Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:37])[NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)[CH2:25][CH2:24]4)=[C:17]3[N:16]=2)=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:37])[CH2:27][CH2:28]4)=[C:17]3[N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
To (4-{6-bromo-7-[4-(thiazol-2-ylcarbamoylmethyl)-piperazin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}-benzyl)-carbamic acid tert-butyl ester (0.053 g, 0.08 mmol) in dichloromethane (4 ml) was slowly added trifluoroacetic acid (0.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was run trough a 2 g SCX cartridge and eluted with 0.1M NH3 in methanol to give the title compound as a pale yellow solid (0.046 g, 100%).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C(N(CC)CC)C.[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32]Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:19]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=C(OCCCOCCl)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Yield: 21.2 %

Procedure:
A solution of trimethylsilylated guanine in benzene (25 ml) prepared as in Example 6 (from 2.0 g of guanine) containing triethylamine was heated at reflux and 3-benzoyloxypropoxymethyl chloride (2.96 g) dissolved in benzene (15 ml) was added over a 3 hour period. The reaction mixture was heated at reflux under nitrogen overnight. The solvent was removed under reduced pressure, and 95% ethanol and methanol were added to the residual oil. The mixture was heated on a steam bath for several minutes and the solvent then evaporated under reduced pressure. Chloroform (200 ml) was added and the resulting solid removed by filtration. The solid was dissolved in a minimal amount of DHF, filtered (to remove any guanine present) and reprecipitated by the addition of water. Recrystallization from methanol (with charcoaling) gave 9-(3-benzoyloxypropoxymethyl)guanine (0.94 g) as a pale yellow solid, m.p. 198°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:31][C@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][CH2:33][C@H:32]([NH:31][C:13]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:11][S:10]1)=[O:15])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)N[C@@H](CCO)c1ccccc1
Temperature: -25 °C

Procedure:
Commercial 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid (III) (1 g, 4.29 mmol) was dissolved in dry THF (50 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to −25° C. and N-methyl morpholine (1.084 g, 10.72 mmol) was added in dry THF (5 ml). A solution of isobutyl-chloroformate (0.615 g, 4.5 mmol) in dry THF (10 ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of a dry-acetone bath. After the complete addition of the chloroformate, the reaction mixture was stirred at −25° C. for 30 min after which time an amine (IV)/(IV*), e.g., (3S)-3-amino-3-phenyl-1-propanol (0.778 g, 5.14 mmol) was added drop-wise over a period of 10 min. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5 g, 95%). The antipodal intermediate, tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, as well as the racemic inter-mediate, tert-butyl 2-({[3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(OC)nc(Cl)n1
Agent: Cl
Product: COC(=O)c1cc(OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 6 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (Intermediate 88).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4](N)[N:3]=1.N[C:13]1[N:18]=[C:17](N)[CH:16]=[C:15](O)[N:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:14]1[C:15]2[C:16](=[N:9][C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]=2)[CH:17]=[N:18][CH:13]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: Nc1cc(O)nc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ncc2nc3cncnc3nc2n1
Temperature: 113 °C
Reaction time: 20 h

Procedure:
A suspension of 6.20 g of commercial 2,4,6-triamino-5-nitrosopyrimidine (Chemie Uetikon, Lahr, Germany), 5.15 g of commercial 2,4-diamino-6-hydroxypyrimidine (Fluka, Buchs, Switzerland) and 11.52 g of commercial toluene-4-sulfonic acid monohydrate in 110 ml of glacial acetic acid (100%) is stirred for 20 hours at 113° C. The reaction mixture is filtered off over a laminated paper filter while still hot, and the residue is washed with hot water (approx. 60° C.) until the pH of the washing water has reached a value of at least 4. The washed residue, moist with water, is dried in vacuo at 110° C. to yield a greenish-yellow powder of the pyrimido[5,4-g]pteridine salt of formula VI
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:21]>O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:21])=[O:17])=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(OCc2ccccc2)c(CO)c1

