Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([CH3:42])[C:25]=1[C:26]1[CH:27]=[C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])[CH:29]=[CH:30][C:31]=1[OH:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:58][C@@H:59]([NH:61]C(=O)OC(C)(C)C)[CH3:60]>C1COCC1>[NH2:61][C@@H:59]([CH3:60])[CH2:58][O:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])=[CH:27][C:26]=1[C:25]1[N:24]([CH3:42])[N:23]=[CH:22][C:21]=1[Cl:20]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)no1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(OC[C@H](C)N)c(-c3c(Cl)cnn3C)c2)no1
Temperature: 65 °C
Yield: 21.34 %

Procedure:
Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq; 1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed with nitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in a rotary shaker for 2 minutes. N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide (30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly then DIAD (diisopropyl azodicarboxylate, 27.94 μl, 144.4 μmol) was added. After 30 minutes in a rotary shaker a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dry THF was added. The resulting suspension was heated to 65° C. and mixed overnight. LCMS showed that the reaction did not go to completion. A fresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to the reaction mixture and the suspension was heated to 65° C. and mixed overnight. The suspension was filtered and the resin washed with THF (3×3 mL). The filtrate and washings were combined and concentrated under vacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL), heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organic solvent was removed under vacuum and the crude residue was dissolved in acetonitrile (0.8 mL), neutralized with saturated NaHCO3 and subjected to purification by preparative LCMS. The desired fractions were pooled, frozen and lyophilized to afford the title compound as an off-white solid (21.34% yield). LCMS m/z=390.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3H), 2.54 (s, 3H), 3.46-3.57 (m, 1H), 3.66 (bs, 3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H), 7.35 (dd, J=9.09, 2.53 Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.95 (dd, J=9.09, 2.53 Hz, 1H), 7.97-8.04 (bs, 2H), 10.76 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][CH:6]([CH3:16])[NH:7][CH2:8][CH:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CCN1CC(C)NCC1C
Temperature: 100 °C

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C., while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, and the filter cake was washed with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans, 1-allyl-2,5-dimethylpiperazine as a dark liquid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:8].[Na+].[CH2:10](Cl)[CH2:11]Cl>>[OH:8][CH2:10][CH2:11][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: NC1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Product: OCCNC1CCCCC1
Temperature: 160 °C
Reaction time: 10 h

Procedure:
Into 100 g of cyclohexylamine was added 41 g of ethylene chloride and the mixture was stirred at about 160° C. for 10 hours. After cooling the reaction mixture to a room temperature, 100 ml of 10 N-NaOH aqueous solution was added to the reaction mixture and the organic layer was obtained by using a separating funnel and thus obtained organic layer was dried with KOH. KOH was removed by filtration and the mother liquor was distilled under a reduced pressure. 48 Grams of N-(2-hydroxyethyl)cyclohexylamine was obtained as an oily substance. Boiling point: 132°-135° C. (18 mmHg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][CH:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: BrC(c1ccccc1)c1cccc2ccccc12
Reactant: Cc1ccc2cccc(N)c2n1
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(NC(c3ccccc3)c3cccc4ccccc34)c2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A mixture of 2.05 g (13.0 mmol) of 2-methyl-8-aminoquinoline, 2.53 g (25 mmol) of triethylamine and 7.43 g (25 mmol) of 8 was stirred for 2 hr at 120° C. One more portion of 2.53 g of triethylamine as well as 7.43 g of 8 was added. The resulting mixture was stirred for additional 2 hr at 120° C. Finally, the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-ethyl acetate=20:1, vol.) to give 0.56 g (12%) of the title compound A5.
Reaction SMILES: Br[CH2:2][CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCCCCCCC>CO.CC(O)C>[CH2:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(Br)CBr
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCCCCCCC
Solvent: CO
Product: C=CCCCCCCCC

