Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
Similar to Example 1, equimolar amounts of (5-nitropyridin-2-yl)hydrazine and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 117° C.–119° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:32])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Yield: 35.2 %

Procedure:
A mixture of 3-tert-butyl aniline (117 mg, 0.78 mmol), 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared as described in Biog. Med. Chem. 2006, 14, 2089) (200 mg, 0.65 mmol), EDCl (375 mg, 0.95 mmol) and a catalytic amount of DMAP in CH2Cl2 was stirred at room temperature overnight. The next day the mixture was partitioned between EtOAc and water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The residue was chromatographed with silica gel column amd 0-30% EtOAc in hexanes gradient to afford the product (100 mg, Yield: 35%). HRMS m/z calcd for C26H35N3O3 [M+H]+: 438.2751. Found: 438.2753.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17])([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:31](O)[CH3:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:19])([F:20])[C:16]([O:18][CH2:31][CH3:32])=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-[(2,6-dinitrophenyl)amino]-2,2-difluoropropanoic acid (3.52 g, 12.09 mmol) in ethanol (30.0 mL) was added sulfuric acid (4 mL) at 0° C. The reaction mixture was stirred at 100° C. for 1 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and the solvent was removed. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (2.94 g, 9.210 mmol, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[OH:10][CH2:9][C:7]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 40 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (30 mL), (3-nitro-1H-pyrazol-5-yl)methanol (1.43 g, 10.0 mmol), Cs2CO3 (490 mg, 1.5 mmol), and ethyl 2-bromoacetate (2.00 g, 12 mmol). The mixture was stirred at 40° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 146a (1.65 g, 72%) as a yellow solid. MS-ESI: [M+H]+ 229.9
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][C@H:15]([NH:14][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][CH2:23]3)[CH2:26][CH2:27]1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCCCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Phenylvaleric acid (1.0 g, 5.6 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (93 mg, 0.47 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.45 mmol) and triethylamine (93 μL, 0.68 mmol) in methylene chloride (15 mL) . After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (66%) of the title compound as viscous oil: [α]21D +7.4° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 405 (11, M+).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH3:37])[N:31]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nccc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CNCC3(C)C)n1

Procedure:
4,4-Dimethyl-7-{2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step D, 0.65 g, 1.26 mmol) in 10 mL of 50% of TFA in CH2Cl2 was stirred at RT for 1 h. The volatiles were removed under reduced pressure, the residue was purified by flash column chromatography, and the titled compound was obtained as a white solid. MS (ES+): 417.1 (M+H)+. Calc'd for C24H28N6O-416.52.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:63]=[CH:62][CH:61]=[CH:60][C:52]=1[O:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:63]=[CH:62][CH:61]=[CH:60][C:52]=1[O:53][CH:54]1[CH2:59][CH2:58][N:57]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:56][CH2:55]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 62.5 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (55 mg, 0.29 mmol) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (140 mg, 0.7 mmol). After 2 minutes of stirring, 4-(2-chloro-phenoxy)-piperidine hydrochloride (98 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was collected. The precipitate was purified by recrystallisation from a mixture of 20% EtOAc in hexane (15 mL) and MeOH (0.1 mL) to afford the 80 mg (62.5% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 98.75%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 2H), 7.48 (m, 2H), 7.34 (m, 2H), 7.1 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.0 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.Cl.[F:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[F:25][CH2:26][C:27]([NH:30][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CC(C)(N)CF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CF)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
WSC HCl (1.15 g, 6 mmol) was added to a mixture of 2,4-difluorobenzoic acid (0.95 g, 6 mmol), 2-fluoro-1,1-dimethylethylamine hydrochloride (J. Med. Chem., 34, 29-37(1991): 0.77 g, 6 mmol), HOBt (0.81 g, 6 mmol) and triethylamine (0.91 g, 9 mmol) in methylene chloride (15 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to give the title compound (0.61 g; 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.OO.S([O-])(O)=[O:29].[Na+]>CO>[OH:29][N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=S([O-])O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Compound 18 (0.35 g, 1.1 mmol) was dissolved in methanol (2.1 mL) and was added with a 31% hydrogen peroxide solution (0.13 g, 1.1 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with sodium hydrogen sulfite (0.1 g, 0.96 mmol), and then the deposited crystals were removed by filtration after confirming the disappearance of hydrogen peroxide using a potassium iodide-starch paper. The solvent of the filtrate was evaporated under reduced pressure, the crude product was purified by preparative silica gel chromatography [amino-modified chemically bound silica gel Chromatorex (registered trademark) NH, Fuji Silysia Chemical Ltd., methanol/chloroform=1/91 to obtain Compound 147 (57 mg, 15%).
Reaction SMILES: [F:1][CH:2]([C:7]([F:10])([F:9])[F:8])[C:3]([O:5][CH3:6])=[O:4].FC(F)(F)S([O-])(=O)=O.C([B+]CCCC)CCC.C(N(C(C)C)CC)(C)C.[C:37](OCC)(=[O:39])C>ClCCl>[OH:39][CH2:37][C:2]([F:1])([C:7]([F:10])([F:9])[F:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)C(F)C(F)(F)F
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(F)(CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl 2,3,3,3-tetrafluoropropanoate (27.0 g) was dissolved in dry dichloromethane and the solution stirred under a dry nitrogen atmosphere at 0° C. A one molar solution of di-n-butylboron trifluoromethanesulfonate in dichloromethane (190 ml) was added in portions over 15 minutes. After a further 15 minutes, the temperature was reduced to -10° C. and di-isopropylethylamine (35 ml) was added in portions, then stirring was continued for a further 2 hours. Paraformaldehyde (100 g) (previously dried under vacuum over P2 O5) was heated to 180°-200° C. and the resulting formaldehyde was passed into the reaction mixture in a stream of dry nitrogen, keeping the temperature close to -10° C. After 30 minutes, the mixture was poured into a mixture of 30% aqueous hydrogen peroxide (150 ml) pH7 phosphate buffer (600 ml) and crushed ice, and was stirred at 0° C. for 45 minutes. The mixture was extracted with dichloromethane (3×200 ml). The combined extracts were washed with sodium disulphite solution, dried (MgSO4) and concentrated under reduced pressure to leave a yellow oil, which was redissolved in ethyl acetate and filtered through a thick plug of silica gel, and then was again concentrated under reduced pressure. The crude product was purified by chromatography on silica, eluting with 25% ethyl acetate in hexane. Subsequent heating to 65° C. under aspirator vacuum (20 mmHg) gave the product as a yellow oil (4.8 g); 1H NMR (270 MHz; CDCl3) δ 3.93(3H,s), 4.05-4.30(2H,m), 2.80(1H,bt) ppm.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:28](O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:1]([N:8]([CH3:28])[C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1c(O[C@@H]2CCC[C@H](NCc3ccccc3)C2)ccc2[nH]ncc12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(O[C@@H]2CCC[C@H](N(C)Cc3ccccc3)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Under nitrogen, the N-benzyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (150 mg, 0.447 mmol) obtained in Example 716 and 36%-formaldehyde (56 mg, 0.671 mmol) were suspended in methanol (5 ml), followed by adding thereto acetic acid (0.2 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (56 mg, 0.894 mmol) was added thereto and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with chloroform and then separated by the addition of a 1N-aqueous sodium hydroxide solution, and the desired compound was further extracted from the aqueous layer with chloroform. The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1) to obtain N-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (136 mg, yield 87.0%) as a white amorphous substance.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:27]1[CH2:30][C:29](=O)[CH2:28]1.C[Si]([C:36]#[N:37])(C)C>C(OCC)(=O)C>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH:1][C:29]1([C:36]#[N:37])[CH2:30][O:27][CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Reactant: O=C1COC1
Reactant: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC1(C#N)COC1)CC2
Temperature: 210 °C
Reaction time: 0.67 h

