Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[Li]CCCC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C([O:36][C:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]2[CH:49]=[C:48]([C:50]3[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=3)[CH:47]=[N:46]2)[CH:39]=1)C>C1COCC1.CO>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:37](=[O:36])[C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]3[CH:49]=[C:48]([C:50]4[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=4)[CH:47]=[N:46]3)[CH:39]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CCOC(=O)c1ccc(C)c(-n2cc(-c3cncn3C)cn2)c1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cncn4C)cn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A solution of N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (81 mg, 0.261 mmol) in THF (4 mL) was stirred in a bath cooled to −78° C., and n-BuLi (0.22 mL, 0.548 mmol) was added slowly. The cold bath was removed, and the reaction was allowed to stir for 30 min. LHMDS (0.261 mmol) was then added slowly. The suspension was transferred dropwise to a stirring solution of compound 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 0.261 mmol) in THF at 0° C. After 30 min cole MeOH was added and the mixture was partitioned between saturated NH4Cl and EtOAc, then extracted with EtOAc (3×). The organic combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated, and chromatographed (1% MeOH (with 5% NH4OH)/CH2Cl2 to 5% MeOH (with 5% NH4OH)/CH2Cl2) to afford N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide (47 mg, 33%) as an orange foam: ESI MS m/z=537 [C27H32N6O4S+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]=1[O:20][CH3:21])(=O)=O.[CH3:22][S-:23].[Na+]>O1CCOCC1>[C:13]([C:11]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]([O:20][CH3:21])=[C:7]([CH2:6][S:23][CH3:22])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(CSC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.64 g 5-tert-butyl-2-methoxy-3-nitro-benzyl methanesulphonate are dissolved in 50 ml of 1,4-dioxane, combined with 950 mg of sodium thiomethanolate and stirred for 12 hours at ambient temperature. A further 600 mg of sodium thiomethoxide are added and the mixture is stirred for 2 hours at 40° C. Then the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 98:2 to 60:40).
Reaction SMILES: [OH-].[Na+:2].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[C:11](=[S:13])=[S:12]>O.CCO>[C:3]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([S-:13])[S-:12])#[N:4].[Na+:2].[Na+:2]
Reactant: S=C=S
Reactant: CCOC(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C#N)=C([S-])[S-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A solution of NaOH (40 g, 999 mmol) in H2O (40 mL) was slowly added via an addition funnel such that the internal temperature did not exceed 10° C. to a cold (0° C.) solution of ethyl 2-cyanoacetate (53.3 mL, 499.5 mmol) and carbon disulfide (30.2 mL, 499.5 mmol) in absolute EtOH (600 mL) Once the addition was complete, the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was then cooled to 5° C. The resulting solids were isolated by filtration and washed with EtOH (100 mL), ether (500 mL) and dried in vacuo to give sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) (110.0 g, 97%) as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].[C:47]([O:51][CH3:52])(=[O:50])[CH:48]=[CH2:49]>CO>[CH3:52][O:51][C:47](=[O:50])[CH2:48][CH2:49][NH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[CH2:15][CH2:16]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40]
Reactant: Cc1c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Yield: 75.5 %

Procedure:
In a closed tube, 3-((R)-2-amino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (3-58) (20 mg, 0.031 mmol), methyl acrylate (9 μl, 0.093 mmol), and methanol (2 mL) were mixed at 70° C. for 4 hrs with stirring. The resulting solution was concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 20/1) and dried in a vacuum to afford 17 mg of the compound as a colorless oil (yield 74%). 1H NMR (300 MHz, CDCl3) δ 2.17 (2H, m), 2.33 (3H, s), 2.38 (2H, t), 2.40-2.77 (6H, m), 3.58 (7H, m), 4.02-4.20 (3H, m), 5.39 (2H, d), 7.20-7.55 (9H, m), 7.77 (1H, d), 8.10 (1H, d), 8.17 (1H, s)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pt]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccccc2)c2ccc(N)cc12

Procedure:
1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) was treated with platinum on carbon (0.05 g, 5%) under an atmosphere of hydrogen at room temperature. When hydrogen uptake was complete, the mixture was filtered and concentrated in vacuo to give the title compound; m/z (M+1)+268.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:31]2[CH:30]=[C:29]([F:28])[CH:36]=[C:35]([F:37])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 507.4 (M+H+).
Reaction SMILES: ClC1C=CC([C:8]2[C:9]([N+:33]([O-])=O)=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18](C4C=CC(Cl)=CC=4)[C:17]=3[N+]([O-])=O)[CH:11]=[CH:12][C:13]=2[Cl:14])=CC=1.CC(C)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:14][C:13]1[CH:12]=[CH:11][C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([CH:8]=1)[NH2:33]
Reactant: O=[N+]([O-])c1c(Oc2ccc(Cl)c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])ccc(Cl)c1-c1ccc(Cl)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(Cl)ccc1Oc1ccc(Cl)cc1

