Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14](CS(N3CCC[C@@H]3C(O)=O)(=O)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:37]([NH2:41])([NH2:40])(=[O:39])=[O:38]>O1CCOCC1.C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14]([NH:40][S:37](=[O:39])(=[O:38])[NH2:41])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
Intermediate R (100 mg, 0.26 mmol in dioxane (4 ml) was treated with sulfamide (125 mg, 1.30 mmol) and heated to reflux for 1 hour, then cooled to room temperature, diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Trituration of the residue in ether afforded the desired product (50 mg, 42% yield). 1H NMR (360 MHz, CDCl3) δ 7.40–7.30 (4H, m), 7.09–7.02 (2H, m), 6.90–6.80 (1H, m), 5.51–5.46 (1H, m), 5.14–5.07 (2H, broad, s) 3.70–3.61 (1H, m), 2.60–2.49 (3H, m), 2.19–2.10 (2H, m) and 1.99–1.45 (3H, m). m/z=465, 467 [MH]+
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:16])([F:15])[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C.CO.O>CCOCC>[OH2:3].[F:16][C:5]([F:15])([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH:4]=[O:3]
Reactant: CCOC(=O)C(F)(F)Oc1ccc(SC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(OC(F)(F)C=O)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-difluoro-2-(4-methylsulfanylphenoxy)acetic acid ethyl ester (19.8 g, 75 mmol) in dry ether (200 ml) at −70° C., a 1 M solution of DIBALH in hexanes (113 ml, 113 mmol) was added slowly. Ater stirring for 2 h at −70° C., methanol (4 ml) and water (27 ml) were dropwise added and the reaction mixture was left stirring at rt for 30 min. The heterogeneous mixture was filtered through a plug of Celite and the filtrate was diluted with ether (200 ml). The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated to yield 2,2-difluoro-2-(4-methylsulfanylphenoxy)-acetaldehyde monohydrate which was then converted to the title compound as described in Example 1, Steps 8-12 above. Note: In step 11, both the sulfur atoms were oxidized to sulfonyl group. 1HNMR (DMSO-d6): δ 9.05 (1H, s), 7.99 (2H, m), 7.52 (2H, dd), 7.41 (2H, d), 7.25 (2H, t), 4.39 (1H, q), 3.80 (1H, m), 3.51 (2H, m), 3.36 (3H, s), 3.35 (2H, m), 3.20 (1H, m), 1.39 (2H, m), 1.13 (1H, m), 1.02 (1H, m), 0.75 (1H, m), 0.59 (2H, m), 0.31 (2H, m). LC/MS: M+1: 600.2; M−1: 598.2.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:18].[H-].[Na+].Cl[CH2:22][C:23]1[N:24]=[C:25]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[O:26][CH:27]=1.O.[CH3:42]N(C)C=O>>[CH3:42][C:7]1[CH:2]=[C:3]([O:18][CH2:22][C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[O:26][CH:27]=2)[CH:4]=[CH:5][C:6]=1[CH2:8][S:9]([CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1cc(CS(=O)CCn2ccnn2)ccc1O
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)ccc1CS(=O)CCn1ccnn1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 133 mg (0.50 mmol) 2-methyl-4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4 ml N,N-dimethylformamide was treated at 0° C. with 24 mg (0.60 mmol) 60% sodium hydride and stirred at that temperature for 30 min, then 152 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued over night at room temperature. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1, ether and purified by chromatography on silica. Gradient elution with ethyl acetate (5 to 10% methanol) gave 65 mg (24%) 1-[2-(2-methyl-4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl-methanesulfinyl)-ethyl]-1H-[1,2,3]triazole as solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:38]C1C=CC(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)=CC=1.C(OC(NCCBr)=O)(C)(C)C>>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C:15]1[C:14]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][C:4]([F:38])=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCBr
