Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([CH:12]([OH:22])[C:13](=[O:21])[NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])(C)C.Cl.C(Cl)(OCC1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(Cl)Cl>[OH:22][CH:12]([C:8]1([NH:7][C:6](=[O:23])[O:5][CH2:1][CH:4]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:9][CH2:10][CH2:11]1)[C:13]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:21]
Reactant: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CCC2)n1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CCC2)n1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
{1-[Hydroxy-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-methyl]-cyclobutyl}-carbamic acid tert-butyl ester (209 mg, 0.64 mmol) was treated with HCl (4M in dioxane, 5 mL) overnight and then concentrated. The resulting hydrochloride salt was added to a solution of Fmoc-Cl (232 mg, 0.89 mmol) in dioxane:water 2:3, whereafter NaHCO3 (181 mg, 2.24 mmol) was added. The reaction mixture was stirred at room temperature and after for 40 min the solution was diluted with DCM and extracted. The organic phase was washed with brine, dried (NaSO4) and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 4:6-6:4) gave the title compound as a white solid (257 mg, 90%). MS m/z 446.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:15]=[C:16](C)[C:17]2[O:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][C:18]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9](O)=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34].C(=O)([O-])[O-].[K+].[K+].[OH-:41].[Na+]>>[CH2:1]([C:3]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][C:18]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:41][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Reactant: O=C1CCCCC1Cl
Reactant: [OH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OC2CCCCC2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-7-methyl-benzofuran-2-carboxylic acid (1000 mg, 2.7 mmol), 2-chloro cyclohexanone (429 mg, 3.3 mmol) and potassium carbonate (759 mg, 5.5 mmol) was made in an analogous manner to Example 30 part D followed by base hydrolysis with 2N NaOH analogous to Example 30 part E to yield (60 mg, 30%) MS (ES) m/e: 433.3 (M−1)
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[O:13][CH2:14][CH2:15][O:16][C:17]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2c(c1)OCCO2

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1,4-benzodioxan-6-carboxylic acid (Maybridge) according to methods A and C; yield 49 mg, 0.14 mmol (43%): 1H NMR (300 MHz, methanol-d4) δ 1.94 (d, J=13 Hz, 2H), 2.18 (s, 2H), 2.30 (d, J=14 Hz, 2H), 2.44 (s, 2H), 3.55 (s, 1H), 3.65 (d, J=2 Hz, 4H), 4.24-4.32 (m, 4H), 4.35 (s, 1H), 6.90 (ddd, J=9, 1 Hz, 1H), 7.33-7.39 (m, 2H); MS (DCI/NH3) m/z 315 (M+H)+; Anal. C18H22N2O3.HCl.0.25H2O: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20](C)[N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.[Cl:27]C1C2=CN(C3C(Cl)=CC=CC=3Cl)N=C2C=CN=1.ClC1N=C(N)C=C(C)N=1>>[Cl:27][C:20]1[N:19]=[C:18]([NH:17][C:13]2[C:12]3=[CH:26][N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[C:11]3[CH:16]=[CH:15][N:14]=2)[CH:23]=[C:22]([CH3:24])[N:21]=1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(C)n1
Agent: Cc1cc(N)nc(Cl)n1
Product: Cc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)nc(Cl)n1
Yield: 57 %

Procedure:
Following the procedure described above for [2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-(2,6-dimethylpyrimidin-4-yl)amine, 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine and 2-chloro-6-methylpyrimidin-4-ylamine were reacted to afford the title compound as a yellow solid (256 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.84-7.80 (m, 2H), 7.73-7.68 (m, 1H), 7.30 (d, J=6.4 Hz, 1H), 2.46 (s, 3H). LCMS (Method D): RT=2.50 min, m/z: 407 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Solvent: CO
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(F)cc3)CC2)c1

