Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)/C=C/c1ccc(Br)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)/C=C/c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 5.55 g (24.7 mmol) of the ketone from Step A dissolved in 100 mL of toluene was added 3.7 mL (3.7 mmol, 1M in toluene) of (R)-2-methyl-CBS-oxazaborolidine catalyst and the resultant mixture was stirred at ambient temperature for 15 min. The mixture was cooled to −78° C. and 4.0 mL (37.1 mmol) of catecholborane in 30 mL of toluene was added dropwise over 30 min. After the addition, the slurry was stirred at −78° C. for 60 min while slowly turning homogeneous. The solution was then stirred at −78° C. an additional 4 h (reaction time varies from 4-24 h) until TLC revealed complete disappearance of starting material. Next, the reaction mixture was diluted with 100 mL of water and the resultant mixture was extracted with three 100-mL portions of diethyl ether. The organic phases were then combined and washed with two 100-mL portions of 1N aqueous sodium hydroxide solution, two 100-mL portions of 5% hydrochloric acid solution, one 100-mL portion of saturated aqueous brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude waxy solid. The crude material was then purified by flash chromatography on a Biotage® system (silica gel, 0 to 20% ethyl acetate/hexanes gradient) to give the alcohol as a colorless crystalline solid. This compound was recrystallized in hexanes to yield the alcohol as colorless crystals (96% ee by Mosher ester analysis). LC/MS 209.0 (M-water+1), 211.0 (M-water+3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:33][CH2:32][C:12]2=[C:13]([N:28]3[CH2:31][CH2:30][CH2:29]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:33][CH2:32][C:12]2=[C:13]([N:28]3[CH2:31][CH2:30][CH2:29]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3c(C#Cc4ccccn4)cnn3c(N3CCC3)c2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc3c(CCc4ccccn4)cnn3c(N3CCC3)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 87 mg (0.2 mmol) 10-azetidin-1-yl-3-pyridin-2-ylethynyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL ethanol was added 11 mg (20% weight) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at room temperature under a balloon of hydrogen for 16 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 3:7).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:28]([C:34]([F:37])([F:36])[F:35])=[N:29][N:30]([CH3:33])[C:31]=2[CH3:32])=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[CH3:38][O:39][CH2:40]Cl.Cl>O1CCCC1>[CH3:38][O:39][CH2:40][N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:19])([F:20])[F:21])[C:14]([F:16])([F:15])[F:17])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:28]([C:34]([F:37])([F:36])[F:35])=[N:29][N:30]([CH3:33])[C:31]=1[CH3:32])=[O:26]
Reactant: COC(c1ccc(NC(=O)c2c(C(F)(F)F)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(C(=O)c1c(C(F)(F)F)nn(C)c1C)c1ccc(C(OC)(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Sodium hydride (32 mg, 60%, 0.8 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,5-dimethyl-3-trifluoromethylpyrazole-4-carboxamide (250 mg, 0.48 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of chloromethyl methyl ether (64 mg, 0.8 mmol) in tetrahydrofuran (2 ml) was added and the mixture was stirred for 5 hr. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired compound (238 mg).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:28][O:27][C:22](=[O:26])[CH:23]([O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Br:1])=[CH:3][C:4]=2[F:16])=[CH:12][CH:11]=1)[CH3:25]
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: COC(=O)C(C)O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 189.6 %

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)-phenol (2.83 g, 0.01 mol), the methanesulfonate of S methyl lactate (18.2 g, 0.01 mol), and potassium carbonate (1.67 g, 0.012 mol) in DMSO (70 ml) was stirred at room temperature for 40 hours, then poured into water (700 ml). The mixture was extracted with ether (2×200 ml). Pentane (100 ml) was added to the combined ether extracts and the resulting solution washed with water (300 ml). The organic phase was dried (MgSO4) and the solvent evaporated to give a light yellow oil (~7 g). This oil was purified via prep HPLC (8:2 hexane-acetone) with the first peak being collected. Removal of the solvent gave the desired product enriched in the "R" enantiomer; Optical rotation=+20.34° @ 25° C. RI=1.5614 @ 25° C.; NMR (CDCl3) was identical with that obtained in Example 4. No attempt was made to determine the optical purity of this material.
Reaction SMILES: O1CCCCC1OC1CCCCO1.[CH3:14][C:15]1([CH3:52])[S:20][CH2:19][CH2:18][N:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38]C3CCCCO3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:16]1[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:33]#[C:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:17]2[CH2:18][CH2:19][S:20][C:15]([CH3:52])([CH3:14])[C@@H:16]2[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCOC3CCCCO3)cc2)CCSC1(C)C
Agent: C1CCC(OC2CCCCO2)OC1
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)CCSC1(C)C
Yield: 83.9 %

