Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[CH3:18]O>[Pd]>[CH3:18][O:16][C:15](=[O:17])[CH2:14][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2F)s1
Reactant: CO
Agent: [Pd]
Product: COC(=O)CCc1ccc(-c2ccccc2F)s1
Reaction time: 168 h

Procedure:
100 mg of 5% palladium on carbon were added to a solution of 5 g (20.1 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 200 ml of methanol, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 7 days. The mixture was filtered and evaporated. The product was purified by silica gel chromatography. Yield: 2.9 g.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[C:20]([O:24][C:25]([NH:27][C:28]([NH:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:55][CH3:56])[CH:53]=2)[N:48]=[C:47]([NH2:57])[N:46]=1)=[N:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:30]([NH:29][C:28]([NH:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:55][CH3:56])[CH:53]=2)[N:48]=[C:47]([NH:57][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:46]=1)=[N:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 366 mg of N,N-diisopropylethylamine in 10 mL of methylene chloride was combined with 60 mg of 4-dimethylaminopyridine and 0.156 mL of 4-chlorobenzoyl chloride. This was treated dropwise with a solution of 500 mg of (1R,2S)-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-(2-amino-6-methoxyquinazolin-4-yl)aminocyclohexylamine in 10 mL of methylene chloride, and stirred at room temperature for 3 hours. The reaction solution was combined with water, extracted with methylene chloride, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 560 mg of the desirable compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[OH-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.3 %

Procedure:
306 mg of methyl 4-[1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 3) were dissolved in 4 ml of methanol. 3 ml of a 1N aqueous solution of sodium hydroxide was added to the resulting solution, and the mixture was stirred at room temperature for 5 hours, and was then heated under reflux for 1 hour. The solvent was removed by distillation, and 1.5 ml of a 1N aqueous solution of sodium hydroxide was added to the residue. The resulting mixture was extracted with chloroform, and the aqueous layer was acidified (pH value 2 to 3) with 6N aqueous hydrochloric acid. The crystals which precipitated were collected by filtration, washed with water and dried, followed by recrystallization from a mixture of ethanol and ethyl acetate, to give 191 mg of the title compound as colorless crystals, melting at 187°-190° C.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:22]([OH:26])[CH2:23][CH2:24][OH:25].[H-].[Na+]>>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[O:25][CH2:24][CH2:23][CH2:22][OH:26]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Product: O=C1Nc2ccc(F)c3c(OCCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (198 mg, 0.5 mmol) in 1,3-propanediol (Fluka, 7.0 g, 92 mmol) was added NaH (Aldrich, 60%, 0.5 g, 12.5 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 110° C. for 2.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to afford 6-fluoro-5-(3-hydroxy-propoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 51.5 mg, 31.6%).
Reaction SMILES: [H-].[Na+:2].NC1C=CC=CC=1.[CH3:10][C:11]1[C:12]([CH3:17])=[C:13]([CH3:16])[CH2:14][CH:15]=1>O1CCCC1>[CH3:10][C:11]1[CH:15]=[CH:14][C:13]([CH3:16])([Na:2])[C:12]=1[CH3:17]
Reactant: CC1=CCC(C)=C1C
Reactant: [Na+]
Agent: [H-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(C)C(C)([Na])C=C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (0.80 g) and aniline (0.046 g) were added to the solution of trimethylcyclopentadiene (1.08 g) dissolved in tetrahydrofuran (6.12 g), and stirred at 50° C. for 3 hours. Thus, trimethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:8]([Cl:14])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1.[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]([CH:26]=[CH2:27])[C:17]=1[CH:18]=[O:19].[NH4+].[Cl-]>C(OC(C)C)(C)C.C1C=CC=CC=1>[Cl:14][C:8]1[C:7]([CH:18]([C:17]2[C:20]([CH:26]=[CH2:27])=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:16]=2[F:15])[OH:19])=[CH:12][C:11]([Cl:13])=[CH:10][N:9]=1
Reactant: C=Cc1ccc(OC)c(F)c1C=O
Reactant: Clc1cnc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: C=Cc1ccc(OC)c(F)c1C(O)c1cc(Cl)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of nBuLi (1.6 M in hexane, 29.0 mL, 46.4 mmol) in diisopropyl ether (80 mL) was added 3-bromo-2,5-dichloropyridine (10.5 g, 46.4 mmol) in diisopropylether (60 mL) slowly at −78° C. The resulting suspension was treated with 2-fluoro-3-methoxy-6-vinylbenzaldehyde (7.6 g, 42.2 mmol) in diisopropylether (60 mL) and benzene (3 mL), and allowed to stir at −78° C. for 30 min followed by warming to room temperature as the bath did. The mixture was treated with saturated NH4Cl solution and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:31][CH:32]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2c(NCc3ccc(NS(=O)(=O)c4ccccc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Benzenesulfonyl chloride (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 434.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH2:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[CH2:10][CH3:11].C(N(CC)CC)C>C1COCC1>[CH2:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:17])=[CH:19][CH:20]=1)[CH2:10][CH3:11]
Reactant: NCCc1cccs1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)NCCc2cccs2)cc1
Yield: 85.7 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-propylbenzoyl chloride (92 μL, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 4-propyl-N-(2-thiophen-2-yl-ethyl)-benzamide (100 mg, 0.36 mmol, 85% yield) as a off-white powder after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [CH2:1](B(O)O)[CH2:2][CH2:3][CH3:4].[CH2:8]([O:15][C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=2)[O:18][C:17]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:8]([O:15][C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:22][CH:23]=2)[O:18][C:17]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Reactant: CCCCB(O)O
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OC)c(OC)c3)oc2c1
Yield: 23.2 %

