Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[O:11]=[C:12]1[O:18][C@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[C:15]([OH:16])=[C:13]1[OH:14].[O:23]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]12>C(#N)C>[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:16][C:15]1[C@@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[O:18][C:12](=[O:11])[C:13]=1[OH:14]
Reactant: C1CCC2OC2C1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=C1O[C@H]([C@@H](O)CO)C(OC2CCCCC2O)=C1O
Temperature: 70 °C
Reaction time: 36 h

Procedure:
Under an argon atmosphere, 4 ml of 1,1,1,3,3,3-hexafluoro isopropanol and 12 ml of acetonitrile were added to L-ascorbic acid (1.00 g), and further, 1,2-epoxycyclohexane (1.42 g) was added. The mixture was heated up to 70° C. and stirred for 36 hours, then, concentrated under reduced pressure, and 3.65 g of the resultant residue was subjected to silica gel column chromatography. Thereafter, it was eluted with chloroform/methanol/water(volume ratio:20/3/0.3) to obtain two elution fractions (first eluted fraction: 244 mg, later eluted fraction: 217 mg). Based on the measurement results of high resolution mass analysis, infrared absorption spectrum, 1H-NMR, 13C-NMR and specific optical rotation on the resultant elution fractions, it was confirmed that these are two 3-O-(2-hydroxycyclohexyl) ascorbic acids which are in mutual stereoisomerism and both of them are represented by the following structural formula.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[O:1][CH2:2][CH2:3][C:4]=12)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: Nc1cccc2c1CCO2
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccc2c1CCO2

Procedure:
To a solution of 19.7 g. of 2,3-dihydro-4-benzofuranamine in 150 ml. of methanol is added 11 ml. of isopropyliodide and 15.5 ml. of triethylamine. The solution is refluxed for 40 hours and then concentrated in vacuo. The resultant oil is extracted and combined, filtered through Celite, and the ether removed in vacuo to give an oil of N-isopropyl-2,3-dihydro-4-benzofuranamine.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1SC.[NH2:17][NH2:18]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1[NH:17][NH2:18]
Reactant: CSC1NCCCN1CCO
Reactant: NN
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)C
Solvent: CCO
Product: NNC1NCCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-hydroxyethyl)-2-methylthio-3,4,5,6-tetrahydropyrimidine mesylate (87.2 g) is suspended in ethyl alcohol (150 ml) and treated with anhydrous hydrazine (22 mL). The mixture becomes clear within a few minutes. It is stirred at room temperature overnight and then diluted with t-butyl methyl ether (2 liters). The solution is kept in the freezer at -20° C. until the solid separates, filters and dries. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 68.12 g of 1-(2-hydroxyethyl)- 2-hydrazino-3,4,5,6-tetrahydropyrimidine mesylate, melting point 82.2°-84.4° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.[NH3:24]>C(O)C>[NH2:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N)ncnc32)CC1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.050 g, 0.148 mmol) in ethanol saturated with ammonia (1 mL) was heated to 80° C. for 30 min. in a sealed tube in the microwave. The mixture was cooled, concentrated, and dried in vacuo to give tert-butyl 4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate which was used without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.93 (s, 1H), 5.60 (bs, 2H), 4.84-4.95 (m, 1H), 4.29 (bs, 2H), 2.95 (bs, 2H), 2.13-2.28 (m, 2H), 1.92-2.03 (m, 2H). LRMS m/z (M+H) Calcd: 319.1, found: 319.1.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=2[Cl:17])[N:7]=[CH:6][C:5]=1[C:18]#[N:19].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].[OH2:30]>CN(C)C=O.C(O)C>[C:18]([C:5]1[CH:6]=[N:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=2[Cl:17])[C:4]=1[N:3]([C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30])[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])#[N:19]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Reactant: O
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 10 °C

Procedure:
Sodium hydride (0.5 g) was added to a solution of 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (5.8 g) in dimethylformamide (20 ml). After the initial exothermic reaction had subsided, the solution was heated on a steam-bath for 5 minutes and then cooled to 10° C. Phenyl chloroformate (2.8 ml) was then added slowly in small portions with occasional cooling with water to keep the temperature below 50° C. The mixture was then heated on a steam-bath for 10 minutes, cooled and evaporated to dryness. The solid residue was treated with diethyl ether (300 ml). The ethereal suspension was filtered and the filtrate was evaporated to dryness. The solid residue thus obtained was boiled in ethanol (200 ml) and separated by filtration, to give 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (1.7 g), m.p. 206°-208° C., in the form of colourless crystals.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23]>>[F:19][C:18]([F:21])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[N:7][CH:6]=[CH:5][N:4]=1)(=[O:11])=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Product: O=C(O)c1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 80 %