Procedure:
According to the procedure of Step 1 of Example 245 the tetrahydropyranyl ether of 0.659 g (1.13 mmol) of tert-butyl (3S)-2,2-dimethyl-4-[(4-{[7-(tetrahydro-2H-pyran-2-yloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-3-thiomorpholinecarboxylate was cleaved to provide 0.472 g (84%) of tert-butyl (3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless oil. Electrospray Mass Spec: 498.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[CH:15][N:16]([CH3:18])[CH3:17])[C:7](=[O:11])[C:6]=2[CH:12]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCSc2ccc(Cl)cc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=C1CSc2ccc(Cl)cc2C1=O
Reaction time: 1 h

Procedure:
A solution of 6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (30 g), N,N-dimethylformamide dimethyl acetal (80 ml), and triethylamine (31.4 ml) in benzene (400 ml) was refluxed with stirring for 1 hour and then about three-fourths of the solvent were distilled slowly at atmospheric pressure over a period of approximately 1 hour. Benzene (300 ml) was added to the reaction mixture and the solvent was distilled again. To the residue was added diethyl ether (150 ml) and the mixture was triturated to give 6-chloro-2,3-dihydro-3-dimethylaminomethylene-4H-1-benzothiopyran-4-one (34 g).
Reaction SMILES: CN(CCN(C)C)C.[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1.C([Li])CCC.[CH3:21][C:22]1[O:27][C:26](=O)[CH2:25][CH2:24][CH:23]=1.C(=O)=O.CC(C)=O>C1COCC1.CS(C)=O.CCCCCC>[CH3:9][C:10]1[CH:14]=[C:13]([C:15]2[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]=2[CH3:21])[O:12][N:11]=1
Reactant: CC1=CCCC(=O)O1
Reactant: Cc1cc(C)on1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC1=C(c2cc(C)no2)C(=O)CCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
4.75 g of TMEDA was dissolved in 10 ml of THF, and 3.3 g of 3,5-dimethylisoxazole was added. The resulting solution was cooled to −78° C. in a dry ice-acetone bath, and 26 ml of an n-hexane solution of n-butyl lithium (1.6M solution) was dropped into it. They were reacted at the same temperature for 30 minutes, and then, at −78° C., a solution of 1.90 g of 3,4-dihydro-6-methyl-2H-pyran-2-one and 5 ml of DMSO in 10 ml of THF was dropped. The resulting solution was stirred at the same temperature for 2 hours. The dry ice-acetone bath was taken away. After gradually returning to room temperature, the solution was stirred for 15 hours. The reaction solution was poured into dilute hydrochloric acid-ice and extracted with ethyl acetate. The organic layer was washed with water and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography to give 1.10 g of the title compound as white crystals. Melting point: 104-105° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:34]=[CH:33][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O:29]C)=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[F:36][C:2]([F:1])([F:35])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[C:31]#[N:32])=[CH:33][CH:34]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(C(F)(F)F)nc3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 21.9 %

Procedure:
Methyl 7-(4-((6-(trifluoromethyl)pyridin-3-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (141 mg, 0.283 mmol) was diluted with THF (1 mL) followed by the addition of sodium hydroxide (0.31 mL, 0.31 mmol) and methanol (300 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 1N HCl. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated. The material was diluted with dichloromethane and a white precipitate formed which was filtered and rinsed with dichloromethane to provide the desired product (30 mg, 21.9% yield). MS (ESI)=484.1 (M+1).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:12]([C:20]([O-:22])=[O:21])=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.BrB(Br)Br>>[OH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]2[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:20](=[O:21])[O:22]2
Reactant: COc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Agent: BrB(Br)Br
Product: O=c1oc2cccc(O)c2c2ccc([N+](=O)[O-])cc12

