Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(F)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Product: Cc1ccc(OC2CCNCC2)cc1

Procedure:
By following the manipulative procedures described in Example 1(a) and (b), 24.0 g of 1-benzyl-4-piperidinol and 24.0 g of p-fluorotoluene produces an oil of 4-(p-tolyloxy)piperidine.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(COCC(F)(F)F)[nH]c(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (1 g, 6.23 mmol), 2,2,2-trifluoroethanol (2.235 mL, 31.14 mmol) and cesium carbonate (6.09 g, 18.68 mmol) in dimethylformamide (10 mL) was heated in a microwave oven at 100° C. for 30 min. The mixture was filtered and the volatiles were removed in vacuum. The residue was treated with diluted HCl (pH 4.5) and cooled to 0° C. The resulting crystals were collected by filtration and dried in vacuum cabinet to yield the title compound, 0.92 g (66%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:37])[CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH:18]=1)=[O:16].[ClH:38]>C(Cl)Cl>[ClH:38].[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C@@H:12]([OH:37])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ccn2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccnc(NC2CCNCC2)c1
Yield: 85.4 %

Procedure:
The mixture of (S)-tert-butyl 4-((4-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl) carbamoyl)pyridin-2-yl)amino)piperidine-1-carboxylate (510 g, 1.0 mol) in DCM (1000 mL) was dropped slowly into a stirred and cooled (−30° C.) solution of HCl (4M in EtOAc, 2000 mL). After addition, the mixture was stirred at −30° C. for 30 min. The resulting solid was then collected by filtration, washed with DCM and dried under reduced pressure to give the title compound (350 g yield: 85.4%, HCl salt) as a white solid. LCMS (m/z): 410.2 [M+H]+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu-]=O>[N:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:20]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=4[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]3)=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Agent: O=[Cu-]
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCOCC1
Temperature: 130 °C
Yield: 81.7 %

Procedure:
A mixture of 4-[(4-iodophenyl)carbonyl]morpholine (1.90 g, 6.0 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (1.14 g, 6.0 mmol), copper (I) oxide (10 mol %, 0.6 mmol, 86 mg), N,N-dimethylglycine (20 mol %, 1.2 mmol, 124 mg), and cesium carbonate (12.0 mmol, 3.91 g) in dimethylsulfoxide (16 ml) was stirred in an oil bath heated at 130° C. for 24 h under argon and then allowed to cool to room temperature. The reaction mixture was partitioned between dichloromethane (30 ml) and water (30 ml). The organic layer was separated and dried over sodium sulphate. The solvent was removed by rotary evaporation to give a dark brown residue that was added to a 20 g isolute pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a brown gum (1.86 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[N:6]2OCOC.Cl.O1CCCC1.C(O)C>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH:6]2
Reactant: COCOn1c(-c2nccs2)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1ccc(F)c2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 51 %

Procedure:
A mixed solution of N-[4-fluoro-1-(methoxymethoxy)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (165 mg), 6N hydrochloric acid (6 mL), tetrahydrofuran (2 mL) and ethanol (4 mL) was stirred at 80° C. for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-3:7), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (73 mg, yield 49%) as colorless needle crystals. melting point 197-198° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:34]([F:37])([F:36])[F:35])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:9]=[C:10]([C:11]2[O:13][N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][C:34]([F:35])([F:36])[F:37])[N:24]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCOCC1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 2 (119 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:30])([C:26]([F:29])([F:28])[F:27])[C:3]([F:25])([F:24])[C:4]([F:23])([F:22])[O:5][C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[O:8][C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:31]([C:38]1[CH:39]=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:31]([C:38]1[CH:43]=[N:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([O:50][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:19])([F:18])[C:6]([F:21])([F:20])[O:5][C:4]([F:23])([F:22])[C:3]([F:25])([F:24])[C:2]([F:30])([F:1])[C:26]([F:29])([F:28])[F:27])([F:17])[F:16])=[CH:48][CH:49]=2)=[N:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride (5.17 g of 95% purity, 8.4 mmol, Example 14) with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (4.0 g, 8.4 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation to provide a yield of 2.9 g.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=[CH:28]1)=O>C1COCC1>[CH3:25][N:27]([CH3:28])[CH2:31][CH2:30][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN(C)C)cc21
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with N1-dimethyl-ethane-1,2-diamine; 1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-10 as an oil in 58% yield.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].O>ClCCl>[C:1]([NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=1)(=[O:14])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butylamine (5.1 g, 70 mmol) in dichloromethane (200 mL) was added dropwise a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in dichloromethane (100 mL) at room temperature over a period of 30 min, and then the reaction mixture was stirred for 2 h. The reaction mixture was poured into water (100 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give 21.3 g (quant.) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 8.38 (1H, d, J=2.0 Hz), 8.02 (1H, dd, J=2.0, 8.6 Hz), 7.70 (1H, d, J=8.6 Hz), 4.95 (1H, br.s), 1.28 (9H, s).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][NH2:36])=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.[C:37](Cl)(Cl)=[O:38].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.O1CCCC1>[CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]3[O:34][C:37](=[O:38])[NH:36][N:35]=3)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N(CCCC(=O)NN)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCCc1n[nH]c(=O)o1)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Temperature: 85 °C
Yield: 71 %