Procedure:
Following the general method as outlined for Intermediate 4, starting from N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide and 4-carboxybenzene boronic acid, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 80% yield (98% purity by HPLC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:25]([CH3:36])=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=1.NC1C=NN(C(OC(C)(C)C)=O)C=1C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:23][C:24]2[C:25]([CH3:36])=[N:26][NH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1N
Agent: Cc1c(N)cnn1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]cc1Nc1ncc(Cl)c(CCc2ccccc2C2(C(N)=O)CC2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.120 g, 0.357 mmol), tert-butyl 4-amino-3-methyl-1H-pyrazole-1-carboxylate or tert-butyl 4-amino-5-methyl-1H-pyrazole-1-carboxylate (isomer not determined) A26 (0.141 g, 0.714 mmol) and p-toluenesulfonic acid monohydrate (0.007 g, 0.04 mmol) in 1,4-dioxane (2.0 mL) was stirred in a microwave reactor at 120° C. for 3 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-10% MeOH in DCM) to give the title compound 25 as a white solid (0.035 g, 25%). LCMS-A: rt 5.62 min; m/z 397 [M+H]+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl.CCOC(C)=O>O.C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)CCCCCN(c1ccccn1)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCN(c1ccccn1)c1ccccn1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
LiOH (12 mg, 0.50 mmol) in water (0.3 mL) was added to II (33 mg, 0.11 mmol) in THF (0.8 mL) at rt. After 2 h, the reaction mixture was neutralized with 2N HCl, and was then poured onto brine (5 mL), and EtOAc (5 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:1 to 100:4) as eluant to furnish III as a colourless oil (18.1 mg, 58%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:23][OH:24])[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>[OH-].[Na+].CO>[OH:24][CH2:23][C:5]1([C:3]([OH:4])=[O:2])[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)C1(CO)CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccccc1)c1cc2c(cc1O)C(CO)(C(=O)O)CC2

Procedure:
A solution of 2.8 g of 1-hydroxymethyl-5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester in 12 ml of 2 N sodium hydroxide solution and 50 ml of methanol is heated to the reflux temperature for 5 hours. It is then evaporated in vacuo to a volume of approx. 10 ml and the evaporation residue is partitioned between twice 50 ml of water and 50 ml of ether. The aqueous phases are combined, acidified to pH 1 with concentrated hydrochloric acid and extracted with twice 50 ml of ether. The organic extracts are washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Chromatography of the evaporation residue on 100 g of silica gel using ether as the eluting agent gives pure 1-hydroxymethyl-5-benzoyl-6-hydroxy-indane-1-carboxylic acid in the form of yellow crystals of melting point 104°-110° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:4][N:3]1[C@H:2]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:7][C:6]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[CH:5][C:19]=3[CH2:20][CH2:11]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: C1CCOC1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cnc5ccccc5n4)cc3CC[C@@H]12
Reaction time: 16 h
Yield: 67 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (187 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-chloroquinoxaline (107 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. Added an additional 23 mg of the palladium reagent, and let stir an additional 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (67%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=357. α[D]589 =+72.94 (c=0.63, chloroform).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)CCc1ccccc1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CCc1ccccc1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), t-butanol (3.6 mmol), a zinc cluster Zn4O (OCOF3)6 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, t-butyl 3-phenylpropionate was obtained quantitatively.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[O:31]([C:33]([C:35]1[S:36][CH:37]=[CH:38][C:39]=1[S:40](Cl)(=[O:42])=[O:41])=[O:34])[CH3:32]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:40]([C:39]3[CH:38]=[CH:37][S:36][C:35]=3[C:33]([O:31][CH3:32])=[O:34])(=[O:41])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2-(methoxylcarbonyl)thiophene-3-sulfonyl chloride (0.014 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 1001C for 30 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane/methanol to give the title compound (15 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 3.89 (s, 3 H) 4.46 (m, 2 H) 7.50 (m, 4 H) 7.65 (d, J=8.82 Hz, 1 H) 8.01 (d, J=5.15 Hz, 1 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 10.74 (s, 1 H) 14.06 (s, 1 H). MS (ESI−) m/z 630 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.C([O:40][C:41](=O)[C:42]([F:45])([F:44])[F:43])C.O>CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:41](=[O:40])[C:42]([F:45])([F:44])[F:43])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC(COCC1CCN(C(=O)C(F)(F)F)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 42.1 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 5 mL of methanol was added triethylamine (0.37 mL, 2.7 mmol) and trifluoroacetic acid ethyl ester (0.20 mL, 2.7 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 10:2:0.5 DCM:hexane:isopropylamine) provided 297 mg (41%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>ClCCCl.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]#[N:19]
Reactant: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: N#CC1=C(Cl)c2ccccc2OC1c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 25.7 g 4-chloro-3-hydroxyiminomethyl-flav-3-ene and 28.3 g triphenylphosphine in 250 ml 1,2-dichloroethane and 8.7 ml carbon tetrachloride is heated at 60° C. To this solution one adds 12.54 ml triethylamine. The temperature is maintained between 62°-65° C. during the addition and for further 25 minutes. The mixture is cooled to 0° C., filtered and evaporated. The crude material is extracted with hexane. The combined extracts are evaporated and purified by column chromatography on silicagel using a mixture of dichloromethane and hexane as eluant. The pure fraction is evaporated and crystallized in diisopropylether. Pure 4-chloro-3-cyano-flav-3-ene is obtained as pale yellow crystalls; m.p. 99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[Cl:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:30])=[O:29])=[CH:25][CH:24]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccc(Cl)s3)cc2c2cc[nH]c12
Yield: 4.4 %

