Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]#[C:24]CO)[CH3:20].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH:12]1([C:7]([OH:18])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:24]#[C:23][CH2:22][N:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:19][CH3:20])=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: CCN(CC#CCO)Cc1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1

Procedure:
reacting methyl α-cyclohexyl-α-hydroxybenzeneacetate with said 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butyn-1-ol in the presence of sodium methoxide in toluene to produce 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate; and
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C=O)C>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2nc3ccccc3s2)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzoic acid (4.0 g, 25.6 mmol) in DMF (250 mL) was added Cs2CO3 (9.2 g, 28.2 mmol) and the reaction mixture was stirred at 80° C. for 1 h prior to the addition of 2-chloro-benzothiazole (3.3 mL, 25.6 mmol). The reaction mixture was stirred at 100° C. for 50 h, then cooled to rt, and the solid was filtered. The filtrate was diluted with EtOAc (200 mL) and water (100 mL), neutralized with 1 M HCl and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to afford the title compound as a colorless solid (4.7 g, 63%). MS (ESI): mass calcd. for C14H8FNO3S, 289.0; m/z found, 290.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21 (t, J=8.5 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.11 Hz, 1H), 7.63-7.45 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1>CN(C=O)C>[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cnc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 46.8 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 48% yield: LCMS (ESI) m/z 409 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[NH2:33][C:34]1[NH:39][C:38]2=[N:40][CH:41]=[C:42]([CH3:43])[C:37]2=[C:36]([Cl:44])[N:35]=1.C(#N)C>C(Cl)Cl>[NH2:33][C:34]1[N:35]=[C:36]([Cl:44])[C:37]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:38]=2[N:39]=1
Reactant: Cc1cnc2[nH]c(N)nc(Cl)c1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2nc(N)nc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.57 g, 3.16 mmol) in CH2Cl2 (50 mL) was added HBr (5.7 M in acetic acid; 3.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×20 mL). The resulting oil was dissolved in MeCN (20 mL) and added dropwise to a solution of the sodium salt of 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see Liebigs Ann. Chem. 1984: 708–721] (1.13 g, 6.2 mmol) in anhydrous acetonitrile (150 mL), and NaH (60% in mineral oil, 248 mg, 6.2 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (300+150 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×7 cm) using ethyl acetate/hexane (0 to 30% EtOAc in 5% step gradient) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.96 g) as a colorless foam.
Reaction SMILES: C[O-].[Na+].[NH2:4]/[C:5](/[C:12]([F:15])([F:14])[F:13])=[CH:6]\[C:7](OCC)=[O:8].[CH3:16][N:17]=[C:18]=[O:19].O>CS(C)=O>[CH3:16][N:17]1[C:7](=[O:8])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:18]1=[O:19]
Reactant: CN=C=O
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)cc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a pre-mixed solution of sodium methoxide (55 mmol, 2.97 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (55 mmol, 10.0 g) in DMSO (19 mL, dried over molecular sieves) was added methyl isocyanate (55 mmol, 3.2 g) in DMSO (2.5 mL) over 15 min at 20° C. The solution was stirred for 15 min and then another portion of sodium methoxide (27.5 mmol, 1.34 g) was added. After stirring for 15 min at 20° C., methyl isocyanate (14 mmol, 0.8 g) was added at this temperature. After a further 15 min, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting yellow suspension was poured into water (50 mL) to obtain a light yellow solution. The neutral impurities were extracted into diethyl ether (3×50 mL). The aqueous layer was acidified with concentrated hydrochloric acid to afford a white solid. The solids were collected by filtration and were washed with water. After air drying, 6.79 g (63% yield) of 3-methyl-6-(trifluoromethyl)uracil was obtained as a white solid: mp 235-237° C. EI-HRMS m/e calcd for C6H5F3N2O2 (M+) 194.0303, found 194.0303.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH:33]1([C:38]([O-:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.[Cs+].[I-].[Na+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:40][C:38]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Reactant: O=C([O-])C1CCCC1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C1CCCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol), cesium cyclopentanecarboxylate (0.20 g, 0.81 mmol) and sodium iodide (0.061 g, 0.41 mmol) in acetonitrile (15 mL) were heated to reflux overnight. Upon cooling to RT, water was added and the reaction mixture was extracted with ethyl acetate and then with dichloromethane. The organic phases were washed with brine, combined, dried over magnesium sulfate, filtered, and conc in vacuo. The isolated residue was subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 63%. 1H NMR (400 MHz, DMSO-d6): δ 7.39 (dd, 1H), 7.35-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.73-6.69 (m, 1H), 4.74-4.70 (m, 1H), 4.12-3.93 (m, 2H), 3.88-3.73 (m, 2H), 3.39-3.28 (m, 2H), 3.26 (s, 3H), 3.18-3.11 (m, 1H), 3.06-3.03 (m, 2H), 2.76-2.68 (m, 1H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97-(m, 2H), 1.80-1.70 (m, 2H), 1.68-1.56 (m, 2H), 1.54-1.43 (m+dd, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[C:16]([NH2:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][C:10]2[N:25]=[C:16]([OH:24])[C:17]3[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:19]=2)[CH2:14][C:13]([OH:12])=[O:15])=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CC(Cc1nc(O)c2ccccc2n1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
The solution of 3-(4-chlorophenyl)glutaric anhydride (449 mg) and anthranilamide (272 mg) in toluene (8 ml) was heated to reflux for 4 h. After removal of the solvent the residue was dried in vacuo. The off-white solid was dissolved in 2M sodium hydroxide (3 ml) and stirred under reflux for 2 h. After cooling to room temperature acetic acid (0.5 ml) was added with stirring. The precipitate formed was isolated by suction filtration, washed, and dried in vacuo to give 3-(4-chlorophenyl)-4-(4-hydroxy-2-quinazolinyl)butanoic acid (0.57 g) as colourless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](NCC1C=CC=CC=1)=[O:15].COCCCCCCCCCCCC(O)=O.C(Cl)(=O)C([Cl:43])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:43])=[O:15]
Reactant: COCCCCCCCCCCCC(=O)NCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: COCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: COCCCCCCCCCCCC(=O)Cl