Procedure:
To a stirring solution of n-butane boronic acid (0.133 g, 1.3 mmol, 1.4 equ) and dichloropalladium (dppf) (0.050 g, 0.06 mmol, 0.07 eq) in tetrahydrofuran (7 ml) and 3M NaOH solution (1.1 ml) was added 34 (0.500 g, 0.9 mmol) added and the reaction heated to reflux for 21 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×). The combined organic layers were washed with IM HCl and brine then dried (MgSO4) and concentrated in vacuo to give a yellow oil. A silica plug (dichloromethane) yielded 39d (0.099 g, 23%) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:37]1([C@@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]2[NH:48][CH3:49])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(Cl)[Cl:51]>>[ClH:51].[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]([CH3:49])[C@@H:43]2[CH2:44][CH2:45][CH2:46][CH2:47][C@H:42]2[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:12])=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Product: CN(C(=O)Cc1ccc(C(F)(F)F)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl
Temperature: 5 °C

Procedure:
To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. Thereaction mixture was cooled to 0°→5° C. and added solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl])(1.35 g, 7.08 mmol) and stirred this temperature for 30 min. A solution (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed byN,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reactionmixture was stirred for 24 h while warming to the room temperature. The reaction mixture was then poured on to excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solventsystem: CH2Cl2 : CH3OH: 28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from1M etherial HCl and recrystallized from CH2Cl2 :Et2O (1:1)to give (±) 5g HCl as a cream colored solid, 0.68 g (30%); 213°-215° C.; 1H NMR (200 MHz, CDCl3) δ1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal Calcd for C20H27F3N2 O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84;N, 6.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.[ClH:20].[N:21](=[CH:29][CH2:30]Cl)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(N(CC)CC)C>C(O)C>[ClH:28].[ClH:20].[N:21]1([CH2:29][CH2:30][N:14]2[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCC=NCCCCCCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCCCCC1)C3

Procedure:
A mixture of 0.02m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 0.022m of 2-(hexamethyleneimino)-ethyl chloride HCl and 0.022m of triethylamine in 200ml of ethanol was refluxed for 6 hours. The mixture was filtered while hot and immediately treated with excess HCl gas. Crystallization of the crude product from methanol gave 2.5g of material, m.p. 233°-4° C.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:15])=[O:16]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 52 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)aniline (90 mg, 0.31 mmol) and 2,3-dichlorophenylisocyanate (70 μL, 0.37 mmnol) were coupled to form the desired urea (77 mg, 52%). EI-MS (m/z) 477.68, 479.72, 481.63 (M−).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([CH:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:7]([CH:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCn2c([N+](=O)[O-])cnc2C=CN(C)C)cc1

Procedure:
2.26 g. (0.01 mole) of 5-nitro-1-(2-hydroxyethyl)-2-(2-dimethylaminovinyl)-imidazole and 1.9 g. (0.01 mole) of p-toluenesulfochloride were agitated in 20 ml. of pyridine at 20° C. for 2 hours. Then, the mixture was poured on ice water and vacuum-filtered; m.p. 116°-118° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:16])[C:7](S(O)(=O)=O)=[CH:8][CH:9]=[CH:10][CH:11]=1.C1(C)C=CC=C(S(O)(=O)=O)C=1>C1(C)C=CC=CC=1>[C:6]1([CH3:16])[CH:7]=[CH:8][C:9]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: Cc1cccc(S(=O)(=O)O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 26 %