Procedure:
1-(4-Benzyloxy-3-hydroxymethylphenyl)ethanone (10.4 g) was added portionwise to a stirred solution of selenium dioxide (5.5 g) in water (0.9 ml) and dioxan (100 ml) at 60°. The mixture was stirred under reflux for 4 hours, filtered whilst hot and allowed to cool. The solid was collected and recrystallised from dioxan as a dimer, mp 180°-181° (7.7 g). (d6DMSO) 5.13 (1H, s), 4.94 (1H, s), 4.72 (2H, s), 3.42 (1H, d, J=10 Hz), 3.24 (1H, d, J=10 Hz), 2.72 (1H, m), 2.54 (5H, m), 2.04 (1H, m), 1.46 (1H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(OC(F)(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-(trifluoromethoxy)benzoic acid. MS (m/e): 461.1 (MH−, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCC(OC)CC4)n2)CCNC3)cc1
Reactant: Fc1cnc(Cl)nc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCC(OC)CC4)n2)CCN(c2ncc(F)cn2)C3)cc1

Procedure:
The compound was prepared following the general procedure in Example 287, substituting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea for 1-ethyl-3-(4-(4-(4-methoxypiperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea and substituting 4-Chloro-6-methylpyrimidine for 2-Chloro-5-fluoropyrimidine: LC-MS m/z=507 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].CO[C:12](OC)(OC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:13]([C:12]1[N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6](=[O:7])[NH:8][N:9]=1)[CH2:14][CH3:15]
Reactant: NNC(=O)c1ncc[nH]1
Reactant: CCCC(OC)(OC)OC
Solvent: CCO
Product: CCCc1n[nH]c(=O)c2nccn12
Temperature: 25 °C

Procedure:
A mixture of 37.0 gm. of 2-imidazolecarboxylic acid hydrazide, prepared by the method of U.S. Pat. No. 3,600,399, 2.5 liters of ethanol and 325 ml. of trimethylorthobutyrate is refluxed overnight and evaporated to a solid. This solid is ground, added to 400 ml. of diphenyl ether and heated in an oil bath at 220°-245° C. for 30 minutes. The mixture is cooled to room temperature and crystallized by the addition of 100 ml. of petroleum ether. The solid is collected, washed twice with petroleum ether, recrystallized from 300 ml. of a hot mixture of ethanol and methanol and treated with charcoal giving 53.5 gm. of the desired final product, m.p. 153°-159° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:15]([NH:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2.[C:25](Cl)(=[O:30])[CH2:26][C:27](Cl)=[O:28]>CO>[C:20]([C:19]1[CH:18]=[C:17]([N:16]2[C:27](=[O:28])[CH2:26][C:25](=[O:30])[NH:6][C:7]3[C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=[CH:14][C:15]2=3)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: N#Cc1cccc(Nc2ccc3c(c2N)CCC3)c1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCC2)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a dry tetrahydrofuran (75 mL) solution of 3-(4-aminoindan-5-ylamino)benzonitrile (0.75 g, 3.00 mmol) was added malonyl chloride (0.35 mL, 3.60 mmol) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the mixture was added methanol (5 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the reaction mixture was added methanol (25 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1-4/1) to slightly yellow crystal (0.40 g). The crystal was recrystallized from ethyl acetate to give the titled compound as white crystal (0.28 g, yield 29%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C[Si](C)(C)C[C:21](F)([F:23])[F:22].[I-].[Na+]>O1CCCC1>[F:22][C:21]1([F:23])[C:1]2([CH2:7][O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: C[Si](C)(C)CC(F)(F)F
Reactant: COc1ccc(COCC2=CCCCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COCC23CCCCC2C3(F)F)cc1
Temperature: 115 °C
Yield: 79.7 %

Procedure:
To a microwave 5 mL vial was added 1-((cyclohexenylmethoxy)- methyl)-4-methoxybenzene (0.46 g, 2.00 mmol), trimethyl(2,2,2-trifluoroethyl)silane (0.57 g, 4.00 mmol) and sodium iodide (0.66 g, 4.40 mmol) in anhydrous tetrahydrofuran (1.0 mL). The vial was degassed with nitrogen and sealed. The reaction mixture was heated in the microwave reactor at 115° C. for 1 hour. The reaction vial was cooled and the TLC showed presence of starting material. To the reaction vial was added trimethyl(2,2,2-trifluoroethyl)silane (0.5 mL) and continued heating in the microwave at the same temperature for another 1 hour. The reaction was filtered, washed with ethyl acetate (10 ml). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (20%) to afford the title compound as colourless liquid (0.45 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH3:25])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (100 mg, 0.31 mmol) in THF was added LiHMDS (0.17 mL, 0.33 mmol) at −78° C. The mixture was stirred at the same temperature for 1 h, and then CH3I (84.00 mg, 0.59 mmol) was added. The mixture was stirred at −78° C. for 2 h, then warmed to room temperature, and maintained at room temperature for 2 h. NH4Cl aqueous (15 mL) was added, and then extracted with DCM (10 mL*3). The product was purified by column chromatography (silica-gel, DCM:MEOH=30:1) to give 6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (40.0 mg, 38%). LRMS (M+H+) m/z: calcd 338.09. found 338.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7](C(O)=O)[CH:8]=[N:9]2)=[N:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)cnc2c1O
Solvent: CC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Oc1ccnc2cc(Br)cnc12
Yield: 88.9 %

