Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH:19]([O:32][C:33](=[O:74])[C@H:34]([CH2:53][S:54][CH2:55][CH:56]([OH:73])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[NH:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)(Cl)Cl.CO>C(Cl)Cl.N1C=CC=CC=1>[CH:19]([O:32][C:33](=[O:74])[C@H:34]([CH2:53][S:54][CH2:55][CH:56]([O:73][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[NH:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCCCCCCCCCCCCCC(O)CSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(CSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)OC(c1ccccc1)c1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
0.56 ml of palmitic acid chloride in 5 ml of methylenechloride are added to 0.8 g of N-palmitoyl-S-[2-(R,S)-hydroxyoctadecyl]-(L)-cysteine benzhydryl ester in 5 ml of pyridine. After standing for 24 hours at room temperature the acylation is completed as can be detected by thin layer chromatography on silicagel Merck, chloroform 2 ml of methanol are added and after 20 minutes the reaction mixture is evaporated under reduced pressure. The residue is taken up in chloroform and the chloroform solution is extracted twice each time with 1 N HCl, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. After purification of the residue over 20 g of silicagel Merck with chloroform as eluant there are obtained colorless crystals of the N-palmitoyl-S-[2(R,S)-palmitoyloxyoctadecyl]-(L)-cysteine-benzhydryl ester, which can be crystallised from acetone-methanol and which melts at 46°-47°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 ml) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 ml) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (2×100 ml), and drying at 40° C. under vacuum, to afford 103 g (95%) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; m.p. 83°-85° C.; NMR (250 MHz, CDCl3), 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2CH3), 8.01 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1c1cc(F)ccc1n2Cc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(F)ccc1n2Cc1ccccc1
Yield: 62.1 %

Procedure:
9-Benzyl-6-fluoro-9H-carbazol-4-ol (0.0587 g, 0.20 mmol), 2-diethylaminoethylchloride hydrochloride (0.0524 g, 0.30 mmol), potassium carbonate (0.0872 g, 0.63 mmol), sodium iodide (0.0062 g, 0.041 mmol) and DMF (2 mL) are heated at 85° C. for 3 h. After the mixture had cooled, it is partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (50 mL) using methanol/dichloromethane (1/99 to 3/97) to give 0.0485 g (62%) of the title compound; mp 68-69° C.; MS (ESI+) for C25H27FN2O m/z 391.3 (M+H)+; IR (drift) 2966, 1584, 1483, 1463, 1345, 1268, 1185, 1162, 1145, 1052, 799, 778, 741, 726, 713 cm−1; 1H NMR (CDCl3) δ1.14, 2.73, 3.10, 4.33, 5.48, 6.68, 6.97, 7.11, 7.21, 7.35, 8.03. Anal. Calcd for C25H27FN2O: C, 76.89; H, 6.97; N, 7.17. Found: C, 77.16; H, 7.28; N, 7.16.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]2[C:16]([C:17]3[CH:33]=[CH:32][O:31][C:18]=3[C:19](=[O:30])[O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:34]([N:36]([CH2:53][CH3:54])[CH2:37]/[CH:38]=[CH:39]\[Sn](CCCC)(CCCC)CCCC)[CH3:35]>O1CCOCC1>[CH2:34]([N:36]([CH2:53][CH3:54])[CH2:37]/[CH:38]=[CH:39]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]2[C:16]([C:17]3[CH:33]=[CH:32][O:31][C:18]=3[C:19](=[O:30])[O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:35]
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1oc(=O)c1occc12
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(oc(=O)c3occc32)c1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 61.5 %

Procedure:
A suspension of tert-butyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 56, 0.330 g) and N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.493 g) in dioxane was warmed slightly then de-gassed and purged with nitrogen. tris-(Dibenzylideneacetone)dipalladium (0.056 g) and tri-tert-butylphosphonium tetrafluoroborate (0.036 g) were added and the mixture was de-gassed and purged with nitrogen again. The resultant mixture was heated at 95° C., under an atmosphere of nitrogen for 75 minutes. This was cooled and concentrated in vacuo and the residue was partitioned between water and ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with methanol and DCM, with a gradient of 0-25%. The product was triturated with ether and the resultant product was dried in vacuo at 50° C. overnight to give tert-butyl 7-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.215 g) as a sand coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([CH2:6][CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:5])=[O:4].O.NN>C(O)C>[CH3:1][N:2]([CH3:20])[S:3]([CH2:6][CH2:7][CH2:8][NH2:9])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)CCCN
Temperature: 25 °C