Procedure:
To a solution of N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-6-yl)-N-(4-hydrazinyl-4-oxobutyl)methanesulfonamide (13 mg, 0.025 mmol) in anhydrous CHCl3 (400 μL) and anhydrous tetrahydrofuran (400 μL) was added 20 wt % phosgene in toluene (66.9 μL, 0.127 mmol) under nitrogen, and the mixture was heated at reflux in an oil bath at 85° C. for 30 minutes. The reaction was cooled to room temperature and concentrated by rotary evaporation to a white solid. The crude material was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 5 g bed) eluting with 5% methanol/CH2Cl2 to afford the title compound as a white solid (10 mg, 0.018 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.60 (m, 1H), 0.80-0.93 (m, 1H), 0.99 (d, J=8.57 Hz, 2H), 1.69-1.85 (m, 2H), 2.34-2.43 (m, 1H), 2.59-2.66 (m, 2H), 3.17 (s, 3H), 3.66-3.87 (m, 2H), 7.09 (s, 1H), 7.18 (s, 1H), 7.26-7.45 (m, 3H), 7.88 (s, 1H), 8.02 (dd, J=8.89, 5.53 Hz, 2H), 11.99 (br s, 1H), 12.41 (s, 1H); MS (ESI+) m/z 538 (M+H)+, 1075 (2M+H)+; MS (ESI−) m/z 536 (M−H)−, 1073 (2M−H)−.
Reaction SMILES: Cl.[N:2]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[CH:24]=3)[N:19]=2)[CH2:14][CH2:13]1>CO.[Rh]>[NH:4]1[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:2]=[C:3]1[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[C:26]([NH2:28])[C:25]3[C:20](=[CH:21][C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[CH:24]=3)[N:19]=2)[CH2:14][CH2:13]1
Reactant: COc1cc2nc(N3CCN(c4nc5cccccc-5n4)CC3)nc(N)c2cc1OC
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COc1cc2nc(N3CCN(c4nc5c([nH]4)CCCCC5)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2-[4-(2-cycloheptimidazolyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine hydrochloride (1.0 g, described in Example 2) and 5% rhodium on carbon (0.10 g) in methanol (600 ml) was hydrogenated under an atmosphere of hydrogen at 50 lb/sq. in. pressure. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in methanol and the solution was acidified with a few drops of 2 N hydrochloric acid. Acetone was added and crystals of the title compound were collected (0.880 g); mp>250° C.; ir (nujol) 3340 and 3160 cm-1 ; uv max (MeOH) 250 (ε=56500), 330 (ε=8200) and 342 nm (ε=7850); and nmr (DMSO-d6) δ 1.65 (m, 6H), 2.6 (m, 4H), 3.75 (m, 4H), 3.85 (s, 6H), 4.05 (m, 4H), 7.7 (s, 1H) and 7.75 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1 of ethyl 8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 27A, 3 mmol, 1 equivalent) were initially charged in 60 ml of methanol/THF (5:1), 15 ml of a 1 N aqueous lithium hydroxide solution (15 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 4 h. The mixture was then cooled and, with ice cooling, adjusted to pH 4 using 6 N aqueous hydrochloric acid. The organic solvents were removed on a rotary evaporator, water was added to the precipitated product and the product was filtered, washed with water and dried under high vacuum. This gave 797 mg (87% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C[O-].[Na+].Cl.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CCO.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[N:3]=1)[C:8]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[NH:9]
Reactant: NC1CC1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
2,6-dichloropyridine-4-carbonitrile (5 g, 28.9 mmol), methanol (50 ml) and sodium methoxide (0.66 ml, 2.89 mmol) were mixed and stirred at r.t. for 3 h. HCl in EtOH (24% w/w, 10 ml) and cyclopropylamine (3 mL, 43.4 mmol) were added at 0° C., followed by stirring at r.t. o.n. The reaction mixture was concentrated in-vacuo. The isolated residue was treated with cold aq. NaOH (1N, 75 ml) and extracted with EA. The combined organic phase was washed sequentially with aq. NaOH and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The isolated residue was triturated with Et2O to isolate the title compound (3.82 g). 1H-NMR: 7.59 (br. s, 2H), 4.96 (br. s, 2H), 2.60 (m, 1H), 0.90 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:8](F)[C:7]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:6][CH:5]=1)[CH3:2].[CH:33]1([O-:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.[Na+]>>[CH:33]1([O:38][C:8]2[C:7]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=2[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCOc1ccc(S(C)(=O)=O)c(F)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1
Reactant: [O-]C1CCCC1
Agent: [Na+]
Product: CCOc1ccc(S(C)(=O)=O)c(OC2CCCC2)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 80 °C

