Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]12[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:23][NH:22][CH2:21][CH2:20]2.O.[OH-].[K+]>C(OCC)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:22]2[CH2:23][CH:24]3[N:19]([CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:21]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CNCCN2C1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCN2CCCC2C1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Yield: 86 %

Procedure:
To 70.6 parts of 2,2-diphenyl-4-bromobutyronitrile is added 27 parts of 1,4-diazabicyclo[4.3.0]nonane, 63 parts of demineralized water and 15.5 parts of potassium hydroxide. The mixture is stirred and heated to 75° - 80° C. and then further heated to reflux. After 3.5 hours at reflux, the mixture is cooled to about 30° C. and 180 parts of ethyl ether is added. The aqueous layer is separated and discarded. The remaining ether layer is extracted three times with 100 parts by volume portions of 1% acetic acid in water, twice with 30% solutions of hydrochloric acid in water, and twice with 50% solutions of hydrochloric acid in water. The hydrochloric acid solution extracts are combined and basified to pH 11.0 with a 50% solution of potassium hydroxide in water. The resulting oil is extracted with three 150 part portions of chloroform. The chloroform extracts are combined, washed with 100 parts of a saturated sodium chloride solution, dried over anhydrous potassium carbonate, and stripped of solvent under reduced pressure. The resulting product, 2,2-diphenyl-4-(1,4-diazabicyclo[4.3.0]non-4-yl)butyronitrile, identical to the product of Example 7, is obtained in 86% yield. Correction of this yield to reflect the purity of the 1,4-diazabicyclo[4.3.0]-nonane (86.4%) results in a yield of 99.5% for this reaction.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[NH2:73][CH2:74][C:75]1([NH2:79])[CH2:78][O:77][CH2:76]1>CN(C)C=O.O>[NH2:79][C:75]1([CH2:74][NH:73][C:15]2[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=[C:13]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[S:2](=[O:1])[CH2:3][CH2:4]3)[N:14]=2)[CH2:78][O:77][CH2:76]1
Reactant: NCC1(N)COC1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(N)COC3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (250 mg, 0.72 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (415 mg, 0.94 mmol) and 1,8-diazabicycloundec-7-ene (165 mg, 1.08 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at r.t. for 10 min, then a solution of 3-aminomethyl-oxetan-3-ylamine (150 mg, 1.44 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After the addition was complete, the mixture was heated at 60° C. overnight, then it was diluted with water (50 mL), extracted by dichloromethane, washed by brine, dried with anhydrous sodium sulfate. The solvent was removed and the residue was purified by preparative HPLC to afford N-[(3-aminooxetan-3-yl)methyl]-6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)thieno[3,2-d]pyrimidin-4-amine as a white solid. MS obsd. (ESI+) [(M+H)+] 430, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67-7.80 (m, 2H), 7.45 (t, J=5.8 Hz, 2H), 6.82 (s, 1H), 5.21 (d, J=15.4 Hz, 1H), 4.71 (br. s., 1H), 4.63 (d, J=6.3 Hz, 2H), 4.46-4.56 (m, 2H), 4.01 (s, 2H), 3.30-3.49 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:17](=[O:19])O[C:15](=[O:20])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[N:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)[CH2:32][CH2:31]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Reactant: NCCN1CCN(c2ccncc2)CC1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2c1C(=O)N(CCN1CCN(c3ccncc3)CC1)C2=O)c1ccc(Cl)s1
Reaction time: 24 h

Procedure:
310 mg (1 mmol) of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thio-phenecarboxamide and 0.64 g (1 mmol) of 2-[4-(4-pyridinyl)piperazino]ethylamine (obtainable by heating 4-chloropyridine with aminoethylpiperazine or according to German Offenlegungschrift 2024350) are boiled in 40 ml of glacial acetic acid overnight. 340 mg of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide are added and the mixture is then boiled for another 24 h and subsequently concentrated under reduced pressure, water is added, the aqueous phase is extracted four times with ethyl acetate and the combined organic phases are dried with Na2SO4, admixed with silica gel and concentrated under reduced pressure. Chromatography on silica gel using a toluene/ethyl acetate->toluene/ethanol gradient gives 140 mg (28.2% of theory) of the target compound of m.p. 168° C. and Rf (SiO2, toluene/ethanol=1:1)=0.28.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[F:30][C:20]([F:19])([F:29])[C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:25][CH:26]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Reaction time: 24 h