Procedure:
In a RBF fitted with a reflux condenser, 7-bromo-4-hydroxy-1,5-naphthyridine-3-carboxylic acid (1 g, 4 mmol) was added in portions over 10 minutes to stirred refluxing quinoline (50 mL), and the resulting mixture was refluxed for 1 h. The mixture was cooled and diluted with acetone. The precipitate was filtered, washed with water and dried to give 0.8 g of a grey-brown powder. The product was reprecipitated from aq. NaOH with glacial acetic acid to give a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1.[F:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[Na+].[Na+].CO>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.C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:2]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)cc12
Temperature: 105 °C
Yield: 124.6 %

Procedure:
A 250 ml pressure flask was loaded with ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (1.39 g, 3.85 mmol, Example 58C), Pd(Ph3P)4 (280 mg, 0.242 mmol), 2-(3-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.30 g, 5.16 mmol), aqueous Na2CO3 (4.2 ml, 8.40 mmol), MeOH (21.00 ml) and Toluene (42 ml), flushed with nitrogen, sealed and heated to 105° C. for 4 hours in an oil bath. The reaction mixture was filtered and the collected solid washed with water. The filtrate was acidified with KHSO4 (1M solution in water) and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated. The MgSO4 was washed with THF and a MeOH+CH2Cl2 mixture. All wash liquids, the extracted product and the collected solid residue were combined to give 1.95 g crude ethyl 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylate. (estimated purity ˜75%). The crude product was used without further purification in the next reaction. MS (ESI) m/e−405 consistent with [M−H]− of product. HPLC retention time 2.13 min. (PHENOMENEX® Luna C18 S10, 3.0×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc), then isocratic at 100% B.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:3]1[C:4]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:11]=[CH:1][CH:2]=1
Reactant: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product of step (iv) (2.1 g) and Lawesson's reagent (1.78 g) in dry 1,4-dioxane (36 ml) was heated at reflux for 16 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.5 g.
Reaction SMILES: [CH:1]1([O:7][C:8]([CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])(=[O:20])=[O:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([O:7][C:8]([CH2:10][O:11][C:12]([CH2:13][CH2:14][NH:15][S:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])(=[O:20])=[O:19])=[O:16])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCC(=O)OCC(=O)OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCNS(=O)(=O)c1cccc(C(=O)O)c1)OCC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-amino-propionic acid cyclohexyloxycarbonylmethyl ester (step 2) (2.30 g, 10.03 mmol) in DCM (200 ml) at RT was treated with 3-chlorosulfonyl-benzoic acid (3.64 g, 16.50 mmol) followed by N,N-diisopropylethylamine (3.04 ml, 17.45 mmol). The resulting mixture was stirred at RT for 1 h. The reaction mixture was washed with 2N HCl (200 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound; LC-MS Rt 1.34 mins; 414.2 [M+H]+, Method 2minLC_v002.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[C:43]4[C:44]5=[C:45]6[C:40](=[CH:41][CH:42]=4)[CH:39]=[CH:38][CH:37]=[C:36]6[CH:35]=[CH:34][C:33]5=[CH:32][CH:31]=3)[N:27]([C:46]3[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:13]1([C:4]2[O:3][C:2]([CH:1]=[CH:50][C:49]3[CH:48]=[CH:47][C:46]([N:27]4[CH:28]([C:30]5[C:43]6[C:44]7=[C:45]8[C:40](=[CH:41][CH:42]=6)[CH:39]=[CH:38][CH:37]=[C:36]8[CH:35]=[CH:34][C:33]7=[CH:32][CH:31]=5)[CH2:29][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:53][CH:52]=3)=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccc3ccc4cccc5ccc2c3c45)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccc4ccc5cccc6ccc3c4c56)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 6, 0.5 g (2.13 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.961 g (2.13 mmol) of 4-(3-phenyl-5-pyren-1-yl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde were added into 50 ml of ethanol, and 0.27 g (3.2 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.