Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 1.6 %

Procedure:
208 mg Of styrene, 328 mg of triethoxysilane, and 52 mg of toluene were placed in a glass reaction tube. Next, 0.002 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with a Teflon tape and heated for 1 hour in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 7.4% and phenethyltriethoxysilane was produced at a yield of 1.6%. The yield of (α-methylbenzyl) triethoxysilane was 0.9%
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([O:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][C:26](=[O:33])[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][C:26]([N:27]2[CH2:32][CH2:31][N:30]([C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:9])[CH2:29][CH2:28]2)=[O:33])=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
3-Methyl-2-thiophene carboxylic acid (74 mg, 0.53 mmol) was added to 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (155 mg, 0.44 mmol) in DMF (5 mL). EDCI.HCl (126 mg, 0.66 mmol), HOBT (71 mg, 0.53 mmol) and DIPEA (227 μL, 1.32 mmol) were then added and the resulting mixture was allowed to stir at room temperature overnight. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford a crude product. Column chromatography purification (using neutral alumina 90:10 EtOAc:MeOH as the eluent) afforded 4-benzyloxy-N-{2-[4-(3-methyl-thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide in 46% yield. LC-MS purity: 87%. 1H NMR (DMSO-D6): δ 8.4 (t, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.4 (m, 5H), 7.1 (d, 2H), 6.9 (d, 1H), 5.2 (s, 2H), 4.2 (d, 2H), 3.5 (d, 8H), 2.3 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:11]1[CH3:29].[Li+].[OH-]>CO.C1COCC1.O>[CH3:27][S:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C:12]2[CH:13]=[C:14]([CH3:15])[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])[C:11]=2[CH3:29])=[O:28])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: COC(=O)c1ccccc1-n1c(C)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1C(=O)O
Yield: 101.5 %

Procedure:
To a solution of 2-[3-(4-methanesulfonyl-phenylcarbamoyl)-2,5-dimethyl-pyrrol-1-yl]-benzoic acid methyl ester (0.7 g, 1.6 mmol) in MeOH/THF (8 mL: 16 mL) was added LiOH (0.275 g, 6.4 mmol). After stirring 14h at room temperature, the reaction mixture was concentrated in vacuo. The crude reaction mixture was re-dissolved in water and washed with EtOAc. The water layer was separated and then acidified with 1N HCl. The resulting suspension was extracted twice with EtOac. The combined extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (0.67 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 13.03 (1H, s), 9.81 (1H, s), 8.06 (2H, d, J=9.1), 8.02 (1H, d J=7.8), 7.87 (2H, d, J=8.6), 7.78 (1H, t, J=7.3). 7.68 (1H, t, J=7.8), 7.39 (1H, d, J=7.6), 6.65 (1H, s), 3.20 (3H, s), 2.23 (3H, s), 1.92 (3H, s); MS (ESI): 413 (MH+).
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]([CH3:18])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:17])[CH:8]=1>C(O)(=O)C>[Br:1][C:8]1[C:9]([CH3:17])=[N:10][C:11]2[C:16]([C:7]=1[NH:6][CH2:5][CH:4]([OH:3])[CH3:18])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: BrBr
Reactant: Cc1cc(NCC(C)O)c2ccccc2n1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(NCC(C)O)c1Br
Reaction time: 1 h

Procedure:
Bromine (32 g) was added dropwise to a solution of 44 g of N-(2-hydroxypropyl)-2-methyl-4-quinolinamine in 600 ml of acetic acid. The solution was stirred for 1 hour and the HBr salt was filtered and washed with a small amount of acetic acid. It was then dissolved in 500 ml of water and an aqueous KOH solution was added, whereupon the free base precipitated. It was filtered and recrystallized from isopropanol. The yield was 22 g, mp 147°-149° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH:9]=[CH:10]I.[C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)#[CH:13]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[CH:9]=[CH:10][C:13]#[C:12][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1
Reactant: CC1=C(C=CI)C(=O)CCC1
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC=CC2=C(C)CCCC2=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 2-(2-methyl-6-oxocyclohex-1-enyl)-1-iodoethene (Compound E, 1.74 g, 6.64 mmol), ethyl 4-ethynylbenzoate (Compound F, 1.73 g, 9.96 mmol) and triethylamine (80 mL) was purged with argon for 10 minutes, and then treated with bis(triphenylphosphine)palladium (II) chloride (23 mg, 0.03 mmol) and copper (I) iodide (6.3 mg, 0.03 mmol). The solution was stirred 40° C. for 3 hours, and concentrated under a water aspirator vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (88:12, hexane:ethyl acetate) to give the title compound as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.S([N:28]=[N+:29]=[N-])(C1C=CC(C)=CC=1)(=O)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.[OH-].[Na+]>[N:1]([C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1)=[N+:28]=[N-:29]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Yield: 62.5 %

