Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH:31]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3]
Reactant: C1COCCN1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(=O)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), morpholine (35 μL), and 1,2-dichloroethane (1.94 mL) was added sodium triacetoxyborohydride (100 mg), followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and water, followed by extraction with chloroform twice. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0-99:1-97:3) to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-({3-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (55 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[C:8]([O:14][CH2:15][O:16][CH3:17])=[C:9]([CH:11]([OH:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.O>[C:1]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[C:8]([O:14][CH2:15][O:16][CH3:17])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1c(-c2ccc(C(F)(F)F)nc2)cc(C(C)(C)C)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: COCOc1c(C(C)=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1-(5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-ol (529 mg, 1.38 mmol) and sodium bicarbonate (1.16 g, 13.8 mmol) in methylene chloride (40 mL) was added Dess Martin periodinane (3.00 g, 6.90 mmol) and the reaction stirred for 1 hour. The reaction mixture was poured onto a 1:1 mixture of saturated aqueous sodium sulfite solution (50 mL) and water (50 mL). The resulting mixture was extracted with ethyl acetate (150 mL). The organic phase was washed with 1 N aqueous sodium hydroxide solution (50 mL), and water (50 mL), an emulsion formed and saturated brine (100 mL) was added to separate layers. The organic phase was dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 1-(5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-one (526 mg, 100% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([O:6][C:7]2=[O:8])=O.[NH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:18][C:19]([OH:21])=[O:20]>C(O)(=O)C>[Cl:1][C:2]12[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[CH:9][CH:3]1[C:4]([N:16]([CH:17]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:18][C:19]([OH:21])=[O:20])[C:7]2=[O:8])=[O:6]
Reactant: O=C1OC(=O)C2(Cl)C(Cl)=C(Cl)C(Cl)=CC12
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)C3C=C(Cl)C(Cl)=C(Cl)C3(Cl)C2=O)cc1
Yield: 91.2 %

Procedure:
A stirred mixture of 2,3,4,5-tetrachlorophthalic acid anhydride (2.85 g, 10.0 mmol) and 3-amino-3-(4'-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) in 25 mL of acetic acid under nitrogen was heated to reflux for 4.5 hours. Solid formed as the reaction mixture cooled. The resulting slurry was filtered and the solid dried in vacuo (60° C., <2 mm) to afford 4.24 g (92%) of 3-(2,3,4,5-tetrachlorophthalimido)-3-(4'-methoxyphenyl)propionic acid as an off-white solid contaminated with ~ 1% acetic acid: mp 235.6°-238° C.; 1H NMR (DMSO-d6) δ 12.44 (br s, 1H, COOH), 7.36 (d, J=8.7 Hz, 2 H), 6.90 (d, 1 H, J=8.7 Hz), 5.64 (m, 1 H), 3.72 (s, 3 H), 3.35 (m, 2 H); 13C NMR (DMSO-d6) δ 171.5, 163.0, 158.8, 138.4, 129.9, 128.6, 128.2, 127.6, 113.8, 55.0, 50.2, 35.6. Anal. Calcd for C18H11NO5Cl4. Theory: C, 46.68; H, 2.39; N, 3.02. Found: C, 46.58; H, 2.31; N, 2.91.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].N1C=CN=C1.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:17]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH2:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(CN)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CN)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
2 g of 3-amino2,2-dimethylpropan-1-ol (19.39 mmol) are placed in 40 ml of DCM. 2.56 g of imidazole (38.77 mmol) are added and the solution is cooled to +4° C. in an ice bath, followed by dropwise addition of 3.36 ml of tert-butyl(chloro)dimethylsilane (19.39 mmol). The medium is stirred for 30 minutes at +4° C., and the ice bath is then removed and the mixture is stirred at room temperature for 18 hours. The medium is then washed with water, and then with brine. The organic phase is dried over Na2SO4, filtered and concentrated to give 4.02 g of 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropylamine.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=O)[N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C(N=C=NCCCN(C)C)C.Cl.[CH2:58]([O:65][NH2:66])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C)C=O.O>[CH2:58]([O:65][NH:66][C:15]([C@H:11]1[CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][N:10]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:17])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylic acid (206 mg, 0.5 mmol) is dissolved in N,N-dimethylformamide (20 mL) and is cooled to 0° C. To this is added 1-hydroxybenzotriazole (203 mg, 1.5 mmol), 4-methylmorpholine (0.16 mL, 1.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (117 mg, 0.61 mmol) followed, after 20 minutes, with O-benzylhydroxylamine hydrochloride (89 mg, 0.56 mmol). The reaction is stirred for 4 hours at room temperature, water (50 mL) is added and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with water (2x), dried (Na2SO4) and concentrated under reduced pressure to give N-benzyloxy 1-benzyl-3-[(4methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine4(R)-carboxamide.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:26]3[O:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[CH3:27][C:24]1[O:25][C:26]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:19][CH:20]=[CH:21][C:22]=2[CH:23]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3cc(C)oc23)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2cccc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)c2o1
Reaction time: 18 h
Yield: 100.3 %