Procedure:
To a solution of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propane-1-sulfonic acid dimethylamide (530 mg) in ethanol (10 mL) was added hydrazine monohydrate (0.80 mL) and the reaction was heated at reflux for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate reduced in vacuo to give 3-amino-propane-1-sulfonic acid dimethylamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[N:10]([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O>F[B-](F)(F)F.[H+].O.[Cu]>[F:1][C:2]1[CH:3]=[CH:5][CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[C:8]=1[F:9]
Reactant: Nc1cccc(F)c1F
Reactant: O=N[O-]
Agent: [Cu]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc(F)c1F

Procedure:
To a solution of 2,3-difluoroaniline (5.0 g, 38 mmol) in aqueous tetrafluoroboric acid (48%, 18 ml) was added sodium nitrite (3.9 g, 57 mmol) over 20 min while cooling in an ice/salt bath. After 1 h the mixture was filtered and washed successively with aqueous tetrafluoroboric acid and a mixture of acetone/diethyl ether (40:60). The precipitate was added to a mixture of copper (8.0 g, 121 mmol) and sodium nitrite (39 g, 570 mmol) in water (90 ml) over 20 min. After 1 h the mixture was acidified with concentrated sulphuric acid, extracted with ethyl acetate and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80); yield 1.4 g (25%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[CH2:27].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]=[CH:27][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C=Cc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccn2)cc1-3
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), 2-vinylpyridine (54 mg, 0.6 mL, 0.51 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (30 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 h. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 90 mg (84%) of Compound I-31 as a yellow solid, purification by column chromatography (silica gel, EtOAc:MeOH, 9:1), mp>320° C. 1H NMR (DMSO-d6, 300 MHz): δ 4.2 (s, 2H), 5.0 (s, 2H), 7.2-7.42 (m, 4H), 7.58-7.7 (m, 4H), 7.8-7.95 (m, 2H), 8.3 (s, 1H), 8.6 (d, 1H, J=6 Hz), 8.63 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.1 (s, 1H). MS(FAB): m/e 414 (m+1)+.
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][N:9]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH3:28]
Reactant: CCCCC(CC)CBr
Reactant: c1ccc2c(c1)ccc1[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c2ccccc2c2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7H-benzo[c]carbazole (0.78 g, 3.59 mmol) in dimethylformamide (DMF) (4 ml) is added sodium hydride (0.21 g, 5.21 mmol) at 0° C., and the mixture is stirred for 1 hour. To the reaction mixture is added 1-bromo-2-ethylhexane (1.04 g, 5.39 mmol). The mixture is stirred at room temperature overnight, and then at 0° C. for 5 hours. After the reaction mixture is cooled at room temperature, it is poured into ice-water, and the crude product is extracted with AcOEt, and washed with water and brine. After drying over MgSO4 and concentration, the desired product is obtained as a brown liquid (1.21 g, 99%). The structure is confirmed by 1H-NMR spectrum (CDCl3) δ [ppm]: 0.83-0.92 (m), 1.20-1.43 (m), 2.07-2.10 (m), 4.24-4.38 (m), 7.37 (td), 7.44-7.50 (m), 7.52-7.54 (m), 7.62 (d), 7.69 (td), 7.87 (d), 7.99 (d), 8.59 (d), 8.80 (d)
Reaction SMILES: I.CS[N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][N:6]=[CH:5]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(C)C.[ClH:34]>CO>[ClH:34].[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:5]2[NH:4][CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][N:6]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CSN1C=NCc2ccccc2C1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: I
Solvent: CO
Solvent: CC(C)O
Product: c1ccc(C(CNC2=NCc3ccccc3CN2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask containing 2-methylthio-2,5-dihydro-1H-2,4-benzodiazepine hydroiodide (3.20 g 1.00×10-2 mole) and 2,2-diphenylethylamine (5.91 g, 3.00×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-160° C. for ca. 30 minutes. The resulting solid mass was treated with isopropanol and that which did not dissolve was collected by filtration. This guanidine hydroiodide was dissolved in a two phase mixture of 5 molar aqueous NaOH (80 ml) and CH2Cl2 (80 ml). After stirring overnight the CH2Cl2 layer was separated. The aqueous alkaline phase was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a foam which was dissolved in methanol (35 ml). The solution was cooled to 0° C. before being treated with a methanolic solution of HCl. The solution was concentrated to ca. 10-15 ml at which point crystallization began. After standing ca. 30 minutes, isopropanol was added and the flask was refrigerated. After 1-1.5 hour the product was collected by filtration. Recrystallization from methanol/isopropanol afforded 3-(2,2-diphenylethylamino)-2,5-dihydro-1H-2,4-benzodiazepine hydrochloride as colorless crystals: 2.53 g (67%), m.p. 243°-245° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[N:3]=[CH:2]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>CN(C=O)C>[Si:18]([O:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCc1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
A solution of 2-(1H-imidazol-4-yl)ethanol (1.24 g, 11.1 mmol) in DMF (10 mL) was treated with imidazole (1.51 g, 22.1 mmol) and TBDPSCl (3.12 mL, 12.2 mmol) and the mixture was stirred at RT for 2 h. The mixture was then poured onto H2O and extracted with AcOEt. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/heptane 0:100 to 100:0) gave the title compound (1.6 g). UPLC-MS: MS 351.2 (M+H+); UPLC rt 1.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 43 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 1-methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (21 mg, Yield 43%).
Reaction SMILES: C[C:2]1(C)[O:7][C:6]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]([CH2:28][C@@H:29]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:5]=2[C:4](=[O:43])[O:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:23]([O:22][C:21]([N:20]([CH2:28][C@@H:29]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:5]([C:4]([O:3][CH3:2])=[O:43])=[C:6]([OH:7])[CH:8]=2)=[CH:17][CH:16]=1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc3c(c2)OC(C)(C)OC3=O)cc1)C[C@H](OC1CCCCO1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a solution of tert-butyl [2-[4-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)phenyl]ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (1.32 g) in methanol (15 ml) was added potassium carbonate (455 mg) at room temperature and the mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and washed with water, brine and aqueous hydrochloric acid solution (0.1N). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-hydroxy-4-biphenylcarboxylate (1.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[NH:8][C:5]2=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([Cl:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c2cc(Br)cnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(Br)cnc2[nH]1