Procedure:
A solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.20 g, 4.86 mmol), tosyl azide (1.91 g, 9.71 mmol) and benzyl trimethylammonium chloride (0.05 g, 0.27 mmol) in dichloromethane (21 mL) and 40% aqueous sodium hydroxide solution (11 mL) was stirred at ambient temperature for 18 h. The reaction mixture was extracted with dichloromethane (100 mL). The separated organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound (0.83 g, 63%): MS (ES−) m/z 272.2 (M−1).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[N+:31]([O-])=O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl>[NH2:31][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:20][CH2:19][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CC(C)(C)OC(=O)NCC(CNc1c([N+](=O)[O-])cnc2ccccc12)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CNc1c(N)cnc2ccccc12)O[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(3-nitroquinolin-4-yl)amino]propylcarbamate (110.18 g, 231.16 mmol) in dichloromethane (500 mL) was added to a Parr vessel. The system was purged with nitrogen, and 10% palladium on carbon (14.76 g, 138.7 mnmol) was added. The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) and shaken for four hours. The reaction mixture was filtered, and, the filtrate was passed through a plug of silica gel and concentrated under reduced pressure to provide 103.45 g of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]-2-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:37](=[O:38])[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and phenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 508.9.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)NC1CCC(O)c2sccc21
Solvent: c1ccncc1
Product: CC(=O)OC1CCC(NC(N)=O)c2ccsc21

Procedure:
Two g (9.43 mm) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea is stirred for 2 days at room temperature with acetic anhydride (5 ml) and pyridine (10 ml). The excess reagents are removed in vacuo, the resulting gum dissolved in methylene chloride (50 ml), the solution washed with water (50 ml), the water wash counter extracted with methylene chloride (25 ml), the combined methylene chloride layers dried with sodium sulfate and evaporated. The resulting gum is treated with ethyl acetate (≈5 ml) to afford a first crop (1.15 g, 48% Y) of the title compound, m.p. 168° C-170° C, dec. and a second crop (0.58 g, 24% Y) m.p. 166° C-172° C, dec. The analytical sample crystallized from ethyl acetate has m.p. 165° C-168° C dec. The isomeric compound prepared in the same manner melts at 182° C-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=O.[BH4-].[Na+]>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH3:18])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C)N2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 0.17 g (0.6 mmole, 1 eq) of 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1 eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)4 are warmed to 70° C. for 2 hours. The reaction solution is cooled to room temperature and 20 mL of anhydrous methanol is added followed by 1.0 g of NaBH4 and the resulting solution is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH and extracted with CH2Cl2. The CH2Cl2 extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with ethyl to afford 1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine (compound 2). Analysis 1H NMR (400 MHz, CDCl3): 7.31 (1H, d), 7.19 (1H, m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H, m). MS (LC-MS): Calculated for C21H24ClF3N2O2 428.88, found 429.30 (M+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][C:11](=O)[CH3:12])=[CH:5][CH:4]=1.C([O-])(=O)C.[C:20]([NH:24][S:25]([C:28]1[CH:29]=[C:30]([C:34]2[N:39]=[C:38]([C:40]([NH2:42])=[NH2+:41])[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]([C:40]3[N:42]=[C:11]([CH3:12])[CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=4)[N:41]=3)[N:39]=2)[CH:29]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)C#Cc1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C(N)=[NH2+])n2)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Yield: 75.8 %

Procedure:
Condensation reaction: The above described 4-(6-trifluoromethyl-pyridin-3-yl)-but-3-yn-2-one (53 mg, 0.25 mmol), 6-(3-tert-butylsulfamoyl-phenyl)-pyridine-2-carboxamidinium acetate (Example 26, amidine part, steps 1 to 4) (118 mg, 0.3 mmol) and sodium carbonate (64 mg, 0.6 mmol) were dissolved in acetonitrile (2 ml) and treated by microwave irradiation at 120° C. for 60 min. The reaction mixture was extracted with ethyl acetate and water, the organic layers were combined, dried over MgSO4, filtered and the solvents were evaporated to give a crude product, which was purified by flash chromatography with n-heptane and ethyl acetate to give the title compound as a light brown foam (100 mg, 76%). MS (ISP) 528.2 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]([NH2:16])=[O:36])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[N:26]=[CH:25][C:24]([C:30]([F:31])([F:33])[F:32])=[CH:23][C:22]=3[CH2:21]2)=[O:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.19 g, 0.396 mmol) in TFA (1.5 mL) and DCM (1.5 mL) was stirred at rt for 1.5 h. Concentration by rotary evaporation was followed by dilution with DCM and additional evaporation to give the product as a TFA salt. LC/MS: C18H22F3N5O2: m/z 398.3 (M+H).
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH2:14]([Li])[CH2:15]CC.C(Br)C>C1COCC1.CCCCCC>[CH2:14]([CH:12]1[C:13]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Solvent: CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1C2=C(CCCC2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 75 %

