Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2ccc(-c3ccccc3)cc2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-n2ccc(-c3ccccc3)cc2=O)sc1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylate (0.25 g, 0.74 mmol) in a mixture of tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide (0.14 g, 3.68 mmol). The reaction mixture was heated at 50° C. for 4 hours, then cooled to ambient temperature and acidified to pH 6 with acetic acid. The solid obtained was collected by filtration, washed with water and dried in air. The title compound was obtained as a yellowish solid (0.20 g, 87%): MS (ES+) m/z 313.5 (M+1).
Reaction SMILES: [CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([N:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35])[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:15]([O:14][C:13]([NH:12][C:8]([CH3:11])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([N:32]([S:36]([CH3:39])(=[O:37])=[O:38])[CH2:33][CH2:34][CH3:35])[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCN(c1cc(CBr)cc(C(=O)OC)c1)S(C)(=O)=O
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)OC)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (1-benzyl-2-hydroxy-1-methylethyl)carbamate (728 mg, 2.75 mmol) and methyl 3-(bromomethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (500 mg, 1.37 mmol) in dichloromethane (30 mL) were added silver triflate (423 mg, 1.65 mmol) and 2,6-ditertbutylpyridine polymer bound (1.53 g, 2.75 mmol, loading=1.8 mmol N/g resin, Aldrich 37, 782-1). The reaction mixture was stirred at rt in a sealed flask for 16 h. The reaction mixture was filtered on celite, rinsed with dichloromethane and MeOH, concentrated in vacuo and purified by flash chromatography (silica, 0-45% EtOAc/hexanes) to provide methyl 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a white foam (intermediate xx). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 7.30-7.20 (m, 3H), 7.18-7.7.14 (m, 2H) 4.60 (s, 2H), 4.56 (s, 1H), 3.95 (s, 3H), 3.68 (t, J=6.7 Hz, 2H), 3.57 (A of AB, d, J=8.9 Hz, 1H), 3.47 (B of AB, d, J=8.9 Hz, 1H), 3.15 (A of AB, d, J=13.2 Hz, 1H), 2.94 (B of AB, d, J=13.2 Hz, 1H), 2.90 (s, 3H), 1.55-1.45 (m, 2H), 1.47 (s, 9H), 1.27 (s, 3H), 0.92 (t, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
A mixture of 6-hydroxy-1-tetralone (50.0 g, 308 mmol), K2CO3 (64.0 g, 434 mmol) and BnBr (58.0 g, 340 mmol) in DMF (400 mL) was stirred at 25° C. for 16 hours. The mixture was diluted in water (1000 mL), extracted with EtOAc (1000 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product as a brown solid (54.0 g, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cl
Product: O=C(Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21)N1CCNCC1

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) piperazine-1-carboxylic acid tert-butyl ester gave, after treatment with HCl, gave the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:8]=1.C(N(CC)C(C)C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][S:2]([O:14][CH2:13][C:11]1[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:19])[F:20])[N:8]=[C:7]([Cl:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: OCc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)OCc1cc(COCC(F)(F)F)nc(Cl)n1
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
A solution of methanesulfonyl chloride (0.13 mL, 1.64 mmol) in DCM (2 mL) was cooled at −30° C. (2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)methanol (0.35 g, 1.36 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.73 mmol) in DCM (15 mL) were added. The mixture was stirred for 10 min. Brine (50%, 50 mL) was added. The organic phase was isolated using a phase separator containing sodium sulfate. The solvents were evaporated to give the title compound 0.47 g (quant).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1.C1C[O:26][CH2:25]C1>>[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]([SH:8])[CH2:25][OH:26])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: SCc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Product: OCC(S)c1ccccc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 12.4 g (0.1 mole) of benzyl mercaptan (ie, benzenemethanethiol) in 150 ml of THF at 0° C. under moisture-free conditions, was added, dropwise, 14 g (0.22 mole) of n-butyllithium (1.6 m in hexane). After stirring at 0° C. for 4 hours (orange precipitate forms), the mixture was cooled to -25°. To this mixture was added a solution of 12.4 g (0.1 mole) of p-fluorobenzaldehyde in 100 ml of THF, dropwise. After stirring at -25° C. for 1 hour, a yellow solution occurs. The reaction was quenched with saturated aqueous ammonium chloride and the organic material was extracted once with MTBE and then once with methylene chloride. The organic solutions were combined and dried, and the solvent was removed under reduced pressure