Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)cnc1N1CCOCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a vial containing 5-bromo-2-chloro-3-nitropyridine (0.99 g, 4.16 mmol) in DMSO (4.0 mL) was added morpholine (0.8 mL, 9.19 mmol) dropwise. The reaction was stirred at 23° C. and monitored with TLC and LC-MS. After 20 h, LC-MS showed that the reaction was complete, then the mixture was diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to afford a yellow-orange solid as 4-(5-bromo-3-nitropyridin-2-yl)morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.3 Hz), 3.70 (4H, m), 3.41 (4H, m).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].N([O-])=[O:27].[Na+].C(O)(=O)C>O.C(#N)C>[C:20]1([C:18]([NH:17][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:27])[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCCC(NC(=O)c1ccccc1)C(=O)NCc1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(NC(CCCCO)C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
2-(N-Benzenecarbonyl)amino-6-amino-N-benzylhexanamide (105) (48 mg) obtained in Step 1-4 was dissolved in water (1.6 ml) and acetonitrile (1.1 ml). To the solution were added sodium nitrite (156 mg) and acetic acid (40.6 mg) under cooling with ice, and the mixture was stirred for 1 hour under cooling with ice. After 1 hour, the reaction liquid was warmed to room temperature and stirred for 1.5 hours. Subsequently, the reaction liquid was heated to 70° C. and stirred for an additional 20 minutes. The reaction liquid was concentrated and extracted with ethyl acetate (60 ml). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=2:1 to n-hexane:ethyl acetate=1:6) to give a compound (106) (19.5 mg, yield: 41%) as a pale yellow solid. 1H NMR data on the compound (106) is shown below.
Reaction SMILES: [F:1][CH:2]([F:17])[S:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[F:17][CH:2]([F:1])[S:3]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1cc(SC(F)F)c(=O)c2ccc(F)cc21
Solvent: ClCCl
Product: Cn1cc(S(=O)C(F)F)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
To a stirred solution (a part remained undissolved) of crude 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone (4) (3.43 g, 13.23 mmol) in DCM (200 ml) at 0° C. was added ˜80% MCPBA (2.50 g, 11.59 mmol) in a few portions over a period of approximately 1 min. The stirred mixture was allowed to warm to room temperature and was stirred for 30 min. An additional amount of MCPBA (640 mg) was added in 5 portions in approximately 1 h intervals, and the progress of the oxidation was monitored by 1H NMR 30 min after each addition. The mixture was washed with 5% aqueous Na2CO3 (70 ml), the aqueous layer was extracted with DCM (2×200 ml), the combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with DCM and then with hexane-ethyl acetate (gradient 2:1,1:1,1:2) to give 980 mg (20.7%; two steps) of the product. The product was further purified by recrystallization from absolute ethanol to give 620 mg (13.1%) of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) as off-white crystals. 1H NMR, CDCl3; δ=3.94 s, 3H, N—CH3; 7.050, 6.870, 6.866, 6.686 (4 lines, X part of ABX), 1H, CHF2; 7.21 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=8.9, 7.9 & 2.2 Hz, H at C6; 7.99 s, 1H, H at C2; 8.44 dd, 1H, J=9.0 & 6.3 Hz, H at C5.