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(4-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 38) and 2-[N-(t-butoxycarbonyl)amino]ethyl bromide.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[NH:23][C:22]1=[O:27])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(F)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:13]3[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[H][H].[C:29]1([CH:35](Br)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.O>[C:29]1([CH:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]([CH:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[C:13]4[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)nc(-c1ccc(OC(c3ccccc3)c3ccccc3)cc1)n2C1CCCCC1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (50 mg, 1.25 mmol) was added in a single portion to a stirred mixture of compound 6 in DMF (3.5 mL). When the rapid evolution of hydrogen had ceased, the mixture was cooled in an ice-water bath. Diphenylmethyl bromide (297 mg, 1.2 mmol) was added. The mixture was stirred at an oil bath temperature of 55° C. for 30 min. The mixture was cooled and poured into cold water to precipitate a solid. The solid was dried and crystallized from ethyl acetate-hexanes to afford 8 as off white needles. ESI-MS m/e 484 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2ccncc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccncc2F)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (0.41 g, 0.0019 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.55 g, 0.0019 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.36, 0.0019 mol), 1-hydroxy-7-azabenzo-triazole (0.25 g, 0.0019 mol), and N,N-diisopropylethyl amine (0.96 mL, 0.0055 mol), in N,N-dimethylformamide (10 mL). Stir the mixture overnight at ambient temperature. Concentrate in vacuo and take up the residue in water and extract with ethyl acetate. Concentrate and elute over silica gel using methanol/dichloromethane resulting in the isolation of 0.66 g (76%) of the desired amide as a light yellowish solid. MS(ES): (M+1)+ 467.0, 468.1 m/z.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Cl)=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2([C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=3)[CH2:20][O:22]2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc(C2(c3ccc(Br)cc3)CO2)cc1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
Part A. A solution of 1,4-dibromobenzene (20.0 g, 0.08 mole) in tetrahydrofuran (200 mL) was cooled to -70+ and treated dropwise with n-butyllithium (1.6 M in hexane; 50 mL, 0.08 mole). The solution was stirred at this temperature for 60 minutes, then was treated dropwise with 4-fluorophenacyl chloride (13.8 g, 0.08 mole). The reaction was stirred at -70° overnight, then warmed to 0° for 3 hours. Saturated aqueous ammonium chloride was added, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude product was chromatographed on silica gel with 9:1 hexane/ethyl acetate to provide 2-(4-fluorophenyl)-2-(4-bromophenyl)-oxirane as an oil (10.5 g, 45% yield). NMR (CDCl3) 7.5-6.9(8H), 3.3-3.1(2H).
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:6]([CH2:7][C:8](=[O:10])[CH2:9]1)[CH2:5][O:4][CH2:3]2.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:11]1[CH:6]2[CH2:7][C:8](=[O:10])[CH2:9][CH:2]1[CH2:3][O:4][CH2:5]2)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=C1CC2COCC(C1)N2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 75 %

Procedure:
A solution of 3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (CAS 1126795-00-3, 2.82 g), TEA (6.12 g, 60 mmol, 3.0 eq) and 2-Nitro-benzenesulfonyl chloride (8.84 g, 40 mmol, 2.0 eq) in DCM (100 mL) was stirred at room temperature for 10 h. Then the solvent was removed in vacuo, the residue was purified by silica gel (EA/PE=1:3) to give 9-(2-nitrophenyl)sulfonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-one 107b as a white solid, 4.90 g, yield: 75%. MS: calc'd (MH+) 327, measured (MH+) 327.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH:4]([CH3:9])[CH2:5][N:6]([CH3:8])[CH3:7].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[CH3:7][N:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[CH2:3][S:12][C:11](=[NH:10])[NH2:13]
Reactant: CC(CCl)CN(C)C
