Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[N:17][NH:18]C(OCC)=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O=[S:25](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:25][N:18]=[N:17][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)NN=C(Cc1ccc(OC)cc1)c1ccccc1
Product: COc1ccc(-c2snnc2-c2ccccc2)cc1
Temperature: 60 °C
Yield: 82.3 %

Procedure:
The acylhydrazone 9 (4.6 g, 14.8 mol), was added to SOCl2 (25 ml) at 0° C. The reaction was stirred to 60° C. and was complete (by TLC) after 1.5 hour. SOCl2 was evaporated under reduced pressure and the crude oil was chromatographed on SiO2 (150 g), eluting with CH2Cl2 to afford 8 (3.25 g, 82.3%), m.p. 56.5°-58° C.
Reaction SMILES: Cl([O-])=O.[Na+].CC(=CC)C.P([O-])(O)(O)=[O:11].[Na+].[F:16][C:17]([F:46])([F:45])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][CH:39]=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>O.CC(C)=O>[F:46][C:17]([F:45])([F:16])[C:18]1[CH:44]=[CH:43][CH:42]=[CH:41][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH2:38][C:39]([OH:11])=[O:40])[N:35]=[N:34]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1
Reactant: O=CCc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)Cc1cn(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)nc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 10-mL round-bottom flask equipped with a magnetic stirbar was added sodium chlorite (28 mg, 0.31 mmol), 2-methyl-2-butene (32 μL, 0.31 mmol) and sodium dihydrogen phosphate (37 mg, 0.31 mmol) in water (1.0 mL). To this solution was added [1-(2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl]acetaldehyde (22 mg, 0.05 mmol) dissolved in acetone (1.0 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated, poured into a 50-mL separatory funnel containing saturated aqueous KH2PO4 solution (30 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the desired product.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[CH3:17][NH2:18].O>C(O)C>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([NH:18][CH3:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: CN
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CNc1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
A solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25 mmol) [Goldstein, H.; Stamm, R.; Helv. Chim. Acta, 1952, 35, 1330-1333] and 40% aqueous methylamine (20 mL) in ethanol (80 mL) is heated in a sealed pressure vessel at 100° C. for 2 h. After cooling, dilution with water gives 2,4-dinitro-5-methylaminobenzamide (5.89 g, 98%). 1H NMR (DMSO) δ8.88 (1H, q, J=4.9 Hz), 8.76 (1H, s), 8.07 (1H, brs), 7.77 (1H, brs), 6.98 (1H,s), 3.07 (3H, d, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:18]([O-])=[O:19].[Na+]>Cl.C(O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:18]=[O:19])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(NCCc2ccc(Cl)nc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N(CCc2ccc(Cl)nc2)N=O)cc1
Temperature: 25 °C