Procedure:
A solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) and powdered KOH (128.5 mg, 2.296 mmol) in NMP (2 mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine (113.5 mg, 0.656 mmol) was added into the reaction mixture and stirring continued for 24 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19]Br)=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C-:21]#[N:22].[Na+].O>CN(C)C=O>[Br:1][C:2]1([C:8]2[O:9][C:10]3[C:18]([CH2:19][C:21]#[N:22])=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [C-]#N
Reactant: O=c1cc(C2(Br)CCCCC2)oc2c(CBr)cccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc2c(=O)cc(C3(Br)CCCCC3)oc12
Temperature: 10 °C
Yield: 42.1 %

Procedure:
2-(1-Bromocyclohexyl)-8-bromomethyl-4-oxo-4H-[1]-benzopyran (11.2 g, 0.028 mole) was dissolved in dimethylformamide (200 ml) and to the solution was added NaCN (1.5 g, 0.0305 mole) with stirring at 10° C. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and crystals precipitated were filtered off. The crude crystals were purified by silica gel chromatography (eluent: chloroform-hexane (10:1)) to obtain the title compound (4.08 g), yield 44.7 %. The product was recrystallized from ethyl acetate to obtain prisms, m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2](=[N:26][OH:27])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O>[C:35]([O:27][NH:26][CH:2]([NH2:1])[C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(N)=NO)cc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)ONC(N)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A solution of Example 2C (0.11 g, 0.29 mmol) and triethylamine (400 μL, 2.9 mmol) in acetone (10 mL) was treated with a solution of acetyl chloride (200 μL, 2.8 mmol) in acetone (1 mL) over 30 minutes, stirred for 1 hour, and concentrated. The concentrate was partitioned between water and dichloromethane. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (Na2SO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 95:5 dichloromethane:methanol to afford 106 mg (87%) of the desired product.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:5])[CH3:4].Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1.CN(C)C=O>[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][N:11]([CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:12]([CH3:15])(=[O:13])=[O:14])(=[O:5])[CH3:4]
Reactant: CCCCCC(CCCNS(C)(=O)=O)OC(C)=O
Reactant: CCOC(=O)C=Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(CCCN(Cc1cccc(C=CC(=O)OCC)c1)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Sodium hydride (0.59 g., 0.025 mole) is suspended in benzene (20 ml.) and dimethylformamide (35 ml.). N-(4-acetoxynonyl)methanesulfonamide [Example 1, Step B] (6.1 g., 0.022 mole) is added and stirred 1 hour at room temperature. Ethyl m-bromomethylcinnamate (6.68 g., 0.025 mole) is added dropwise with stirring over 1 hour. The suspension is stirred at room temperature for 20 hours and then separated between ethyl acetate and water. After being washed with water, the organic layer is dried over anhydrous magnesium sulfate. Removal of the ethyl acetate by evaporation in vacuo gives an oil which, after chromatograpy on silica gel, gives ethyl m-[N-(4-acetoxynonyl)-methanesulfonamidomethyl]cinnamate, 4.1 g. (40% yield). Anal. Calcd. for C24H37NO6S: C, 61.64; H, 7.98; N, 3.00 Found: C, 61.36; H, 8.40; N, 3.07
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[SiH](CC)(CC)CC.[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1>>[CH:2]12[O:9][CH:1]1[CH2:22][CH2:17][CH2:18][CH2:19][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:3]2
Reactant: Cc1ccccc1
Reactant: c1ccc(C2CO2)cc1
Agent: CC[SiH](CC)CC
Product: C1CCCCCC2OC2CCCC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
The preparation of reaction mixtures is conducted under an inert atmosphere, for example, in a nitrogen-filled dry box. 70 mg (0.38 mmol) styrene oxide, 88 mg (0.76 mmol) Et3SiH and 20 mg (0.018 mmol) of the catalyst [Ni(NPtBu3)]4 are dissolved in 6 mL toluene. The solution is transferred into a Teflon-sealed glass reactor equipped with a Teflon-sealed magnetic stir bar. The reaction mixture is then stirred at 1200 rotations per minute (rpm) for 12 hours in an oil bath at 90° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][S:25][CH2:24][CH2:23][O:22][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (1.40 g, 7.77 mmol), 2-[2-[bis(4-chlorophenyl)methoxy]ethylthio]ethanol (2.80 g, 7.80 mmol) and triphenylphosphine (2.0 g, 7.8 mmol) in dry benzene (30 ml) was treated at 22° C. with diethyl azodicarboxylate (1.34 g, 7.8) added dropwise over 5 min. After 18 h at 22° C., the reaction mixture was diluted with ethyl acetate (200 ml) washed with saturated sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was triturated in a mixture of hexane and toluene (6:4) to crystallize the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel (elution ethyl acetate 0-5% in toluene) to give 2.90 g (71%) of the title material as an oil.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH2:16]O)[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:16][CH:15]=[CH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1
Reactant: OCC=Cc1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C=CCCl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
Dimethylformamide (5 mL) was added to a solution of 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in dichloromethane (500 mL) at 0 to 5° C. Thionyl chloride (44.2 g) was slowly added to the above mixture maintaining the temperature at about 0 to 5° C. The reaction mixture was stirred at 0 to 5° C. for 1-2 hours. After completion of the reaction, the mixture was quenched with ice-chilled de-ionized water (250 mL) at 0-10° C. and stirred for 30 minutes. Organic layer was separated, washed twice with a solution of sodium chloride (10%; 250 mL) and concentrated under vacuum to give 1-[3-chloroprop-1-en-1-yl]-3-(trifluoromethyl)benzene.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:33])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (65 mg, 0.17 mmol) and 1-(2-methanesulfonylethyl)piperazine (38 mg, 0.20 mmol) in DCE (4 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol). The reaction mixture was stirred for 16 h then partitioned between brine and DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 312 as a cream solid (29 mg, 30%). LCMS (Method G): RT 5.97 min [M+H]+ 568.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.73 (m, 1 H); 7.30-7.24 (m, 2 H); 4.35 (m, 4 H); 3.90-3.83 (m, 7 H); 3.77 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 3.22-3.11 (m, 2H); 3.04 (s, 3 H); 2.91 (t, J=6.4 Hz, 2 H); 2.59 (m, 8 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[CH3:16][S:17]([O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:13])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(C(C)(C)C)cc1

