Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:42])=[O:41])=[CH:38][CH:39]=1)#[N:33]
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C#N)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-cyanobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.99 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 7.45-7.15 (9H, m), 6.16 (1H, br.s), 3.36-3.34 (2H, m), 2.77-2.73 (2H, m), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2[C:18]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:34][CH:33]=4)[O:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>CO.[Pd]>[C:26]1([C:25]2[C:18]3[C:17]([NH:16][CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:22][CH:21]=[N:20][C:19]=3[O:23][C:24]=2[C:32]2[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:36][CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCC(CCNc3ncnc4oc(-c5ccc(OCCN6CCCC6)cc5)c(-c5ccccc5)c34)CC2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CO
Product: c1ccc(-c2c(-c3ccc(OCCN4CCCC4)cc3)oc3ncnc(NCCC4CCNCC4)c23)cc1

Procedure:
N-(2-(1-benzylpiperidin-4-yl)ethyl)-5-phenyl-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)furo[2,3-d]pyrimidin-4-amine 29 (Prepared in a manner analogous to Steps 1-3 of Example 5; 20 mg, 0.033 mmol), ammonium bicarbonate (−30 mg, 0.5 mmol) and 10% Pd/C (˜5 mg) were taken up in MeOH (3-5 mL). The mixture was heated at reflux for 48 h, then filtered through a pad of Celite, washing with MeOH and EtOAc and concentrated. Preparative TLC (SiO2, 15% MeOH in CH2Cl2) afforded the title compound 30. Mass for C31H37N5O2 found: 512 (M+H+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)C)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Isopropylamine (2 mL, 48.72 mmol) was added to a solution of Example 57k (0.3 g, 0.59 mmol) in DMF (5 mL) and stirred at 80° C. for 3 h. The reaction mixture was concentrated, treated with water, and extracted with chloroform. The organic layer was washed with water, brine and concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 2% methanol/chloroform). Yield: 0.16 g, (55.17%); 1H NMR (CDCl3,): δ 1.10 (d, 6H, 2CH3), 2.7 (s, 3H, CH3), 2.8 (q, 1H, CH), 2.86 (t, 2H, CH2), 3.41 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.38 (d, 1H, Ar), 7.46 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH:21]=[C:16]3[CH2:15][CH:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[O:32][C:17]3=[CH:18][N:19]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (190 mg) and trifluoro acetic acid (0.40 mL) in dichloromethane (3 mL) is stirred at room temperature for 2 h. The reaction mixture is diluted with dichloromethane and washed with aqueous Na2CO3 solution. The aqueous phase is extracted dichloromethane and the combined organic phases are washed with water, dried over MgSO4, and concentrated in vacuo. LC (method 7): tR=0.62 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (Intermediate AAAA) (56.22 mg, 0.118 mmol), (4-chloro-2-methoxyphenyl)boronic acid (Combi-Blocks, San Diego, Calif., 26.4 mg, 0.141 mmol), Pd(AmPhos)2Cl2 (4.17 mg, 5.89 μmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (442 μl), and water (147 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed fairly clean protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of MeOH. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 6% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (26.3 mg, 0.061 mmol, 51.5% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97 (br. s., 1H), 9.92 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32-7.22 (m, 2H), 6.91 (d, J=4.6 Hz, 1H), 3.70 (s, 3H); m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH2:15].[H-].[Na+].Br[CH2:19][C:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=2)[N:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=1>CN(C=O)C>[Cl:31][C:25]1[CH:24]=[C:23]2[C:28]([C:29](=[O:30])[C:20]([CH2:19][NH:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][N:22]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1
Reactant: COc1cc2ncnc(N)c2cc1OC
Reactant: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
In a 25 mL round-bottomed flask, 6,7-dimethoxyquinazolin-4-amine (69.3 mg, 0.338 mmol) was combined with DMF (2.0 mL) to give a colorless solution. Sodium hydride (60% suspension in oil) (23.0 mg, 0.575 mmol) was added in three portions. The reaction mixture was stirred at room temperature for 15 min. After this time, the reaction mixture was a yellow solution. A DMF solution of the crude 3-bromomethyl-7-chloro-1-phenyl-1H-quinolin-4-one was next added dropwise via a syringe. The reaction mixture was stirred at 50° C. for 3 hr. After this time, TLC is quite messy, but LC/MS gives a strong peak for the desired product (approx 44%). The reaction mixture was cooled to room temperature, then was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, then concentrated to furnish a brown oil. This crude product was dissolved in methylene chloride, then this solution was concentrated over silica gel. The silica gel-supported crude product was loaded onto a 80 gram SiliCycle column. Flash chromatography (2.5% methanol-methylene chloride ramped to 6% methanol-methylene chloride) afforded 7-chloro-3-[(6,7-dimethoxy-quinazolin-4-ylamino)-methyl]-1-phenyl-1H-quinolin-4-one. MS calcd. for C26H21ClN4O3 [(M+H)+] 472.9, obsd. 473.0.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][CH2:1][C@H:33]1[CH2:32][CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]1
Reactant: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7β-Hydroxymethylandrostane-3,17-dione (II-by) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.66 (m, 2H), 3.64 (t, 1H), 2.51-0.80 (m, 21H), 1.07 (s, 3H), 0.89 (s, 3H)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@@H:17]1[OH:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.O>ClCCl.CO>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@@H:17]1[O:22][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred solution of (R)-4-benzyl-3-((1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hexane-3-carbonyl)oxazolidin-2-one (25 g, 83 mmol) and 2,6-lutidine (38.2 mL, 332 mmol) in dichloromethane (300 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (47.6 mL, 207.5 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 30 minutes and then room temperature for 1 hour. After diluted with methanol (25 mL), the mixture was poured into water and extracted with ether (2×400 mL). The combined ether extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:8) to afford the title compound (29 g, 86%) as a colorless oil. MS (ES+) C23H33NO4Si requires: 415, found: 416 [M+H−H2O]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=458.0, tR (minutes, Method G)=2.91
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H](C=CBr)[CH2:13][CH2:12]1)[CH2:9][CH3:10].[Cu](C#N)C#N>Cl>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:6]([CH:5]=[CH:4][C:3]#[N:2])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CN1CCCC1=O
Reactant: CCC[C@H]1CC[C@H](C=CBr)CC1
Agent: N#C[Cu]C#N
Agent: Cl
Product: CCC[C@H]1CC[C@H](C=CC#N)CC1

