Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]#[N:49].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]#[N:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Reactant: N#CCBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CC#N)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2.50 g (4.05 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)] and 0.968 g (8.10 mmol, 2.0 equiv.) of bromoacetonitrile in 15 ml of toluene and 2 ml of N-methyl pyrrolidone was treated with 2.88 g (20.27 mmol, 5.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was stirred for 18 h at 50° C., allowed to cool to room temperature, poured into 100 ml of an ice/water mixture and extracted three times with 200 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 10:1 v/v mixture of dichloromethane and ethyl acetate as eluent to yield 2.28 g (3.48 mmol, 85.9% of theory) of (3R,4R)-3-(1-cyanomethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 656 (M+H)+.
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>C(Cl)Cl>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][C:11](=[O:13])[CH2:10][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:9]
Reactant: COC(=O)CN
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of Boc-sarcosine (9.0 g, 048 mol) in 70 ml of CH2Cl2 at −20° C. was added isobutyl chlorofomate (7.1 g, 0.052 mol) and N-Methylmorpholine (4.8 g, 0.047 mol). After 2 min glycine methyl ester, hydrochloride (7.19g, 0.057 mol) and N-methylmorpholine (5.76g, 0.057 mol) in CH2Cl2 (60 ml) was added. The reaction was stirred at −10° C. for 1 h and allowed to warm to room temperature. After 4h at room temperature, the reaction was filtered and washed with salt. NaHCO3 (100 ml), 1N NaHCO3 100 ml, twice with 1N KHSO4 (100 ml), water (100 ml) and brine (70 ml). The organic phase was dried with Na2SO4 and evaporated. The yield of Boc sarcosyl-glycine methyl ester was 89%.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10]1([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N+]=[N-])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: CCCCC(Br)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Product: CCCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
α-Bromohexanoic acid (1.95 g) in light petroleum spirit (25 ml, b.p. 40°-60°) was treated with a stock solution of diphenyldiazomethane in petroleum spirit (b.p. 40°-60°) (ca. 3.8 mmole/10ml) dropwise with stirring until a faint violet colour persisted. The mixture was stirred for 2 hours at room temperature, whereupon the solvent was removed in vacuo. The resulting oil in ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate then with water and dried. Removal of the solvent gave the title ester (3.0 g, 90%), λmax (EtOH) 252, 258, 263.5, 267.5 and 276 nm (ε 1650, 1600, 1350, 1150 and 850).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:5]1.C(O)C>O>[OH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:5]1
Reactant: O=C1CC(N2CCCC2)CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CC(N2CCCC2)CCc2ccccc21
Temperature: 10 °C
Yield: 97.8 %

Procedure:
5.75 g of sodium borohydride were slowly added to a solution of 11.5 g of the product of Step A in 11 5 ml of ethanol and 11.5 ml of water cooled to 10° C and the mixture was stirred for an hour at 20° C. The ethanol was evaporated and 100 ml of water were added. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 11.35 g of 5ξ-hydroxy-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>CCOCC>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
8 g (0.024 Mol) of trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine are reacted in 300 ml of ether with 4.6 g (0.026 Mol) of 4-chlorobenzoylchloride in the presence of 2.7 g (0.026 Mol) of triethylamine. 10.3 g of the title compound are obtained, melting point 152°-154° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C>C(O)C>[OH:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[CH:31][CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccc(CO)cc3)cc12
Solvent: CC(=O)Cl
Solvent: CCO
Product: OCc1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)cc1

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(4-hydroxymethylphenyl)-1H-indole (450 mg, 0.973 mmol) (see Preparation 39) in ethanol was reduced using catalytic hydrogenation as described in Example 35 except that no acetyl chloride was used in the reaction. This gave the title compound as an off-white powder, m.pt. 65°-69° C. (210 mg). Found: C,76.15; H,7.43; N,8.66; C20H22N2O.1/2H2O requires: C,76.16; H,7.35; N,8.88%.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:8]=1[NH:9][C:10]1[C:11]([CH2:15][C:16]#[N:17])=[CH:12][S:13][CH:14]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:4][C:14]1[S:13][CH:12]=[C:11]([CH2:15][C:16]#[N:17])[C:10]=1[NH:9][C:8]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:7]=1[Cl:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#CCc1cscc1Nc1c(Cl)cccc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCc1csc(Cl)c1Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 135 mg of sulfuryl chloride in 5 ml of methylene chloride is added dropwise to a solution of 283 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetonitrile in 20 ml of methylene chloride at -15°. After 10 minutes, a sodium dithionite solution and 3 ml of 2 N sodium hydroxide solution are added. The organic phase is separated off, dried, clarified with bleaching earth (for example Tonsil®) and concentrated. Recrystallization of the residue from methanol yields 5-chloro-4-(2,6-dichloroanilino)-3-thiophenacetonitrile (m. 128° to 128.5°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][NH:18]2)=[CH:13][CH:12]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][N:18]2[CH3:24])=[CH:13][CH:12]=1
Reactant: CI
Reactant: O=C(Nc1ccccc1F)Oc1ccc2c(c1)NCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2ccc(OC(=O)Nc3ccccc3F)cc21
Reaction time: 0.5 h