Procedure:
treating 2′,6′-dimethoxy-4-nitro-1,1′-biphenyl-2-carboxylate with tribromoborane in a second solvent to provide 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one;
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1.FC(F)(F)OC1C=C(/C=C\C#N)C=CC=1.Cl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1.[O-]CC.[Na+]>C(O)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:5]=3)[CH2:11][C:12]([NH2:13])=[N:40]2)=[CH:35][CH:34]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#C/C=C/c1cccc(OC(F)(F)F)c1
Agent: CC[O-]
Agent: Cl
Agent: N#C/C=C\c1cccc(OC(F)(F)F)c1
Solvent: CCO
Product: NC1=NN(c2ccc(F)cc2)C(c2cccc(OC(F)(F)F)c2)C1
Reaction time: 8 h

Procedure:
To a solution of a mixture of (E)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile and (Z)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile (1.28 g) in ethanol (13 ml) were sequentially added 4-fluorophenylhydrazine hydrochloride (979 mg) and sodium ethoxide (20 wt % in ethanol, 5.0 ml), and the mixture was stirred overnight at reflux. This reaction solution was concentrated under reduced pressure, and then water was added thereto, and the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1 to 1/1) to give the titled compound (1.29 g).
Reaction SMILES: [OH-].[Li+].[OH:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[OH:3][CH:4]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)O)C(C)=O)cc1
Reaction time: 16 h
Yield: 76.3 %

Procedure:
Lithium hydroxide (0.3 mL of a 0.5N solution in H2O, 0.14 mmol) was added to a solution of the ester 105 (23 mg, 0.062 mmol) in THF (0.3 mL) at 23° C. After stirring for 16 h the reaction was acidified with 10% citric acid and extracted with EtOAc. The organic portion was washed with brine twice and then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, 9:1 CH2Cl2/MeOH) to afford 17 mg (77%) of the acid 106.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:34])=[C:31]([CH3:33])[CH:32]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH3:34])=[C:31]([CH3:33])[CH:32]=3)=[CH:21][N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: Cc1cc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cnc1C

Procedure:
2-(2-Guanidino-4-thiazolylmethylthio)ethylamine is heated under reflux in pyridine for 12 hours with 1.5 molar equivalents of 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: Br[C:2]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]([NH2:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][C@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:8][C:9]=1[NH:10]2.[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]([CH3:34])[C:31](=[O:35])[N:30]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:29]2=[O:52].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:15][C:14]1[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([N:30]3[C:29](=[O:52])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[N:32]([CH3:34])[C:31]3=[O:35])[C:37]=2[CH3:51])=[C:3]2[C:11](=[C:12]([C:16]([NH2:18])=[O:17])[CH:13]=1)[NH:10][C:9]1[CH2:8][C@@H:7]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6][CH2:5][C:4]2=1
Reactant: CC(C)(O)[C@H]1CCc2c([nH]c3c(C(N)=O)cc(Cl)c(Br)c23)C1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(Cl)cc(C(N)=O)c3[nH]c4c(c23)CC[C@H](C(C)(C)O)C4)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 50 °C
Yield: 49.8 %

Procedure:
A mixture of (S)-5-bromo-6-chloro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide [Intermediate 31] (100 mg, 0.259 mmol), 8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (112 mg, 0.272 mmol), Cs2CO3 (169 mg, 0.519 mmol) and PdCl2(dppf) DCM adduct (16.9 mg, 0.021 mmol) in THF (4.3 mL) and water (1.1 mL) was heated at 50° C. for 17.5 h. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 50-80%). The impure product was further purified by preparative HPLC to give 6-chloro-5-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (mixture of four atropisomers) (76 mg, 50% yield). Mass spectrum m/z 589 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.13 (br. s., 1H), 7.94 (d, J=7.9 Hz, 1H), 7.76-7.68 (m, 2H), 7.46 (br. s., 1H), 7.40-7.28 (m, 3H), 7.22-7.16 (m, 1H), 4.21-4.13 (m, 1H), 3.77-3.64 (m, 3H), 2.95-2.82 (m, 1H), 2.40 (d, J=16.3 Hz, 1H), 1.94-1.70 (m, 3H), 1.70-1.61 (m, 3H), 1.58-1.48 (m, 1H), 1.16-1.02 (m, 7H).
Reaction SMILES: C(NC([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[N:18]=1)(C(OCC)=O)C(OCC)=O)(=O)C.[Br:25]C1C(F)=CC=C(C)N=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]([F:23])=[CH:21][CH:22]=[C:17]([CH2:16][Br:25])[N:18]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: CCOC(=O)C(Cc1ccc(F)c(Br)n1)(NC(C)=O)C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)nc1Br

