Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1cccc(-c2cn3cccc(Cl)c3n2)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3c(Cl)cccn3c2C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
N,N-Dimethylformamide (30 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.08 mL, 11.6 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine (2.0 g, 7.75 mmol) and the resulting solution was stirred for 48 hours. Water was added to the reaction. The solids were then filtered and azeoptroped with methanol to give 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (2.2 g, 99%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:25])[C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19](Cl)=[O:20])[CH:17]=1.C(Cl)(=O)[C:28]1[CH:36]=[CH:35][C:31](C(Cl)=O)=[CH:30][CH:29]=1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:15](=[O:25])[C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([O:1][C:28]4[CH:29]=[CH:30][CH:31]=[CH:35][CH:36]=4)=[CH:9][CH:10]=3)=[O:20])[CH:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1

Procedure:
N,N'-Bis-(4-phenoxyphenyl)isophthalamide was prepared by the reaction of p-phenoxyaniline with isophthaloyl chloride. This amide (10.5117 g, 0.0210moles) was polymerized with terephthaloyl chloride (4.3243 g, 0.0213 moles)by the procedure of Example 27. The cream colored fibrous polymer which wasobtained had the repeat unit ##STR37##
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH3:14][N:15]([CH3:28])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27]CNC[CH2:23]2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:23][N:22]([CH3:27])[C:19]1[CH:20]=[CH:21][C:16]([N:15]2[CH2:28][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:14]2)=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 44.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.4450 g, 2.54 mmol) and 1-(4-dimethylaminophenyl)piperazine (0.55 g, 2.68 mmol) in toluene (20 ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the solid formed was collected. Recrystallisation from methanol gave the title compound (0.382 g, 45%) as colourless neddles, m.p. 199°-201° C.; (Found C, 71.32; H, 7.37; N, 20.71. C20H25N5 requires C, 71.61; H, 7.51; N, 20.88%); δH (DMSO-d6) 2.52 (4H, m, 2×piperazinyl CH2), 2.76 (6H, s, N(CH3)2), 2.95 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.66 (2H, m, ArH), 6.80 (2H, m, ArH), 7.03 (1H, dd, J 7.8, 4.7 Hz), 7.35 (1H, d, J 2.0 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), 8.19 (1H, dd, J 4.7, 1.5 Hz, 6-H), and 11.41 (1H, br s, NH); m/z (CI+, NH3) 336 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[OH-:9].[Ba+2].[OH-]>O>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:9]
Reactant: [OH-]
Reactant: CN1CCCCC1=O
Agent: [Ba+2]
Solvent: O
Product: CNCCCCC(=O)O
Temperature: 110 °C
Yield: 83.4 %

Procedure:
1-methyl-2-piperidone (5 ml, 44.1 mmol) was combined with barium hydroxide (3.8 g, 26.95 mmol) and water (55 ml). The suspension was warmed to 110° C. for 6 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 5-(methylamino)pentanoic acid as a white solid (2.95 g). 5-(Methylamino)pentanoic acid (5 g, 38 mmol), and Sodium hydroxide (50% aqueous solution, 6.6 g, 82 mmol) were suspended in water (30 ml) and dioxane (20 ml). Di-tert-butyl dicarbonate (11 g, 50 mmol) was added, then the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, acidified to approximately pH 5 with concentrated HCl and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give crude 5-[(tert-butoxycarbonyl)(methyl)amino]pentanoic acid as a thick clear oil (14 g).
Reaction SMILES: [Cl:1]Cl.[NH:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][C:4]1=S>Cl>[OH2:13].[ClH:1].[Cl:1][C:4]1[NH:3][C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]=1
Reactant: ClCl
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Agent: Cl
Product: O
Product: O=c1[nH]c(Cl)nc2nc[nH]c12