Procedure:
A 140 g. portion of the above nitro derivative in 1400 ml. of acetone is reduced with 560 g. of sodium hydrosulfite in 1400 ml. of water as described in Example 1, giving 5-chloro-2-(p-chlorophenoxy)aniline.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.BrC1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:9][C@H:8]([NH:7][C:6]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)[CH2:11]2)[C:13]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Reactant: Cc1csc(Br)n1
Product: Cc1csc(N[C@H]2C[C@H](N3C(=O)C(C)(C)c4cccnc43)C2)n1

Procedure:
3,3-Dimethyl-1-(trans-3-((4-methylthiazol-2-yl)amino)cyclobutyl)-1 h-pyrrolo[2,3-b]pyridin-2(3h)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-bromo-4-methylthiazole (0.0585 g, 0.329 mmol) at 120° C. for 96 h. M+1: 329.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 2.25 (s, 3 H) 2.33-2.42 (m, 2 H) 3.38-3.49 (m, 2 H) 4.35 (br. s., 1 H) 5.27 (quin, J=8.56 Hz, 1 H) 5.60 (br. s., 1 H) 6.09 (s, 1 H) 6.96 (t, J=6.16 Hz, 1 H) 7.43 (d, J=6.85 Hz, 1 H) 8.17 (d, J=5.30 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]([OH:8])=[CH:3][C:2]=1[OH:9].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:10]([O:7][C:6]1[CH:5]=[C:4]([OH:8])[CH:3]=[C:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCO
Reactant: Oc1cc(O)cc(O)c1
Product: CCCCCCCCCCOc1cc(O)cc(OCCCCCCCCCC)c1
Temperature: 70 °C
Yield: 37 %

Procedure:
Into a suspension of phloroglucin 8 (5.00 g, 39.7 mmol) in 1-decanol (80 ml) dry gaseous HCl is introduced for 40 min, and the orange/red mixture is subsequently heated to 70° C. for an additional 3.5 h. After finalization of the reaction, the excess 1-decanol is distilled off in vacuo, and the residue of the reaction is purified by means of column chromatography (silica gel, CH2Cl2). 5.92 g (37%) of compound 9 are obtained as a colorless solid. Melting point: 48-50° C.; IR (KBr) 3340, 2880, 2810 cm−1; 1H-NMR (CDCl3) δ 6.06 (t, 2.1 Hz, 1H), 5.99 (d, 2.1 Hz, 2H), 4.80 (s, 1H, OH), 3.89 (t, 6.7 Hz, 4H), 1.80-1.69 (m, 4H), 1.48-1.23 (m, 28H), 0.88 (t, 6.8 Hz, 6H); MS (FD) m/z 407 (M+). Anal. calc. for C26H46O3. C, 76.79; H, 11.40. Found C, 76.74; H, 11.44.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[C:24]([C:28]([O:30][CH2:31]C)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[O:33][CH3:34])=[CH:14][CH:13]=1)#[N:5]>CO>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[O:33][CH3:34])=[CH:16][CH:17]=1)#[N:5]
Reactant: CCOC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12

Procedure:
A solution of 5.2M sodium methoxide in methanol (0.5 ml) was added to a solution of ethyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-carboxylate (1.3 g) in methanol (50 ml). The mixture was heated for 4 Hours under reflux. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration. Recrystallization from methanol afforded colorless prisms (1.1 g, 85%), m.p. 149-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([OH:19])[CH:21]=1)=[O:14]
Reactant: NCc1cccc(O)c1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1cccc(O)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-hydroxybenzyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.22 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.35 mmol of 3-hydroxybenzylamine. LC/MS [6.01 min; 464 (M+1)]
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][NH:2]1.[CH3:12][N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12>C1(C)C(C)=CC=CC=1>[CH3:12][NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:11])[NH:2]1)=[O:17]
Reactant: O=C1NNCc2ccccc21
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: CNc1ccccc1C(=O)N1Cc2ccccc2C(=O)N1
Temperature: 25 °C

Procedure:
To 3.3 g (0.022 ml) of 3,4-dihydro-phthalazin-1(2H)-one dissolved in 100 ml of xylene was added 3.9 g (0.022 mol) of N-methylisatoic anhydride and the solution was stirred and heated at reflux under N2 for 16 hours. The mixture was then cooled to room temperature (about 25° C.) whereupon a heavy precipitate formed. The 3-(o-methylaminobenzoyl)-3,4-dihydro-phthalazin-1(2H)-one was collected as a solid, washed well with xylene to give an off-white powder, mp 199°-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](CO)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(C[O:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[CH:30][NH:31]3)C1)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(COc2cccc3[nH]ccc23)C1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Product: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C

Procedure:
In a similar manner, using 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester in place of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester, 3-(1H-Indol-4-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester was prepared, (25%), (M−H)−=301.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.C(OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.5 %

