Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:12].[N:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: Nc1csc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(Nc3ccncc3)csc2c1
Yield: 95.1 %

Procedure:
A solution of 3-aminobenzo[b]thiophene (3 g, 20 mmol) and 4-chloropyridine hydrochloride (3.5 g, 23 mmol) in 50 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for three hours, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 5 g of an amber oil. Conversion to the hydrochloride salt in methanol-ether yielded 3 g of a hygroscopic solid. Recrystallization from 50% methanol in ether yielded 1.8 g of rust colored crystals, mp 268-270° (dec.).
Reaction SMILES: Cl[S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26].ClCCl>N1C=CC=CC=1>[CH2:25]([O:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:17][S:2]([C:5]1[N:13]=[C:12]2[N:7]([C:8]([O:15][CH3:16])=[N:9][C:10]([CH3:14])=[CH:11]2)[N:6]=1)(=[O:4])=[O:3])[CH3:26]
Reactant: CCOc1ccncc1N
Reactant: COc1nc(C)cc2nc(S(=O)(=O)Cl)nn12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccncc1NS(=O)(=O)c1nc2cc(C)nc(OC)n2n1

Procedure:
2-Chlorosulfonyl-5-methoxy-7-methyl[1,2,4]triazolo[1,5-c]pyrimidine (1.5 g, 5.7 mmol) was added to a solution of 0.8 g (5.7 mmol) of 3-amino-4-ethoxypyridine in 30 mL of dry pyridine in portions over 10 minutes with stirring. After 16 hours the reaction mixture was poured into 400 mL of dichloromethane. The resulting mixture was washed with 150 mL of water, dried over magnesium smlfate, and filtered. The liltrate was combined with 5 g of silica gel and the mixture was concentrated by evaporation under reduced pressure. The resulting silica plug was placed onto a 200 g silica gel column and eluted with dichloromethane containing increasing amount of ethanol. The product fractions were combined and concentrated by evaporation under reduced pressure and the solid obtained was dried to obtain 0.75 g (36 percent of theory) of the title compound as a white solid melting at 184°-186° C.
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Pd]>[NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (0.175 g) and tert-butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)-4-fluorophenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A36) (0.191 g, 0.320 mmol) in DMF (10 mL) and Et3N (1 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL), filtered through Celite and the volatiles were removed under reduced pressure. The residue was adsorbed onto silica gel, then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A37 as a yellow solid (0.168 g, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.48 (s, 1H), 7.23-7.15 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.00 (td, J=8.4, 2.7 Hz, 2H), 4.07 (d, J=11.8 Hz, 2H), 3.50 (s, 2H), 3.13-3.04 (m, 2H), 3.04-2.95 (m, 2H), 2.79 (brs, 2H), 2.69-2.57 (m, 1H), 1.74 (d, J=12.9 Hz, 2H), 1.54-1.43 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.612 min; m/z 602 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:22])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichlorophenyl)-6-methyl-pyrimidine (example E.62) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.39 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][C:60]([F:64])([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (120.0 mg, 0.310 mmol) in tetrahydrofuran (3.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (156.4 mg, 0.620 mmol) and tributylphosphine (154.5 μL, 0.620 mmol). After 10 min, to the mixture was added 2,2,2-trifluoroethanol (225.9 μL, 3.100 mmol). The reaction mixture was stirred at 60° C. for 5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (56.5 mg, 0.120 mmol, 39).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1.O>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-ol (1 g, 6.32 mmol) and triethylamine (1.3 mL, 9.48 mmol) taken in anhydrous THF and treated with methanesulfonyl chloride (0.73 mL, 9.48 mmol). Stirred for 18 h. Diluted with water and extracted with EtOAc. The ethyl acetate layer washed with sat NaCl, dried over Na2SO4 and evaporated to give the expected product. Used without further purification.
Reaction SMILES: N[C:2]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.CCN(CC)CC.Cl[S:22]([NH:25][C:26](=O)OCCCl)(=[O:24])=[O:23].C[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=1>C(Cl)Cl.CC#N>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([N:25]([CH3:26])[S:22](=[O:23])(=[O:24])[NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=2)[CH2:3]1
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Reactant: CCCCCCCCc1ccc(NC)cc1
Reactant: COC(=O)CC1(N)CCCN(C)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCc1ccc(NS(=O)(=O)N(C)C2(CC(=O)OC)CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of methyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (186 mg, 1 mmol) and Et3N (0.42 mL, 3 mmol) in CH2Cl2 was added the solution of 2-chloroethyl chlorosulfonylcarbamate in CH2Cl2 (0.77 M, 1.3 mL, 1 mmol). After addition, the resulting mixture was stirred overnight at rt. Evaporation of solvents gave a light yellow oil which was used without further purification. A solution of this crude mixture, N-methyl-4-octylaniline (241 mg, 1.1 mmol) and Et3N (0.42 mL, 3 mmol) in CH3CN (10 mL) was refluxed for 2 h. After cooling to rt and evaporating solvents, the residue was purified by a short column (EtOAc/hexance=10:1) to give the title compound (105 mg, 22%) as white solid. MS ESI 468.3 [M+H]+, calcd for [C24H41N3O4S+H]+ 468.29.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]([O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2,4-Dihydroxy-butyl)-carbamic acid tert-butyl ester in dichloromethane (15 ml) was added triethylamine (1.96 ml). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.82 ml) was added drop wise. The mixture was stirred at 0° C. for 2 hours. The mixture was filtered and dichloromethane was added (200 ml). The mixture was washed with 0.2M hydrochloric acid (50 ml), water (30 ml) and 0.2M sodium carbonate (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) which was used in the next step without further purification. 1H-NMR (CDCl3, 400 MHz): 4.95 (m, 1H), 3.85 (m, 2H), 3.95 (m, 2H), 3.10 (m, 6H), 2.15 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[NH2:10][C:11]1[S:12][C:13]2[CH2:22][CH2:21][CH2:20][CH2:19][C:14]=2[C:15]=1[C:16](N)=[O:17]>S(Cl)(Cl)=O.O1CCOCC1.O>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([NH:10][CH:11]1[S:12][C:13]2[CH2:22][CH2:21][CH2:20][CH2:19][C:14]=2[C:15]1=[C:16]=[O:17])=[O:6]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: COC(=O)CCC(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(=O)NC1SC2=C(CCCC2)C1=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Monomethyl hydrogen succinate (4.7 g, 0.035 mol) was refluxed in thionyl chloride (20 ml) for 2 hrs. After consumption of starting material, excess of thionyl chloride was distilled off. The reaction mixture dissolved in dioxane (10 ml) and was added drop wise to 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide 1 (7 g, 0.035 moles) in dioxane (10 ml) at 0° C. and stirred at room temperature (R.T) for 2 hrs. The reaction mixture was diluted with water to give crude product which was filtered and washed with water. The crude was purified by chromatography on silica gel using 1:1 Ethyl acetate:Hexane to give 5 g (46%) of N-(3-carbonyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-succinamic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=1.72 (m, 4H), 2.6 (m, 4H), 2.68 (m, 4H), 3.59 (s, 3H), 6.99 (s, 1H), 7.55 (s, 1H), 11.48 (s, 1H). LC-MS: [M−H]=308.9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1CCCCC1>[CH:11]([NH:24][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCBr
Solvent: C1CCCCC1
Product: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1