Procedure:
Solutions were prepared by dissolving all of the following in a total volume of 5 mL methanol and 2-propanol, respectively: (a) 60.0 mg 1,2-dibromodecane, 10.8 mg of benzophenone and 12.6 mg of dodecane; (b) 65.2 mg 1,2-dibromodecane, 11.2 mg benzophenone and 11.2 mg dodecane. Two 2mL-aliquot of each solution were placed in quartz cells (7×7 mm2) and deaerated by bubbling oxygen-free nitrogen for 15 minutes. Samples were then irradiated at 350 nm using a photoreactor equipped with two RPR-350 lamps. Samples were rotated with a "merry-go-round" (to ensure that all samples received the same irradiation dose) and irradiated for 1 hour (methanol) or 40 minutes (2-propanol). A valerophenone solution (prepared as described above) was used as a relative actinometer. Product (i.e. 1-decene) quantification and quantum yields were carried out as described above. Results are summarized in the table below. No 1-decene was formed in the absence of benzophenone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[S:11].[I:12]C.[CH2:14](OCC)C>C(O)C>[I-:12].[CH3:14][S:11][CH:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4]1
Reactant: CI
Reactant: Cn1c(=S)sc2ccccc21
Reactant: CCOCC
Solvent: CCO
Product: CSC1Sc2ccccc2N1C
Product: [I-]
Yield: 90 %

Procedure:
2.0 g (11 mmol) of 3-methylbenzothiazole-2-thione and 3.5 mL (55 mmol) of iodomethane were refluxed in 50 mL of absolute ethanol for 4 hours. Diethyl ether was added to the cooled mixture to precipitate the product. Recrystallization from ethanol:diethyl ether gave 3.2 g (90%) of pure 2-methylmercapto-3-methylbenzothiazole iodide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)[CH:16]=[CH:17][C:11]=3[C:10](=[O:29])[NH:9][C:8]=2[CH:30]=1.[Cl:31][C:32]1[N:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CO.CS(C)=O>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[NH:13][C:12]4[CH:14]=[C:15]([C:18]5[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=5)[CH:16]=[CH:17][C:11]=4[C:10](=[O:29])[NH:9][C:8]=3[CH:30]=2)=[CH:34][CH:33]=1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCO)cc2NC3=O)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CO
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(Cl)nc4)cc2NC3=O)ccc1[N+](=O)[O-]

