Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[S:5][CH2:4][C:3]1([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14].[CH2:23]([Si](C)(C)C)[CH:24]=[CH2:25]>ClCCCl.[I-].[Zn+2].[I-]>[CH2:25]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[S:5][CH2:4][C:3]1([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:14])[CH:24]=[CH2:23]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2O)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: C=CCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (11.4 g, 36.3 mmol) in 1,2-dichloroethane (360 ml) was added zinc iodide (13.9 g, 43.5 mmol) and allyltrimethylsilane (11.5 ml, 72.5 mmol) which was stirred for 1 day at room temperature. The reaction solution was added saturated aqueous NHCl solution, extracted with CHCl3, and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica-gel with 1% AcOEt in hexane to give 9.19g (74%) of (3RS,4RS)-4-allyl-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]([CH3:17])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]([CH3:17])=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1C(=O)OCC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])c(C)[nH]c(=O)c1C(=O)OCC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In 13 ml of acetic anhydride was suspended 5.0 g of 3,4-diethyoxycarbonyl-6-methyl-2-pyridone, and the suspension was cooled to -10° C., whereto 1.22 ml (2.1 eq.) of fuming nitric acid was added dropwise over 30 minutes. The mixture was stirred for 30 minutes. After 40 ml of water was added, the mixture was stirred overnight at room temperature. The resulting crystals were collected by filtration and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([OH:21])[CH:3]=1.[CH:22]#[C:23][CH:24](O)[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([O:21][CH:24]([CH3:25])[C:23]#[CH:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2O)c1=O
Reactant: C#CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)Oc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
1.7 g (5.3 mmol) of 3-(4-chloro-2-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, 0.63 g (9.0 mmol) of 1-butyn-3-ol and 1.57 g (6.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran, and 1.0 g (6.0 mmol) of diethyl azodicarboxylate was dropwise added thereto under cooling with ice. After stirring at room temperature for 1 hour, the solvent was distilled off. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.86 g (yield: 93.9%) of the desired product as white crystals. Melting point: 96-99° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:27]([C@@H:29]([C@@H:31]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40]CC2C=CC=CC=2)=[CH:36][CH:35]=1)[OH:30])[OH:28])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]([C@H:27]([C@@H:29]([C@@H:31]([CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[OH:30])[OH:28])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]([C@H](O)[C@@H](COCc1ccccc1)OCc1ccc(OCc2ccccc2)cc1)[C@@H](COCc1ccccc1)OCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: Oc1ccc(CO[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H](COCc2ccccc2)OCc2ccc(O)cc2)cc1
Yield: 87 %