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CC(CSC(=N)N)CN(C)C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of 1-chloro-3-(dimethylamino)-2-methylpropane hydrochloride (200 g), thiourea (97.3 g) and ethanol (950 ml) was stirred and heated under reflux for 72 hours. The solution was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in a small volume of ethanol and ether was added until the first permanent opalescence was observed. The mixture was stored at 4° C. for 16 hours. The solvent was removed in yacuo to afford a waxy/oily solid which was dried in vacuo over calcium chloride for 48 hours, then triturated with propan-2-ol. The resulting solid was collected by filtration, washed with propan-2-ol, and dried in vacuo to give S-[3-(dimethylamino)-2-methylpropyl]isothiourea dihydrochloride as a pale brown solid (90 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:4]=[N:3]1.[CH3:21][O:22][CH:23]([O:33][CH3:34])[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OCC)(=O)C>CCCC(C)C>[CH:26]1([N:25]([CH2:24][CH:23]([O:33][CH3:34])[O:22][CH3:21])[C:15](=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCCCC1)OC
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCCC1)OC

Procedure:
The subtitled compound (1.2 g) was prepared from 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] and N-(2,2-dimethoxyethyl)cycloheptanamine [Preparation 6], using a similar method to that described in Preparation 3 Step iii) and the elution gradient used was 50-80% ethyl acetate in isohexane. 1H NMR (400 MHz, DMSO-d6) δ 8.10 and 8.09 (2×s, 1H), 7.82 (s, 1H), 7.44-7.40 (m, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.06-7.02 (m, 1H), 4.51 and 4.39 (2×t, J=5.0 Hz, 1H), 3.85 (s, 3H), 3.86-3.66 (m, 1H), 3.68-3.56 (m, 4H), 3.31 (s, 3H), 3.30 and 3.16 (2×d, J=5.0 Hz, 2H), 3.25 (s, 3H), 2.81-2.76 (m, 2H), 2.61-2.51 (m, 2H), 1.79-1.23 (m, 12H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[CH2:14][NH2:15].C(N(C(C)C)CC)(C)C.C(OCC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:15][CH2:14][C:13]1[CH:16]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=1[F:17])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCc1cc(Br)ccc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NCc1cc(Br)ccc1F
Yield: 91.8 %

Procedure:
Add ethyl chloroformate (0.24 mL, 2.49 mmol) to a solution of 5-bromo-2-fluorobenzylamine hydrochloride (500 mg, 2.08 mmol) in dichloromethane (8 mL) and diisopropylethylamine (0.90 mL, 5.20 mmol). After 3 h dilute the reaction with diethyl ether and wash twice with 1 N hydrochloric acid and once with an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate to give the title compound as a colorless oil (0.527 g, 92%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([C:19]2[CH:28]=[C:27]([C:29](O)=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][CH2:62][O:63][CH3:64]>ClCCl.N1C=CC=CC=1>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][CH2:62][O:63][CH3:64])[N:47]([CH2:46][CH2:45][CH2:44][CH2:43][NH:42][C:29]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:28]=3)=[O:30])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 44.6 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.57 g, 3.0 mmol) was added dropwise to a chilled (0° C.) solution of 2-phenyl-4-quinolinecarboxylic acid (0.5 g, 3.7 mmol), 1-hydroxybenzotriazole (0.5 g, 3.7 mmol), pyridine (2.2 ml), and dichloromethane (20 ml). The reaction was maintained for 15 min followed by the dropwise addition of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.8 g, 2.55 mmol) in dichloromethane (100 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.62 g of N4-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenyl-4-quinolinecarboxamide as a yellow crystalline solid, m.p. 118° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.88 (t, J=5.7 Hz, 1H), 8.24-8.21 (m, 2H), 8.13-8.01(m, 4H), 7.83-7.78 (m, 1H), 7.62-7.48 (m, 5H), 7.36 (m, 1H), 7.20 (dt, J=7.6, 1.2 Hz, 1H), 6.54 (broad s, 2H), 4.62 (t, J=7.2 Hz, 2H), 3.83 (t, J=6.7 Hz, 2H), 3.45 (m, 2H), 3.29-3.20 (m, 5H), 1.96 (m, 2H), 1.79 (m, 2H); MS (EI) m/e 544.2589 (544.2587 calcd for C33H32N6O2)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.C([O:16][C:17]1[N:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(C)(C)C>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17](=[O:16])[NH:22][CH:21]=2)[S:25][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: CC(C)(C)Oc1ccc(C(N)=S)cn1