Procedure:
This compound is prepared according to synthesis 45, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 29 μL (0.21 mmol) of 5-chloro-thiophene-2-sulfonyl chloride. After recrystallization from methanol and trituration in hot methanol, 4 mg (3%) of 8-(5-chloro-thiophene-2-sulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1=[O:28])[CH3:2].[Cl:30]N1C(=O)CCC1=O>ClCCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]1[C:11]([Cl:30])=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:7]1=[O:28])[CH3:2]
Reactant: CCOC(=O)Cn1ccnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: CCOC(=O)Cn1c(Cl)cnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Yield: 90.3 %

Procedure:
A solution of {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (250 mg, 0.61 mmol, preparation described in example 21, step D) and N-chlorosuccinimide (73 mg, 0.55 mmol) in 1,2-dichloroethane (4.2 ml) was heated to 80° C. for 1.5 h. Additional N-chlorosuccinimide (8 mg) was added and the reaction mixture was heated for 1 h. Concentration and flash chromatography (silica gel, hexane-ethyl acetate, 80:20) gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-6-chloro-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (0.22 g, 81%); 1H NMR (CDCl3, 400 MHz) δ 6.94 (s, 1H), 4.90 (s, 2H), 4.26 (q, 2H, J=7.1 Hz), 3.40 (m, 4H), 3.10 (m, 2H), 1.87 (m, 2H), 1.48 (s, 9H), 1.31 (t, 3H, J=7.1 Hz), 0.97 (m, 1H), 0.49 (m, 2H), 0.21 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc2ncccc2c1
Solvent: CCOCC
Product: c1ccc(-c2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Quinoline (40 g) was dissolved in dry ether (250 ml) and treated dropwise with a solution of phenyl lithium (160 ml of 1.88 m solution in benzene/ether). The mixture was stirred at room temperature for 18 hr., then washed with aqueous ammonium chloride solution (20% w/v 2×100 ml) and then water (2×100 ml). The aqueous phase was extracted with ether (2×100 ml) and the combined ether layers were dried (magnesium sulphate) and evaporated in vacuo to give an oil. Unreacted quinoline was removed from the product by distillation in vacuo (80°-90°/10-15 mm Hg). A portion of the residue was crystallised from industrial methylated spirit to afford 2-phenylquinoline m.pt. 84°-86° characterised by its nmr spectrum. The bulk of the product was also characterised by its nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH2:15]([SH:17])[CH3:16]>CC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([S:17][CH2:15][CH3:16])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncccc2n1
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCSc1nc(Cl)nc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A suspension of 15 gm (0.075 mol) of 2,4-dichloropyrido[3,2-d]pyrimidine in 100 ml of acetone at -40°C was admixed with a solution of 3.2 gm (0.08 mol) of sodium hydroxide and 4.9 gm (5.8 ml) of ethylmercaptan in 25 ml of water, and the mixture was stirred for two hours at room temperature. Thereafter, 200 ml of water were added to the reaction mixture, and the precipitate formed thereby was collected and recrystallized from petroleum ether, yielding 11.0 gm (65% of theory) of 2-chloro-4-ethylmercapto-pyrido[3,2-d]pyrimidine, m.p. 101°-103°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]([N+:21]([O-:23])=[O:22])[CH3:20])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C=O.[CH3:26][O:27][Na]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:26][OH:27])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CO[Na]
Reactant: CCCCCCCOc1ccc2cc(C(C)[N+](=O)[O-])ccc2n1
Agent: C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCOc1ccc2cc(C(C)(CO)[N+](=O)[O-])ccc2n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
2-(heptyloxy)-6-(1-nitroethyl)quinoline (1.823 g, 5.77 mol) and paraformaldehyde (346 mg, 11.54 mmol, 2.0 eq.) were dissolved in THF (10 mL). CH3ONa (115 mg, 2.13 mmol, 0.37 eq.) in methanol (2 mL) was added to the solution. The mixture was stirred at 80° C. under nitrogen atmosphere for 15 h. The mixture was extracted with ethyl acetate and the organic layer was concentrated and purified by silica gel column chromatography using petroleum/ethyl acetate (5/1) as eluent to give product as a slight red oil (823 mg, 43%). ESI-MS: 347.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.56 (q, 1H), 6.93 (d, 1H), 4.62 (d, 1H), 4.47 (t, 2H), 3.90 (d, 1H), 2.15 (s, 3H), 1.84-1.80 (m, 2H), 1.49-1.24 (m, 8H), 0.89 (t, 3H).