Procedure:
A mixture of 1,6-di-O-benzyl-2,5-di-O-(4-benzyloxybenzyl)-D-mannitol, obtained as in example 15, (97 mg, 0.10 mmol) in MeOH (1 mL), pyridine (8.0 mg, 0.1 mmol) and 5% palladium on charcoal (70 mg) was hydrogenated at normal pressure and room temperature for 1 h. The reaction mixture was filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with 50% EtOAc in hexane afforded the title compound in 87% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24](=[CH2:27])[CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:30])[CH3:29])=[CH:4][CH:3]=1.C(=O)(O)[O-:33].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:31])[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][C:24]4([O:33][CH2:27]4)[CH2:23]3)=[O:21])[CH:16]([CH3:17])[CH3:18])[CH2:10][C:9]2([CH3:29])[CH3:30])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: C=C1CCC(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](NC(=O)C1CCC2(CO2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-methylenecyclopentanecarboxamide (535 mg, 1.197 mmol) and sodium bicarbonate (141 mg, 1.676 mmol) in methylene chloride (4 mL) and water (2 mL) was cooled to 5° C. and treated with m-CPBA (318 mg, 1.436 mmol). The mixture was stirred at 5° C. for 1 hour, then allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled to 5° C., treated with saturated sodium sulfite, and stirred at room temperature for 30 minutes. The layers were separated, and the aqueous phase was extracted 3× with methylene chloride. The organic phases were combined and concentrated in vacuo, and the residue was taken up in ethyl acetate. The solution was washed 3× with saturated sodium carbonate, once with water, and once with brine, then dried over sodium sulfate, and concentrated in vacuo to yield the title compound (535 mg, 1.155 mmol, 97% yield) as a glass and a mixture of diastereomers. 1H NMR (400 MHz, CD3OD) (NMR shows several rotomers) δ ppm 7.54-7.40 (m, 2 H), 7.37-7.26 (m, 2 H), 4.90-4.82 (m, 1 H+H2O), 4.63-4.48 (m, 0.6 H), 4.12-3.96 (m, 1 H+residual ethyl acetate), 3.68-3.46 (m, 1.6 H), 3.23-3.02 (m, 1.6 H), 2.98-2.90 (m, 0.4 H), 2.90-2.77 (m, 2 H), 2.76-2.53 (m, 1 H), 2.31-1.79 (m, 6 H+residual ethyl acetate), 1.79-1.64 (m, 1.6 H), 1.60 (bd, 0.4 H, J=14.1 Hz), 1.57-1.48 (m, 0.6 H), 1.04 (dd, 1.4 H, J=6.6, 3.1 Hz), 1.00 (t, 1.6 H, J=6.4 Hz), 0.96-0.90 (m, 3.2 H), 0.87-0.79 (dd, 3 H, J=5.5, 3.0 Hz), 0.79-0.71 (m, 3 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>CN(C=O)C>[CH3:16][O:17][CH2:18][O:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(CO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COCOC)nc1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
Ethyl 6-hydroxymethylnicotinate (30 g, 1.65×10−1 mol) is added dropwise to a suspension of sodium hydride (8 g, 1.98×10−1 mol) in DMF (250 ml) cooled to −15° C. and maintained under a nitrogen atmosphere, and the mixture is stirred for 10 minutes and then cooled to −23° C. Chloromethyl methyl ether is then added dropwise, the mixture is stirred for 5 minutes after the end of the addition and then poured into 600 ml of ice-cold saturated NaHCO3 solution. The mixture is extracted with petroleum ether and the combined organic phases are washed with water until neutral, and then with brine and dried over Na2SO4. After filtration, the solvent is evaporated off under vacuum and the residue is distilled (P: 4.2×10−2 mb; b.p.: 120-130° C.). The title product is obtained in the form of a yellow oil (21 g), which is used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]2[CH2:26][O:25]2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Cl:13][C:14]1[N:15]([CH2:22][CH2:23][CH:24]([OH:25])[CH2:26][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(OC(F)(F)F)cc2)c(Cl)n1
Temperature: 81 °C
Reaction time: 12 h
Yield: 67.2 %

Procedure:
4-Trifluoromethoxyphenol (0.375 mL, 2.89 mmol) was added to a mixture of epoxide 129 (250 mg, 1.15 mmol) and powdered K2CO3 (558 mg, 4.04 mmol) in anhydrous 2-butanone (3 mL) under N2, and the mixture was stirred at 81° C. for 12 h. The resulting cooled mixture was diluted with water (50 mL) and extracted with CH2Cl2 (4×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-25% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 25-33% EtOAc/petroleum ether gave 4-(2-chloro-4-nitro-1H-imidazol-1-yl)-1-[4-(trifluoromethoxy)phenoxy]-2-butanol (130) (306 mg, 67%) as a pale yellow oil; 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.16 (br dd, J=9.1, 0.8 Hz, 2H), 6.88 (dt, J=9.2, 3.0 Hz, 2H), 4.37-4.24 (m, 2H), 4.02-3.93 (m, 2H), 3.86 (dd, J=10.0, 7.8 Hz, 1H), 2.47 (dd, J=4.2, 1.1 Hz, 1H), 2.13-1.98 (m, 2H); HRESIMS calcd for C14H14ClF3N3O3 m/z [M+H]+ 398.0540, 396.0569. found 398.0538, 396.0567.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23](=[O:25])[CH:24]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:21][CH:22]=3)=[O:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.4 %

