Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.O1CCOCC1>CO>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3[nH]ncc3c2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1cc2[nH]ncc2cc1OC1CCCNC1
Reaction time: 3 h
Yield: 101.2 %

Procedure:
To a solution of the tert-butyl 3-(1H-indazol-5-yloxy)piperidine-1-carboxylate (150 mg, 0.473 mmol) obtained in Example 376 in methanol (2 ml) was added a 4N-hydrochloric acid-dioxane solution (1 ml) at room temperature. After 3 hours, the mixture thus obtained was concentrated under reduced pressure, and the resulting residue was dissolved in methanol. The resulting solution was adjusted to pH 8 to 9 with a 2M-aqueous sodium hydroxide solution and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/chloroform/methanol/(1%-aqueous ammonia)) to obtain 5-(piperidin-3-yloxy)-1H-indazole (104 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 80 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10 gm, 0.3 mmoles), acetic anhydride (0.5 mL) and triethylamine (0.7 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 90 mg (80%) of 2-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-fluorobenzofuran, mp. 85°-88° C.
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+]([O-])=O)[CH:10]=[C:6]([N+:7]([O-])=O)[CH:5]=1)[N+]([O-])=O.[N+]([C:20]1C=CC=CC=1)([O-])=O.[CH2:26](C(C)=O)[CH:27]([CH3:29])[CH3:28]>[Fe]>[CH3:26][C:27]([CH2:29][CH2:10][CH2:11][CH2:15][CH2:1][CH2:5][CH2:6][NH2:7])([CH3:20])[CH3:28]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)C
Agent: [Fe]
Product: CC(C)(C)CCCCCCCN
Reaction time: 24 h

