Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4]1.[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(C)C>[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][CH:28]([NH:2][C@H:3]2[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[CH2:4]2)[CH2:27][CH2:26]1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of N-{2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride (22.10 g, 47.1 mmol) and 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (12.7 g, 47.1 mmol) in isobutyl alcohol (80.0 mL) was added triethylamine (19.7 mL, 141 mmol). The reaction mixture was cooled in an ice bath and stirred for 30 minutes. To it was added sodium triacetoxyborohydride (11.0 g, 51.8 mmol) in portion. After being stirred at room temperature for 4 hours, the solvent was removed by evaporation under reduced pressure. Saturated aqueous NaHCO3 solution was added and the solution was extracted with ethyl acetate (150×3). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was columned on silica gel, eluting with ethyl acetate (1% NH4OH aqueous solution)/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated to give the title compound as a white powder (17.77 g). MS (M+H) 569.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CC(C)=O.C(OCC)(=O)C>[CH2:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1c(Br)cccc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 105.7 %

Procedure:
To a solution of 3-bromo-2-fluorophenol (1.8 g, 9.42 mmol) in acetone (25 ml) was added sodium carbonate (2.55 g, 20 mmol) and the mixture was stirred for 5 min. Benzylbromide (1.2 ml, 10.3 mmol) was added and the reaction mixture was heated at reflux for 20 h. Water (50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane/ethyl acetate, 5:1) to give the title compound (2.8 g). MS m/z (rel. intensity, 70 eV) 282 (M+, 2), 280 (M+, 2), 163 (2), 161 (2), 91 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:39])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)(=[O:27])=[O:26])[N:21]=[C:8]2[N:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[C:6]=1[CH3:50])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:39])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:26])=[O:27])[N:21]=[C:8]2[N:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:47])[F:49])[CH:41]=2)[C:6]=1[CH3:50])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO[Si](C)(C)C(C)(C)C)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO)c(=O)n2[C@@H]1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
Intermediate 27 (620 mg, 0.85 mmol) was dissolved in THF (7 mL), and then a solution of 1 M TBAF in THF (1.3 ml, 1.3 mmol) was added. The reaction mixture was stirred at RT for 16 hours and then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 4-5% methanol in DCM to afford the title compound as a colourless oil (476 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]([NH:5][C@H:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[N:8]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:7]1=[O:29])=[O:4].C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[S:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:44]1([NH:50][C:51](=[S:52])[NH:1][C@@H:2]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:3]([NH:5][C@H:6]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[N:8]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:7]2=[O:29])=[O:4])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (12 g) and triethylamine (3.83 ml) in tetrahydrofuran (240 ml) was added phenyl isothiocyanate (2.99 ml) at room temperature. After stirring for 4 hours at room temperature, the solvent of the reaction mixture was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S)-3-[[(2S)-2-[N'-(phenyl)thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.26 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:3]1.C([N-]C(C)C)(C)C.[Li+].[C:22](=[O:24])=[O:23].[OH-].[Na+]>C(OCC)C.C1COCC1.CCCCCCC.O>[CH3:1][N:2]1[C:6]([C:22]([OH:24])=[O:23])=[CH:5][C:4]([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[N:3]1
Reactant: Cn1ccc(C(F)(F)C(F)(F)F)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: Cn1nc(C(F)(F)C(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Yield: 19.7 %

Procedure:
Under an argon atmosphere, 5.00 g (24.99 mmol) of 1-methyl-3-pentafluoroethyl-1H-pyrazole are initially introduced in diethyl ether and the solution is cooled to −78° C. 11.09 ml (27.73 mmol) of 2M lithium diisopropylamide solution in THF/heptane are added dropwise and, at −30° C. with vigorous stirring, 450 g of crushed dry ice are added. When the evolution of gas has finished, the reaction mixture is admixed with 235 ml of water and adjusted to a pH of 11 with 1N sodium hydroxide solution. The alkaline solution is extracted three times with ethyl acetate and then adjusted to pH 2 with 1N hydrochloric acid. The aqueous phase is extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate. Distilling off the solvent on a rotary evaporator under reduced pressure gives 1.20 g (17.75% of theory) of 1-methyl-3-pentafluoroethyl-1H-pyrazole-5-carboxylic acid as a solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26].[ClH:32]>C1COCC1>[NH2:1][C@H:2]([C:6]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([O:27][CH3:28])=[O:26])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:32]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-Val-OH (3.00 g, 13.8 mmol) was dissolved in 10 ml of dry THF and cooled down to −15° C. To the mixture CAIBE (1.80 ml, 13.8 mmol) and NMM (1.52 ml, 13.8 mmol) where added and the solution was stirred until the formation of the mixed anhydride was complete. Then the mixture was brought to −10° C. and NMM (1.52 ml, 13.8 mmol) was added followed by H-Pro-OMe.HCl (2.29 g, 13.8 mmol). The mixture was allowed to reach room temperature and left overnight. After removing the solvent and the usual workup the resulting ester 1 was taken without further characterisation. The ester 1 was dissolved in HCl/HOAc (5 ml, 6N) and left at 0° C. until the removal of the Boc-group was complete. The solvent was then removed and the resulting oil was treated with diethylether to give a white solid 2.
Reaction SMILES: [OH:1][CH:2]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClC(Cl)=C(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:1]=[C:2]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCCCc1ccccc1)c1c[nH]cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=C(CCCCc1ccccc1)c1c[nH]cn1