Procedure:
Reaction Scheme 4 illustratively shows the preparation of 12-methoxy-N-(phenyl-methyl) dodecanamide wherein 12-methoxydodecanoic acid (8) is treated with oxalyl chloride in anhydrous toluene to form 12-methoxydodecanoyl chloride (9) which in turn reacts with benzylamine in methylene chloride to give the desired fatty acid amide (10).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.[I-].[Na+]>O.CC(N(C)C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(Cl)CCC(F)(F)F
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(Br)cc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 231.4 %

Procedure:
A reaction mixture of 4-bromo-1-(1-chloro-4,4,4-trifluorobutyl)-2-methylbenzene (369 g), sodium carbonate (245% g), methyl 4-aminobenzoate (194 g), sodium iodide (347 g) and DMA (1.2 L) was stirred at 50° C. for 3 hr. The reaction mixture was added to water. This reaction was performed for 3 batches, the obtained respective reaction mixtures were combined, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with petroleum ether to give the title compound (1164 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:15][C:14]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cc(Oc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
The product from Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol) and K2CO3 (0.78 g, 5.6 mmol) in DMF (10 ml) was heated at 110° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound. The residue was treated with i-Pr2O and insoluble material was filtered off. The filtrate was evaporated and purified by silica gel column chromatography eluting with 5:2 EtOAc/hexane to give the title product as pale yellow oil (0.51 g, 43%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13][CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2F)[C:23]#[N:24])[O:17][N:16]=1)[CH3:2].[H-].[Na+].CN(C=[O:35])C>>[CH2:1]([N:3]1[C:7]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13][CH2:14][C:15]1[N:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[OH:35])[C:23]#[N:24])[O:17][N:16]=1)[CH3:2]
Reactant: CCn1c(SCc2noc(-c3cc(C#N)ccc3F)n2)nnc1-c1ccco1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCn1c(SCc2noc(-c3cc(C#N)ccc3O)n2)nnc1-c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
The title compound was prepared using the general procedure of Rogers et al., Tetrahedron Letters (2002) 43: 3585-3587. To a stirring solution of 3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile (20 mg, 0.050 mmol), 2-(methylsulfonyl-ethanol) (9.38 mg, 0.075 mmol), and DMF (0.05 M) at 0° C. was added NaH (5.8 mg, 0.150 mmol). Stirred for 20 min and removed the ice bath. Stirred an additional 20 min while warming to room temperature. The reaction mixture was quenched with 1 N HCl solution and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4), filtered and concentrated to dryness. The crude organics were purified by flash column chromatography using ethyl acetate followed by 5% methanol in ethyl acetate to give the title compound (8.1 mg, 41%, white solid). 1H NMR (CDCl3), δ (ppm): 8.25 (m, 1H), 7.75 (m, 1H), 7.60 (s, 1H), 7.18 (m, 2H), 6.60 (m, 1H), 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: COc1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (368 mg) in DMF (5 mL) was added potassium carbonate powder (567 mg) and 3-methoxybenzyl bromide (825 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by dissolution in CH2Cl2 and trituration with hexanes to yield the title compound as a peach solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(OC(Cl)(Cl)Cl)=O.C([O:22][C:23]([N:25]1[CH2:47][CH2:46][CH2:45][C@H:26]1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH:34]([OH:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:28])=O)(C)(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([N:25]2[CH2:47][CH2:46][CH2:45][C@H:26]2[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH:34]([OH:44])[CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)=[O:28])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Reactant: NCc1ccc(F)cc1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1