Procedure:
Dissolve the picric acid in the methyl isobutyl ketone; add the N-butyl alcohol and elemental iron. The reaction time during stirring is 24 hours. Add the kerosene, nitrobenzene, and Primene.
Reaction SMILES: C([C:3](CC)(CC)[CH:4](P(O)(O)=O)[C:5]([O-:7])=[O:6])C.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-][CH2:29][CH3:30].[Na+].C(O)C>C1COCC1>[CH3:3]/[C:4](=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[C:5]([O:7][CH2:29][CH3:30])=[O:6]
Reactant: CCC(CC)(CC)C(C(=O)[O-])P(=O)(O)O
Reactant: CC[O-]
Reactant: O=CCCCCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/CCCCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Triethyl-2-phosphonopropionate (12 g, 50 mmol) and 5-phenylpentanal (7 g, 43 mmol) are dissolved in dry THF (100 mL) and cooled to 10° C. A solution of sodium ethoxide in ethanol (23 mL, 21%, 43 mmol) is added slowly over 20 minutes and the reaction is warmed to 23° C. After stirring 1 hour, the reaction is quenched by the addition of a saturated NH4Cl solution (30 mL). The reaction is concentrated to remove the THF in vacuo, diluted with petroleum ether (400 mL) and washed with 1 N HCl (100 mL), H2O (100 mL), NaHCO3 (100 mL), brine (100 mL) and dried (MgSO4). The solution is concentrated in vacuo and purified by filtration through a plug of silica gel using 2% ether/pet ether as the eluant to yield (E)-ethyl 2-methyl-7-phenylhept-2-enoate, (8.9 g, 84%) which contains a small amount (10%) of the Z-isomer: 1H NMR (CDCl3) δ 7.29-7.23 (m, 2H), 7.19-7.14 (m, 3H), 6.75 (dt, J=15.5, 1.5 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 2.18 (q, J=7.0 Hz, 2H), 1.81 (s, 3H), 1.70-1.59 (m, 2H), 1.54-1.42 (m. 2H), 1.28 (t, J=7.1 Hz, 3H); MS (FAB) m/e 247 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N#N.[C:37]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:38][CH2:39]C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.[Cu]I>[CH2:44]([O:43][C:37](=[O:42])[CH2:38][CH2:39][CH:3]=[CH:2][CH2:1][CH:4]1[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]2=[N:9][C:10]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH2:6][CH2:5]1)[CH3:45]
Reactant: C=CCCC(=O)OCC
Reactant: C=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [Cu]I
Agent: N#N
Solvent: ClCCl
Product: CCOC(=O)CCC=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Tert-butyl 6-allyl-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2)(97 mg, 0.213 mmol) in DCM (3 ml) degassed with N2 was treated with ethyl pent-4-enoate (0.036 ml, 0.255 mmol), copper(I) iodide (4.05 mg, 0.021 mmol) and Grubbs (II) catalyst (9.04 mg, 10.65 μmol). After stirring at 40° C. for 4 hours, the mixture was concentrated under reduced pressure and purification by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the titled compound as a brown oil;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)=[CH:6][CH:5]=1)(O)=[O:2].[O:43]([CH2:50][CH2:51][NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][N:33]1[C:32]2[CH:42]=[C:28]([CH2:27][O:26][CH:11]3[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:2])[NH:52][CH2:51][CH2:50][O:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:9][CH:8]=4)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12]3)[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21
Reactant: NCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)NCCOc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.36 g of benzyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.125 g of 2-phenoxyethylamine in 5 ml of N,N-dimethylformamide is admixed under argon with 0.172 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.0037 g of 4-dimethylaminopyridine. The reaction solution is stirred at room temperature over 3 days, subsequently poured onto 25 ml of water and extracted with 50 ml of tert-butyl methyl ether. The organic phase is dried over potassium carbonate, filtered and concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (2:1 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:24]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (Parish Chemical Company, 1.0 g, 3.23 mmol) and benzyl bromide (0.60 g, 3.5 mmol) in THF (50 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and heated to a gentle reflux for 16 h. After cooling to room temperature the reaction was quenched by addition of water and then partitioned between water and EtOAc. The organic phase was dried over MgSO4, and concentrated to yield ethyl 1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish solid (1.20 g, 93%): 1H NMR (DMSO-d6) δ 0.93 (t, J=7.0 Hz, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 5.91 (s, 2 H), 7.12 (d, J=8.3 Hz, 2 H), 7.30-7.32 (m, 3 H), 7.50-7.55 (m, 5 H), 7.92 (d, J=9.2 Hz, 1 H), 8.22 (dd, J=9.2, 2.0 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H); MS (EI) m/z 400.1 (MH+); Anal. calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C, 71.77; H, 5.14; N, 6.71.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:20].[C:1]([C:5]1[CH:6]=[C:7]([C:21]2[CH:22]=[C:23]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[N:24]=[N:25][CH:26]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nccn1Cc1cc(-c2cccc(C(C)(C)C)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=307.3 (M+H+), was prepared from 2-(3-tert-butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1>C(O)CCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:31][CH2:32]3)=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:12][CH:11]=1
Reactant: C=Cc1ccccn1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Solvent: CCCCO
Product: Fc1ccc(Cn2c(NC3CCN(CCc4ccccn4)CC3)nc3cncnc32)cc1
Yield: 15 %

Procedure:
A mixture of 1.93 parts of 2-ethenylpyridine, 5 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine and 80 parts of 1-butanol was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (15%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9H-purin-8-amine; mp. 172.3° C. (compound 141).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[NH3:16].CCCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:16])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: N
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (2.00 g, 8.49 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.85 mL, 25.4 mmol). The reaction mixture was heated at reflux for 20.5 hours, then distilled for 1 hour, collecting 9 mL of distillate. Toluene (10 mL) was added and the reaction was distilled for 30 minutes, collecting 10 mL of distillate. The reaction mixture was cooled to ambient temperature resulting in a suspension. Toluene (10 mL) saturated with ammonia gas was added to the reaction mixture followed by bubbling ammonia gas through the reaction for 10 minutes. The reaction was stirred at ambient temperature for 1 hour. Heptane (10 mL) was added, and the reaction stirred at ambient temperature for 15 minutes, then 0° C. for 1 hour. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford 4-bromo-3-chlorobenzamide (2.327 g, 116.8%) as a white solid which was carried on without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1.OC1C=CC=C2C=1[N+](=CCCS([O-])(=O)=O)CC=C2>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][N+:9]2=[CH:13][CH2:12][CH2:18][S:15]([O-:17])(=[O:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: Oc1ccc2cccnc2c1
Agent: O=S(=O)([O-])CCC=[N+]1CC=Cc2cccc(O)c21
Product: O=S(=O)([O-])CCC=[N+]1CC=Cc2ccc(O)cc21