Procedure:
Diethyl 2-acetamido-2-((6-bromo-5-fluoropyridin-2-yl)methyl)malonate: 2-Bromo-3-fluoro-6-methylpyridine (2.24 g, 11.79 mmol), NBS(2.34 g, 13.15 mmol), CCl4 (40 mL), and AIBN (0.10 g, 0.609 mmol) were added together and heated to reflux under argon for 4.5 h. The CCl4 was removed. The residue was dissolved in EtOAc and washed with water and brine. It was dried over Na2SO4, and concentrated to give 2-bromo-6-(bromomethyl)-3-fluoropyridine which was used in the next step without purification. MS (ESI) m/z: 269.9 (M+H)+. NaH (0.707 g of 60% dispersion, 17.69 mmol) was placed in a three-neck flask with 15 mL of DMF. It was cooled in an ice-bath. A solution of diethyl 2-acetamidomalonate (3.59 g, 11.79 mmol) in 15 mL of DMF was added dropwise via an additional funnel White foam formed and the mixture was stirred in the ice-bath for 20 minutes after the addition. A solution of 2-bromo-6-(bromomethyl)-3-fluoropyridine in 10 mL of DMF was added through an additional funnel dropwise. The ice-bath was removed and it was stirred at rt under argon for 2 h. It was quenched with water and extracted with EtOAc. The EtOAc solution was washed with water and brine, dried over Na2SO4, and concentrated. It was purified by normal phase chromatography to give 106A as an off-white solid (2.39 g, 50%). MS (ESI) m/z: 405.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])[CH3:17]>C(OCC)C.CCCCCC>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([C:24]2([OH:27])[CH2:23][CH2:22][N:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:26][CH2:25]2)=[C:3]([F:10])[CH:4]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(c2cc(F)c(Br)cc2F)CC1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
A solution of 16.55 g (60.85 mmol) 1,4-dibromo-2,5-difluorobenzene in 400 ml of ethyl ether stirred at -75° C. under an argon atmosphere was treated dropwise with 24.3 ml of 2.5 M n-butyl lithium in hexane. The mixture was let warm to -50° C. and treated dropwise with a solution of 11.00 g (64.33 mmol) 1-ethoxycarbonyl-4-piperidone in 100 ml ethyl ether. After stirring a further 0.25 hour, the mixture was let warm to room temperature and extracted with ammonium chloride solution. The organic layer was dried (MgSO4), evaporated and the crude product chromatographed on a silica gel column and crystallized from toluene hexane to afford the title compound, mp 133°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN1CCN(CCCCl)CC1
Agent: Cl
Product: CN1CCN(CCCN2C(=O)S/C(=C\c3ccc4c(ccn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-[(1-{[4-Chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[3-(4-methylpiperazin-1-yl)propyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 4-(3-chloropropyl)-1-methylpiperazine dihydrochloride following General Procedure H.
Reaction SMILES: [C:1](C(C#N)=C(C#N)C#N)#[N:2].ClCCO[CH:15]([O:23][CH2:24][CH2:25][Cl:26])[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[N:20][CH:21]=1>C(#N)C>[Cl:26][CH2:25][CH2:24][O:23][CH:15]([C:16]1[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:1]#[N:2]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: ClCCOC(OCCCl)c1ccc(Cl)nc1
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 471.2 %

Procedure:
Trimethylsilyl cyamide (1.88 mL) and tetracyanoethylene (240 mg) were added to a solution of 5-[bis-(2-chloroethoxy)methyl]-2-chloropyridine (2.67 g) in acetonitrile (50 mL), and the reaction solution was heated under reflux for five hours. The reaction solution was left to cool to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the resulting residue. The organic layer washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=8:1) to obtain 2.04 g of the title compound. The property values of the compound are as follows.