Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH:26][C:28]4[CH:29]=[CH:30][C:31]5[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=5)[N:33]=4)[CH2:19][CH2:18]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC2c3ccccc3CCc3ccccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC4c5ccccc5CCc5ccccc54)CC3)ccc2n1
Temperature: 170 °C
Reaction time: 7 h
Yield: 24.3 %

Procedure:
1.69 g of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-oxy)-1-piperidinepropanamine and 645 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were dissolved in 3 ml of 1-methyl-2-pyrrolidone, followed by stirring in an oil bath (170° C.) for 7 hours. After cooling, saturated aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with water and saturated saline, dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, the residue was subjected to silica gel column chromatography again and eluted with dichloromethane:methanol:triethylamine (100:1:2). The desired fraction was collected and concentrated to yield 340 mg of the title compound.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C(N)C.Cl[C:12]1[N:20]2[CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[C:15]([F:37])[CH:16]=[C:17]3[C:30]2[C:31]([CH3:36])=[N:32][O:33][C:34]=2[CH3:35])[N:13]=1>CN1CCCC1=O.CO>[CH3:36][C:31]1[C:30]([C:17]2[C:18]3[O:23][CH2:22][CH:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:20]4[C:12]([NH:3][CH2:1][CH3:2])=[N:13][C:14]([C:19]=34)=[C:15]([F:37])[CH:16]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Reactant: CCN(CC)CC
Agent: CCN
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNc1nc2c(F)cc(-c3c(C)noc3C)c3c2n1C(c1cccnc1)CO3
Temperature: 150 °C
Yield: 19.1 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and ethylamine (0.2 mL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C21H21FN5O2 (M+H)+: m/z=394.2. found: 394.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12]([N:51]1[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]1=[O:52])[CH3:13])=[N:7]2
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol (0.08320 g, 0.2468 mmol) in tetrahydrofuran (2.468 mL, 0.2468 mmol) were added triphenylphosphine (0.07766 g, 0.2961 mmol), phthalimide (0.04357 g, 0.2961 mmol), and diisopropyl azodicarboxylate (0.05735 mL, 0.2961 mmol). The reaction mixture was stirred at room temperature. After 6 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 3 min as eluent to give 2-(1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione as a tan solid: LC-MS (ESI) m/z 466.0 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH:15]([CH3:52])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([CH3:51])[N:50]=[C:24]23)[CH2:19][CH2:18]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH:15]([CH3:52])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([CH3:51])[N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogen carbonate (0.42 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 1.5 hr, 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.14 g) was added, and the mixture was stirred at 90° C. for 14 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.044 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL) were added, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.078 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[CH:24](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][CH:24]=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnco2)cc2[nH]cnc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.048 g, 0.144 mmol) is suspended in 3 mL absolute EtOH and HC(OEt)3 (0.60 mL, 3.54 mmol) is added followed by catalytic pTsOH.H2O. The reaction mixture is heated to reflux under N2. After 2 hours, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (97:3 ethyl acetate:MeOH) provides 36 mg (73%) desired product as a light yellow solid. LC/MS ESI (+) m/z 344, 346 (M+Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ13.10 (bs, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.10 (bs, 1H), 7.78 (bs, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.41 (bs, 1H), 2.18 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]2.Cl[C:25]1[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27][C:26]=1[C:32]#[N:33]>C1COCC1.CCOC(C)=O>[Cl:31][C:29]1[N:28]=[C:27]([NH:3][C:4]2[CH:5]=[CH:6][C:7]([N:15]3[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]3)=[C:8]3[C:12]=2[C:11](=[O:13])[N:10]([CH3:14])[CH2:9]3)[C:26]([C:32]#[N:33])=[CH:25][CH:30]=1
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ccc3C#N)c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (0.557 g, 13.93 mmol) was added portionwise to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (1.004 g, 3.48 mmol), in THF (30 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.602 g, 3.48 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The mixture was filtered and the organic layer separated, dried over Na2SO4 and then evaporated. The residue was triturated in Et2O and MeOH and the mixture filtered. The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 5-10% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to leave 6-chloro-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-1-yl)-1H-isoindol-4-yl]amino]pyridine-3-carbonitrile (316 mg, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.02 (6H, d), 2.60 (4H, t), 2.70 (1H, t), 3.02-3.08 (7H, m), 4.51 (2H, s), 7.04 (1H, d), 7.15 (1H, dd), 7.44 (1H, dd), 8.53 (1H, d), 9.68 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=425.30.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2,6-diamine (7.0 g, 34.1 mmoL) described in Manufacturing Example 13-1-2 in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 17 mL, 17 mmol) on an ice bath, which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 3 times. The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.35 g, 73.8%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29].CC(O)=O.O>CCO>[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])(=[O:30])[CH3:29]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(=O)NCCN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.065 mmol) and N-(2-amino-ethyl)-acetamide (20 mg, 0.19 mmol), in EtOH (2 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.1 mL) and water (20 mL) were added. The resulting cloudy solution was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 13 mg of the title compound as an off-white solid. MS: (+) m/z 381.34 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].[CH3:10][N:11]([CH3:24])[C:12]1(C#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[NH4+].[Cl-].[Cl:27][Si](C)(C)C>CCOCC.C1COCC1.O>[ClH:27].[F:8][C:4]1[CH:3]=[C:2]([C:12]2([N:11]([CH3:24])[CH3:10])[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Fc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-3-fluorobenzene (5.00 g, 28.6 mmole) in absolute ether (15 ml) was added dropwise to a suspension of magnesium (694 mg, 28.6 mmole) in absolute ether (10 ml) at such a rate that the ether boiled. After completion of the addition the reaction mixture was stirred for 10 minutes at RT, following which the magnesium had completely dissolved. The reaction solution was cooled in an ice bath and 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (3.00 g, 14.3 mmole) in absolute THF (30 ml) was added dropwise at 10° C. The reaction mixture was stirred at room temperature overnight, 20% NH4Cl-solution (20 ml) and water (30 ml) were added thereto while cooling with ice, and the mixture was extracted with ether (3×50 ml). The organic phase was washed with water (50 ml) and then with saturated NaCl solution (50 ml), dried over Na2SO4 and concentrated by evaporation in vacuo. The crude product was dissolved in ethyl methyl ketone (25 ml), ClSiMe3 (3.2 ml, 25 mmole) was added while cooling with ice, and the mixture was stirred at room temperature for 5 hours. The precipitate formed was filtered off and dried in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][O:40]C1CCCCO1.Cl>CN(C=O)C.CO>[F:28][C:26]([F:29])([F:27])[CH2:25][N:21]1[C:20]([C:14]2[CH:15]=[C:16]3[N:12]([C:11]4[CH:30]=[C:7]([CH:4]5[CH2:3][CH2:2][N:1]([CH2:38][CH2:39][OH:40])[CH2:6][CH2:5]5)[CH:8]=[CH:9][C:10]=4[O:19][CH2:18][CH2:17]3)[N:13]=2)=[N:24][CH:23]=[N:22]1
Reactant: BrCCOC1CCCCO1
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: OCCN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (180 mg, 0.43 mmol) in DMF (1 mL), potassium carbonate (89 mg, 0.65 mmol) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (97 L, 0.65 mmol) was heated at 50° C. for 18 h. The cooled reaction mixture was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH (+2M NH3) in DCM) to give a colourless oil. The oil was dissolved in methanol and treated with 1M HCl in methanol (2 mL, 2 mmol) and the reaction mixture stirred for 2 h at RT before concentrating in vacuo. The resultant residue was triturated in a mixture of diethyl ether and methanol to give 142 as a pale yellow solid (115 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 9.81 (br s, 1H); 8.22 (s, 1H); 7.70 (s, 1H); 7.32-7.24 (m, 2H); 6.99 (s, 1H); 5.72 (q, J=8.7 Hz, 2H); 5.36 (br s, 1H); 4.51 (t, J=6.0 Hz, 2H); 3.80 (t, J=4.9 Hz, 2H); 3.67-3.57 (m, 2H); 3.22-3.06 (m, 6H); 2.97-2.85 (m, 1H); 2.10-2.00 (m, 4H). LCMS: RT=6.62 min, M+H+=463.1
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11](Br)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.[C:36]1([N:42]2[C:54]3[CH:53]=[CH:52][C:51](B4OC(C)(C)C(C)(C)O4)=[CH:50][C:49]=3[C:48]3[C:43]2=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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(O)C>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([C:51]4[CH:52]=[CH:53][C:54]5[N:42]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:43]6[C:48]([C:49]=5[CH:50]=4)=[CH:47][CH:46]=[CH:45][CH:44]=6)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc3c(c1)c1ccccc1n3-c1ccccc1)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 73 °C
Reaction time: 5 h
Yield: 45.1 %