Procedure:
25.1 g of ethyl 5-bromovalerate, 66 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 15 days. Processing analogously to Example 19 yields 23.4 (62.6%) of ethyl 5-benzhydrylaminovalerate [B.P. 158° to 163° (0.01 mm Hg)].
Reaction SMILES: [OH-:1].[Na+].[N+:3](C1C=CC=C(C(O)=O)C=1C(O)=O)([O-:5])=[O:4]>C(O)C>[OH2:4].[OH2:1].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[N+:3]([O-:5])([OH:1])=[O:4]
Reactant: [OH-]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Na+]
Solvent: CCO
Product: O
Product: O=[N+]([O-])O

Procedure:
Chromic (III) chloride hexahydrate, 13.3 grams, was dissolved in 150 milliliters of ethanol. While this solution was being stirred, a solution of 2 grams of sodium hydroxide in 50 milliliters of ethanol was added. The mixed solution was refluxed for 15 minutes with stirring. Then, a solution of 2.6 grams of nitrophthalic acid in 50 milliliters of ethanol was added, and the reaction mixture was refluxed for 30 minutes with stirring. Thereafter, the by-product, sodium chloride, was removed by filtration. Thus, nitrophthalatotetrachromium (III) complex was obtained as an ethanol solution.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:22][O:23][C:24](=[O:29])[C@H:25]([CH2:27][OH:28])[NH2:26].C(N(CC)CC)C>ClCCl>[C:2]([NH:26][C@H:25]([C:24]([O:23][CH3:22])=[O:29])[CH2:27][OH:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
Chlorotriphenylmethane (265 g, 950 mmol) dissolved in 750 mL of dichloromethane was added dropwise to a stirred solution of L-serine methyl ester hydrochloride (148 g, 950 mmol) and triethylamine (260 mL, 1900 mmol) in 1.5 L of CH2Cl2 at 0° C. The cloudy yellow solution was stirred for 18 hours at ambient temperature. The reaction mixture was filtered to remove solids and the filtrate was washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil. The oil was concentrated from acetonitrile and then stirred in hexanes until a precipitate formed. The resulting solid was filtered to afford 310 g of methyl N-trityl-L-serinate as an off white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[CH2:15]2)[N:7]=1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)C)nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)n1
Temperature: 160 °C
Yield: 87.1 %