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(COC)OC.O>[O:3]=[C:4]([CH2:11][CH3:12])[CH:5]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)CC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.75 g, 43.7 mmol) was added in portions over 1 minute to an ice-cooled, stirring solution of ethyl 3-oxopentanoate (6.30 g, 43.7 mmol) in dry dimethoxyethane (87 mL). After 5 minutes, the flask was removed from the cooling bath and stirring continued at room temperature. After 30 minutes, a solution of 4-(trifluoromethyl)benzyl bromide (10.4 g, 43.7 mmol) in dry dimethoxyethane (10 mL) was added dropwise over 2 minutes. After 2.5 hours, ethyl acetate (300 mL) and water (100 mL) were added. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by flash-column chromatography on silica gel eluting with hexanes initially, grading to 50% dichloromethane-hexanes to provide the title compound as a colorless liquid.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C([O:32][C:33]([CH:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1)=[O:34])C1C=CC=CC=1>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:37]3[CH2:38][CH2:39][O:40][CH:35]([C:33]([OH:34])=[O:32])[CH2:36]3)=[CH:14][N:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: Cl
Product: O=C(O)C1CN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CCO1

Procedure:
Prepared 11 mg (58%) following the general procedures (P) and (F) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (70 mg. 0.21 mmol) and morpholine-2-carboxylic acid benzyl ester hydrochloride (77 mg, 0.30 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:57]=[CH:56][C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH:18]3[CH2:21][CH:20]([N:22]([CH2:24][C@@H:25]4[C@H:29]5[O:30]C(C)(C)[O:32][C@H:28]5[C@H:27]([N:35]5[C:39]6[N:40]=[CH:41][N:42]=[C:43]([NH:44]CC7C=CC(OC)=CC=7OC)[C:38]=6[CH:37]=[CH:36]5)[CH2:26]4)[CH3:23])[CH2:19]3)=[N:15][C:11]=2[CH:10]=1.C([SiH](CC)CC)C>O>[NH2:44][C:43]1[C:38]2[CH:37]=[CH:36][N:35]([C@@H:27]3[CH2:26][C@H:25]([CH2:24][N:22]([CH:20]4[CH2:19][CH:18]([CH2:17][CH2:16][C:14]5[NH:13][C:12]6[CH:56]=[CH:57][C:9]([Br:8])=[CH:10][C:11]=6[N:15]=5)[CH2:21]4)[CH3:23])[C@@H:29]([OH:30])[C@H:28]3[OH:32])[C:39]=2[N:40]=[CH:41][N:42]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Br)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Br)ccc3[nH]2)C1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Trifluoroacetic Acid (20 ml) added to a mixture of Water (2 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-bromo-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.9 g, 1 mmol) at RT. The reaction mixture was stirred for one hour, Triethylsilane (0.39 ml, 2.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was purified twice by flash chromatography (DCM/7N NH3 in MeOH 87:13). The residue was taken up in MeOH/H2O (5:0.5 ml) and K2CO3 (100 mg) added. The mixture was stirred for 1 hour, then concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product (0.15 g) as an off-white foam/gum. cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol (0.15 g; 20%) as an off-white foam/gum. MS (ESI+) for C26H32BrN7O2 m/z 554.1 [M+H]−; MS (ESI−) C26H32BrN7O2 m/z 552.1 [M−H]−; HPLC purity >90% (ret. time, 2.298 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.080 (s, 1H), 7.652 (s, 1H), 7.425-7.403 (m, 1H), 7.342-7.7.312 (m, 1H), 7.232-7.217 (m, 1H), 6.620-6.611 (d, J=3.6 Hz, 1H), 4.358-4.318 (m, 1H), 3.928-3.888 (m, 1H), 3.099-3.039 (m, 0.5H (methine of trans isomer)), 2.898-2.829 (m, 2H), 2.777-2.726 (m, 0.5H (methine of cis isomer)), 2.580-2.529 (m, 1H), 2.453-2.397 (m, 2H), 2.307-2.141 (7H), 2.068-2.017 (m, 1H), 1.955-1.891 (m, 3H), 1.695-1.506 (m, 2H).