Procedure:
To 30 ml of N-methylpyrrolidone was dissolved 3 g of 2-(trans-4-propylcyclohexyl)ethenyl bromide, 2 g of copper cyanide was added thereto, and then stirred under reflux by heating for 7 hours. A solution of ferric chloride in 6N hydrochloric acid was added to the reaction liquid, and extracted with toluene. The organic layer thus obtained was washed with water, dried, and then concentrated under a reduced pressure to obtain a brown oily product. This product was isolated and purified by using silica gel column chromatography to obtain 1.5 g of an oily product. As a result of various instrumental analysises, the product was confirmed to be the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.[CH2:16](O)[CH2:17][OH:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2
Reactant: OCCO
Reactant: COc1ccc(C=O)c2c1NC(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)c2c1NC(=O)CC2
Yield: 70 %

Procedure:
8-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde (42 g) was suspended in toluene (400 ml), and ethylene glycol (33.7 ml) and p-toluenesulfonic acid monohydrate (0.78 g) were added, and the resulting mixture was heated under reflux in a Dean-Stark apparatus for 4.5 hours. The reaction mixture was cooled, and 10 ml of an aqueous solution containing 1.72 g of sodium bicarbonate was added. Stirring was carried out for some time, and the produced solid was collected by filtration. The solid was washed with water and toluene and dried at 60° C. to thereby obtain 35.5 g (yield: 70%) of 5-(1,3-dioxolan-2-yl)-8-methoxy-3,4-dihydro-1H-quinolin-2-one as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O.N(C(CC)C#N)=NC(CC)C#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)c1ccc(C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CCC(C#N)N=NC(C#N)CC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(CBr)c(F)c1
Yield: 80.1 %

