Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11](OC)=[CH:10][CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]([OH:39])=[O:38])([OH:3])=[O:2].C1C2C(=CC=CC=2)CC1.[OH-:49].[Na+].O.[CH3:52]O>>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:49][CH3:52])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]([OH:39])=[O:38])([OH:3])=[O:2]
Reactant: [OH-]
Reactant: CCCOc1ccc2c(c1)C(c1cccc(OC)c1OCC(=O)O)C(CC(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CO
Agent: [Na+]
Solvent: c1ccc2c(c1)CCC2
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
(1RS,2SR,3RS)-3-(2-Carboxymethoxy-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-ylacetic acid. To a solution of 1RS,2RS,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy)indane (290 mg, 0.56 mmol) in methanol (ca. 1 ml) was added aqueous 2 N NaOH solution (0.3 ml) followed by H2O (8 ml) then (with caution) Na2O2 (120 mg). The mixture was heated to 70° C. and stirred for 20 h at which time HPLC showed only 15% hydrolysis. The mixture was stirred at 85° C. for 3 days with 3 (100 mg) portions of Na22 added each day. the reaction mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the product as an oil (228 mg, 90% pure by HPLC) Final purification was obtained by crystallization as the bis cyclohexylamine salt. mp 210-212° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:32]4[NH:33][CH2:34][CH2:35][N:36]=4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[N:11]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:32]4[NH:36][CH:35]=[CH:34][N:33]=4)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: c1cc(C2(C3=NCCN3)CCOCC2)ccc1OCCCN1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1c[nH]c(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Dimethylsulphoxide (0.156 mL, 2.19 mmol) and dichloromethane (15 mL) were combined and cooled to −78° C. under nitrogen, oxalyl chloride (0.191 mL, 2.19 mmol) was added and the reaction mixture was stirred at −78° C. under nitrogen for 1 hour. A solution of 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}4,5-dihydro-1H-imidazole (0.314 g, 0.88 mol) in dichloromethane (15 mL) was added slowly. The reaction was stirred at −78° C. for 1 hour. Triethylamine (0.611 mL, 4.4 mmol) was then added and the reaction was stirred for a further hour. The reaction mixture allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL) and washed with an aqueous ammonia solution (20 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1) to provide a yellow oil, which was triturated with diethyl ether. A cream solid was filtered to provide the title compound (0.07 g, 22%). 1H NMR (400 MHz, CDCl3) δ 1.80 (m, 4H), 2.05 (m, 2H), 2.30 (m, 2H), 2.50 (m, 2H), 2.60-2.78 (m, 6H), 3.73 (m, 2H), 3.83 (m, 2H) (4.0 (t, 2H), 6.85 (d, 2H), 6.95 (s, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 356.2327 [MH]+.
Reaction SMILES: B.CSC.[C:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])(O)=[O:6]>C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:5][OH:6])=[CH:17][C:13]=1[CH2:14][OH:15]
Reactant: O=C(O)Cc1ccc(Cl)c(C(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of borane-methyl sulfide complex (2M in THF, 6.50 mL) was added portionwise over 5 minutes to a solution of 5-(carboxymethyl)-2-chlorobenzoic acid (example 61, step a) (1.37 g) in dry THF (20 mL) at room temperature. The resulting effervescing solution was stirred at room temperature for 1.5 hours, then heated to reflux for 1 hour. The cooled mixture was quenched by the portionwise addition of methanol (5 mL) over 5 minutes. The solution was stirred at room temperature for 2 hours and then purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a colourless oil. Yield 0.933 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH:10]([NH2:30])[C:11]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2[C:13](=[CH:14][C:15]([Cl:29])=[CH:16][CH:17]=2)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:41]1([CH3:49])[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH:10]([C:11]1[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:19](=[O:28])[C:18]2[C:13](=[CH:14][C:15]([Cl:29])=[CH:16][CH:17]=2)[N:12]=1)[NH:30][CH2:49][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CNC(CCNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Formula 107 where R1, R2, R4, R6, R7, R8 and R9 are H: R3 is Chloro; R5 is Benzyl; and R10 is p-Methyl-benzyl: To a solution of [3-amino-3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid tert-butyl ester (700 mg, 1.58 mmol) and DIEA (275 μL, 2.37 mmol) in 50 mL of DCM was added p-tolualdehyde (188 μL, 1.58 mmol). The mixture was stirred for 1 hour, after which sodium triacetoxyborohydride (500 mg, 2.37 mmol) was added. After stirring an additional 3 hours, the mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate. The solvents were evaporated to dryness and the residue was purified by flash silica gel chromatography (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the corresponding, pure compound of Formula 107, [3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-3-(4-methyl-benzylamino)-propyl]-carbamic acid tert-butyl ester (760 mg, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:10]2[CH:21]=[CH:22][N:23]=[C:9]2[NH:8][C:7]=1[CH:24]=[N:25]O)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.O>C(O)(=O)C>[C:24]([C:7]1[NH:8][C:9]2[N:10]([CH:21]=[CH:22][N:23]=2)[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:25]