Procedure:
Example 42 was prepared from 2-(4-fluoro phenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 2H), 7.32–7.22 (m, 4H), 7.01–6.92 (m, 3H), 6.90–6.83 (m, 1H), 3.50 (q, 1H, J=7.1 Hz), 3.39–3.26 (m, 2H), 2.93–2.86 (m, 1H), 2.55–2.42 (m, 2H), 2.40–2.34 (m, 2H), 2.16 (s, 1H), 2.01–1.91 (m, 2H), 1.89–1.77 (m, 2H), 1.72–1.54 (m, 4H), 1.49 (d, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz); ESMS m/e: 454.3 (M+H)+; Anal. Calc. for C27H36FN3O2.1.1 CH3OH: C, 69.04; H, 8.33; N, 8.60. Found: C, 69.06; H, 8.61; N, 8.79.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH:3]([C:25]1[CH:30]=[C:29](Cl)[C:28]([Cl:32])=C(Cl)[CH:26]=1)/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][C:13]2([C:16]([OH:18])=O)[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CCN=C=NCCCN(C)C.[ClH:47].Cl[CH2:49][Cl:50]>>[F:34][C:2]([F:1])([F:35])[CH:3]([C:25]1[CH:30]=[C:29]([Cl:47])[C:28]([Cl:32])=[C:49]([Cl:50])[CH:26]=1)/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:9]([C:10]2[O:11][C:16](=[O:18])[C:13]3([CH2:15][CH2:14]3)[N:12]=2)=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1
Reactant: ClCCl
Reactant: Cl
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Product: O=C1OC(c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2C(F)(F)F)=NC12CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A 500 mL rb flask equipped with a magnetic stir bar and a temperature probe was charged with (E)-1-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamido)cyclopropanecarboxylic acid (9.2 g, 16.41 mmol), dichloromethane (DCM) (30 mL) and cooled in an ice water bath. With stirring, EDC HCl (3.15 g, 16.4 mmol) was added in one portion. After 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (100 mL), washed with brine (1×100 mL), dried over sodium sulfate and concentrated. The crude material was purified via an ISCO Rf medium pressure chromatography apparatus using a 330 g normal phase silica gel column and eluting with 0-30% EtOAc/hex gradient to afford the title compound (6.5 g, 73%): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.1 Hz, 1H), 7.80 (dd, J=1.8, 0.8 Hz, 1H), 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.42 (s, 2H), 6.66 (d, J=15.9 Hz, 1H), 6.51 (dd, J=15.9, 7.8 Hz, 1H), 4.15 (p, J=8.7 Hz, 1H), 1.99-1.91 (m, 2H), 1.89-1.79 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −59.47, −68.51; ESIMS m/z 544.2 ([M+H]+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:10]#[C:11][NH2:12].[C:13](=[O:16])([O-:15])[O-:14].[Na+].[Na+]>>[C:13](=[O:14])([OH:16])[OH:15].[F:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[NH:10])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)cc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Product: N=C(N)Nc1ccc(F)cc1
Product: O=C(O)O
Temperature: 87 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
882 g (747 ml) of 32% hydrochloric acid was added to 1000 g (8.9 mole) of 4-fluoroaniline, the mixture was warmed to 87° C., and 780 ml (9.9 mole) of 50% cyanamide solution was added dropwise thereto over 2 hours. The reaction solution was adjusted to pH 2.4 by adding thereto 120 ml of 32% hydrochloric acid, stirred for 3 hours, and cooled to 60° C. Aqueous sodium carbonate solution (Na2CO3 578 g/water 1640 ml) was added dropwise to the reaction solution over 30 minutes. The reaction mixture was stirred for 40 minutes and then cooled to 15° C. The resulting gray solid product was filtered, washed first with 600 ml of water and then with 2000 ml of ethyl acetate, and finally dried to obtain 1395 g of the title compound, which had a light gray color.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)CCC>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)c1cccnc1Cl
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c2ncccc12
Yield: 72 %

Procedure:
To a solution of 1-(2-Chloropyridin-3-yl)ethanone (III) (0.311 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-1H-pyrazolo[3,4-b]pyridine (IV) as a white solid (192 mg, 1.44 mmol, 72% yield). 1H NMR (CDCl3) δ ppm 2.64 (s, 3 H), 7.14 (dd, J=8.01, 4.62 Hz, 1 H), 8.14 (dd, J=7.54, 1.88 HZ, 1 H), 8.59 (dd, J=4.52, 1.32 HZ, 1 H), 11.68 (brs, 1H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH2:13].C(=O)([O-])[O-].[K+].[K+]>CCCCO>[F:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1cc(F)cc(N2CCNCC2)c1

