Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH2:20][C:19]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:18]=2)=[CH:13][CH:12]=1.Br[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:28]1([N:24]2[CH2:23][CH2:22][C:19]3([N:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][CH:2]5[CH3:1])=[CH:16][CH:15]=4)[O:21][CH2:20]3)[CH2:26][CH2:25]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC3(CCNCC3)CO2)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCN(C4CCCC4)CC3)CO2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of 2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 36 (0.11 g, 0.245 mmol) in acetonitrile (4 ml) is placed under an argon atmosphere. Bromocyclopentane (0.039 ml, 0.368 mmol, 1.5 eq), potassium carbonate (0.068 g, 0.49 mmol, 2 eq) and potassium iodide (0.08 g, 0.05 mmol, 0.2 eq) are added and the mixture is stirred at 50° C. overnight. The mixture is then filtered and the filtrate is concentrated under reduced pressure, taken up in dichloromethane, and washed twice with a saturated aqueous solution of ammonium chloride. The aqueous phases are extracted with dichloromethane and the organic extracts are collected together and dried over magnesium sulfate. Dichloromethane is removed under reduced pressure to give 0.086 g of yellow oil. This crude product is purified by chromatography over silica gel (eluent: dichloromethane/ethanol/ammonia 89:10.9:0.1) to afford 0.034 g of 8-cyclopentyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 32.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 21.6 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 3.9 minutes, to give 50 mg (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min. 1H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.09-1.13 (t, J=7.07 Hz, 3H), 1.34-1.42 (m, 1H), 1.72-1.79 (m, 1H), 2.24-2.29 (m, 2H), 2.36-2.40 (m, 2H), 2.64-2.74 (m, 2H), 3.33 (s, 1H), 3.86-3.93 (m, 1H), 3.95-4.01 (q, J=7.33 Hz, 14.40 Hz, 2H), 7.25-7.27 (m, 2H), 7.39-7.41 (m, 1H), 7.46-7.50 (t, J=7.58 Hz, 1H), 7.61-7.64 (m, 3H), 7.70 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.08 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
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: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cccnc3)ccc2n1
Yield: 48.9 %

Procedure:
150 mg of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 1), 0.237 g of pyridine-3-boronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 2 mL of aqueous 2M sodium carbonate solution, 4 mL of acetonitrile and 4 mL of toluene are placed in a microwave tube. The mixture is heated for 20 minutes in a microwave machine set at 150° C., and then cooled and filtered, the insoluble matter being washed with a mixture of methanol and dichloromethane. The combined filtrates are concentrated to dryness under reduced pressure. The residue is concreted with aqueous methanol to give 73 mg of N-phenyl-6-(pyrid-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]3=4)[O:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CO)O2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC3(O2)c2ccn(S(=O)(=O)c4ccc(C)cc4)c2CCC3Br)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
To a solution of 4'-hydroxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]-dioxolane (100 parts) in dichloromethane (2000 parts) is added a solution of p-toluenesulfonyl chloride (1.1 molar equivalent) and pyridine (1.2 molar equivalents) in dichloromethane (500 parts), and the mixture is kept at room temperature for 10 hours. The mixture is evaporated, and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give 4'-p-toluenesulfonyloxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane in 87% yield. The physical constants are given in Table I, No. 18.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=2.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=2)[C:12]([CH3:13])=[C:4]1[CH3:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(F)cc1F
Reaction time: 0.5 h

