Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)([O-])=O.C.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1-n1cccn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1-n1cccn1
Yield: 90 %

Procedure:
Into a Parr hydrogenation apparatus is successively added 20 g. (0.106 M.) of 1-(o-nitrophenyl)-pyrazole and 150 ml. of methanol and the resultant solution is hydrogenated in the presence of 1.0 g. of hydrogenation catalyst (10% Pd on active charcoal) at between 40 and 50 p.s.i. of hydrogen pressure at room temperature. After the theoretical uptake of hydrogen is achieved, the reaction mixture is filtered to remove the palladium and the solvent is removed on a rotary evaporator. Ether is then added to the resultant mixture and after removing the precipitated solids by filtration, the solvent is evaporated to yield a light amber colored oil (Yield: 90%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Reactant: CN1CCN(C2CNC2)CC1
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (40.0 mg, 0.0694 mmol) described in Production Example 1-1-6 and NMP (2.0 mL) was added a mixture (112 mg) of 1-(azetidin-3-yl)-4-methylpiperazine and benzylbenzene described in Production Example 3-2 at room temperature, and the resultant mixture was irradiated with a microwave at 140° C. for 12 hours. After the mixture was cooled to room temperature, water was added to the reaction mixture, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and then further purified by NH silica gel thin-layer chromatography (ethyl acetate) to give the title compound (26.0 mg, yield: 53%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[NH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20]2[N:29]=[C:28]([N:30]([CH3:31])[CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:17][CH2:18]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](CCNC(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CCN)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cis-{2-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-ethyl}-carbamic acid benzyl ester (4.47 g, 10 mmol) in EtOH (20 mL) was added 1,4-cyclohexadiene (20 mL) and 200 mg of 10% Pd/C. The reaction mixture was stirred at ambient temperature for 18 hr, filtered through pad of celite, and concentrated. The residue was purified by column chromatography (silica gel, 5% to 15% 2 M NH3/MeOH in CH2Cl2) to give cis-N2-[4-(2-amino-ethyl)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (2.41 g, 77%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([NH:21][C:22](=[O:25])[CH2:23]Cl)[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:34]1([OH:44])[C:43]2[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:20]=[C:19]([NH:21][C:22](=[O:25])[CH2:23][O:44][C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: Oc1cccc2c1CCCC2
Reactant: Cc1cc(NC(=O)CCl)ccc1C(=O)N1CCCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)COc2cccc3c2CCCC3)ccc1C(=O)N1CCCCc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
1-[2-Methyl-4-(2-chloroacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide (5 ml), and thereto are added potassium carbonate (0.47 g), sodium iodide (0.51 g) and 5,6,7,8-tetrahydro-1-naphthol (0.40 g), and the mixture is stirred at 60° C. for three hours. To the reaction solution is added ethyl acetate, and the mixture is washed with a saturated aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The resulting residue is allowed to stand for one day, washed with dichloromethane, filtered, and dried to give 1-{2-methyl-4-[2-(5-tetrahydronaphthyloxy)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.72 g) as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cc(Br)cs1
Product: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1

Procedure:
1-(4-(4-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from (4-bromothien-2-yl)ethanone and 4-trifluoromethylphenylboronic acid according to general procedure A.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=O)[CH2:4][CH2:5][C:6]1[C:14]2[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1
Reactant: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCc1c[nH]c2c1CCCC2
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
N,N-Dimethyl-3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionamide (8 g, 0.034 mol) was suspended in 125 ml of tetrahydrofuran and lithium aluminum hydride (5.2 g, 0.136 mol) was slowly added. The mixture was refluxed over night, cooled in ice, and 5 ml of water and then 5 ml of 15% sodium hydroxide solution was slowly added. The mixture was stirred for 45 minutes. Water (15 ml) and sodium sulfate were added and the mixture filtered to remove solids. The solids were washed with ethyl acetate and the filtrate was concentrated to give dimethyl-[3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-amine (6.3 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29]>CO.Cl.[OH-].[OH-].[Pd+2].[C]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCNCC1
Yield: 76.5 %