Reactant: CCOC(=O)C1=C(C=NO)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C#N)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Yield: 42.1 %

Procedure:
A solution of 6-ethoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine (1.25 g), 0.29 g of sodium acetate and 0.4 ml of acetic anhydride in 15 ml of acetic acid is stirred with heating at 80°-90° C. for 30 minutes. The reaction solution is poured into water and precipitated crystals are collected by filtration. Recrystallization from a mixture of chloroform and ethanol gives 0.5 g of 7-cyano-6-ethoxycarbonyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 260°-261° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11]([OH:13])=O)[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:25][P:26]([NH2:31])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].[H-].[Na+]>C1COCC1.CN(C=O)C.O>[CH2:23]([O:25][P:26]([NH:31][C:11]([CH:10]1[C:5]2[CH:4]=[C:3]([CH3:16])[C:2]([CH3:1])=[CH:15][C:6]=2[C:7](=[O:14])[CH2:8][S:9]1)=[O:13])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24]
Reactant: CCOP(N)(=O)OCC
Reactant: Cc1cc2c(cc1C)C(C(=O)O)SCC2=O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(NC(=O)C1SCC(=O)c2cc(C)c(C)cc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.945 g) in THF (10 ml) were added oxalyl chloride (0.609 g) and DMF (2 drops), and the mixture was stirred at room temperature for 1 hour. On the other hand, a mixture of diethoxyphosphorylamine (4.9 g), sodium hydride in oil (60%, 0.32 g) and THF (30 ml) was stirred with ice-cooling for 30 minutes and, then, the above solution was added. The mixture was stirred with ice-cooling for 30 minutes, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give N-diethoxyphosphoryl-6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.29 g, 19%). Recrystallization from ethyl acetate gave colorless prisms melting at 192°-1931/2° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
4.62 ml (0.03 mol) of ethyl piperidine-4-carboxylate were dissolved in 50 ml of dimethylformamide and treated with 4.98 ml (0.036 mol) of triethylamine. 3.9 ml (0.033 mol) of benzyl bromide were added while cooling with ice and the mixture was stirred for 10 min., warmed to 40° and stirred under an argon atmosphere for 18 hrs. The solvent was then distilled off, the residue was added to 100 ml of water, extracted three times with 100 ml of ether each time and the organic phase was dried over magnesium sulfate. 5.33 g (72%) of ethyl 1-benzyl-piperidine-4-carboxylate were obtained as a yellow oil. MS: me/e=248 (C15H22NO2+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[C:25]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>O>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:25]3[N:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(N2CCC(N3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate (764 mg, 2.34 mmols) were added to DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform/methanol=100/3) to obtain the entitled compound (349 mg, 69%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:9]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.C(Cl)(=O)OCC.O.O.[N:31]1([CH:37]2[C:47]3[C:42](=[N:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][C:39]3[CH:48]=[CH:49][CH:50]=[CH:51][C:38]2=3)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([N:34]3[CH2:35][CH2:36][N:31]([CH:37]4[C:47]5[C:42](=[N:43][CH:44]=[CH:45][CH:46]=5)[CH2:41][CH2:40][C:39]5[CH:48]=[CH:49][CH:50]=[CH:51][C:38]4=5)[CH2:32][CH2:33]3)=[O:15])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(/C=C/C(=O)O)cc21
Reactant: c1ccc2c(c1)CCc1ncccc1C2N1CCNCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1ccc2ccc(/C=C/C(=O)N3CCN(C4c5ccccc5CCc5ncccc54)CC3)cc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1.01 g of (E)-3-(1-methyl-6-indolyl)acrylic acid was suspended in 20 ml of methylene chloride. 560 mg of triethylamine was added thereto. To the mixture was dropwise added 570 mg of ethyl chlorocarbonate at -30° to -20° C. The mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 1.73 g of 5-(piperazin-1-yl)-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine dihydrate. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 20 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=5/1) to obtain 1.73 g of 5-[4-{(E)-3-(1-methyl-6-indolyl)acryloyl}piperazin-1-yl]-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:34](=[O:33])[CH2:35][OH:36])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CO