Procedure:
A 50 mL flask containing the 2-[(2-methylbenzofuran-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (0.40 g, 1.10 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH (115 mg, 2.75 mmol). After 18 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜12 mL). The contents of the flask are poured into a reparatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by vacuum to constant weight to give 0.37 g of white solid.
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][CH:24]([CH3:34])[CH2:25][C@H:26]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:27]O.[Cl-].C([NH3+])C(C)C.[N+:41]([C:44]1[CH:49]=[CH:48][C:47]([N:50]=[C:51]=[S:52])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[N+:41]([C:44]1[CH:45]=[CH:46][C:47]([N:50]=[C:51]2[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:26]([CH2:25][CH:24]([CH3:34])[CH3:23])[CH2:27][S:52]2)=[CH:48][CH:49]=1)([O-:43])=[O:42]
Reactant: CC(C)CN[C@H](CO)CC(C)C
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Agent: CC(C)C[C@H](N)CO
Agent: CC(C)C[NH3+]
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2-(isobutylamino)pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride according to Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride to Method C1f to afford (4S)-2-(4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:18].[Na+].O.O.P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>O.C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]([OH:18])=[O:6]
Reactant: COc1ccc(C=O)cc1Br
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
3-Bromo-4-methoxybenzaldehyde (15 g, 70 mmol), t-butanol (140 ml), 2-methyl-2-butene (50 ml, 469 mmol) were mixed, and to this solution was added dropwise a solution prepared by mixing sodium chlorite (10.42 g, 91 mmol), sodium dihydrogenphosphate dihydrate (14.2 g, 91 mmol) and water (70 nil). The mixture was stirred at room temperature for 16 hours. A 1N aqueous sodium hydroxide solution (50 ml) was added, and t-butanol was evaporated under reduced pressure. Conc. hydrochloric acid was added to make the mixture acidic. The precipitated crystals were collected by filtration and washed with hexane. The obtained crystals were dissolved in ethyl acetate (200 ml), and this solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-bromo-4-methoxybenzoic acid (10.5 g, 65%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:7]([C:15]([CH3:19])=[CH:16][C:17]#[N:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([C:5]1[C:6]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:7]([CH:15]([CH3:19])[CH2:16][C:17]#[N:18])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1c(C(C)=CC#N)cc(C(C)(C)C)cc1C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCOc1c(C(C)CC#N)cc(C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.02 h
Yield: 89.7 %