Procedure:
To a solution (11 ml) of the compound (2.0 g, 11 mmol) obtained in Example 189a in ethyl acetate were added N-bromosuccinimide (2.9 g, 17 mmol) and 2,2′-azobisbutyronitrile (AIBN) (180 mg, 1.1 mmol), and the mixture was heated under reflux for 5 hr under light irradiation. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give a crude title compound (2.3 g, 81%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27]>C1COCC1>[CH2:16]([O:15][C:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])=[O:27])=[CH:7][CH:6]=2)[CH:12]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Ethyl 3-(4-aminophenyl)isoxazole-5-carboxylate (4 g) was dissolved in THF (80 ml). 2-Fluorophenyl isocyanate (2.83 g) was added and stirred at RT overnight. Reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography in 1:9 EtOAc: CHCl3 to get off white solid which was crystallized from CH2Cl2/Pet ether to yield 5 gm (78%) white solid. MS (ES+): m/z 370 (M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.32 (s, 1H), 8.62 (s, 1H), 8.12 (m, 1H), 7.89 (d, 2H), 7.81 (s, 1H), 7.59 (d, 2H), 7.24 (m, 1H), 7.12 (m, 1H), 7.05 (m, 1H), 4.38 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:22]2[C:31]([CH3:32])=[CH:30][C:29]3[C:24](=[C:25](O)[CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([C:22]2[C:31]([CH3:32])=[CH:30][C:29]3[C:24](=[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2cccc(O)c2nc1-c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc2cccc(OS(=O)(=O)C(F)(F)F)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
16.9 ml (110 mmol) of trifluoromethane-sulfonic anhydride are added dropwise, at 0° C., to a solution of 12.5 g (53 mmol) of 2-phenyl-3-methyl-8-hydroxyquinoline in 150 ml of pyridine. The reaction mixture is then stirred for 16 hours at ambient temperature. After evaporating the pyridine, the residue is taken up in 200 ml of water and 100 ml of ethyl acetate. The aqueous phase is extracted with 2×100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to give 17.8 g of 2-phenyl-3-methyl-8-trifluoromethanesulfonyloxyquinoline in the form of a beige solid; M.p.=85° C. (Yield: 91%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:21](OC(=O)C)(=[O:23])[CH3:22].CO>N1C=CC=CC=1>[C:21]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Oc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 49 was suspended in pyridine (6 ml), and acetic anhydride (0.18 ml) was added to the suspension. The mixture was stirred at room temperature for 40 minutes and a small amount of methanol was added dropwise to the reaction mixture. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol and ether in succession to obtain the title compound (160 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)CCC.[F-].[K+].O>C1(C)C=CC=CC=1.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>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(-c3ccco3)n1)C(=O)OCC2
Temperature: 0 °C
Yield: 77.6 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) and Pd(PPh3)4 (146 mg, 0.127 mmol) were dissolved in 12 mL of anhydrous toluene, dropwisely added with 2-(tributylstannyl)furan (0.80 mL, 2.530 mmol) and then heated to reflux for about 15 hours under the nitrogen atmosphere. The mixture was added with 15 mL of 2% KF solution and 20 mL of distilled water while stirring at 0° C. and then extracted twice with 50 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (5% EtOAc/MC) was performed on the resulting residue and 225 mg (78%) of 6-methyl-8-furan-2-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:20][CH:21]3[CH2:26][CH2:25][C:24]([CH:33]([NH2:36])[CH2:34][CH3:35])([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.Cl>CC(O)C>[NH2:36][CH:33]([C:24]1([CH:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH2:25][CH2:26][CH:21]([O:20][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][C:16]=2[Cl:19])[C:9](=[O:8])[NH:10][CH:11]=[CH:12]3)[CH2:22][CH2:23]1)[CH2:34][CH3:35]
Reactant: CCC(N)C1(C2CCOCC2)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCC(N)C1(C2CCOCC2)CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
A solution of 1-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(tetrahydropyran-4-yl)-cyclohexyl]propylamine (8, 83 mg, 0.16 mmol) in 2-propanol (1 mL) was treated with 2N aqueous hydrochloric acid (0.5 mL) and stirred at room temperature until complete conversion was observed. The reaction mixture was evaporated and lyophilized from water twice to give 68 mg of the title compound (Example 1) as its hydrochloride. Rt 2.40 min (Method A). Detected mass: 419.4 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>CCO>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc(Br)cc2)cc1

Procedure:
1 equivalent of 1-iodo-4-nitrobenzene (IV) and 4-bromobenzenethiol (or a corresponding 4-substituted-benzenethiol) (V) were dissolved in EtOH. 8 equivalents of sodium bicarbonate were added and the mixture was stirred at reflux for 22 hours. The solvent was removed and the residue was suspended in water. The precipitate was filtered and washed with 1 M sodium hydroxide and water. The final product was obtained after re-crystallization from ethanol/water (yield: 60%).