Procedure:
5.3 g (31.1 mmol) of the above-obtained 1,2,3,4-tetrahydrofluorene was placed in a 500 mL four-neck flask, to which 100 mL of THF was added under a nitrogen atmosphere. 10 mL (2.6 mol/L) of a hexane solution of n-butyllithium was slowly added dropwise to the solution under stirring at −78° C., followed by stirring at room temperature for 2 hours. 0.89 g (8.2 mmol) of ethyl bromide was added thereto at 0° C. over 2 minutes, followed by stirring at room temperature for 4 hours. After completing the reaction, THF was removed to provide 3.4 g of 9-ethyl-1,2,3,4-tetrahydrofluorene (9-Et-4HFluH) as a colorless oily matter (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)[OH:11])=[CH:4][CH:3]=1
Reactant: CC1(C(=O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1
Agent: c1c[nH]nn1
Product: CC1(C(O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1

Procedure:
The NMR spectrum of the starting material, II-B isomer of 3-(4-chlorophenyl)-1-(1-methylcyclopropyl)-2-(1,2,4-triazole-1-yl)-2-propene-1-one, is as follows: 8.12 (1H, s, triazole proton), 8.03 (1H, s, triazole proton), 7.55 (1H, s, olefin proton), 7.21 (2H, d, phenyl proton, J=8 Hz), 6.81 (2H, d, phenyl proton, J=8 Hz), 1.50-1.25 (2H, m, methylene proton of cyclopropyl group), 1.28 (3H, s, methyl proton), 0.90-0.65 (2H, m, methylene proton of cyclopropyl group).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=3[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[CH:9]=[CH2:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C=CC(CC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 2 h

Procedure:
To a solution of the product of Step B (40 mg, 0.128 mmol) and N-methylmorpholine (26 mg, 0.256 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (18 mg, 0.192 mmol) at room temperature. The mixture was stirred for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless solid. LC/MS m/z=388.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]2[N:6]([C@H:9]3[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:30][C:7]1[N:6]([C@H:9]2[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC[C@@H]1O[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 80 °C

Procedure:
5,6-Dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.0 g, 2.25 mmol) was combined with N-bromosuccinimide (0.88 g 4.94 mmol) in anhydrous 1,4-dioxane (50 mL). This solution was heated in an 80° C. oil bath for 15 min. The solution was cooled, diluted with ethyl acetate and extracted with 10% sodium bicarbonate (2×50 mL). The organics were dried with anhydrous Na2SO4, decanted and concentrated. The residue was purified on a silica gel column (5×11 cm, 230-400 mesh) with (1:50) methanol:dichloromethane to give a white solid which was identified as product by comparing it's 1H NMR to that of Example 1.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)(=O)=O.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+]>[C:35]([NH:39][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[N:10]=[C:9]1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)N
Reactant: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCOS(C)(=O)=O)CC3)c21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CC(=O)Nc2ncnc(N3CCC(c4nc(C(F)(F)F)cn4CCNC(C)(C)C)CC3)c21
Temperature: 50 °C
Yield: 55 %

Procedure:
Add (R)-2-(2-(1-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)ethyl methanesulfonate (0.50 g, 0.99 mmol), tert-butylamine (0.52 mL, 7.1 eq), and triethylamine (0.69 mL, 5.0 eq) in dimethylformamide (5 mL). Heat to 50° C. in a sealed tube for 48 hours. Dilute the solution with saturated aqueous sodium chloride. Add the mixture into ethyl acetate. Wash the organics with saturated aqueous sodium chloride and concentrate in vacuo. Purify by silica gel chromatography, eluting with 20% ethanol/acetone, to give the title compound (0.27 g, 55%). MS (ES) m/z=480 [M]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1O)([O-:3])=[O:2].C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1.CCN(C1C=CC=CC=1)CC.[N+](C1C=CC=CC=1)([O-])=O>Cl>[Cl:26][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:14](=[O:16])[CH3:15])=[CH:7][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 95 °C
Yield: 87.5 %

Procedure:
A mixture of 22.6 grams (0.1 mole) of 3',5'-dinitro-4'-hydroxyacetophenone, 19.0 grams of p-toluenesulfonyl chloride (0.1 mole), 16.0 grams (0.107 mole) of diethylaniline, and 18.0 grams of nitrobenzene was heated at about 95° C. for 8 hours. The reaction mixture was poured into 200 milliliters of 10 percent aqueous hydrochloric acid and the nitrobenzene steam distilled from the mixture. The residue was cooled to room temperature, the aqueous layer decanted, and the dark oil which slowly solidified (yield 87.5 percent) recrystallized from ethanol (charcoal) to give a pale yellow crystalline compound, melting point 86°-86.5° C.