Procedure:
To a solution of 3-(3,5-di-t-butyl-2-n-heptyloxyphenyl)-but-2-enenitrile (900 mg, 2.64 mmol) in EtOAc (5 mL) was added 10% Pd on carbon (20 mg, catalytic amount). The mixture was placed under vacuum for 1 min followed by addition of H2. After stirring for 24 h under an atmosphere of H2, the solution was filtered through celite. The celite washed with EtOAc (3×5 mL) and the solution was concentrated to give the reduced product 3-(3,5-di-t-butyl-2-n-heptyloxyphenyl)-butyronitrile 880 mg (97%): TLC (5% EtOAc-95% hexanes) Rf0.8; 1H-NMR (CDCl3) δ 7.00(d, J=2.2 Hz, 1H, Ar—H) 6.89(d, J=2.2 Hz, 1H Ar—H), 3.73 (t, J=6.5 Hz, 2H, OCH2), 3.52(m, 1H, CH), 3.27(m, 1H, CH), 2.86(m, 1H, CH), 2.63(m, 2H, CH2CN), 1.79(m, 2H, CH2), 1.50(m, 2H, CH2), 1.44(m, 6H, 3CH2), 1.39(d, J=13.2 Hz, 3H, CH3), 1.27(d, J=4.7 Hz, 2CH3), 1.21(d, J=4.7 Hz, 2CH3), 0.89(t, J=6.6 Hz, 3H, CH3).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:25]=[C:26]=[O:27]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:26]([NH:25][C@@H:6]([CH3:7])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:4]=2)=[O:27])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Product: C[C@H](NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1)c1ccccc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[CH:6][N:7]=1.[O-:11][CH2:12][CH3:13].[Na+]>CCO>[CH2:12]([O:11][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[CH:6][N:7]=1)[CH3:13]
Reactant: CC[O-]
Reactant: Clc1cc2ccsc2cn1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ccsc2cn1
Temperature: 175 °C
Yield: 68.8 %

Procedure:
A sealable vial was charged with 5-chlorothieno[2,3-c]pyridine (240 mg, 1.41 mmol), sodium ethoxide (557 mg, 7.78 mmol) and EtOH (6.5 mL). The reaction was heated in a microwave reactor at 175° C. for 2 h, then purified by ISCO chromatography (0 to 25% EtOAc:hexane) to afford 174 mg (69%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.69-8.70 (m, 1 H), 7.63 (d, J=5.6 Hz, 1 H), 7.20 (dd, J=5.6, 0.8 Hz, 1 H), 7.08 (d, J=0.8 Hz, 1 H), 4.39 (quartet, J=7.2 Hz, 2 H), 1.43 (t, J=7.2 Hz, 3 H); MS (ESI): 180.04 [M+H]+; HPLC tR=1.39 min (TOF: polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccc(F)nc3)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccc(-c3ccc(F)nc3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])O)=[CH:15][CH:14]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[NH:32][CH:31]=[CH:30]2>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])[C:30]2[C:29]3[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=[C:27]([F:26])[CH:28]=3)[NH:32][CH:31]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1(F)F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3(F)F)c[nH]c12

Procedure:
97.1 mg (0.44 mmol) of indium(III) chloride and 0.05 ml (0.07 mmol) of trifluoroacetic acid were added to 80.0 mg (0.37 mmol) of the compound from Example 159A and 100 mg (0.44 mmol) of the compound from Example 87A in 4 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 6.0 mg (4% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N:13]=[N:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.CCOCC>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N:13]=[N:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)nnc3ccc(Cl)cc32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)nnc5ccc(Cl)cc54)CC3)nc2N1
Yield: 32.3 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one (Intermediate 207, 67 mg) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (360 mg) and sodium acetoxyborohydride (76 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane and trituration from ether gave 33 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:12][C:13]1=[C:14]([CH3:20])[C:15]([O:17][C:18]1=O)=[O:16]>C(O)(=O)C>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[N:1]1[C:15](=[O:16])[C:14]([CH3:20])=[C:13]([CH3:12])[C:18]1=[O:17]
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)ccc2F)C1=O
Reaction time: 12 h
Yield: 89.1 %