Procedure:
This compound is prepared from 7-hydroxyquinoline and 1,3-propanesultone as published (GB 1,122,704) for 3-(8-hydroxyquinolinio-1-yl)propanesulfonate.
Reaction SMILES: [C:1]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:44])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39])=[C:29]([Cl:42])[CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[F:51][C:52]([F:99])([F:98])[C:53]1[CH:54]=[C:55]([CH:91]=[C:92]([C:94]([F:97])([F:96])[F:95])[CH:93]=1)[C:56]([N:58]1[CH2:62][C@@:61]([CH2:70][CH2:71][N:72]2[CH2:77][CH2:76][C:75]3([C:85]4[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=4)[CH2:79][C@@H:78]3[O:86][CH2:87][C:88](O)=[O:89])[CH2:74][CH2:73]2)([C:63]2[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=2)[O:60][CH2:59]1)=[O:57]>>[ClH:42].[ClH:42].[ClH:42].[C:1]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:44])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH2:35][CH2:36][CH2:37][N:38]([C:88](=[O:89])[CH2:87][O:86][C@@H:78]3[C:75]4([CH2:76][CH2:77][N:72]([CH2:71][CH2:70][C@:61]5([C:63]6[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=6)[O:60][CH2:59][N:58]([C:56](=[O:57])[C:55]6[CH:91]=[C:92]([C:94]([F:95])([F:96])[F:97])[CH:93]=[C:53]([C:52]([F:99])([F:51])[F:98])[CH:54]=6)[CH2:62]5)[CH2:73][CH2:74]4)[C:85]4[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=4)[CH2:79]3)[CH3:39])[CH3:40])=[C:29]([Cl:42])[CH:28]=2)[CH3:19])[CH2:12][CH2:11]1
Reactant: CNCCCN(C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1Cl
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)c(Cl)c1
Product: Cl
Yield: 134.1 %

Procedure:
The compound (92.0 mg, 0.130 mmol) obtained in Example 85c and the compound (108 mg, 0.156 mmol) obtained in Example 1j were used to give the title compound (65 mg; yield, 34%) as a white solid according to the method described in Example 80c.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C([Li])CCC.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH2:42][CH:43]3[CH2:45][O:44]3)[C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][C:36]([Br:41])=[CH:35][CH:34]=3.C[CH2:47][O:48]C(C)=O>C1(C)C=CC=CC=1>[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH2:42][CH:43]([OH:44])[CH2:45][N:9]([C:6]3[CH:5]=[CH:4][CH:3]=[C:8]([O:48][CH3:47])[CH:7]=3)[S:10]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)(=[O:11])=[O:12])[C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][C:36]([Br:41])=[CH:35][CH:34]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: COc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
A heterogeneous mixture of N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide (100.2 mg, 0.32 mmol) in toluene (2.5 ml, 0.13 M) under a N2 atmosphere was cooled in a dry ice/acetone bath before dropwise addition of n-butyllithium (200 ul of 1.78 M in hexanes, 0.36 mmol). The reaction was stirred at −78° C. for 10 minutes before addition of carbazole epoxide 2-A. The heterogeneous mixture was stirred at room temperature for 5 minutes before heating at 100° C. for 48 hours. The cooled reaction was diluted with EtOAc and washed three times with 5% acetic acid solution, followed by a brine wash. The organic layer was dried over Na2SO4, filtered and condensed. The crude mixture was purified in 100% dichloromethane. Yield=88%
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[C:17]([O:18]C)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:20])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:20][C:13]1[C:12]([C:4]2[N:3]=[C:2]([Cl:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[C:17]([OH:18])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(Cl)c1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-6-methoxyphenyl)quinazoline (0.3 g, 0.98 mmol) in CH2Cl2 at −78° C. was added 5 equivalents of 1 M BBr3 solution (4.9 mL, 4.9 mmol) in CH2Cl2. The reaction was complete after 30 minutes After allowing it to warm to room temperature, the reaction mixture was quenched with aqueous NaHCO3 to pH 7, the layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 2:1 CH2Cl2:hexanes yielded 3-chloro-2-(4-chloroquinazolin-2-yl)phenol (0.17 g, 60%). LC/MS: m/z 291.1 (M+H)+ at 3.16 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].[OH-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2cc(Cl)ccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 177.6 %