Procedure:
5,5 g of 4-(1-hydroxy-5-phenylpentyl)-1H-imidazole and 7,0 g of manganese dioxide are refluxed stirring in tetrachloroethylene for four hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Water is added and the product is extracted into methylene chloride. The combined extracts are washed with water and evaporated to dryness.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[C:7]([O:12]C)(=O)[C:8]([CH3:10])=[CH2:9]>[O-2].[Ca+2].[OH-].[Li+].O.COC1C=CC(O)=CC=1>[C:7]([O:6][CH2:1][CH2:2][CH:3]([O:5][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:4])(=[O:12])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OC
Reactant: CC(O)CCO
Agent: COc1ccc(O)cc1
Agent: [Ca+2]
Agent: [Li+]
Solvent: O
Product: C=C(C)C(=O)OCCC(C)OC(=O)C(=C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
792 kg of 1,3-butanediol, 2650 kg of methyl methacrylate (MMA), 0.125 kg of hydroquinone monomethyl ether as inhibitor and a mixture of 5 kg of calcium oxide, 1 kg of lithium hydroxide and 3 kg of water as catalyst are combined in a 6 m3 stirred tank reactor provided with agitator, steam heating, distillation column and condenser and the mixture is stirred while passing in air. To stabilize the column, a total of 151 kg of MMA containing 0.24 kg of hydroquinone monomethyl ether and 0.016 kg of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in dissolved form are introduced into the column runback during the course of the reaction. The apparatus is heated to a temperature at the bottom of 100° C., with the column initially being operated under total reflux. As soon as the temperature at the top of the column drops to below 70° C., the methanol/MMA mixture is taken off at a reflux ratio of 4:1. The MMA stock in the reactor is supplemented by introduction of equal parts of fresh MMA per part of methanol/MMA mixture taken off. Thus, a total of 1226 kg of MMA are introduced over a period of 5 hours. Over a period of 8 hours, the reflux ratio is adapted to the decreasing formation of methanol up to a value of 1.5:1. At a temperature at the bottom of 130° C., the reaction is complete and excess MMA is taken off under reduced pressure, with the pressure being gradually reduced to 100 mbar. When no more MMA distills off, the vacuum is broken. The contents of the tank, comprising the catalyst-containing 1,3-butanediol dimethacrylate, is admixed with 9 kg of bleaching earth and 6 kg of aluminium silicate (Perlite) as filter aid and freed of catalyst by washcoat filtration. The filtrate is fed into a continuous evaporator (area: 3.5 m2) having a rotating wiper system at a pressure of 18 torr and a vaporizer temperature of 134° C. A total of 1810 kg of 1,3-butanediol dimethacrylate are obtained from the bottom product:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10](=[O:12])[N:35]([CH3:36])[CH3:33])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The hydrogenated compound 4 (8.0 g, 18.0 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (3.02 mL, 21.6 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 8.78 g, 20.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 45.2 mL, 90.0 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 5 (8.4 g, ˜98%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.23 (m, 1H), 3.58 (s, 3H), 2.91 (s, 3H), 2.70-2.86 (m, 7H), 2.62 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH:2]2[CH2:7][CH2:6][O:5][C:3]2=[O:4])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: O=C1OCCC1Br
Agent: [Na+]
Solvent: CCO
Product: O=C1OCCC1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of α-bromo-γ-butyrolactone (1.58 g; 9.62 mmol) and 4-chlorobenzenesulfinic acid sodium salt (2.39 g; 12.03 mmol) in ethanol (75 mL) was heated at 65° C. for 10 hours and the volatiles removed in vacuo. The residue was diluted with ethyl acetate and filtered. Removal of the volatiles from the filtrate provided as residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 1.58 g of the desired product. 1H NMR (CDCl3) δ 7.89 (d, 2H), 7.58 (d, 2H), 4.54 (m, 1H), 4.42 (m, 1H), 4.03 (dd, 1H), 3.07 (m, 1H), 2.77 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([N:15](CC2C=CC(OC)=CC=2OC)[S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([O:26][C@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]3[C:33]3[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=3)=[CH:21][C:20]=2[F:39])(=[O:18])=[O:17])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:23]1[C:22]([O:26][C@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[CH:21][C:20]([F:39])=[C:19]([S:16]([NH:15][C:13]2[NH:14][C:9](=[O:8])[N:10]=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:24]=1
Reactant: COc1ccc(CN(c2ccnc(OCc3ccccc3)n2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccnc(=O)[nH]2)cc1Cl
Yield: 89.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-[2-(benzyloxy)pyrimidin-4-yl]-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}benzenesulfonamide (0.48 g, 0.66 mmol) prepared in Example 153c, triethylsilane (1.6 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (6.6 mL), to yield the title compound (285 mg, 89%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[Cu](I)I.O.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: BrCCc1ccccc1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2)CCN(C)CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by following general procedure 4. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1.0 mmol) was taken with copper iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), potassium phosphate tribasic (426 mg, 2.0 mmol) and (2-bromoethyl)benzene (185 mg, 1 mmol) and DMF was added, the reaction was stirred at 90° C. under argon atmosphere for 12 h. The reaction was monitored by LCMS. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude so obtained was purified by column chromatography (silica gel 100-200 mesh) (gradient 5% MeOH:DCM). The pure product was converted to oxalate salt using oxalic acid and THF.
Reaction SMILES: [CH3:1][S:2](OCC1C=CC=C(C2N=C(N3CCOCC3)C3=CC(CN(C)C)=CN3N=2)C=1)(=[O:4])=[O:3].[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[N:45]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[C:43]3=[CH:52][C:53]([CH2:55][N:56]([CH3:58])[CH3:57])=[CH:54][N:42]3[N:41]=2)[CH:37]=[CH:38][CH:39]=1.ClCCl>CO>[CH3:57][N:56]([CH2:55][C:53]1[CH:52]=[C:43]2[N:42]([CH:54]=1)[N:41]=[C:40]([C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[N:45]=[C:44]2[N:46]1[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1)[CH3:58]
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CN)c3)nn2c1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Solvent: CO
Solvent: ClCCl
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CNS(C)(=O)=O)c3)nn2c1
Yield: 26.7 %