Procedure:
A mixture of 1-[4-(4H,10H-pyrazolo[5,1-c][1,4]benzodiazepine-5-carbonyl) phenyl]ethanone (0.73 g), tert-butoxybis-[dimethylamino]methane (0.964 g) in dichloromethane (10 ml) was stirred at room temperature for 2 days. The mixture is concentrated in vacuo and the residue crystallized from dichloromethane-hexane to give 0.65 g of the title compound as yellow crystals, m.p. 225-230° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:34]1([C:40]#[C:41][C:42]2[S:43][CH:44]=[C:45]([C:47](O)=[O:48])[N:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:4][C:47]([C:45]2[N:46]=[C:42]([C:41]#[C:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:43][CH:44]=2)=[O:48])[CH2:3][CH2:2]1
Reactant: O=C(O)c1csc(C#Cc2ccccc2)n1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1csc(C#Cc2ccccc2)n1
Reaction time: 16 h

Procedure:
Cyclopropylamine (2.49 mg, 0.00436 mmol), 1-hydroxybenzotriazole (0.589 mg, 0.00436 mmol), triethylamine (1.82 μL, 0.0131 mmol), N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.09 mg, 0.0109 mmol) and CH2Cl2 (2 mL) were combined, and then 2-phenylethynyl-thiazole-4-carboxylic acid (10 mg, 0.004 mmol) was added. The reaction was left standing for about 16 hours and then purified by preparative HPLC. LC/MS (Method 5), RT=1.33 min. Calculated [M+H]+=269; Observed [M+H]+=269.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
The 1-benzyl-4-aminopiperidine prepared in Example 30 was treated with p-chlorobenzoyl chloride in a similar manner to that described in the same example and the product converted to a salt.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[O:23][B:24](OC)[O:25]C.O>C(OCC)C>[Si:15]([O:14][CH2:13][CH2:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[B:24]([OH:25])[OH:23])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexanes, 5.78 mL) was added to a solution of [2-(3-bromofuran-2-yl)-ethoxy]-tert-butyldimethylsilane (Intermediate 34, 4.01 g) in diethyl ether (130 mL) at −60° C. under nitrogen and the resultant mixture was stirred for 30 minutes. Trimethylborate (2.73 g) was then added to the mixture and it was stirred for a further 10 minutes. The reaction mixture was warmed to 0° C., water was added and the mixture was stirred for 15 minutes. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (1.23 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4](Br)[CH:3]=1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C(OCC)C>[CH3:15][Si:16]([CH3:19])([CH3:18])[C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Si:16]([CH3:19])([CH3:18])[CH3:15])[CH:5]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 141.4 %

Procedure:
1,3,5-Tribromobenzene (125 g, 0.4 mol), was dissolved in anhydrous diethylether (1 L), and cooled to -70° C. n-Butyllithium (250 mL, 1.6 M in hexanes, 0.4 mol) was added dropwise over a one-hour period keeping the temperature near -70° C. The solution was stirred for an additional 20 minutes at -70° C. and then warmed to -10° C. over a two-hour period. The solution was then recooled to -70° C. and trimethylchlorosilane (45 g, 0.4 mol) was added over a one hour period. The solution was allowed to stir and warm to room temperature overnight. The solution was cooled to -70° C. and an additional 0.4 mol n-butyl lithium was added over a one-hour period. The resulting slurry was stirred for one hour at -70° C., warmed to -10° C. over a two-hour period and then recooled to -70° C. An additional 0.4 mol of trimethylchlorosilane was added and the slurry was allowed to warm to room temperature overnight. The mixture was quenched with water and the layers were separated. The organic layer was washed twice with sodium bicarbonate solution and with salt brine then dried over magnesium sulfate. The solvents were evaporated under vacuum and the product distilled twice under vacuum to yield 85.2 g (70%) of a colorless liquid. b.p. 100-105° C. @ 0.5 mmHg.
Reaction SMILES: C(OC([N:8](C1C=CC=CC=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl.C(O[CH2:39][CH3:40])(=O)C.Cl>C(OCC)(=O)C>[NH2:8][CH:9]([C:40]1[CH:39]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCN1CCN(C(=O)CN(C(=O)OC(C)(C)C)c2ccccc2)CC1
Agent: Cl
Product: CCCCCCCCCCN1CCN(C(=O)C(N)c2ccccc2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
2.9 g (6.32 mmole) quantity of 1-(N-t-butoxycarbonylphenylglycyl)-4-decylpiperazine was dissolved in 5 ml of ethyl acetate, and 20 ml of 4N hydrochloric acid-ethyl acetate solution was added thereto with ice-cooling and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration, washed with a small quantity of ether and dried under reduced pressure, giving 2.5 g (yield: 90 %) of 1-(2-amino-2-phenylacetyl)-4-decylpiperazine as a hydrochloride.
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:5][CH2:2][C:3]#[N:4])[CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:12][CH:13]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reactant: CC(Br)C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromopropionitrile (10 uL, 0.120 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone hydrochloride and diisopropylethylamine (42 uL, 0.240 mmol) in dimethylformamide (1.0 mL). The reaction was stirred at room temperature overnight. Evaporation of the solvent and purification of the crude residue by flash chromatography over silica gel using 1-2% methanol in methylene chloride gave 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile hydrochloride as an off-white powder (20 mg, 39% yield). LR-MS (APCI): 644.4 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=C[C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC(F)=C[N:19]=1>>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:19][CH:3]=1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Reactant: Fc1ccc(Br)nc1
Product: Fc1cnc(-n2cnc3cnccc32)nc1