Procedure:
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.050 g of triethylamine and 0.083 g of 2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromethane is stirred at room temperature for 1 hour and then 4 mg of 4-(N,N-dimethylamino)pyridine is added. After another hour, 93 mg of 2,5-dichlorobenzenesulfonyl chloride is added along with 50 mg of triethylamine. The mixture is stirred at room temperature for 2 days and 1N NaOH added. The mixture is extracted with ethyl acetate and the extract washed with 50% ammonium chloride solution, brine and dried (Na2SO4). The solvent is removed to give 0.30 g of solid. Trituration with ether-hexane gives 0.26 g of solid. This solid is dissolved in a mixture of 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of 1N NaOH and the mixture stirred for 18 hours at room temperature. The organic solvents are removed and the mixture extracted with ether acetate. The extract is washed with NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue (0.16 g) triturated with ether to give 0.14 g of yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.Cl.C(#N)C>CO>[O:1]=[C:2]1[N:7]2[NH:8][CH2:9][C:10]3[C:15]([C:6]2=[C:5]([C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[O:17])[CH:4]=[C:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12)N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1CN2)N1CCOCC1

Procedure:
from 4-[(4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-yl)carbonyl]morpholine in methanol/glacial acetic acid (10:1), but without the addition of saturated methanolic hydrochloric acid, there is obtained 4-[(6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]morpholine of m.p. 254°-257° (acetonitrile);
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.CCN(CC)CC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:19](=[O:22])[CH2:20][CH3:21])=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: NCc1c[nH]c2ccccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Compound 25 (1.00 g, 6.84 mmol) and Et3N (1.4 mL, 10.26 mmol) were dissolved in MeOH and cooled to 0° C. Propionyl chloride (633 mg, 6.84 mmol) was added dropwise and the reaction was stirred at room temperature for 4 hours. The volatiles were removed and the residue was taken up in CH2Cl2 (40 mL), washed with 10% citric acid (20 mL), satd. NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried with Na2SO4, filtered and the volatiles were removed to yield 1.33 g of a white, crystalline solid (1.33 g, 96% yield). An analytical sample was recrystallized from EtOAc/hexanes. m.p.=91-92° C. 1H NMR (CDCl3) δ 8.80 (br s, 1H, NH), 7.62 (d, 1H, ArH, J=7.85 Hz), 7.38 (d, 1H, ArH, J=7.2 Hz), 7.20 (3H, ArH), 5.80 (br s, 1H, NH), 4.60 (d, 2H, ArCH2, J=5.1 Hz), 2.20 (q, 2H, COCH2CH3, J=7.6 Hz), 1.14 (t, 3H, COCH2CH3, J=7.6 Hz). 13C NMR (CDCl3) δ 173.6, 136.5, 126.6, 123.3, 122.5, 119.9, 118.8, 112.8, 111.4, 35.2, 29.7, 9.9. IR (KBr) vmax cm−1: 3405, 1891, 1634, 1532, 1097.