Procedure:
The pyridin-2-one from step (a) above (1 g, 4.7 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 232 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O.[Cu]I>[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[N:16]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH:17]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: N#Cc1ccc(I)cc1F
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Temperature: 140 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A mixture of 2-fluoro-4-iodobenzonitrile (4000 mg, 16.19 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (2357 mg, 16.19 mmol), 4,7-dimethoxy-1,10-phenanthroline (778 mg, 3.24 mmol), copper(I) iodide (617 mg, 3.24 mmol) and potassium carbonate (4476 mg, 32.4 mmol) in DMSO (40 mL) was stirred at 140° C. under N2 for 3 h. After cooled to rt, the reaction mixture was diluted with H2O (50 mL) and added 1N HCl to adjust the pH to ˜2 (pH paper). The resulting mixture was extracted with EtOAc (400 mL, 2×). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give black oil. The residue was purified by flash chromatography (SiO2, 0 to 7% MeOH/CH2Cl2) to give brown oil (3.2 g, 43.3%). MS (ESI) 265 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])C.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:14][C:12]1[S:11][C:9]2[NH:10][C:6]([C:4]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:5])=[CH:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Reactant: C1CNCCN1
Product: O=C(c1cc2cc(Cl)sc2[nH]1)N1CCNCC1
Yield: 35 %

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (102 mg, 0.45 mmol) was hydrolyzed (Procedure B) and then coupled with piperazine (Procedure D) to provide the title compound (42 mg, 35% for two steps) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C11H12ClN3OS, 269.04; m/z found, 270.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): 10.5 (br s, 1H), 6.87 (s, 1H), 6.61 (s, 1H), 3.87 (t, J=4.8 Hz, 4H), 2.96 (t, J=5.2 Hz, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[CH:31][N:30]([CH2:33]C)[N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[N:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(NC2C=CN=CN=2)C(=O)N(C)N=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1CC2C(=CC=C(C(C)(C)C)C=2)C1=O)(=O)C>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[CH:31][N:30]=[CH:33][N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[N:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCn1ccc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)nn(C)c2=O)n1
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: Cn1nc(Cl)cc(Nc2ccncn2)c1=O
Product: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Yield: 49 %

Procedure:
Using the same general procedure as described for the preparation of 102, reaction of 103b (192 mg, 0.810 mmol) with 102f (413 mg, 0.891 mmol) afforded 103 in 49% yield (196 mg) as an amorphous off-white solid: mp 236-238° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.49 (d, J=6.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.55-7.53 (m, 3H), 7.52-7.47 (m, 1H), 4.93 (s, 2H), 4.73 (t, J=5.0 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.80 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 497.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:25]2[CH2:26][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopropylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:6]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(OCC(F)(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OCC(F)(F)F)c1
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (0.71 g, colorless oil) from 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.67 g, 3.08 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.