Procedure:
230 g (3.24 mol) of chlorine are introduced into a suspension of 168.2 g (1.0 mol) of 2-thioxanthine in 68 liters of conc. hydrochloric acid in the course of about 5 hours at 3°-5° C. Then about 1 liter of hydrochloric acid is distilled off in a water jet vacuum, the residue is cooled to 0°to +5° C., suction filtered and washed with 0.5 liters of saturated, ice-cold brine and finally with 300 ml of isopropanol. After drying at 50° C. over a period of about 12 hours, 93 g (85.7% of theory) of colourless crystal powder are obtained. By preparing the free base and again converting it into the hydrochloride the title compound is obtained in analytically pure form. Elemental analysis corresponds to the composition C5H4Cl2N4O×H2O.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.[N+](C1C=C(C=CC=1NC1C=CC=CC=1)[C:24](O)=[O:25])([O-])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:49][NH:50][O:51][CH3:52]>C1COCC1>[CH3:52][O:51][N:50]([CH3:49])[C:5]([C:4]1[CH:8]=[CH:9][C:10]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24](=[O:25])[NH:1][C:2]=2[CH:3]=1)=[O:7]
Reactant: CNOC
Reactant: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Reactant: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2c(c1)[nH]c(=O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-amino-4-phenylamino-benzoic acid (prepared from 3-nitro-4-phenylamino-benzoic acid as described in the general procedure, 2.04 gm, 8.94 mmol) in THF (25 mL) was added carbonyl diimidazole (3.62 gm, 22.34 mmol). After stirring for 1 hour at room temperature, N,O-dimethylhydroxyl amine (1.31 gm, 13.41 mmol) was added in one portion. Stirring was continued at room temperature for an additional 2 hours after which time the reaction was determined to be complete by LC-MS. The THF was removed in vacuo and the residue was diluted with water and extracted with methylene chloride three times. The combined methylene chloride extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2.23 gm of the title compound as a tan solid which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([S:26][C:23]5[CH:24]=[CH:25][C:27]([OH:30])=[CH:21][CH:22]=5)[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cccc(Sc3ccc(O)cc3)c2C(=O)c2cccc(Sc3ccc(O)cc3)c21
Temperature: 145 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 27.7 grams (0.1 mole) of 1,5-dichloroanthraquinone, 28.5 grams (0.22 mole) of p-hydroxythiophenol, 30 grams (0.22 mole) of potassium carbonate, and 200 milliliters of dimethyl formamide was heated with stirring at 145° C. for 4 hours. The mixture was then cooled to room temperature, and poured into 1.5 liters of water. Thereafter, the above product was isolated by filtration, washed with 500 milliliters of water, and air dried. The product was then recrystallized from acetic acid to yield 30 grams of 1,5-bis(p-hydroxyphenylthio)anthraquinone as a yellow powder, m.p. (melting point) 298° to 300° C.; ms 456 (M+); vis (DMF), λmax 450 nm (nanometers) (ε 6300); Analysis Calculated for C26H16O4S2 : C, 68.4; H, 3.53; O, 14.02; S, 14.05. Found: C, 67.93; H, 3.60; O, 14.05; S, 14.26.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5].Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>CC(N(C)C)=O>[CH2:20]([O:19][C:17]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])=[O:5])=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)Cl
Reactant: C[C@H](N)C(=O)NC(=O)c1ccccc1S
Solvent: CC(=O)N(C)C
Product: CC(C)COC(=O)Sc1ccccc1C(=O)NC(=O)[C@H](C)N
Reaction time: 8 h

Procedure:
To a solution of N-(2-mercaptobenzoyl)-L-alaninamide (0.22 g, 1.00 mmol) in DMA (5 ml) was added iso-butyl chloroformate (0.2 g, 1.50 mmol), and the mixture was stirred for 8 h. The solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml). The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield, 73%. The product was further purified by column chromatography on silica using chloroform-methanol (7:3 v/v) as eluent with 82% recovery. 1H NMR (DMSO-d6): 0.94 (d, 6H, 2CH3), 1.34 (d, 3H, CH3), 1.96 (m, 1H, CH), 4.06 (d, 2H, CH2), 4.44 (quintet, 1H, CH), 7.16 (brs, 1H, NH2), 7.38 (brs, 1H, NH2), 7.54-7.80 (m, 4H, Ar—H), 8.42 (d, 1H, NH).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=O>C(O)C.N1CCCCC1>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (40.6 mg, 38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2NN[C:16](=[O:19])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][CH2:29]C(OC)=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[O:35]C(=O)OC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[CH:15]([CH3:20])[C:16](=[O:19])[CH2:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COCc1ccccc1
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Reactant: COC(=O)OC
Product: CC(C(=O)COCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared using a procedure analogous to that described for Piperidine 15, Step B, except benzyloxyacetic acid, methyl ester was substutited for dimethylcarbonate. RF: 0.27 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.27 (d, J=6.9, 3H), 1.43–1.86 (m, 15H), 2.54–2.70 (m, 3H), 3.78–4.76 (m, 5H), 7.27–7.40 (m, 5H).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[C:4](=O)[O:3]1.OC1C=C2C(=CC=1OC)C(=O)OC2.BrN1C(=O)CCC1=O.O.[NH2:37][NH2:38]>C(Cl)(Cl)Cl.C(O)(=O)C>[OH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:13][CH3:14])[C:4](=[O:3])[NH:38][N:37]=[CH:2]2
Reactant: COc1cc2c(cc1O)C(Br)OC2=O
Reactant: NN
Agent: COc1cc2c(cc1O)COC2=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]ncc2cc1O