Reaction SMILES: NC1C=CC(N=NC2C=CC(N)=CC=2)=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1C(O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(OC(N1C2C(=CC=CC=2)C=CC1)=O)C>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: CCOC(=O)N1CC=Cc2ccccc21
Agent: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 166.6 %

Procedure:
4-(4-aminophenylazo)-phenylamine (3.02 g) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (7.00 g) were dissolved in DCM (90 mL), and 1-ethoxycarbonyl-1,2-dihydroquinoline (8.45 g) was added. The reaction mixture was stirred at ambient temperature for 19 hours and evaporated under vacuum. Oil was dissolved in ethyl acetate, forming a precipitate, which was collected by vacuum filtration and dried under vacuum, giving 2-(4-{4-[(1-carboxylic acid tert-butyl ester-pyrrolidine-2-carbonyl)-amino]-phenylazo}-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.28 g) as a brown solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:35]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:35]1([C:39]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)[CH2:5][CH2:4]2)=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)C1CCC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3CCC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by cyclobutanecarboxylic acid (28 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-[cis-4-(cyclobutanecarbonyl-amino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (101 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1onc(C(F)(F)F)c1CO
Solvent: O
Solvent: CCOCC
Product: Cc1onc(C(F)(F)F)c1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 0.45 g (2.5 mmoles) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol dissolved in 10 ml of diethyl ether was cooed to 0° C. Thereto was added 0.2 g (8.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 74.0%) of 4-bromomethyl-5-methyl-3-trifluoromethylisoxazole.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[C:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCNC1
Yield: 48.7 %

Procedure:
A solution of 1-benzyl-3-carboethoxypyrrolidine (2 g, 8.6 mmol) in ethanol (75 ml) was subjected to hydrogenolysis over Pd(OH)2 on a parr shaker for 48 hr. The catalyst was filtered off, the solvent removed under vacuum, and the residue chromatographed through alumina using dichloromethane/methanol (85:15) as eluant, to give the title product as a clear liquid (0.6 g); δ(60 MHz, CDCl3) 1.20 (3H, t, J=7 Hz, OCH2CH3); 1.70-2.30 (2H, m, CH2); 2.50-3.20 (5H, m, 2×CH2 --N, and CH--CO2Et); 4.10 (2H, q, J=7 Hz, OCH2CH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24](=[N:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=1[F:37]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[N:10]1[C:21](=[O:20])[NH:22][C:23]([CH:24]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]#[N:46])=[CH:43][CH:44]=2)[C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH2:34][CH2:35][OH:36])[C:26]=2[F:37])=[N:11]1)=[O:4]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCO)c1F
Reactant: COC(=O)c1scnc1NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1scnc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
After adding 153 mg of 4-hydrazinothiazole-5-carboxylic acid methyl ester (Example (162c)) and 600 μl of triethylamine to a solution of 394 mg of {2-(4-cyanophenylimino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-1-methylsulfanylethylidene}carbamic acid methyl ester in 6 ml of THF, the mixture was stirred at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was dissolved in 5 ml of DMF, 600 μl of triethylamine was added and the mixture was stirred overnight at 85° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH2:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 10.85 g (65.0 mmol) of carbazole, 2.60 g (65.0 mmol) of sodium hydroxide and 6.1 mL (72.0 mmol) of allylbromide in 100 mL dimethylsulfoxide was heated to 60° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then concentrated. The crude product was purified using column chromatography (silica, 1:4 dichloromethane:hexane). Yield: 9.85 g (73%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N=Cc2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
(a) 2.38 g of 50% sodium hydride is suspended in 75 ml of anhydrous dimethylformamide, and 7.5 g of 4-[N-(4-methoxyphenyl)formimidoyl]phenol is added in four portions to the suspension at room temperature with stirring. Subsequently, 9.65 g of ethyl 2-bromo-2-methylpropionate is added dropwise to the resulting mixture at 20° to 25° C. over a period of about 40 minutes. The mixture is stirred at room temperature for 1 hour and then at 50° to 55° C. for 2 hours. The reaction mixture is poured into cold water, extracted with ether, and the extract is washed with 5% aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the ether is distilled off to give 7.5 g of ethyl 2-[4-{N-(4-methoxyphenyl)formimidoyl}phenoxy]-2-methylpropionate in the form of an oil.