Procedure:
By the same procedure as in Example 28-B), while using 4-fluorobenzylamine (0.54 ml), trichloromethyl chloroformate (0.28 ml) and (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-[2-(4-fluorophenoxy)-1-hydroxyethyl]pyrrolidine (1.85 g), there was obtained 1.38 g of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C@@H:12]([OH:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10].[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[NH:21]1>C1COCC1>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:18][C@@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:34])[CH2:31][CH2:32]2)[CH2:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[NH:21]1
Reactant: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CCOC(=O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
450 mg (55% in mineral oil, 10.3 mmol) NaH were added batchwise to a solution of 2.6 g (9.9 mmol) ethyl(R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionate in 50 mL THF cooled to 0° C. and stirred for a further 30 min at this temperature. Subsequently 3.7 g (11.9 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloride were added batchwise while being cooled and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue combined with DCM, the organic phase was separated off, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained which was reacted without any further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.C(O)(C)C.C(=O)=O.[CH:16]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:23]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:24])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C=NC1CCCCC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-1,4-diaminocyclohexane (6.15 g, 0.054 mmol) was added in a flame dried Schlenk flask and dissolved in THF (500 mL) under argon atmosphere. The solution was cooled to −40° C. in a cooling bath (isopropyl alcohol/dry ice) and cyclohexyl isocyanate (6.75 g, 0.054 mmol), diluted in THF (100 mL), was added slowly under heavy stirring. The reaction mixture was stirred for 12 h at room temperature. The precipitated white solid was filtered off, suspended in water and acidified to pH 2 (HCl). The emerging clear solution was again filtrated and the filtrate was brought to pH 8 (NaOH) whereupon the trans-1-(4-aminocyclohexyl)-3-cyclohexylurea precipitated as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH:12](O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:36]#[N:37])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:20])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:36]#[N:37])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4]
Reactant: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-hydroxy-3-(4-pyridyl)propionate (0.60 g, 2.0 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.50 g, 2.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (4 ml), and trimethylsilyl cyanide (0.39 g, 3.9 mmol) and N,N-dimethylcarbamoyl chloride (0.38 g, 3.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 50 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (20 g) column chromatography. The fractions eluted with 4hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.54 g, 85%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].C([NH+](CC)CC)C>C1C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CC[NH+](CC)CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
The solution of 13 g of 1-phenyl-3-methyl-2-pyrazolin-5-one in 150 ml of benzene and 9.1 g of triethylamine is combined at ambient temperature with the solution of 14.0 g of 3,4-dichlorophenylisocyanate in the minimum amount of benzene. The triethylammonium salt separates after 2 hours standing at room temperature and the mixture is evaporated. The residue is poured into 0.3 N hydrochloric acid, the solid collected, washed with water, dried, triturated with cold methanol and recrystallized from ethyl acetate to yield the 1-phenyl-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=H, R'=3--Cl and R"=Cl, melting at 228°-231° (dec.).
Reaction SMILES: [Na].[SH:2][CH:3]([CH3:5])[CH3:4].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[CH3:4][CH:3]([S:2][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)S
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CSC(C)C
Reaction time: 12 h

Procedure:
To sodium (4.2 g, 0.18 mol) in ethanol (100 mL) was added 2mercaptopropane (20 mL), 0.21 mol) followed by ethyl bromoacetate (10 mL, 0.090 mol). The mixture was stirred for 12 hours, concentrated, partitioned between ether and water and washed with water. The organic phase was dried over MgSO4, evaporated and distilled to afford the desired product. B.P. 58°-62° C. (1 mm).