Procedure:
Sulfuric acid (1.0 g, 10.2 mmol) was added to toluene (50.0 g) under the same conditions as Example 1. The analysis by HPLC showed 26% yield p-toluenesulfonic acid, 11% o-toluenesulfonic acid, and 1.3% m-toluenesulfonic acid (ratio p/o=2.4) for a total yield of 38.3%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3CC=C[C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CC[O:33]CC1.[CH3:37][C:38]([CH3:40])=[O:39].O>S([O-])([O-])(=O)=S.[Na+].[Na+].O=[Os](=O)(=O)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][C:13]=3[N:14]3[CH2:40][C@H:38]([OH:39])[C@H:37]([OH:33])[C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
OsO4 (23 mg, 0.09 mmol) was added to a stirred solution of methyl 13-cyclohexyl-7H-indolo {2,1-a][2]benzazepine-10-carboxylate (341 mg, 0.92 mmol) and 4-methyl-morpholine N-oxide (430 mg, 3.68 mmol) in acetone-water (50 mL-6 mL) at rt. The reaction mixture was stirred at rt for 18 hr and then diluted with aqueous sodium thiosulfate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine (3×) and dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified utilizing a Biotage apparatus with a prepacked silica column and using gradients of hexanes:ethyl acetate of from (98:2) to (80:20) to afford the product as a light yellow solid (340 mg, 91%). ESI-MS m/z 406 (MH+); 1H NMR (500 MHz, MeOD) δ 1.25 (m, 1 H) 1.43 (m, 2 H) 1.58 (d, J=13.12 Hz, 1 H) 1.77 (d, J=8.85 Hz, 2 H) 2.02 (m, 4H) 2.93 (m, 1 H) 3.31 (m, 1 H) 3.93 (s, 3 H) 4.40 (d, J=4.58 Hz, 1 H) 4.52 (m, 1 H) 4.68 (dd, J=14.19, 7.17 Hz, 1 H) 7.40 (t, J=7.32 Hz, 1 H) 7.44 (t, J=7.32 Hz, 1 H) 7.51 (t, J=7.48 Hz, 1 H) 7.70 (d, J=8.55 Hz, 1 H) 7.78 (d, J=7.63 Hz, 1 H) 7.86 (d, J=8.55 Hz, 1 H) 8.15 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.[C:19](=[O:21])=[O:20].O>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]([OH:21])=[O:20])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(Br)cc21
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C(=O)O)cc21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 5.14 g (0.02 mmol) of 4,4-dimethyl-6-bromothiochroman in 40 ml of dry ether at -78° C. was added dropwise 28.2 ml of 1.7 M 0.048 mmol) tert-butyllithium in pentane. The mixture was stirred at -78° C. for 2.5 hours and then treated with an excess of solid carbon dioxide. The mixture was warmed to room temperature and treated with sufficient water to dissolve the solids. The aqueous layer was then separated, acidified with dilute sulfuric acid and extracted with three portions of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo and the residue recrystallized from ethyl acetate and hexane to give the title compound as a white solid. PMR (CDCl3): δ1.37 (6H, s), 1.97 (2H, m), 3.08 (2H, m), 7.17 (1H, d, J~ 8.0 Hz), 7.74 (1H dd, J~8.0, 1.9 Hz), 8.11 (1H, d, J~1.9 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[CH3:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[CH2:21][CH2:20][CH2:19][N:18]=1>>[ClH:1].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[CH2:21][CH2:20][CH2:19][N:18]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: O=C(Cl)CCl
Agent: Cl
Product: Cc1cc(NC(=O)CCl)ccc1NC1=NCCC1

Procedure:
The title compound was prepared by the method of Example 16 using 30.5 mmole of chloroacetyl chloride and 1.0 g (3.8 mmole) of the product compound of Example 9. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Product: CCOc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-ethoxy-4-iodo-benzene. MS (ESI) 322.2 (M•)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([OH:36])=O)=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[N:41]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34]([NH:48][CH2:47][CH2:46][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:36])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: NCCN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCn1nc(C(=O)NCCN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a suspension of 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (Example 8c) (2.5 g, 5.10 mmol) in dichloromethane (50 mL) at room temperature was added thionyl chloride (0.446 mL, 6.12 mmol), and the mixture was heated to reflux for 1 h. After cooling to room temperature the mixture was added dropwise to a solution of 2-(pyrrolidin-1-yl)ethanamine (0.711 mL, 5.61 mmol) and triethylamine (1.066 mL, 7.65 mmol) in dichloromethane (50.0 mL) in an ice bath. The resulting mixture was then allowed to warm up to room temperature, and stirred for another 0.5 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo, and the residue was purified twice by automatic silica gel column chromatography (Combiflash RF), eluting with a mixture of [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichloromethane (0-50%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydrocinnoline-3-carboxamide (2.2 g, 3.75 mmol, 73.6% yield) as a light yellow solid. LCMS: (M+H)+: 587.3.