Procedure:
3-Bromo-5-hydroxy-6-methoxyphthalide may be prepared by treating 5-hydroxy-6-methoxyphthalide with N-bromosuccinimide in chloroform. Treatment of 3-bromo-5-hydroxy-6-methoxyphthalide with hydrazine hydrate in boiling aqueous acetic acid gives 6-hydroxy-7-methoxy-1(2H)-phthalazinone, which may be converted into the sulphate of the title compound by the general procedure of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-morpholine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and morpholine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1.CCN(C(C)C)C(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1>ClCCl.O1CCOCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:2](=[O:3])[NH:35][C:36]2[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[CH:20]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccccc1-c1cc(N)ncn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)Nc2cccc(CC(=O)O)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl chloroformate (0.15 g, 99 mmol) was added dropwise to a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.20 g, 0.99 mmol) and DIPEA (0.250 g, 1.98 mmol) in dry dichloromethane (10 ml) at −78° C. and the mixture was allowed to stir overnight at room temperature. Then dichloromethane was evaporated, dry 1,4-dioxane and (3-amino-phenyl)-acetic acid (0.15 g, 0.99 mmol) were added and the mixture was heated overnight at 70° C. The solvent was evaporated and the crude product was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with water (2×50 ml) and by brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor. The residue was washed with ether to give (3-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-phenyl)-acetic acid as a coloured solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1.[C:17]([C:19]1[N:20]=[C:21]([C:32]([O-])=[O:33])[N:22]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=1)#[N:18].[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:32]([C:21]2[N:22]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[C:19]([C:17]#[N:18])[N:20]=2)=[O:33])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a mixture of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in the previous step, 770 mg, 2.75 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 840 mg, 2.75 mmol) and PyBroP (1.28 g, 2.75 mmol) in 20 mL of DMF was added DIEA (1.44 mL, 8.25 mmol). The resulting mixture was stirred at RT for 16 h under Ar. Treated with 80 mL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5-10% EtOAc/hexane) gave 1.28 g (88%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C25H33BrN4O2Si, 529.2 (M+H). found 528.9.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([N+:17]([O-])=O)[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(O)(=O)C>[Fe].O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])c2nc(NC(C)=O)ccc2c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c2nc(NC(C)=O)ccc2c1
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A mixture of 10.5 g (0.04 mole) of crude 2-acetamido-6-methoxy-8-nitroquinoline, 14 g of iron filings, 2 ml of glacial acetic acid, and 120 ml of water was stirred on the steam bath for 18 hr. The mixture was filtered and the solid residue was washed thoroughly with acetone. The acetone washings were concentrated and the residue was eluted through a short silica gel column with methylene chloride to give 7.3 g (78%) of 2-acetamido-8-amino-6-methoxyquinoline. A sample recrystallized from 95% ethanol melted at 192°-194°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1(O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCCCC1

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (240 mg, 0.793 mmol) obtained in Example 5 was dissolved in toluene (20 ml). To the resulting solution were added cyclohexanol (0.11 ml, 1.0 mmol) and cyanomethylenetri-n-butylphosphorane (250 mg, 1.0 mmol). The resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then, added with cyclohexanol (0.22 ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.08 mmol). The mixture was heated under reflux for 14 hours under an argon atmosphere. After the reaction mixture was allowed to cool down and concentrated under reduced pressure, the residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=30:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (188 mg, 62%) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])/[NH:6]1.[C:22]([N:29]1[CH:33]=[CH:32]N=C1)(N1C=CN=C1)=[O:23].C(N)[C:35]1[CH:40]=[CH:39]C=[CH:37][CH:36]=1.C(OCC)C>CN(C=O)C.CO>[CH2:33]([NH:29][C:22](=[O:23])[NH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][NH:8]/[C:7](=[N:10]\[C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])/[NH:6]1)[C:32]1[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccccc1
Reactant: NCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)NCc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(3-amino-propyl)-imidazolidin-(2E)-ylidene]-amide (Ex. 31) (0.040 g, 0.128 mmol) in DMF (2 ml) is added 1,1′-carbonyldiimidazole (0.023 g, 0.141 mmol) and the reaction mixture is stirred for 1 hour at room temperature. Benzylamine (0.014 ml, 0.128 mmol) is added and additional benzylamine (0.014 ml, 0.128 mmol) is added at hourly intervals for a total of 3 hours. Purification is by diluting the reaction with 2N NaOH (30 ml) and extracting the product into EtOAc (40 ml). The organic phase is washed with 2N NaOH (30 ml), dried over MgSO4 and the solvent evaporated in vacuo to yield a yellow oil. The oil is dissolved in methanol (0.75 ml) and diethyl ether (5 ml) added to triturate a yellow solid. This solid is filtered off and the filtrate formed a further precipitate. This yellow solid is collected by filtration and rinsed with diethyl ether to give the title compound; [M+H]+ 446.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH:28]([CH3:30])[CH3:29])=[C:26]([CH:31]=O)[NH:25][C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH:28]([CH3:30])[CH3:29])=[C:26]([CH:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:25][C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC(C)c1[nH]c(C=O)c(C(C)C)c1C(=O)NCCCN1CCCC1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C(C)C)c1C(=O)NCCCN1CCCC1
Yield: 15.2 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (130 mg, 0.6 mmol) was condensed with 5-formyl-2,4-diisopropyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (150 mg, 0.45 mmol) to give 36 mg (15%) of the title compound as a tan-orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[NH:77]1[CH:81]=[C:80](B2OC(C)(C)C(C)(C)O2)[CH:79]=[N:78]1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:80]5[CH:81]=[N:77][NH:78][CH:79]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cn[nH]c5)cccc4c3=O)cc2)CCC1
Yield: 74 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 4-pyrazoleboronic acid pinacol ester to give the title compound as a colourless oil (108 mg, 74%). LCMS (Method G): RT=3.86 min, [M+H]+=534.