Procedure:
A solution of 1,2,3,4-tetrahydroquinolin-7-yl 2-fluorophenylcarbamate (300 mg, 1.84 mM) in dry dimethylformamide (DMF, 5 mL) was added to the stirred solution of sodium hydride in dry DMF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, methyl iodide (285 mg/ml, 2 mM), was added to the stirring reaction mixture. The mixture was stirred further for 3 hours during which the temperature was allowed to reach the room temperature (37° C.). The reaction mixture was quenched with water, diluted with water, extracted with ethyl acetate and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford the pure compound 8l as oil. Yield: 300 mg, 54.33%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:17]2[NH:21][C:20](=[O:22])[O:19][N:18]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)(C)(C)C.[ClH:24].CCOCC>O1CCOCC1>[ClH:24].[NH2:7][CH2:8][C:9]1([C:17]2[NH:21][C:20](=[O:22])[O:19][N:18]=2)[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of [1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester (4.30 g, 13.3 mmol) in 1,4-dioxane (90 mL) was added 4N HCl in 1,4-dioxane (45 mL). The solution was stirred for 18 hours, ether (200 mL) was added and the precipitate isolated by vacuum filtration. The residue was chromatographed on a wet-packed silica gel column (5.5×30 cm) eluting with 80:20:5 CH2Cl2/MeOH/NH4OH. The appropriate fractions were combined and evaporated under reduced pressure. The solid was stirred with 1N HCl in ether (150 mL). The solid was isolated by vacuum filtration, dried in a vacuum oven at 48° C. to give 2.22 g (64%) of 3-(1-aminomethyl-spiro[2.5]oct-1-yl)-4H-[1,2,4]oxadiazol-5-one hydrochloride as a white solid: mp: 179-181° C. (decomposition); 1H NMR (300 MHz, CD3OD) δ 1.05 (d, J=5.8 Hz, 1H), 1.21 (m, 1H), 1.41 (d, J=5.8 Hz, 1H), 1.4-1.72 (m, 9H), 3.12 (d, J=14 Hz, 1H), 3.54 (d, J=14 Hz, 1H); MS (APCI) m/z 224 [M+H]+. Anal. Calc'd For C11H17N3O2—HCl: C, 50.52; H, 7.01; N, 16.07; Cl, 13.56. Found: C, 50.23; H, 7.05; N, 15.89; Cl, 13.53.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CCO>[CH3:11][N:12]([CH3:13])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNC
Solvent: O
Solvent: CCO
Product: CN(C)c1ncccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (1.00 g, 0.00631 mol) in absolute EtOH (17 ml), under nitrogen, was treated, dropwise during 10 minutes, with 3.86 g (0.0214 mol) of 25% aqueous dimethylamine and kept at ambient temperature (25° C.) for 30 minutes. The mixture was mixed with water and extracted with EtOAc. The extract was washed with water, dried (MgSO4) and concentrated to give 1.05 g of the titled product, a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[CH:13][CH:12]=[C:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:24][CH2:21][CH2:22][N:23]2[C:17](=[O:19])[C:11]2[N:10]([C:15](=[O:16])[CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C(Cn1c(C(=O)O)cccc1=O)c1ccc(Cl)cc1
Solvent: O
Solvent: ClCCCl
Product: O=C1c2cccc(=O)n2CC2(c3ccc(Cl)cc3)NCCN12
Yield: 93.1 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyridine-2-carboxylic acid (50 mg, 0.17 mmol) in 1,2-dichloroethane (15 mL) was added ethane-1,2-diamine (0.1 mL, 1.5 mmol). The mixture was heated at reflux until completion (2 h, monitored by LMCS) and then diluted with water and extracted with CH2Cl2 (1×10 mL, 2×5 mL). The organic extracts were combined, dried (MgSO4), filtered and the filtrate concentrated in vacuo to yield a yellow oil that was purified by flash chromatography (Biotage SP4, 4 g cartridge, 0-10% MeOH gradient in CH2Cl2) to give 11a-(4-chlorophenyl)-2,3,11,11a-tetrahydro-1H-imidazo[1,2-a]pyrido[1,2-d]pyrazine-5,9-dione as a yellow oil (50 mg, yield 92%). 1H NMR (400 MHz, CDCl3): δ 1.73 (br s, 1H), 2.50 (br s, 1H), 2.89-3.02 (m, 1H), 3.33 (ddd, 1H, J 11.8, 7.5, 3.9 Hz), 3.50 (d, 1H, J 13.4 Hz), 3.59 (ddd, 1H, J 11.6, 7.5, 3.9 Hz), 3.97 (dt, 1H, J 11.4, 7.4 Hz), 5.55 (d, 1H, J 13.4 Hz), 6.60 (dd, 1H, J 9.2, 1.3 Hz), 7.07 (dd, 1H, J 6.8, 1.3 Hz), 7.22-7.28 (m, 4H), 7.34 (dd, 1H, J 9.2, 6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:30][C:21]3[CH:20]=[C:19]([CH3:18])[N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:22]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)cc1
Yield: 22.1 %