Procedure:
A solution of 4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol) and 3,4-dihydropyran (1.8 mL, 20.1 mmol) in methylene chloride (50 mL) under a nitrogen atmosphere was treated with pyridinium p-toluenesulfonate (336 mg, 1.34 mmol). After stirring for 3 hours at room temperature, thin layer chromatography indicated that no starting material remained. The reaction mixture was diluted with ethyl ether (300 mL). The ether extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to give 4.47 g of the product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[OH:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])=[N:3][CH:4]=1
Reactant: Oc1cc(F)ccc1F
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)ccc1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 2,5-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.12 (1H, d, J=2.6 Hz), 8.00–7.87 (3H, m), 7.43–7.37 (2H, m), 7.25–7.11 (2H, m), 7.05–6.96 (1H, m), 5.42–5.32 (1H, m), 1.61–1.58 (12H, m); MS (ESI) m/z 489 (M+H)+, 487 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:20])[CH2:8][N:7]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:5])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[C:39]2[CH:40]=[C:41]([CH2:44]OC(=N)C(Cl)(Cl)Cl)[CH:42]=[CH:43][C:38]=2[O:37][CH2:36][C:35]1=[O:52].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:44][C:41]2[CH:42]=[CH:43][C:38]3[O:37][CH2:36][C:35](=[O:52])[N:34]([CH2:33][CH2:32][CH2:31][O:30][CH3:29])[C:39]=3[CH:40]=2)[CH2:8][N:7]1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: COCCCN1C(=O)COc2ccc(COC(=N)C(Cl)(Cl)Cl)cc21
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1c1ccc(OC)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)C(=O)CO3)CN1c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 5.20 g of (2S,4R,5R)-5-hydroxy-1,4-bis(4-methoxy-phenyl)piperidine-2-carboxylic acid ethyl ester and 5.62 g of 2,2,2-trichloro-acetimidic acid 4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl ester in 150 ml of dichloromethane is added 1.1 ml of trifluoromethanesulfonic acid at −0° C. The reaction mixture is allowed to stir for another hour at this temperature and then allowed to warm to 0° C. within 2 hours. The mixture is quenched by addition of 2N sodium hydroxide, extracted with dichlormethane, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a brown oil. Rf=0.15 (EtOAc-heptane 1:1); Rt=4.73.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: OCc1ccc(I)cc1
Reactant: Oc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1ccccn1-c1ccc(CO)cc1

Procedure:
2-Hydroxypyridine (10.0 mmol; 956 mg ) ,4-iodobenzyl alcohol (17.09 mmol, 4.0 g), K2CO3 (11.0 mmol, 1.52 g), and copper (0.2 mmol, 15 mg ) were mixed under argon and heated to 150° for 16 hours. The solid was partitioned between saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was back extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to yield a yellow oil which was purified by flash chromatography (EtOAc) to give pure the title compound as a crystalline solid
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12].[H][H].Cl>[Ni].C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(Cl)ccc(O)c1Cl
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ccc(O)c1Cl
Yield: 70.4 %

Procedure:
85 g. of 2,4-dichloro-3-nitrophenol was reduced in 900 ml. of ethanol with 9 g. of Raney nickel as a catalyst at 40° C. and 20 excess atmosphere hydrogen pressure. After the reduction, the solution was liberated of the catalyst, acidified with hydrochloric acid, and prepared in the usual manner. 62 g. of 2,4-dichloro-3-aminophenol hydrochloride (equivalent to 70.4% of theory) was obtained in the form of white crystals with a decomposition point of 177°-183° C. The mass spectrum showed 178 mols (calc. 178). Analysis yielded the following values:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C:23]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24]1>C(#N)C>[NH2:22][C:23]1([CH3:28])[CH2:27][CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:24]1
Reactant: CC1(N)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CC#N
Product: CC1(N)CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.8 g), 3-amino-3-methylpyrrolidine (0.8 g), and acetonitrile (35 ml) was stirred at 50° C. for 30 minutes. The precipitated crystals were collected by filtration, and washed with water. The crystals were dissolved in 10% aqueous ammonia, treated with activated carbon, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with water and dried to give 7-(3-amino-3-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline 3-carboxylic acid (0.81 g), m.p. 280°-282° C.
Reaction SMILES: [C:1](=[S:3])=S.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=2[NH2:15])=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:13]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=3[N:15]=[C:1]2[SH:3])=[CH:7][CH:6]=1
Reactant: Nc1cc(F)ccc1NCc1ccc(Cl)cc1
Reactant: S=C=S
Solvent: CCO
Product: Fc1ccc2c(c1)nc(S)n2Cc1ccc(Cl)cc1

Procedure:
25 ml of carbon disulfide are added to 35.2 g of 2-(4-chlorophenylmethylamino)-5-fluoroaniline, prepared in Example 8, dissolved in 500 ml of ethanol. The mixture is refluxed for 12 hours and allowed to return to room temperature. After standing for a few hours, the crystals are filtered off and washed with ethanol and then with isopropanol and ether to give 33 g of 1-(4-chlorophenylmethyl)-2-mercapto-5-fluorobenzimidazole in the form of crystals melting at 215° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:30]3[NH:29][CH:33]=[CH:32][N:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ncc[nH]1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ncc[nH]4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1H-imidazole-2 carbaldehyde. MS (ESI) m/z 457.