Procedure:
A mixture of Example 239 (41 mg, 0.1 mmol), 6-chloro-pyridin-3-ol (19 mg, 0.15 mmol), PPh3 (39 mg, 0.15 mmol), and di-tert-butyl azodicarboxylate (35 mg, 0.15 mmol) in THF (2 ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with MeOH/DMSO (1:1), and purified by preparative HPLC to provide the desired product. MS (ESI) m/e 517 (M+H)+; 1H NMR (499 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.11 (d, J=3.12 Hz, 1H), 8.01 (d, J=8.42 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J=8.11 Hz, 1H), 7.52 (s, 1H), 7.47 (m, 1H), 7.40 (d, J=8.73 Hz, 1H), 7.34 (m, 2H), 7.30 (dd, J=8.11, 1.56 Hz, 2H), 6.95 (m, 2H), 4.21 (t, J=6.55 Hz, 2H), 4.03 (s, 3H), 2.92 (t, J=6.55 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NS(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A solution of 2-chloro-4-methylaniline (5.00 g) and triethylamine (3.57 g) in dichloromethane (100 ml) was cooled to 0° C. Methanesulphonyl chloride (4.04 g) was added dropwise and the mixture stirred at ambient temperature overnight. The mixture was then washed with 2N aqueous hydrochloric acid solution (50 ml) and the solvent removed by evaporation. The residue was dissolved in ethyl acetate (75 ml) extracted with 2N aqueous sodium hydroxide solution (2×50 ml). The aqueous phase was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×75 ml). This was subsequently dried (MgSO4) and the solvent evaporated. Thus was obtained N-(2-chloro-4-methylphenyl)methanesulphonamide (2.5 g, 32%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:20][CH2:19]4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][CH:21]3[C:22]4[C:18](=[CH:17][C:16]([O:15][CH:12]5[CH2:13][CH2:14][N:9]([C:6]6[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:33])=[CH:4][CH:5]=6)[CH2:10][CH2:11]5)=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)[CH2:27][CH2:28]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: FC(F)(F)c1ccc(N2CCC(Oc3ccc4c(c3)CCC4NC3CCNCC3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCC(NC3CCc4cc(OC5CCN(c6ccc(C(F)(F)F)cc6)CC5)ccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred mixture of N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine.3HCl (0.06 g, 0.1 mmol) in anhydrous dimethylformamide (0.5 mL) at room temperature was added 1-bromomethyl-4-fluorobenzene (0.02 g, 0.1 mmol) and N,N-diisopropylethylamine (0.07 g, 0.5 mmol). The resulting mixture was stirred at room temperature overnight. After this time the mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.05) to afford the title compound as a off-white solid (0.05 g, 88%). 1H NMR (CDCl3, 300 MHz) 7.46 (m, 2H), 7.25 (m, 3H), 6.96 (m, 4H), 6.75 (m, 2H), 4.47 (m, 1H), 4.29 (m, 1H), 3.58 (m, 2H), 3.48 (s, 2H), 3.06-2.54 (m, 6H), 2.38 (m, 1H), 2.14-1.74 (m, 9H), 1.49 (m, 2H) ppm; MS (ES) 568.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10]C(=O)C(F)(F)F)[CH3:9])=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[F:20].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[F:20]
Reactant: CC(NC(=O)C(F)(F)F)c1ccc(Cl)c(F)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(N)c1ccc(Cl)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
N-[1-(4-Chloro-3-fluoro-2-nitro-phenyl)-ethyl]-2,2,2-trifluoro-acetamide (286 mg, 0.909 mmol) was dissolved at room temperature in THF (10 mL). Then, a solution of lithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (2 mL) was added. The reaction was followed by TLC, using ethyl acetate as solvent. After 2 h., more lithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (2 mL) was added. The reaction was stirred at room temperature for three days. Then, the reaction was extracted with ethyl acetate-sodium hydroxide (1N) and brine. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel to yield 148 mg of 1-(4-chloro-3-fluoro-2-nitro-phenyl)-ethylamine. 1H NMR (400 MHz, Cl3CD) δ 7.90 (d, J=6.43 Hz, 1H), 7.64 (d, J=10.07 Hz, 1H), 4.62 (m, 1H), 1.58 (br s, 2H), 1.33 (d, J=6.43, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.ClC(OCC(C)C)=O.[N:22]1([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34][CH2:33]3)=[O:29])[CH2:23][CH2:24]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Into 100 ml of dimethylformamide, 2.6 g of 3,4-dimethoxybenzoic acid and 1.65 g of 1.8-diazabicyclo[5,4,0]undecene-7 were added, then the outside of the reaction vessel was ice-cooled and stirring condition, 1.5 ml of isobutyl chloroformate was added dropwise. Then the reaction mixture was further stirred for 30 minutes, a solution of 2.6 g of 6-(1-piperazinyl)carbonyl-3,4-dihydrocarbostyril dissolved in 40 ml of dimethylformamide was added to the reaction mixture and stirred at a room temperature for 5 hours. After the reaction was completed, the solvent was removed by distillation and the residue was extracted with about 300 ml of chloroform, then washed with a diluted sodium hydrogencarbonate aqueous solution, water, a diluted hydrochloric acid and water in this order. After removal of chloroform by distillation, the residue was recrystallized from ethanol-chloroform to obtain 1.8 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cnc(C(=O)CBr)s1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncc(C)s2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-methylthiazole hydrobromide*.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:11]=[C:10](Br)[S:9][C:8]=1[O:13][CH3:14].CI>C1COCC1>[Br:6][C:7]1[CH:11]=[C:10]([CH3:1])[S:9][C:8]=1[O:13][CH3:14]
Reactant: COc1sc(Br)cc1Br
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1sc(C)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (2.0M in pentane, 0.97 mL, 1.93 mmol) was added to a stirred solution of 3,5-dibromo-2-methoxythiophene (Step A, 500 mg, 1.84 mmol) in THF (5 mL) at −78° C. under an atmosphere of N2. The reaction stirred at −78° C. for 1 h prior to addition of methyl iodide (114 μL, 1.84 mmol). The reaction was allowed to warm to room temperature and stirred for 20 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (15 mL0 and H2O (15 mL). The aqueous layer was re-xtracted with ether (2×15 mL) and the combined organic layers were washed with H2O (15 mL) and brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 3-bromo-2-methoxy-5-methylthiophene as a yellow oil. 1H NMR (CDCl3, 500 MHz): δ 6.44 (s, 1H), 3.95 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [H-].[Na+].C[C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:12]1[N:13]([CH3:25])[C:14](=[O:24])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[N:17]=1.O1CCC[CH2:27]1>>[CH3:25][N:13]1[C:14](=[O:24])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[N:17]=[C:12]1[O:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH3:27]
Reactant: CC1(O)CCCCC1
Reactant: C1CCOC1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: [H-]
Agent: [Na+]
Product: CC1CCCCC1Oc1nc(-c2ccncn2)cc(=O)n1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 326 mg, 8.15 mmol) in tetrahydrofuran (14.0 ml) was added 1-methyl cyclohexanol (racemate; cis/trans mixture, 930 mg, 8.15 mmol) at room temperature. The mixture was stirred at 40° C. for one hour. The mixture was cooled to room temperature, and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (1.51 g, 6.78 mmol) was added to the mixture. The mixture was stirred at 60° C. for 8 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-(2-methyl-cyclohexyloxy)-1H-[4,4′]bipyrimidinyl-6-one (cis/trans-mixture) as a colorless solid (752 mg, 2.50 mmol, 37%)
Reaction SMILES: [CH2:1]([N:8]([CH2:31][CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[C:9](=[O:30])[C@@H:10]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.ClCCl>>[NH2:12][C@@H:10]([CH3:11])[C:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:31][CH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[O:30]
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To (S)-(9H-fluoren-9-yl)methyl 1-(benzyl(2,2-diethoxyethyl)amino)-1-oxopropan-2-ylcarbamate (Compound XV-1) 1.12 g (2.1 mmol), 25%-piperidine/dichloromethane 16 ml was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30, chloroform:methanol=100:0 to 80:20) to obtain the title compound 640 mg (yield 100%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.[C:17](O)(=[O:19])[CH3:18]>>[OH:19][CH2:17][CH2:18][N:4]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1)[CH2:2][CH2:1][OH:3]
Reactant: CC(=O)O
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: C1CO1
Product: COC(=O)COc1ccc(N(CCO)CCO)cc1