to give 25 g of the title product of this step as an oil (80:20 mixture of isomers), which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[NH:8]2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cc2ccc(C)cc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2cc(CCC(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 46 (0.69 g, 3.17 mmol) in THF:MeOH:H2O (1:1:1) (9 mL) was added LiOH.H2O (0.25 g, 5.96 mmol). The reaction was stirred at rt for 16 h, diluted with water, acidified to pH 3 with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated in vacuo to provide 0.58 g (90%) of product 47 as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 2.65 (t, J=8 Hz, 2H), 2.93 (t, J=8 Hz, 2H), 6.05 (s, 1H), 6.75 (d, J=8 Hz, 1H), 7.04 (s, 1H), 7.27 (d, J=8 Hz, 1H), 10.74 (brs, 1H), 12.19 (brs, 1H). LC-MS (CI): m/z 202.0 [(M−H)− C12H13NO2 requires 203.09].
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:13][CH:14]([CH3:19])[CH2:15][C:16]([N:9]1[CH2:10][CH2:11][O:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:17]
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-methyl-butyryl chloride (301.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 3-methyl-1-(2-phenylmorpholin-4-yl)butan-1-one are collected and the solvent is removed in vacuo to give 465 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:23][C:24]1[C:25](I)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[C:25]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[Cl:1])=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of [2-chloro-4-(trifluoromethyl)phenyl]boronic acid (4.5 g, 20.06 mmol) in water (30 mL) and dioxane (200 mL) was added K3PO4 (5.7 g, 26.85 mmol), 5-chloro-4-iodo-2-nitroaniline (4 g, 13.40 mmol) and Pd(PPh3)4 (800 mg, 0.69 mmol) maintained with an inert atmosphere of nitrogen and stirred overnight at 95° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline as a yellow solid (3 g, 32%). Next, to a solution of 5-chloro-4-[2-chloro-4-(trifluoromethyl)phenyl]-2-nitroaniline (3 g, 8.54 mmol) in ethanol (80 mL) was added hydrochloric acid (2 mL) and Zn powder (3.4 g, 52.3 mmol) in portions. The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum and dissolved in water (100 ml) adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 20% ethyl acetate in petroleum ether to produce 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (1 g, 36%). Finally, the solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in TFA (5 mL) and hydrochloric acid (conc, 1 mL) was stirred overnight at 80° C. and quenched with water (100 ml), adjusted pH to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (107.8 mg, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:25][C:24]2[C:18]4[O:17][C:16]([CH3:15])=[CH:20][C:19]=4[CH:21]=[CH:22][CH:23]=2)=[N:9]3)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(NS(=O)(=O)c5ccc(F)cc5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=448.0 (M+H+), was prepared in accordance with the general method of example 58 from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 4-fluorobenzenesulfonylchloride.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.Cl.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[C:30]1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)(C)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccccc12
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: CN1CCN(CCC(=O)c2c(-c3ccccc3)oc3ccccc23)CC1

Procedure:
To a solution of 23.6 grams of 2-phenyl-3-acetylbenzofuran in 100 milliliters of isopropanol were added 4.2 grams of paraformaldehyde and 19.1 grams of N-methylpiperazine dihydrochloride and the mixture was heated under gentle reflux for a period of 12 hours. The dihydrochloride of the compound named in the heading of this example precipitated from the reaction mixture and was separated therefrom by suction filtration, washed with a small quantity of ethanol, and recrystallized from ethanol. The dihydrochloride had a melting point of 174°-177°C and 22.8 grams thereof was thus obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[ClH:1].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[NH:13][C:12]([C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)=[N:11][C:10]=3[C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])=[CH:5][CH:4]=2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CCl)cc1
Product: CN1CCN(Cc2ccc(-c3[nH]c(-c4ccc([N+](=O)[O-])cc4)nc3C(=O)Nc3nccs3)cc2)CC1
Product: Cl
Yield: 177.5 %

Procedure:
5-(4-Chloromethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (900 mg) obtained in Example 94 and 1-methylpiperazine (309 mg) were reacted and treated in the same manner as in Example 95 to give 5-(4-(4-methylpiperazin-1-ylmethyl)-phenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide trihydrochloride (742 mg), melting point 248-252° C. (decomposition).
