[C:3]1([CH:9]([CH2:19][CH:18]=[CH:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([CH3:13])[CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Cc1cccc(C=CCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1cccc(C)c1)c1ccccc1

Procedure:
Sodium hydride (6 g., 0.14 mole, oil dispersion) is suspended in glyme (250 ml.) and phenyl acetone (18.6 g., 0.14 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for one hour. The mixture is cooled in a cold water bath and a solution of m-methylcinnamyl bromide (29.16 g., 0.14 mole) in glyme (50 ml.) is added dropwise. When addition is complete the mixture is refluxed for 20 hours. The cooled mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in ether and washed with dilute hydrochloric acid, water and saturated brine. After drying (MgSO4) and evaporation of ether the residue is vacuum distilled and the product is collected at 161°-164°/0.4 mm; 25.24 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][O:33][C:34]1[CH:38]=[C:37]([C:39](O)=[O:40])[O:36][N:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:39]([C:37]4[O:36][N:35]=[C:34]([O:33][CH3:32])[CH:38]=4)=[O:40])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Product: COc1cc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)COC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow viscous oil. MS: 568.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:26])[C:14]2[C:19]([NH:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>C(O)C.[Ni]>[CH3:27][C:2]([CH3:3])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:26])[C:14]2[C:19]([NH:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: C=CC(C)(C)Nc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CCO
Product: CCC(C)(C)Nc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 21 h

Procedure:
To a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[N-methyl-N-(3-(1,1-dimethylprop-2-enylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 62, 2.41 g) in absolute ethanol (40 ml) under nitrogen is added wet Raney Nickel (620 mg). The mixture is put under a hydrogen atmosphere at 40 psi for 21 hrs, filtered through diatomaceous earth, and concentrated to give an oil which is chromatographed (silica gel, 70-230 mesh, 250 g; eluting with a gradient of ethyl acetate/hexane (10/90-35/65)), to give the title compound, NMR (CDCl3) 7.67, 7.04, 6.87, 4.87, 4.04, 3.20, 2.76, 2.61, 1.71, 1.50, 1.45, 1.31 and 0.86δ.
Reaction SMILES: [Cl:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].[Cl:15]CC1C=CC(CNC(=O)C)=CC=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.Cl.O1CCOCC1>C(O)C>[ClH:1].[ClH:15].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([CH:2]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=2)[CH3:3])[CH2:38][CH2:37]1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccccc1N1CCN(C(C)c2ccc(CNC(C)=O)cc2)CC1

Procedure:
In Example 1(5), N-((4-(1-chloroethyl)phenyl)methyl)acetamide was used for reaction instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-methoxyphenyl)piperazine instead of 1-phenylpiperazine, which was followed by treatment with 4M hydrochloric acid-dioxane in ethanol to give the title compound as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[N:3]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([NH:32][CH3:33])=[CH:30][CH:29]=1>C(OCC)(=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([N:32]([CH3:33])[C:2]2[N:3]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]4)=[C:15]([O:25][CH3:26])[CH:14]=3)[N:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:7]=2)=[CH:30][CH:29]=1
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Reactant: CNc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(OC(C)C)nc(N(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 27 %

Procedure:
This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methyl aniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 27% yield.
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])C.Cl.C1C=CC2N(O)N=[N:19][C:17]=2C=1.[OH2:23]>CN(C=O)C>[N:19]1[CH:17]=[CH:11][N:9]=[CH:8][C:7]=1[C:6]([NH2:5])=[O:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: O
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cnccn1
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of the product from step 6 (140 mg, 0.45 mmol), EDC.HCl (128 mg, 0.67 mmol) and HOBt.H2O (102 mg, 0.67 mmol) in anhydrous DMF (25 mL) was stirred together at room temperature for 30 min. To this stirred mixture was added (R)-dibenzyl 2-aminosuccinate p-TsOH salt (213 mg, 0.44 mmol) followed by TEA (1 mL). The resulting mixture was stirred for 16 h thereafter. The reaction mixture was concentrated and partitioned with EtOAc and saturated sodium bicarbonate solution. The EtOAc layer was separated and washed with saturated sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated to afford 240 mg (88% yield) of the pyrazine amide as an orange foam: LCMS (15-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time=8.76 min on 250 mm column, (M+H)+=610, (M+Na)+=632.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16](=[O:19])[NH:17][CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:18][NH:17][C:16](=[O:19])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)NC
Reaction time: 0.75 h
Yield: 23.7 %

Procedure:
N-Methyl-N-((R)1-(methylcarbamoyl)-2-phenylethyl)carbamic acid tert-butyl ester (1.39 g, 7.23 mmol) was dissolved in a mixture of trifluoroacetic acid (5 mL) and methylene chloride (10 mL) and stirred for 45 min. The volatiles were removed in vacuo and the residue was stirred with a mixture of ethyl acetate (100 mL) and water (100 mL). Sodium hydrogen carbonate (50 mL, saturated) was added and the phases were separated. The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 330 mg of (R)-N-methyl-2-methylamino-3-phenylpropionamide.
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])[CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH2:14][CH2:13]2
Reactant: C1COCCN1
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCOCC1)CC2
Temperature: 65 °C

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (425 mg, 1.62 mmol) in methanol (5 mL) was treated with morpholine (1.00 mL, 11.5 mmol, Aldrich) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 25% methanol/dichloromethane) to give 6-(methyloxy)-2-[3-(4-morpholinyl)propanoyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline. This material was taken directly to the next step without a determination of yield. 1H NMR (400 MHz, DMSO-d6) is complicated by amide rotomers δ ppm 2.32-2.41 (m, 4 H), 2.52-2.62 (m, 4 H), 2.79-2.97 (two app triplets at 2.83 and 2.94, 2 H), 3.48-3.58 (m, 4 H), 3.63-3.72 (m, 2 H), 3.89 (s, 3 H), 4.55-4.69 (two singlets at 4.57 and 4.67, 2 H), 7.18-7.21 (m, 1 H), 7.80 (s, 1 H); ESIMS (M+H)+=350.
Reaction SMILES: C(O)C.C(O)(=O)C.C[O:9][C:10](=O)[CH:11]([CH3:27])[CH2:12][N:13]([C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=1)[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[Cl:26][C:21]1[N:22]=[CH:23][C:24]2[NH:25][C:10](=[O:9])[CH:11]([CH3:27])[CH2:12][N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:19]=2[N:20]=1
Reactant: COC(=O)C(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Yield: 65.5 %

Procedure:
A mixture of 1500 mL of ethanol, 25 mL of acetic acid and 35.2 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-propanoic acid methyl ester (V-1) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to give 31 g of the crude product. Trituration of the residue with ether, provided 20.7 g of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1).