Procedure:
NaH (1.1 equiv) was added to a solution of ethyl 2,3-dimethyl-1H-indole-5-carboxylate in DMF at room temperature. After 30 min, 2,4-difluorobenzyl bromide (1.1 equiv) was added to the reaction mixture and stirred for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the compound. LC-MS 344 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19]=[C:20]1[C:25]2[S:26][CH:27]=[C:28]([S:29](Cl)(=[O:31])=[O:30])[C:24]=2[CH2:23][CH2:22][CH2:21]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH3:11])[S:29]([C:28]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20](=[O:19])[C:25]=3[S:26][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:7]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (520 mg) and triethylamine (474 μL) in tetrahydrofuran was added a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (800 mg) in tetrahydrofuran. The solution was stirred on an ice bath for 30 minutes, and at room temperature for 30 minutes. The residue resulting from the removal of the solvent by evaporation was purified by NH silica gel column chromatography (hexane/ethyl acetate), and the title compound (834 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27]([NH:33][C:34]4[C:39]([Cl:40])=[CH:38][N:37]=[C:36]5[O:41][CH2:42][O:43][C:35]=45)=[N:28][CH:29]=[N:30]3)=[CH:25][C:24]=2[O:44][CH3:45])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:40][C:39]1[C:34]([NH:33][C:27]2[C:26]3[C:31](=[CH:32][C:23]([O:22][CH2:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[C:24]([O:44][CH3:45])[CH:25]=3)[N:30]=[CH:29][N:28]=2)=[C:35]2[O:43][CH2:42][O:41][C:36]2=[N:37][CH:38]=1
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxyquinazoline (0.253 g) in methylene chloride (10 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated. Toluene was added to the residue and the mixture was evaporated. The residue was purified by column chromatography on silica (Isolute SCX column) using a 7M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.187 g); NMR Spectrum: (DMSOd6) 1.25 (m, 2H), 1.75 (d, 2H), 1.93 (m, 1H), 2.54 (m, 2H), 3.0 (d, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.76 (s, 1H), 7.78 (s, 1H), 8.23 (s, 1H); Mass Spectrum: M+H+ 444 and 446.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(O)(=O)C>[CH2:20]([NH:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](N)CO
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (36.7 g) was added portion wisely to a mixture of (2S)-2-amino-1-propanol (10.0 g) and benzaldehyde (13.53 ml) in a mixture of dichloromethane (140 ml) and acetic acid (8.38 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed successively with 2N sodium hydroxide and brine, and dried over sodium sulfate. The solution was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (30:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-benzylamino-1-propanol (15.96 g).
Reaction SMILES: [NH2:1][C:2]1[S:17][C:5]2[CH2:6][N:7]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.[Cl:30][CH2:31][C:32]([CH2:34][Cl:35])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]3[C:2]([S:17][C:5]=2[CH2:6]1)=[N:1][C:32]([CH2:34][Cl:35])=[C:31]([Cl:30])[C:18]=3[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCN(Cc2ccccc2)C3)cc1OC
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 90 °C
Reaction time: 4 h
Yield: 28.6 %

Procedure:
A mixture of 2-amino-6-benzyl-3-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (10.0 g), 1,3-dichloroacetone (3.4 g), concentrated sulfuric acid (2.6 g) and acetic acid (200 ml) was stirred at 90° C. for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was alkalinized with 2 N NaOH and then extracted with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-2-chloromethyl-4-(3,4,-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno-[2,3-b:5,4-c']dipyridine (for structural formula, see below) (3.5 g, 29%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 171 to 172° C. ##STR61##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[C:3]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Br)cc1C(=O)c1cccc(Cl)c1
Yield: 120.2 %

Procedure:
A solution of intermediate 2 (0.328 mol) and acetic acid anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed for one night. The mixture was evaporated and the product was used without further purification, yielding 139 g (quant.) of N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 3).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](I)[CH:14]=[CH2:15]>CS(C)=O.O>[CH2:15]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCn1ccc2cc(Br)ccc21
Yield: 60.6 %