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10]C)=[O:8])[NH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].[CH3:18][I:19]>CC#N>[I:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:12])[N:3]=1.[I:19][C:18]1[N:3]([CH3:2])[N:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: CCOC(=O)c1cc(I)n[nH]1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(I)n(C)n1
Product: COC(=O)c1cc(I)nn1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-iodo-1H-pyrazole-5-carboxylate (600 mg, 2.56 mmol) and K2CO3 (609 mg, 4.51 mmol) in dry CH3CN (10 mL) was added MeI (974 mg, 6.77 mmol). The mixture was stirred at room temperature overnight under N2. After TLC showed that starting material had disappeared, the solid was filtered. Solvent was removed and the residue was purified to give methyl 3-iodo-1-methyl-1H-pyrazole-5-carboxylate and methyl 5-iodo-1-methyl-1H-pyrazole-3-carboxylate.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1.C(=O)(O)[O-].[Na+].ClCCl>O1CCCC1>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2)C1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Benzoyl isothiocyanate (81.37 μL, 603.33 mmol) is added to a 0° C. solution of tert-butyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (0.168 g, 574.60 mmol) in tetrahydrofuran (2.3 mL). The mixture is warmed to room temperature and stirred overnight. Benzoyl isothiocyanate (15.50 μL, 114.92 mmol) is added and the mixture is stirred for 2 hr. Sodium bicarbonate solution and dichloromethane are added and the aqueous layer is separated, the aqueous mixture is extracted with dichloromethane (3×25 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product is purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give the title compound (0.178 g, 68%). ES/MS (m/e): 454.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[ClH:1].[NH:10]([C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Cc1ncnc(Cl)c1C
Product: Cc1ncnc(Nc2ccccc2)c1C
Product: Cl
Yield: 45.3 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 2.8 g (0.03 mole) of aniline; the mixture was then heated at 100°-150° C. for about 3 minutes. The reaction mixture quickly became a solution and soon produced a precipitate, which was collected by filtration and then recrystallised from ethanol to give 3.2 g(yield 40%) of the desired Compound No. 23, in the form of a colourless powder melting at 243°-245° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:27]([CH2:30][NH2:31])[CH:28]=C.[CH3:32]N(C=O)C>>[CH2:30]([N:31]([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH3:32])[CH:27]=[CH2:28]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CN(C)C=O
Reactant: C=CCCN
Product: C=CCN(C)CCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 55 %

Procedure:
100 mg (0.26 mmol) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester and 0.5 ml (5.2 mmol) N-allylmethylamine were stirred in 1 ml DMF at 60° C. for 1.5 h. The solution was concentrated, and the residue was dissolved in water and CH2Cl2. 2M NaOH was added and the inorganic phase was extracted with CH2Cl2. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography with CH2Cl2/MeOH 19:1 yielded 50 mg (55%) Allyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine as light yellow oil, MS: 347 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
A mixture of ethyl 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoate (10.00 g), 2N aqueous sodium hydroxide solution (40 mL), tetrahydrofuran (100 mL) and ethanol (40 mL) was stirred overnight at room temperature. The reaction mixture was acidified by adding hydrochloric acid and concentrated. The residue was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, v/v). The organic layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol-diisopropyl ether to give 3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoic acid as a white solid (3.93 g, yield 44%). melting point: 219-220° C.