Procedure:
Compound 37 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2c(Cl)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg of the above-prepared 7-chloro-2-n-propyl-3H-imidazo[4,5-b]pyridine and 380 mg of methyl 2-(4-bromomethylphenyl)benzoate were dissolved in dimethylformamide, and 50 mg of sodium hydride was added to the solution. The mixture was stirred at room temperature for 20 min, and water was added thereto, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=40:1→20:1) to prepare the intended product as a colorless oleaginous substance. The yield was 140 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4].[C:16]([CH:18]1[CH2:20][CH2:19]1)#[CH:17]>C(N(CC)CC)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]#[C:16][CH:18]2[CH2:20][CH2:19]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (602 mg) and then copper(I) iodide (164 mg) were added to a mixture of 5-bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester (1 g), ethynylcyclopropane (463 mg) in triethylamine (9.5 mL) and THF (4.5 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 276.36 (C14H16N2O2S) was obtained in this way; MS (ESI): 277 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.75 g, 3.5 mmol) and (4-methylsulfonylphenyl)boronic acid (1.0 g, 5.0 mmol) in a manner analogous to Step 2c. The product was isolated as tan solid (0.60 g, 59%). MP=236-239° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J=7.3 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS=289 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:32]([CH2:34][NH2:35])[OH:33].O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([NH:35][CH2:34][CH2:32][OH:33])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: NCCO
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 12) (30 mg, 0.035 mmol) was dissolved in NMP (0.5 ml), ethanolamine (30 mg) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The organic phase was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column and eluted with 2M methanolic ammonia/DCM (0-10%). The product-containing fractions were evaporated in vacuo to give 2-({7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-yl}amino)ethanol (8.4 mg, 0.018 mmol, 53.0% yield) as a light brown glass. LCMS (formate) Rt 0.77 min, MH+ 458
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=O)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.[CH:21]1[C:26]([NH:27][NH2:28])=[CH:25][CH:24]=[C:23]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:22]=1.Cl>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:22][CH:21]=2)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(/C=C/c3ccc(O)cc3)c2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=Cc4ccc(O)cc4)c32)cc1
Yield: 27 %

Procedure:
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3-dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 3734–44), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of tri-o-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): δ 6.6–7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCI-MS m/z 264 (M−1)−. Condensation of trans-4-[2-(4-hydroxyphenyl)-vinyl]-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): δ 6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), ), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz, 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCI-MS m/z 433 (M−1)−.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.N#N.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([Br:49])[CH:44]=1>N1C=CC=CC=1>[Br:49][C:45]1[CH:44]=[C:43]([NH:42][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:31]=3)[N:36]=[CH:35][C:34]=2[C:40]#[N:41])[CH:48]=[CH:47][CH:46]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Isobutyl chloroformate (0.261 g, 1.91 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.456 g, 2.94 mmol) and N-methylmorpholine (0.294 g, 2.94 mmol) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.5 g (1.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.2 g (28.5%) of pale greenish yellow solid; ESMS m/z 476.2, 478.2 (M+H+); mp 133-135° C.