Procedure:
A mixture of 46.5 g of 3-amino-4-fluorobenzoic acid and 37.8 g of dimethylmaleic anhydride in 200 ml of glacial acetic acid is stirred for 12 hours at an oil bath temperature of 130°-40°. After cooling, the mixture is poured onto ice-water, and the resulting precipitate is filtered with suction, washed with water and dried. Recrystallisation from ethanol/water yields 70.3 g of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide which melts at 238°-240°.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=O.[NH3:30]>O1CCCC1.CO>[NH2:30][C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])=[O:3]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 8) (5 mg) was dissolved in a mixture of tetrahydrofuran (1 mL) and 2 M ammonia in methanol solution (2 mL). After stirring for 16 h at room temperature, the solvent was evaporated and the residue was coevaporated with methanol (3 mL twice) under vacuum. Purification by reverse phase preparative HPLC provided the title compound (2.2 mg). HPLC/MS [M+H]+, 397.
Reaction SMILES: ClC[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][N:14]=[C:15](C3C=CC(OC)=CC=3)[N:5]2[N:4]=1>N1CCCC1>[N:13]1[N:14]=[CH:15][N:5]2[N:4]=[CH:3][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=12
Reactant: COc1ccc(-c2nnc3c4ccccc4c(CCl)nn23)cc1
Solvent: C1CCNC1
Product: c1ccc2c(c1)cnn1cnnc21
Yield: 108.1 %

Procedure:
6-(Chloromethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine (3 g) and pyrrolidine (30 ml) are heated at 100° C. for 8 h in autoclave. The amine excess is removed, the residue is washed with a small amount of water and crystallized from ethyl acetate, yielding 3-(4-methoxyphenyl)-6-[1-pyrrolidinyl)methyl]-1,2,4-triazolo[3,4-a]phthalazine (1.7 g). M.p. 184°-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][OH:12]>C1C=CC=CC=1>[CH3:11][O:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C)cc1
Reaction time: 20 h

Procedure:
544 g. of 4-methyl-benzoic acid was boiled with 550 ml. of thionyl chloride until a clear solution was obtained. After the excess thionyl chloride was distilled off, the residue was fractionated, yielding 605 g. of 4-methyl-benzoyl chloride; b.p. 91°/9 mm Hg., nD24 = 1.5532. This was dissolved in 550 ml. of absolute benzene and the so-formed solution added to a mixture of 248 ml. of absolute methanol and 550 ml. of absolute benzene. After the exothermic reaction had terminated, the reaction mixture was boiled for a further 20 hours, then concentrated in vacuo and the product, 4-methyl-benzoic acid methyl ester, isolated by conventional means. It could be purified by distillation, and the purified product boiled at 91°/9 mm Hg., m.p. 32°.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:37])[S:5]([N:8]1[CH:12]=[C:11]([C:13]([C:15]2([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17][CH2:16]2)=[O:14])[N:10]=[C:9]1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][CH:26]=1)(=[O:7])=[O:6].C(OCC)(=O)C.CCCCCC>CO.O>[OH:14][CH:13]([C:15]1([C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17][CH2:18]1)[C:11]1[N:10]=[C:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[N:8]([S:5]([N:4]([CH3:3])[CH3:37])(=[O:7])=[O:6])[CH:12]=1
Reactant: CN(C)S(=O)(=O)n1cc(C(=O)C2(C(F)(F)F)CCC2)nc1CCc1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)n1cc(C(O)C2(C(F)(F)F)CCC2)nc1CCc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (8 mg, 0.21 mmol) was added to a solution of N,N-dimethyl-2-[2-(4-pyridin-2-ylphenyl)ethyl]-4-{[1-(trifluoromethyl)cyclobutyl]carbonyl}-1H-imidazole-1-sulfonamide (106 mg, 0.21 mmol) in methanol (3 mL) at 0° C. followed by 1 drop of water. The resulting solution was stirred at rt for 1 hr. The reaction mixture was partially concentrated and partitioned between 1N aqueous sodium hydroxide and ethyl acetate. The organic phase was washed with brine, dried (sodium sulfate) and concentrated to give a residue. Chromatography of the residue over silica gel eluting with 40-100% ethyl acetate/hexane afforded 4-{hydroxy[1-(trifluoromethyl)cyclobutyl]methyl)-N,N-dimethyl-2-[2-(4-pyridin-2-ylphenyl)ethyl]-1H-imidazole-1-sulfonamide.