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.O>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:6]([C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1coc(NC(=O)C(C)C)n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1coc(N(Cc2cccc(Cl)c2)C(=O)C(C)C)n1
Temperature: 70 °C

Procedure:
2-iso Butyramido-4-methyloxazole (11.1 g., 0.066 mol) prepared in a manner similar to that described in Example 20, was dissolved in dry dimethylformamide. Solid potassium carbonate (10.47 g., 0.076 mol) and 3-chlorobenzyl bromide (15.6 g., 0.076 mol) were added and the stirred mixture was heated at 70° C for 2 hours, cooled and poured into cold water. The solution was extracted with ether and the extract was dried over magnesium sulphate and evaporated. The residue b.p. distilled to give the product, 12.3 g., b.p, 115°-120° C/0.08 mm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17](=O)([O:20]C)[O:18][CH3:19].[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1>[CH3:19][O:18][C:17]([CH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)=[O:20]
Reactant: COC(=O)OC
Reactant: Cc1nc(-c2ccccc2)ncc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
A solution of 3.00 g (14.0 mmol) of 4-Methyl-2-phenyl-pyrimidine-5-carboxylic Acid and 2.53 g (28.0 mmol) of dimethyl carbonate in 75 mL of THF is added dropwise with rapid overhead stirring to a slurry of 6.00 g (56.1 mmol) of LDA in 24 mL of THF at −78° C. The mixture is stirred at 25° C. for 5 h and then chilled to −78° C. The reaction is added all at once and rapidly (overhead stirring) to 81 mL (1.40 mol) of glacial HOAc in 210 mL of THF, also held at −78° C. The mixture is warmed to 25° C. and the THF and some HOAc is removed. Water (180 mL) is added and the product is extracted into EtOAc. The extract is washed with H2O (5×), dried (MgSO4) and evaporated. The residue is dissolved in excess aqueous NaHCO3 and extracted with Et2O (5×). These washes were discarded. The aqueous solution is acidified with 2M HCl and extracted with Et2O. The ethereal extracts were backwashed with H2O (6×), dried (MgSO4) and evaporated to give 3.4 g (89%) of orange crystals: mp 173-175° C. (dec); 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 8.44 (m, 2H), 7.60 (m, 3H), 4.45 (s, 2H), 3.65 (s, 3H); MS (ESI) m/z 271.0 (M−H). Analysis for C14H12N2O: Calcd: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.90; H, 4.73; N, 10.11.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].CCN(CC)CC.C(Cl)Cl.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CO>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:31](=[O:32])[CH2:30][Cl:29])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(CCl)NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a mixture of 2-amino-1-(4-benzyloxy-phenyl)-ethanol (20.10 g; 82.6 mmol), Et3N (13.82 mL; 99.1 mmol), CH2Cl2 (200 mL) and MeOH (20 mL) was added dropwise chloroacetyl chloride (7.24 mL; 90.9 mmol) at −10° C. The resulting mixture was allowed to warm to RT and stirred overnight, and subsequently concentrated in vacuo. The residue was purified by flash chromatography (SiO2, EtOAc) to afford N-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.45 g).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.CS(O[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)(=O)=O>O>[Cl:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][N:12]([C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:13])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(Cl)c1
Reactant: CN[C@@H]1CCCC[C@@H]1N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 60 °C

Procedure:
(±)-cis-2-Pyrrolidinyl-N-methylcyclohexylamine (3 gm) was combined with anhydrous dimethylformamide (70 ml) and warmed to 60° C. 2-(3,4-dichlorophenyl)ethyl methanesulfonate (14 gm) was added to the warm amine solution over 3 days. The reaction mixture was diluted to 500 ml with water and extracted with chloroform. The combined extracts were washed with water and treated with a solution of hydrogen bromide in methanol. The solution was concentrated on a rotary evaporator and the residual dimethylformamide removed by distillation under high vacuum. The residue was triturated with 2-propanol to provide a white solid. The solid was recrystallized from 2-propanol. Analytical data are reported in Table I.