Procedure:
A solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-3-carboxamide (Example 52, 0.9 g, 2.21 mmol) in MeOH (44.2 ml) with a few drops of conc. HCl was passed through an H Cube apparatus using a 20 wt % Pd(OH)2/Carbon cartridge, at 10 bar. The solvent was removed under reduced pressure and the residue was purified with silica chromatography CH2Cl2/10% MeOH (1% NH4OH) to give 692 mg (77%) of a light yellow solid. 1H NMR: MeOD 7.61 (s, 1H), 7.37 (m, 1H), 7.23 (m, 1H), 7.12 (m, 2H), 4.09 (s, 3H), 3.38 (m, 2H), 3.22 (m, 1H), 3.12 (m, 2H), 2.43 (s, 3H), 1.90 (m, 2H), 1.36 (m, 2H); m/z 410.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CCN(CC)CC>ClCCCl.CN(C=O)C.CCOCC>[C:1]1([CH:7]([CH3:11])[C:8]([N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 2-phenyl propionic acid (1.0 g, 6.7 mmol) in 1,2-dichloroethane (15 mL) was added a few drops of DMF and excess thionyl chloride. The resulting mixture was heated at reflux for 2 h, when bubbling ceased the mixture was evaporated to dryness. The crude residue was co-evaporated with toluene and 1,2-dichloroethane. The residue was dissolved in CH2Cl2 and cooled to 0° C. To the stirred solution, BOC-piperazine (1.24 g, 6.7 mmol) and Et3N were added. A white precipitate formed and the reaction was stirred 12 h at RT. Et2O was added and the mixture was washed with water and brine. The ether layer was separated and dried over anhydrous Na2SO4, filtered, and evaporated. The residue was treated with 20% ether/hexanes and the resulting solid filtered. The filtrate was evaporated and the procedure repeated. After drying, there remained a white solid (1.3 g, 62%). 1H NMR (CDCl3) δ: 1.4 (s, 9H), 1.42 (d, 3H), 2.7 (m, 1H), 3.1-3.6 (m, 6H), 3.85 (m, 2H), 7.2-7.4 (m, 5H). [M+Na] 341.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][C:5]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:4]1.[OH-].[Na+].C1C=CC=CC=1>O>[CH2:2]=[C:3]1[CH2:6][C:5]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:4]1
Reactant: BrCC1CC2(C1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: C=C1CC2(C1)OCCO2

Procedure:
A mixture of 2-(bromomethyl)-5,8-dioxaspiro[3.4]octane (1.3 gm, 6.28 mmol) (step e), polyethylene glycol (PEG-600) (0.5 gm), 50% aqueous sodium hydroxide solution (5 ml) and benzene was refluxed for about 12 hours. The reaction mixture was cooled, diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:10][C:11](=O)[NH:12][C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.P(Br)(Br)(Br)(Br)[Br:30].[Br-].[K+].ClC1C=CC=CC=1Cl>C(Cl)Cl.O>[Br:30][C:11]1[CH:10]=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]([F:17])([F:16])[F:15])[N:12]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(=O)[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: BrP(Br)(Br)(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(Br)nc(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 0.35 g of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-oxo-pyridine (step 5 of Example 1), 3 g of phosphorus pentabromide, 0.3 g of potassium bromide and 10 mL of 1,2-dichlorobenzene was held at reflux for 2 hours. The reaction mixture was cooled. An addition 3.7 g of phosphorus pentabromide was added to the reaction mixture and the reaction mixture was held at 90° C. for 8 hours, and at 180°-190° C. for 2 days. The reaction mixture was cooled and stirred with water and methylene chloride. The methylene chloride layer was dried over MgSO4 and filtered through silica gel. The methylene chloride filtrate was concentrated in vacuo and the residue was purified by HPLC (20% ethyl acetate/hexane then 50% ethyl acetate/hexane). The fraction eluted with 50% ethyl acetate/hexane yielded a solid. Recrystallization from methylene chloride/hexane yielded 150 mg of white solid: mp 187.5°-189° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](N(OC)C)=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:30][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[C:24]([C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]=1[NH2:1])(=[O:25])[CH3:30]
Reactant: CON(C)C(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Reaction time: 5 h