Procedure:
Bis(2-chloroethyl)amine hydrochloride (2.07 g, 11.60 mmol) was added to a solution of 3,5-difluoroaniline (1.50 g, 11.62 mmol) in n-BuOH (20 mL). After the resulting solution was refluxed for 48 h, anhydrous potassium carbonate (1.61 g, 11.62 mmol) was added. After being refluxed for another 24 h, the reaction mixture was cooled, partitioned between water and CHCl3, and the aqueous layer was extracted with CHCl3. The combined organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. Et2O and 1 N HCl/EtOH were added to the residue, and the precipitate was filtered to give TC-IV-174 (1.17 g, 30%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:22]([F:23])=[CH:21][C:9]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[OH:20])=O)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:22]([F:23])=[CH:21][C:9]([C:10]3[O:20][C:14]4[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(O)cc1O)c1cc(F)c(OCC2CC2)c(F)c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-N-(2,4-dihydroxyphenyl)-3,5-difluorobenzamide (3.78 g), hexachloroethane (6.67 g) and triphenylphosphine (7.39 g) in acetonitrile (50 mL) was added triethylamine (3.42 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 1 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.92 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[CH2:31][O:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[C@H:32]([CH2:34][OH:35])[CH2:31][O:30][C:29]4=[O:28])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 57.9 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.6 g) described in Preparation Example 61 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (903 mg), the title compound (1 g) was obtained.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][C:26](=[O:28])[CH3:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:29].[Na+]>CC(C)=O>[C:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:29])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OC(CCCI)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A solution of 4-acetoxy-5-(4-fluorophenoxy)- 1-pentanol tosylate (73.5 g., 0.179 mole) and sodium iodide (79.5 g., 0.53 mole) in acetone (500 ml.) is allowed to stand at 25°-27° for 18 hours. The precipitated sodium tosylate is filtered off. Most of the acetone is evaporated from the filtrate and the residue is treated with 300 ml. of water. The oily product is taken up in ether, washed with dilute sodium thiosulfate solution, water and brine and dried over sodium sulfate. The solvent is distilled in vacuo to give 66 g. (a quantitative yield) of the crude title compound as a yellowish oil which is used without further purification; pmr (CDCl3) δ 2.05 (3H, s CH3CO); 3.20 (2H, t CH2I); 3.97 (2H, d CH2O); 5.20 (1H, m CHO); 6.85 (4H, m aryl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[NH:7][C:6]([C:14](OCC)=[O:15])=[C:5]2[S:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)(=[O:21])=[O:20].BrC1C([N+]([O-])=O)=C2C(=CC=1)[NH:34]C(C(OCC)=O)=C2S(N1CCOCC1)(=O)=O>>[Br:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:8](=[CH:4][CH:3]=1)[NH:7][C:6]([C:14]([NH2:34])=[O:15])=[C:5]2[S:19]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)(=[O:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2cc([N+](=O)[O-])c(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)c([N+](=O)[O-])c2c1S(=O)(=O)N1CCOCC1
Product: NC(=O)c1[nH]c2ccc(Br)c(N)c2c1S(=O)(=O)N1CCOCC1

Procedure:
Using the procedures described in Example 47, replacing in Step A ethyl 5-bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 403.2 [M+H]+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([C:18]([Cl:21])=[CH:19][CH:20]=1)[O:14][CH:15](Cl)[CH3:16].[C:30](OC)(=O)[CH2:31][SH:32].CS(C)=O>CCOCC>[Cl:7][C:8]1[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([C:18]([Cl:21])=[CH:19][CH:20]=1)[O:14][CH2:15][CH2:16][CH2:30][C:31]([O:4][CH3:1])=[S:32]
Reactant: COC(=O)CS
Reactant: CC(Cl)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=S)CCCOc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
20.7 g of potassium carbonate, 19.2 g (0.05 mole) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-chlorophenoxy-chloroethane and 5.3 g (0.05 mole) of methyl thioglycolate are added at room temperature to 80 ml of dimethyl sulfoxide. In the course of the exothermic reaction, the temperature rises to about 42° C. The reaction mixture is then stirred overnight at room temperature. On the next day, the batch is diluted with 300 ml of ether and the ethereal solution is washed with two 400 ml portions of 20% K2CO3 solution. The organic phase is dried over magnesium sulfate and concentrated, affording 17.8 g of a light yellow oil with a refractive index of nD21 1.5487. The following compounds were obtained in analogous manner:
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>CCO>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]=[CH:3][CH:4]=[CH:5]3)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2ncccc2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 51.3 %