Procedure:
As in Example 56, 5.1 g of 2-(p-tert-butylphenoxy)-1-propanol is reacted with 2.3 ml of methanesulfonyl chloride in 150 ml of dichloromethane in the presence of 8 ml of triethylamine. The product (7.4 g) is obtained as an amber-colored liquid.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:33]Br)=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.[C:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:33][N:42]2[CH2:43][CH2:44][N:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:40][CH2:41]2)=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)N1CCNCC1
Reactant: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CBr)n(-c2cccnc2)c(=O)c2c(F)cccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCN(Cc2c(C(=O)N[C@H](c3cccc(F)c3)C3CC3)c3cccc(F)c3c(=O)n2-c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromomethyl-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (118 mg, 0.225 mmol) was dissolved in THF (6 mL) mmol) and 1-tert-butyl-piperazine (64.0 mg, 0.450 mmol) and triethylamine (62 μL, 0.44 mmol) were added. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was subjected to preperative TLC on silica gel (eluent: 80% ethyl acetate, 10% methanol, 10% triethylamine). The product-containing fraction was dissolved in methanol and the product precipitated on addition of water. After filtration and drying 3-(4-tert-butyl-piperazin-1-ylmethyl)-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added tert-butyl piperidin-3-ylcarbamate (700 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, the residue was dissolved in dichloromethane and washed with 1 N HCl aq. and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (850 mg, 93%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17](Cl)=[O:18])=[CH:16][C:3]1=2.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:17]([C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)=[O:18])[CH3:21]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CCO
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Next, 30.44 g of oxepincarboxylic acid III obtained above was allowed to react with 30 ml of thionyl chloride in 200 ml of toluene by heating under reflux for one hour. Concentration of the reaction mixture to dryness under reduced pressure gave 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid chloride IV in a quantitative yield. One half of this acid chloride IV was added to 300 ml of ethanol, and the mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, dehydrated and concentrated to dryness to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid ethyl ester V in a quantitative yield. Recrystallization from n-hexane gave pure crystals having a melting point of 104°-105° C. IR spectrum (KBr tablet, cm-1): 2980, 1710, 1650, 1610, 1250, 1010.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: NCCc1cccs1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCCc2cccs2)cc1
Yield: 95.2 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with p-anisoyl chloride(74 μL, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 4-methoxy-N-(2-thiophen-2-yl-ethyl)-benzamid (105 mg,0.40 mmol, 95% yield) as a white powder after purification by chromatography on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:26]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([O:15][CH3:14])[CH:17]=1)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Product: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(Cl)cccc2Cl)cc1OC
Yield: 86.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2,6-dichlorobenzoyl isocyanate (1.0 g, 3.38 mmol), tert-butyl 2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (Intermediate-14, 0.805 g, 3.72 mmol) and DCM (20 mL) to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.42 (s, 9H), 3.76 (s, 6H), 6.99 (d, J=6.0 Hz, 1H), 7.10 (s, 1H), 7.60-7.37 (m, 3H), 7.67 (d, J=7.8 Hz, 1H), 9.86 (br s, 1H), 11.30 (br s, 1H).