Procedure:
A mixture of 2-chloro-4-dimethylamino-6-methylpyrimidine (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.38 g), triethylamine (0.30 g), and isopropanol (2.9 mL) was heated at 160° C. in a microwave reaction apparatus for 3.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=95:5) to obtain 1-((S)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.43 g). (2) 1-((S)-3-(4-Dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone obtained in (1) was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.58 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diisopropyl ether to obtain the title compound (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:5](=[O:20])[N:4]([CH2:21][C:22](O)=[O:23])[C:3]=1[CH3:25].[CH3:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=2)[NH:29][CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([NH:37][CH2:36][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[C:27]3[CH3:26])=[O:23])[C:3]=1[CH3:25]
Reactant: Cc1c(Cl)nc(NC[C@H]2CCCCN2CC2CC2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)c(Cl)nc(NC[C@H]4CCCCN4CC4CC4)c3=O)cc12

Procedure:
The title compound was prepared by a similar method to preparation 45 from 2-[3-chloro-5-({[(2R)-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetic acid [see preparation 72] and (3-methyl-1H-indol-5-yl)methylamine (preperation 36) to afford the product as a white solid, (14%). LRMS: m/z=511 (M+).
Reaction SMILES: [Br:1][C:2]1C(=O)[CH2:4][CH2:5][CH2:6][C:7]=1O.[CH:10](OC)(OC)[O:11][CH3:12].S(=O)(=O)(O)O.S(O)(O)(=O)=O.[NH2:27][OH:28].C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[C:7](=[N:27][OH:28])[CH2:6][CH2:5][CH2:4][C:10]=1[O:11][CH3:12]
Reactant: COC(OC)OC
Reactant: O=C1CCCC(O)=C1Br
Reactant: NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1=C(Br)C(=NO)CCC1
Temperature: 40 °C
Reaction time: 2.25 h
Yield: 55 %

Procedure:
2-Bromo-3-hydroxy-cylohex-2-enone (80.0 g, 420 mmol) is added to a mechanically stirred reactor followed by methanol (300 mL). To the mixture is then added trimethyl orthoformate (186 mL, 1.70 mol, 4 eq) and sulfuric acid (9 mL). The resulting mixture is stirred for 2 h until completion and hydroxylamine sulfate (34.4 g, 210 mmol, 0.5 eq) is added as a solid. The mixture is heated to 40° C. and stirred at that temperature until complete conversion (2-2.5 h). The solution is then cooled to 5° C. and the pH is adjusted to 7 with saturated sodium bicarbonate (˜1100 g). The precipitate formed is collected by filtration (filter 10 cm diameter, 1.5 cm cake thickness, <1 min total filtration time) rinsed with heptane (200 mL) and dried under nitrogen flow for 4-6 h to provide 50.8 g, (55% yield) of 2-bromo-3-methoxy-cylohex-2-enone oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:29](=[O:30])[CH2:28][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)COc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added phenoxyacetyl chloride (0.55 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.76 g (93%) of product as an off-white solid: mp 236–238 ° C.; 1H NMR (DMSO-d6) d 11.19 (s, 1H), 10.53 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H) 7.14–7.01 (m, 3H), 5.21 (dd, J=5.3 and 12.6 Hz, 1H), 4.81 (s, 2H), 3.00–2.86 (m, 1H), 2.67–2.51 (m, 2H), 2.13–2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.77, 169.77, 168.37, 167.59, 166.67, 156.85, 136.58, 135.84, 131.28, 129.74, 124.45, 121.91, 118.50, 116.28, 114.86, 67.03, 49.02, 30.96, 21.93; Anal. Calcd. For C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 61.87; H, 4.27; N, 10.25.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2)#[N:2].C(=O)(O)[O-].[Na+].Cl.[NH2:25][OH:26]>C(O)C>[OH:26][NH:25][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=[CH:6]2
Reactant: NO
Reactant: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Ethyl 3-(5-cyano-1H-indazol-1-yl)propanoate (D47) (1 g, 4.11 mmol) was dissolved in ethanol (30 ml) and sodium bicarbonate (1.73 g, 20.88 mmol) and hydroxylamine hydrochloride (571 mg, 8.22 mmol) were added. The reaction was left at room temperature overnight and then heated to 50° C. for 4 hours then left to cool overnight. The reaction mixture was filtered and the residue washed with ethanol. The ethanolic filtrate was evaporated to dryness in vacuo and then triturated with ether to give the title compound (764 mg) as a white solid of approximately 90% purity. MS (ES): C13H16N4O3 requires 276; found (MH+) 277.