Procedure:
N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)propane-1-sulfonamide (0.104 g, 0.279 mmol) and 3-oxetanone (0.040 g, 0.558 mmol) were sealed in a vial and heated at 210° C. for 2 minutes. Trimethylsilyl cyanide (0.074 mL, 0.558 mmol) was added, the vial was resealed and the mixture was heated again at 210° C. for 2 minutes. The mixture was diluted with ethyl acetate (40 mL) and washed with 1 N NaOH (1×20 mL) and brine (1×20 mL). The organic extract was collected, dried on MgSO4 and evaporated under reduced pressure to give a brown oil. The residue was purified by flash-chromatography on silica gel (100% heptane then gradient to 60% ethyl acetate in n-heptane in 40 mins). (0.054 mg, 0.12 mmol, 43%).
Reaction SMILES: C([Si](CC)(CC)O[C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=O)[CH:7]=[CH:6]1)C.Cl.[NH2:21]CC(OCC)=O.C(=O)(O)[O-].[Na+].C(O)C>O>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:21])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CN
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 400 mg (1.4 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one, 572 mg (4.2 mmol) of ethyl glycinate hydrochloride, 298 mg (3.6 mmol) of sodium bicarbonate, and 10 mL of 95% ethanol was heated to reflux for 6 hours, allowed to cool to room temperature, and poured into 25 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. The organic layers were combined and extracted with six 5 mL portions of 1N HCl. Combination of the aqueous layers and treatment with solid sodium bicarbonate until neutral to pH paper gave a cloudy mixture that was extracted with three 10 mL portions of dichloromethane. The organic layers were combined, dried (MgSO4), and stripped to give a residue which was purified by PTLC (one 2 mm silica gel plate eluted with dichloromethane), affording 160 mg (73% yield) of 4-trifluoromethylaniline.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C@@H:9]1[CH3:25])=[O:7].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:35](=[O:37])[CH3:36])[CH2:10][C@@H:9]1[CH3:25])=[O:7]
Reactant: C[C@H]1C[C@@H](Nc2ccccc2)c2ccccc2N1C(=O)c1ccco1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccco2)c2ccccc21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of (±)-cis-furan-2-yl-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-methanone (360 mg, 1.0 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (1.9 mL, 10 mmol) followed by acetyl chloride (388 uL, 5 mmol). The mixture was stirred at room temperature over night. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M (aq) NaOH and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (50% hexanes/50% ethyl acetate) to afford the amide (230 mg, 57%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][C:8]1=2.[H-].[Na+].CI.[C:30](OCC)(=O)C>CN(C)C=O.O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[CH2:6][N:7]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][C:10]([N:18]([CH3:30])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:9][C:8]1=2
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.15 g of tert-butyl (5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)carbamate in 2 mL of N,N-dimethylformamide, 21 mg of 60% sodium hydride and 32 μL of methyl iodide were added, and the mixture was stirred at room temperature for 2 hours 20 minutes. Thereto were further added 9 mg of 60% sodium hydride and 13 μL of methyl iodide, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=1:1 to 3:7 to obtain 0.13 g of tert-butyl (5-(1,3-dioxolan-2-yl)methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)(methyl)carbamate as a brown oily substance.
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:5][S:6][CH:7]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[CH3:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:19][NH:20][C:21]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[C:3]([Br:2])=[CH:7][S:6][N:5]=1)=[S:22]
Reactant: CN=C=S
Reactant: NCCSCc1nscc1Br
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCSCc1nscc1Br
Yield: 108.8 %

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g.)) was performed under conditions similar to those described in Example 122. From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.), m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium hydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.). The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.