Procedure:
The resulting 10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (16.5 g), 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (14.2 g), a toluene/ethanol (4/1, v/v) mixed solvent (250 ml), and a 2M potassium carbonate aqueous solution (48 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (1.9 g), and stirred at 73° C. for 5 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (450 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by crystallization using 1,2-dichlorobenzene (150 ml) and n-hexane (300 ml) was performed to obtain a white powder of 10-(biphenyl-4-yl)-12,12-dimethyl-7-(9-phenyl-9H-carbazol-3-yl)-10,12-dihydroindeno[2,1-b]carbazole (9.8 g; yield 45.2%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Reaction time: 2 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (3.0 g., 0.012 mol) and 1,1'-carbonyldiimidazole (2.0 g., 0.012 mol) in tetrahydrofuran (180 ml) and dimethylformamide (3.5 ml) is refluxed under nitrogen for 5 hours. The solution is cooled in an ice-bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice-bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off and washed with tetrahydrofuran. The precipitate is treated with hot 0.5 mol aqueous sodium bicarbonate solution, filtered, washed with water, washed with acetone and sucked dry to give the product (2.0 g.), mp 334° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([CH3:37])[CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[C:32]([CH3:37])[CH:31]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 49%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][C:25]4[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 23.2 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methylbenzyl bromide (18.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-methylbenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (9.2 mg).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1>C1COCC1.O>[Br:2][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCO)c2c1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCBr)c2c1
Reaction time: 3.5 h

Procedure:
Phosphorus tribromide (0.03 ml) was added dropwise to a solution of N-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]methanesulphonamide (0.18 g) in dry THF (20 ml) stirred in an ice bath. There was an immediate reddish colour produced. The solution was stirred for 2 h and then at room temperature for a further 3.5 h, then again chilled in ice, diluted with water (40 ml) and extracted with ether (2×50 ml, 3×25 ml) combined extracts were washed with brine (3×20 ml) and dried (Na2SO4). Removal of the solvent by rotary evaporation at 35°-40° afforded the title compound as a viscous pink oil (0.22 g).