Procedure:
Intermediate 6 was prepared in a manner analogous to Intermediate 1, substituting 2-bromo-5-fluoropyrimidine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C10H6FN5, 215.06. m/z found 216.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[N:17]=[C:33]=[O:35])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1

Procedure:
To a solution of 3-amino-1-benzyloxycarbonyl-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5D (1.78 g, 4.10 mmol) in anhydrous toluene (40 mL) was added triphosgene (0.42 g, 1.41 mmol) and triethylamine (0.83 g, 8.22 mmol). The reaction mixture was heated under reflux for 2 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)=[C:4]([CH3:19])[CH:3]=1.[CH3:20]O>[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:14][C:13]([OH:15])=[CH:12][CH:11]=[C:10]3[N:16]=[CH:20]2)=[C:4]([CH3:19])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)ccc1Nc1nc(O)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: Cc1cc(Br)ccc1-n1cnc2ccc(O)nc21
Temperature: 50 °C
Reaction time: 45 h

Procedure:
To a solution of 6-(4-bromo-2-methylphenylamino)-5-nitropyridin-2-ol (4.50 g, 13.9 mmol) in MeOH (30 mL) was added Raney Ni (1.00 g). The mixture was stirred vigorously under H2 atmosphere overnight at which time additional Raney nickel (500 mg) was added. After stirring for an additional 45 h under H2 atmosphere, the mixture was filtered through Celite® and concentrated. The residue was dissolved in THF (20 mL) and trimethoxymethane (25 mL) and trifluoroacetic acid (100 μL) was added. The mixture was heated at 50° C. for 12 h followed by additional heating at 80° C. for 4 h. After cooling to room temperature, the solution was concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (442 mg). LCMS m/z=304.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.07 (s, 3H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.48 (dd, J1=8.3, J2=1.9 Hz, 1H), 7.55 (s, 1H), 7.82 (s, 1H), 8.04 (d, J=8.6 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH:13]([F:15])[F:14]>O1CCOCC1.O>[F:14][CH:13]([F:15])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(OC(F)F)cc1
Temperature: 70 °C
Yield: 59.4 %

Procedure:
Sodium hydroxide (48 g; 1.2 mole) is added to a stirred suspension of p-hydroxybenzaldehyde (48.9 g; 0.4 mole) in dioxane (142 ml) and water (87 ml). The mixture is heated to 70° C. and chlorodifluoromethane (33 g) added slowly. When this addition is completed, 50% sodium hydroxide solution (32 ml) is added to the reaction mixture, followed by the slow addition of chlorodifluoromethane (33 g). This recharging is repeated three times, and a total of 96 g (2.4 mole) of sodium hydroxide and 133 g (1.54 mole) of (1.54 mole) of chlorodifluoromethane is used in the reaction. The reaction mixture is cooled down, diluted with water (1500 ml) and extracted with ether several times. The ether layers are combined, washed with 10% sodium hydroxide and then dried over magnesium sulfate. Concentration of the ethereal solution yields 39 g (57%) of a yellow oil. This oil is purified by chromatography on a silica gel column using a mixture of hexane:methylene chloride (1:3), to afford 27 g (39%) of title product.