Procedure:
Under ice-bath cooling, to a suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methoxy-N-methyl-5-phenyl-2-pyrazinecarboxamide (200 mg) in THF (4.0 ml) was added 3.0M solution of methylmagnesium chloride in THF (0.85 ml) dropwise. The mixture was stirred at the same temperature for 5 hours. The mixture was poured into sat. aq ammonium chloride (20 ml) and an organic layer was extracted with EtOAc (50 ml), washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (CH2Cl2:MeOH=50:1-15:1). The desired fraction was recrystallized from MeOH and dried in vacuo to give 5-(6-acetyl-5-amino-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (111 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[S:13]([Cl:17])(=O)(=[O:15])[OH:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([Cl:17])(=[O:15])=[O:14]
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: O=S(=O)(O)Cl
Product: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (10 g) in chlorosulfuric acid (29.9 mL) was heated at 90° C. for 2 h. Chlorosulfuric acid (29.9 mL) was added, and the reaction mixture was poured onto ice (CAUTION). The resulting solid was filtered, washed with water, and dried in vacuo (25° C.) to give the subtitle compound as a beige solid (12.31 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH:28]([NH:31][C:32]([O:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)OCC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 1.0 g (2.56 mmol) of benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate and 0.97 g (10.24 mmol) of isopropyl isocyanate in 20 ml of dry toluene was heated to 100o for 4 hours. Subsequently, the reaction solution was evaporated under reduced pressure. The benzyl rac-α-[[[2-[(isopropylcarbamoyl)oxy]-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate was obtained in quantitative yield as a yellowish oil, MS: 384 (M-benzyl)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1)=[O:30])[CH3:27]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c1

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and 3-ethoxycarbonylphenylboronic acid was prepared the title compound as a yellow oil, MS (ESI+): m/z=464.22 ([M+H]+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[C:26]([CH3:27])([CH3:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:30])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)cc1
Yield: 21.9 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 0.22 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), cyclopropane sulfonamide (80 mg, 0.66 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (25 mg, 22%) as a light yellow solid: LC/MS m/e calcd for C30H34N2O4S (M+H)+: 519.68, observed: 519.4.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (88 mg, 92%), MS (ISP) m/z=384.4 [(M+H)+], mp 254° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 95 %

Procedure:
Potassium t-butoxide (1.05 g, 9.37 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2.4 g, 8.95 mmol) in 25 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (6.35 g, 44.73 mmol) and the resulting mixture was allowed to stir at 0° C. for 0.5 hour and at room temperature for 4 hours. The resulting mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 2.4 g (95%) of 2-phenylmethyl-4-propyl-5-methyl-1,2,5-thiadiazol-idin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl, R3 =methyl) as an oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:7]=2[N:8]=1)#[N:2]>FC(F)(F)C(O)=O.ClCCl>[N:8]1[C:7]2[CH2:9][NH:10][CH2:11][C:6]=2[CH:5]=[N:4][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C#N)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc2c(n1)CNC2

Procedure:
A solution of tert-butyl 2-cyano-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (150 mg) in trifluoroacetic acid and dichloromethane (1:1, 1 mL) was stirred for one h and evaporated. The residue was purified by flash column chromatography (silica, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to yield 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carbonitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([CH2:23][CH2:22][NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[N:15][CH:16]=2)=[O:27])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)NCCC3CC3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(C2=CCNCC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 5-(2-cyclopropylethylcarbamoyl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.338 g, 0.910 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.7 mL). The resulting mixture was stirred at room temperature for 6 hours and then quenched with a saturated aqueous solution of Na2CO3 (5 mL). The organic phase was washed with water (10 mL), saturated NaCl (10 mL), dried over MgSO4 and then concentrated in vacuo. The crude title compound was obtained and used without further purification.