Procedure:
0.12 mmol of (6-Ethoxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 55) was added to a solution of sodium cyclopentanolate (prepared from 1 mmol sodium dissolved in 1 ml of cyclopentanol). The mixture was heated for 1 hour at 80° C., poured on ice/water and extracted with ethyl acetate. Chromatography (SiO2; ethyl acetate) yielded the title compound as a slightly yellow solid. MS (m/e): 551.1 (MH+, 29%)
Reaction SMILES: C([O:3][P:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)([CH3:6])=[O:5])C.Cl>>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([P:4]([CH3:6])(=[O:3])[OH:5])=[CH:12][CH:11]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)c1ccc(P(C)(=O)OCC)cc1
Agent: Cl
Product: CP(=O)(O)c1ccc(C(=O)O)cc1
Yield: 86.4 %

Procedure:
200 g of p-ethoxycarbonylphenyl-methylphosphinic acid ethyl ester are refluxed with concentrated hydrochloric acid in excess. After the reaction is complete, the water and the hydrogen chloride are distilled off in a water jet pump vacuum. The residue is recrystallized from water. 135 g of p-carboxyphenyl-methylphosphinic acid having a melting point of 238° C to 240° C are obtained, corresponding to a yield of 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25]C(OCC2C=CC=CC=2)=O)[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Product: C[C@H](N)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a nitrogen purged solution of 4-[2-((S)-1-benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester (308 mg, 0.644 mmol) in IMS (10 mL) was added 10% Pd/C (32 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 2 h. Additional quantities of 10% Pd/C were subsequently added (41 mg after 2 h and 33 mg after 4 h) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 17 h. The suspension was filtered through a PTFE frit and washed with additional IMS. The filtrate was concentrated in vacuo affording 4-[2-((S)-1-Aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a pale yellow oil (202 mg). LCMS: RT 2.34 min [M+H]+ 345.2
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)#[N:16]
Reactant: N#CCc1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of [4-(4-oxo-cyclohexyl)-phenyl]-acetonitrile (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(C(OCC)=O)[OH:4]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:11]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][C:3]([CH3:2])=[O:4]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCOC(=O)CC(C)=O

Procedure:
In the same way as in Example 1, 60 g (0.21 mol) of tetraisopropyl titanate were reacted with 116.6 g (0.42 mol) of triethyl citrate. The mixture was freed of alcohol under vacuum and 154.6 g of a clear, pale yellow liquid was obtained.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:30][C@@H:31]1[C:37](=[O:38])[N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:35]2[CH:47]=[CH:48][CH:49]=[CH:50][C:34]=2[O:33][CH2:32]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:12])[CH3:9]>>[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:30][C@@H:31]1[C:37](=[O:38])[N:36]([CH2:39][C:40]([OH:42])=[O:41])[C:35]2[CH:47]=[CH:48][CH:49]=[CH:50][C:34]=2[O:33][CH2:32]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5N hydrogen chloride-ethyl acetate solution (5 ml) and tert-butyl 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried in vacuo to give 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride (0.08 g).
Reaction SMILES: [O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([O:31][CH3:32])[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH:30]=NC=N4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.N1(CCCN)C[CH2:37][O:36][CH2:35][CH2:34]1>>[O:1]=[C:2]1[CH:10]([C:11]2[C:16]3=[C:17]([O:31][CH3:32])[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:37][O:36][CH2:35][CH2:34]4)=[O:21])=[CH:19][N:15]3[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: NCCCN1CCOCC1
Reactant: COc1c(C(=O)NCCCn2cncn2)cn2ncnc(C3C(=O)Nc4ccccc43)c12
Product: COc1c(C(=O)NCCCN2CCOCC2)cn2ncnc(C3C(=O)Nc4ccccc43)c12

Procedure:
Compound A of Example 128 was converted to the title compound by the procedure same as that for Example 126 except N-[3-(4-morpholinyl)propylamine was used. MS: (M+H)+=451.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:23]([OH:28])[OH:24])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCCc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 26 (35.5 g, 0.15 mol), n-butyllithium (15 cm3, 10M in hexanes, 0.15 mol) and triisopropyl borate (56.4 g, 0.3 mol). The experimental procedure was as described in Example 28.