Temperature: 4 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as described in Example 31-starting materials) was dissolved in a mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (5 ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight the solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine). The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a white solid (0.1 g, 38%); 1H NMR Spectrum: (CDCl3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m, 2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H); 7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48 (s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: COc1ccnc(C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)ncc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
To a stirred solution of 4-methoxy-2-methylpyridine (25 g, 0.148 mol) in conc. H2SO4 (17 mL, S. D. Fine, India), a mixture of H2SO4 (17 mL, S.D. Fine, India) and 65% HNO3 (22 mL, Rankem, India) was added in a drop-wise fashion at 0° C. over 30 min. The resulting solution was heated at 65° C. for 12 h. After completion, the reaction mixture was poured in to ice water and neutralized (PH-8) with 40% NaOH solution to give a yellow precipitate. The precipitate was further stirred and filtered, dried to give a mixture of 3-nitro (major product) and the desired 5-nitro isomers. The product was isolated by column chromatography, silica gel (230-400), eluting with 15% EtOAc in petroleum ether to give the title compound as yellow needles. 1H NMR (400 MHz, DMSO-d6) δ: 8.86 (s, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 2.52 (s, 3H). MS (ESI, positive ion) m/z: 169.0 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:42]1([CH:45]=O)[CH2:44][CH2:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH:42]1([CH2:45][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH2:44][CH2:43]1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), cyclopropanecarbaldehyde (0.195 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 44 mg (83%) of the title compound as a yellow solid. MS (ESI) m/z 529.4 (M+H)+1.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([C@H:12]([N:24]([C:26](=[O:47])[C@H:27]([NH:39]C(OC(C)(C)C)=O)[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:3].FC(F)(F)C(O)=O>ClCCl>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:11]=[C:10]([C@H:12]([N:24]([C:26](=[O:47])[C@H:27]([NH2:39])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[O:9][N:8]=1)=[O:6])[CH3:1]
Reactant: CC(C)OC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reaction time: 0.17 h
Yield: 124.2 %

Procedure:
5-{(1R)-1-[N-((2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)-propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester (2.1 g, 3.3 mmol) was suspended in a saturated mixture of trifluoroacetic acid and dichloromethane (1:1, 60 ml). After 10 min at 20° C., the reaction mixture was concentrated in vacuo to give 2.2 g of 5-{(1R)-1-[N-((2R)-2-amino-3-(2-naphthyl)propionyl)-N-methylamino]-2-(2-naphthyl)ethyl}-[1,2,4]oxadiazole-3-carboxylic acid (2-propyl)ester, trifluoroacetate, that was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolane-4-ylidene)-N-methoxy-acetamide (1.0 g, 2.8 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in MeOH (20 mL) was stirred at room temp for 1 h. The suspension was diluted with EtOAc and washed with 1N HCl followed by brine. The organic phase was dried (sodium sulfate) and concentrated. The title compound was purified by flash chromatography eluting with 100% hexane followed by 25% EtOAc/hexane to give a white solid (0.3107 g, 33% yield). 1HNMR (300 MHz, CDCl3) δ: 13.28 (1H, s), 7.41 (2H, m), 7.15 (1H, dd, J=9.52, 1.47 Hz), 6.45 (1H, s), 4.77 (2H, s), 3.89 (3H, s), 3.72 (3H, s).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NC1CC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylamine; ESI-MS [M+H]+: 482.2
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:7][S:8]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])=[O:9]>O1CCCC1>[ClH:18].[CH2:1]([NH:3][CH2:4][CH2:5][NH:6][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([NH:11][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCNCCN
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCNCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4.45 g (50.5 mmoles) of N-ethylethylenediamine in 50 ml of tetrahydrofuran cooled in an ice/ethanol bath under a nitrogen atmosphere add dropwise a solution of 11.8 g (50.5 mmoles) of 4-[(methylsulfonyl)amino]benzoyl chloride in 100 ml of tetrahydrofuran. When the addition is complete, allow the mixture to warm to room temperature and stir overnight. Filter the resulting solid and wash the solid with tetrahydrofuran then with diethyl ether. Triturate the solid in acetone, then recrystallize from 90% aqueous methanol to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:20]1(N)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC1C=CC(C(C)C)=CC=1>[CH:20]1([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)cccc21
Yield: 92.1 %

Procedure:
25.3 g of 1-nitroanthraquinone (99% pure) in 120 ml of p-cymene are boiled together with 29.8 g of cyclohexylamine (molar ratio 3:1) for 2 hours under reflux. After cooling the reaction mixture, 150 ml of petroleum ether are added, the mixture is filtered and the residue is washed with petroleum ether and dried. 28.1 g (94% of theory) of cyclohexylamino-anthraquinone are obtained. No further starting material can be detected by means of thin layer chromatography.