Procedure:
A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and cone. HCl (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column chromatography to yield 3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.8 g, 51% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.84 (d, J=4.2 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52 (m, 1H), 5.46 (s, 1H), 5.40 (brs, 2H), 1.29 (s, 9H). MS (ESI) m/z (M+H+): 267.2.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.C(N(CC)CC)C.[CH2:23]([C:25]1([C:35](=[O:39])[C:36](Cl)=[O:37])[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[C:27]([CH2:33][CH3:34])[CH2:26]1)[CH3:24]>CCCCCC>[CH2:23]([C:25]1([C:35](=[O:39])[C:36]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:37])[CH:30]=[C:29]([CH2:31][CH3:32])[CH:28]=[C:27]([CH2:33][CH3:34])[CH2:26]1)[CH3:24]
Reactant: CCC1=CC(CC)(C(=O)C(=O)Cl)CC(CC)=C1
Reactant: CNN=C(C)CS(C)(=O)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC1=CC(CC)(C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O)CC(CC)=C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a 3 L volume four-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (116.0 g), tetrahydrofuran (anhydrous) (600 ml), and triethylamine (98.5 ml) were added under a nitrogen atmosphere, and cooled to about 1° C. to the mixture, 2-(1,3,5-triethylphenyl)-2-oxoacetyl chloride (6-b) (178.5 g) was added dropwise, and stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to hexane (3 L) at room temperature, and stirred for 1 hour. The precipitated solids were collected by filtration, washed with hexane (0.5 L×2) and water (0.5 L×6), and dried under reduced pressure to give 200.9 g of 1-[2-(1,3,5-triethylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-40).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>C(#N)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH:28]3[O:30][CH2:29]3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Yield: 48.3 %

Procedure:
1-(diphenylmethyl)piperazine (10.0 g) was dissolved in acetonitrile (50 ml) and sodium carbonate (6.5 g) and epibromohydrin (6.8 g) were added thereto and heated at reflux for 2.5 hours. After the resultant salt was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Waco Gel C-200, 200 g) and eluted with a mixed solvent of chloroform (99 parts)+methanol (1 part) to give 1-(diphenylmethyl)-4-(1-(2,3-epoxy) propyl)piperazine (5.9 g).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=O>CC(C)=O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 104.4 %

Procedure:
105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:27](OS(C(F)(F)F)(=O)=O)([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[CH:28]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)([CH3:30])[CH3:29]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1ccc(CC(=O)OCc2ccccc2)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To benzyl 2-(4-hydroxyphenyl)acetate (E301) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf and the solution stirred for 2.5 h at 0° C. The mixture was poured into NH4Cl(sat) and extracted with CH2Cl2. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hex) gave pure benzyl 2-(4-(triisopropylsiloxy)phenyl)acetate (E302).
Reaction SMILES: C(N=C(SC)NCCCOC1C=CC=C(CN2CCCCC2)C=1)#N.O.NN.[N:28]1([CH2:34][C:35]2[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=2)[O:38][CH2:39][CH2:40][CH2:41][N:42]2[C:46]([NH2:47])=[N:45][C:44]([NH2:48])=[N:43]2)[CH2:33]CCC[CH2:29]1.N>C(O)(C)C.O.C(OCC)(=O)C>[CH3:29][N:28]([CH2:34][C:35]1[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=1)[O:38][CH2:39][CH2:40][CH2:41][NH:42][C:46]1[NH:47][N:43]=[C:44]([NH2:48])[N:45]=1)[CH3:33]
Reactant: Nc1nc(N)n(CCCOc2cccc(CN3CCCCC3)c2)n1
Agent: CSC(=NC#N)NCCCOc1cccc(CN2CCCCC2)c1
Agent: N
Agent: NN
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)Cc1cccc(OCCCNc2nc(N)n[nH]2)c1

Procedure:
Similarly prepared from N'-cyano-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-carbamimidothioic acid, methyl ester (14.1 g) and hydrazine hydrate (10 ml) was N3 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (10.4 g) m.p. 100°-101.5°. TLC silica; ethyl acetate:water:isopropanol:0.088 ammonia 25:8:15:2; Rf 0.4.