Procedure:
To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for three hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added allyl iodide (0.466 mL., 5.1 mmol., 1 eq.) via syringe. After 2 h. the mixture was diluted with water and extracted 2×with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (4:1 hexanes/acetone) affording 730 mg 1-allyl-5-bromoindole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=O.[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[O:19]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH:21]([C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:20](=[O:25])[O:19]1
Reactant: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Methyl-5-nitro-phenylamino)-propionic acid [2.95 gm, 13.2 mmol], 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid (2.08 gm, 14.5 mmol), and 4-dimethylaminopyridine (DMAP) [2.42 gm, 198 mmol) in anhy. dichloromethane (70 ml) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (EDC.HCl) [3.04 gm, 158 mmol), and the resulting solution was stirred overnight at room temperature. The reaction mixture was washed (50 ml×4) with 5% potassium bisulfate (aq). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, thereby affording crude 2,2-Dimethyl-5-[3-(2-methyl-5-nitro-phenylamino)propionyl]-[1,3]dioxane-4,6-dione (7), that was dissolved in 60 ml of ethyl acetate and refluxed for 4 hrs, The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography (eluent: 2% methanol in chloroform) to give desired produced i.e., 1-(2-Methyl-5-nitro-phenyl)-piperidine-2,4-dione [8] as yellow solid [Yield: 1.91 gm, 58.6%]
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[N+:23]([O-])=O)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[NH:13][CH:7]([C:4]1[CH:3]=[CH:2][C:1]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1N)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-(1,1′-biphenyl)-4-yl-3-(2,4-dinitroanilino)propanoate (320 mg, 760 μmol) in ethanol (3 mL) was added palladium on carbon (64 mg, 10% active Pd), ammonium formate (239 mg, 3.80 mmol) and water (1 mL). The solution was stirred at room temperature for 1.5 hour, and was then filtered through a pad of Celite®. The filter pad was washed with ethyl acetate, and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=3.44 min, MH+ 392].
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)(=[O:15])=[O:14])=[CH:10][CH:9]=1.[CH3:32][O:33][CH2:34]Cl.O>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([N:16]([CH:17]2[CH:23]3[CH2:24][CH2:25][CH:18]2[CH2:19][C:20]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:21]=2[CH2:22]3)[CH2:32][O:33][CH3:34])(=[O:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COCCl
Reactant: N#Cc1ccc2c(c1)CC1CCC(C2)C1NS(=O)(=O)c1ccc(Cl)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCN(C1C2CCC1Cc1cc(C#N)ccc1C2)S(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Potassium t-butoxide (1.0M in THF; 1.33 ml, 1.33 mmol) was added to a solution of 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)thiophene-2-sulfonamide (Example 176) (350 mg, 0.89 mmol) in THF (10 ml) and stirred for 20 mins. Chloromethyl methyl ether (108 μl, 1.42 mmol) was added and the reaction stirred overnight at RT. More reagents were added as necessary until the reaction was complete by NMR. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give 5-chloro-N-(2-cyano-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-yl)-N-(methoxymethyl)thiophene-2-sulfonamide (388 mg, quant.).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[N:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][CH:3]=[N:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc2nc3ccc4ncccc4c3nc12
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4ncccc4c3nc12

Procedure:
Pyrido[3,2-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrido[3,2-α]phenazine-11-carboxylic acid (II.5) and N,N-dimethylethylenediamine
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[CH3:16][C:13]1[C:12](=[O:17])[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:15]=2[N:14]=1
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Cc1nc2c(Oc3cccc(NC(=O)c4cccc(OC(F)(F)F)c4)c3)ccnc2[nH]c1=O

Procedure:
Method G1 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-trifluoromethoxybenzoyl chloride to afford the title compound as a slightly yellow solid (74 mg, 87%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:22][C:19]2[CH:20]=[N:21][C:16]([C:15]([F:24])([F:14])[F:23])=[CH:17][CH:18]=2)[CH:9]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 6-(trifluoromethyl)pyridin-3-ol (0.16 g, 1.0 mmol), and Cs2CO3 (0.33 g, 1 mmol) in DMF (10 mL) was stirred at 60° C. for 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzonitrile (0.29 g, 87% yield). LC/MS: m/z 333.5 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1NCCc2c(-c3ccc(F)c(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-chloro-4-fluorophenylboronic acid (217 mg, 1.24 mmol) were coupled to yield 2-(3-chloro, 4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 217 mg (61%), as a pale-yellow solid. mp 234-235° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.61 (m, 2H), 7.69 (dd, 1H, J=7.5, 0.9 Hz), 7.85 (dd, 1H, J=7.2, 2.1 Hz), 8.10 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H13ClFN2O. 315.0700, Found: 315.0704; Anal. (C17H12ClFN2O.1.0 H2O.0.5 MeOH) C, H, N.