Procedure:
Ethylene oxide (10 g; 227 mmol) was added under ice cooling to a solution of 4.0 g (22 mmol) of methyl 4-aminophenoxyacetate in 22 ml of 30% acetic acid. After the resultant mixture was stirred overnight at room temperature, nitrogen gas was bubbled to eliminate excess ethylene oxide. Subsequent to neutralization with sodium hydrogencarbonate, sodium chloride was added, followed by extraction with n-butanol. The extract was dried over magnesium sulfate and the solvent was distilled out. The residue was purified by chromatography on a silica gel column (chloroform/methanol=20/1), whereby 5.29 g of the title compound were obtained as a colorless oil (yield: 89%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O.[C:16]([CH:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:22][CH2:21][NH:20]1)(=[O:18])[NH2:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:14][C:2]([F:1])([F:15])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:20]1[CH2:21][CH2:22][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:24][CH:19]1[C:16](=[O:18])[NH2:17])=[O:13]
Reactant: O=C(O)Cc1ccccc1OC(F)(F)F
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccccc2OC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-trifluoromethoxyphenylacetic acid (0.10 g, 0.48 mmol) from Step 4 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.10 g, 0.46 mmol) from Step 4 of Example 1 in DMF (10 mL) was added HOBT (0.075 g, 0.5 mmol), EDC (0.22 g, 0.75 mmol), and DIEA (0.13 mL, 0.75 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the title compound as an amorphous solid.