Product: Cc1ccncc1-c1csc(-c2ccc(=O)[nH]c2)n1
Yield: 56.1 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (188 mg) and 6-tert-butoxy-3-pyridinecarbothioamide (167 mg), the title compound (120 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]([NH:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)=[O:11].[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40](ON3C(=O)CCC3=O)=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]([NH:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH:19][C:40]([O:39][CH2:38][CH:36]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:37]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:41])=[CH:15][CH:14]=1)=[O:11]
Reactant: N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine hydrochloride salt (30 mmol, 10.59 g), N-(9-fluorenylmethoxycarbonyloxy)succinimide (30 mmol, 10.12 g) and sodium carbonate (300 mmol, 31.8 g) were added dioxane (75 mL) and water (25 mL) at room temperature. The suspension was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. The inorganic solids were filtered through celite and washed with ethyl acetate. While washing with ethyl acetate some organic compound was precipitated out from filtrate which was collected and air dried. The filtrate was concentrated under vacuum and the residue was combined with the above organic solid compound and the product was taken up in hot THF and precipatated with ether to obtain 14.1 g (81%), as a white solid, mp 230-234° C. LR MS (C31H24Cl2N2O5): Obs mass, 597. Calcd mass, 597, (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[C:18]([NH:26][NH2:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C=O)C.C>CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][N:27]=1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Reactant: NNC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(-c2cccc(CO)c2)nc1-c1nnc(-c2ccccc2)[nH]1
Temperature: 190 °C
Yield: 29 %

Procedure:
A mixture of 3-amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (0.11 g, 0.5 mmol) and benzoic hydrazide (0.15 g, 1 mmol) were heated at 180-200° C. for 30 min. After cooling, the reaction mass was taken up with 5 mL DMF and the obtained solution was diluted with EtOAc and water, clarified with charcoal and filtered on Celite. The organic layer was separated. After drying over sodium sulfate, the ethyl acetate was evaporated under reduced pressure. Purification of the residue by preparative HPLC (Acetonitrile/water) gave desired product (50 mg): 1H NMR (400 MHz; DMSO-d6): 8.3 (s, 1H); 8.1 (m, 2H); 7.6-7.3 (m, 7H); 5.45 (t, 1H); 4.6 (d, 2H); MS (EI) for C23H22N5OF3 HCl: 442 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15]N(C)C)[C:10](OCC)=[O:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[NH:21]([C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:28])=[CH:25][N:24]=1)[NH2:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:15]=[N:22][N:21]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:28])=[CH:25][N:24]=3)[C:10]=2[OH:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.1 Hz, 11H) 1.22 (d, J=9.6 Hz, 3H) 1.62 (d, J=12.1 Hz, 2H) 3.19 (dd, J=11.6, 5.6 Hz, 4H) 3.86 (d, J=9.6 Hz, 2H) 3.97 (s, 3H) 7.38-7.57 (m, 2H) 8.43 (br. s., 2H) 8.72 (br. s., 1H) 8.92 (s, 1H). MS m/z [M+H]+ 434.4.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[BH3-][C:14]#N.[Na+].C(O)(=O)C>CC#N.CCOCC>[CH3:14][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1ccc2c(c1)CCCN2
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
1,2,3,4-tetrahydroquinoline (2.0 g, 0.0015 mol) and formaldehyde (12 ml of 38% aqueous, 0.015 mol) were combined in 60 ml CH3CN. NaBH3CN (2.85 g) and then, over a 10 minute period, glacial acetic acid (1.50 ml) were added and the mixture stirred 2 hours, at which time additional acetic acid (0.5 ml) was added. After stirring an additional 30 minutes, the reaction mixture was poured into 200 ml ether, washed 3×30 ml IN NaOH, dried (K2CO3) and stripped in vacuo to yield title product, 2.27 g.