Procedure:
Compound I-26 was prepared by the method which was identical with that for preparing compound 19, wherein compound 20 (37 mg, 0.1 mmol) was used as the starting material. Light yellow solid (12 mg, 26.7%) were obtained by a preparative plate (dichloromethane:methanol=8:1). m.p. 238-240° C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.19 (d, J=7.1 Hz, 1H), 7.60 (s, 1H), 7.47-7.38 (m, 2 H), 6.88 (s, 1H), 4.41 (s, 2H), 4.02 (br, s, 4H), 3.81 (t, J=4.4 Hz, 4H), 2.95 (s, 2H), 2.94 (s, 3H), 2.87 (s, 1H), 2.51 (s, 6H). MS (EI) m/e (%): 444 (M+, 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[OH:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)c2cccnc2)cc1OC
Agent: Cn1cncc1C(O)c1ccccn1
Product: COc1ccc(C(=O)c2cccnc2)cc1OC

Procedure:
The title compound was prepared analogously to the method in Intermediate 33: step b using (3,4-dimethoxyphenyl)(pyridin-3-yl)methanol (Intermediate 88: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:28]1([C:27]2[N:35]=[C:5]([C:7]3[CH:8]=[C:9]([P:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:34]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Solvent: CCO
Product: c1ccc(-c2nccc(-c3cccc(P(c4ccccc4)c4ccccc4)c3)n2)cc1
Yield: 79 %

Procedure:
10 mmol of 4 are dissolved in 100 ml of ethanol and mixed with 10 mmol of benzamidine. The mixture is refluxed for 90 min, subsequently the solvent is removed. Recrystallization from acetic acid ethyl ester gives a colorless solid. Yield: 79%. ESI MS, m/z (%): 417.4674 (100) [M+H]+. 31P{1H} NMR (101.2 MHz, 25° C., DMSO-d6): δ −7.37.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[C:5](=O)[NH:6][C:7]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[K+]>O1CCCC1>[CH3:1][O:2][C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[CH2:5][NH:6][CH2:7]1
Reactant: COC12C=CC(CC1)C1C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC12C=CC(CC1)C1CNCC12

Procedure:
20.5 g (0.1 mol) of 1-methoxy-4azatricyclo[5.2.2.02,6 ]undec-8-ene-3,5-dione in 100 ml of absolute tetrahydrofuran are added dropwise to 6 g of LiAlH4 in 200 ml of absolute tetrahydrofuran and the mixture is stirred under reflux overnight. 6 ml each of water, 15% strength KOH solution and water again are added, the inorganic salts are filtered off with suction and boiled out twice with tetrahydrofuran, the filtrates are concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1>>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:1][C:2]5[CH:6]=[C:5]([C:7]6[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=6)[NH:4][N:3]=5)=[O:21])=[CH:17][CH:18]=4)=[CH:27][CH:26]=3)=[O:30])[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Product: O=C(Nc1cc(-c2ccccc2)[nH]n1)c1ccc(-c2ccc(C(=O)Nc3cc(-c4ccccc4)[nH]n3)cc2)cc1

Procedure:
Compound 475 was prepared from 3-amino-5-phenylpyrazole and biphenyl-4,4′-dicarboxylic acid. [M+H]+ calcd for C32H25N6O2: 525.20; found: 524.98.