Procedure:
A 250 mL reaction flask was charged with N-(2-(6-chloropyridin-3-yl)ethyl)-4-methylaniline (5 g, 20.3 mmol; Example 117B) in 1 N HCl (22 mL) and ethanol (20 mL). The mixture was stirred at room temperature until complete dissolution was obtained (˜2 hours). The reaction then was cooled in an ice bath and a solution of sodium nitrite (1.55 g, 22.47 mmol; Aldrich) in water (10 mL) was added dropwise with stirring. After the addition was complete, the reaction mixture was allowed to warm briefly to room temperature, then it was cooled again in an ice bath before filtering. The filter cake was washed with water several times and then dried to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.38 (s, 3H), 2.88 (t, J=7 Hz, 1H), 4.34 (t, J=7 Hz 2H), 7.25-7.39 (m, 5H), 7.63 (dd, J=8, 2 Hz, 1H), 8.11 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)C(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=491.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-isopropyl-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[CH:68][CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)(=[O:71])[NH2:72]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[NH:10][C:7]2=[N:8][CH:9]=1.I[CH3:27].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:10]([CH3:27])[C:7]2=[N:8][CH:9]=1
Reactant: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ncc(Cl)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)n(C)c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 15 mg, 0.38 mmol) was added to a stirred, cooled (0° C.) solution of methyl 5-chloro-2-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-propanoate (Description 4, 82 mg, 0.23 mmol) in dimethylformamide (5 mL) and the mixture was stirred at room temperature for 10 min. Iodomethane (24 μL, 54 mg, 0.38 mmol) was added and the mixture was stirred at room temperature for 5 min. Water (15 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (82 mg, 96%). 1H NMR (360 MHz, CDCl3) δ 8.27 (1H, d, J 2.2 Hz), 7.87 (1H, d, J 2.2 Hz), 7.50 (2H, m), 7.34 (2H, m), 3.64 (3H, s), 3.60 (3H, s), 2.98 (2H, t, J 7.8 Hz), and 2.51 (2H, t, J 7.8 Hz).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][OH:32])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][N:57]4[C:61](=[O:62])[C:60]5[C:59](=[CH:66][CH:65]=[CH:64][CH:63]=5)[C:58]4=[O:67])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Diisopropyl azodicarboxylate (6.47 mL, 32.9 mmol) was added dropwise over ten minutes to a stirred solution of 3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propan-1-ol (10.0 g, 27.4 mmol), triphenylphosphine (8.62 g, 32.9 mmol), and N-hydroxyphthalimide (5.36 g, 32.9 mmol) in DMF (110 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford a solid that was slurried in ethyl acetate, isolated by filtration, washed with ethyl acetate, and dried under vacuum to yield 11.45 g of 2-{3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propoxy}-1H-isoindole-1,3(2H)-dione as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1csc(N)n1
Solvent: ClCCl
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 51.2 %

Procedure:
Step 1 A solution of 2-amino-4-methylthiazole (11.42 g, 0.10 mol) in DCM was cooled to 0° C. and treated with TEA (12.1 g, 0.12 mol), then phenyl chloroformate (15.6 g, 0.10 mol) was added dropwise with stirring. The mixture was stirred for 10 minutes, then was washed with NaHCO3 (aq), water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with 60:40 hexane-EtOAc) to give phenyl 4-methylthiazol-2-ylcarbamate as a white solid (12 g, 51%). 1H NMR (300 MHz, chloroform-d) δ 12.38 (bs, 1H) 7.47-7.40 (m, 2H) 7.30-7.19 (m, 3H) 6.52 (d, J=1.1 Hz, 1H) 2.41 (d, J=0.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2.[C:11](=O)=[O:12].C(=O)(O)N>ClC1C=CC=CC=1>[N:1]([CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[C:11]=[O:12]
Reactant: NCCC12CCC(CC1)C2
Reactant: O=C=O
Agent: NC(=O)O
Solvent: Clc1ccccc1
Product: O=C=NCCC12CCC(CC1)C2

Procedure:
Following the procedure of Example 1 (Stage 3), 140 g (0.62 mol) 2-aminoethyl-2-(3-aminopropyl)5- (or 6) -aminoethyl-bicyclo-[2,2,1]-heptane in 1.5 liters of boiling chlorobenzene are initially converted with CO2 into the carbamic acid derivative which is thereafter phosgenated, first in the cold and then at boiling temperature. The 2-isocyanatomethyl-2-(3-isocyanatopropyl)-5- (or 6) -isocyanato ethyl-bicyclo-[2,2,1]-heptane is obtained from the clear reaction solution in the form of a pale yellow liquid by distillation at a boiling point of 186°-188° C./ 0.1 Torr. Yield 170 g (90%). Viscosity 80 cP/20° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.CCCCCCC.[CH2:16]=[C:17]=[O:18].[C]=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:17]([CH3:16])=[O:18]
Reactant: C=C=O
Reactant: CCCCCON=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Product: CCCCCOC(C)=O
Reaction time: 5 h
Yield: 18.8 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.198 g, 0.25 mmole), stannous chloride (0.095 g, 0.5 mmole), tetra-n-butylammonium chloride (0.139 g, 0.5 mmole) and n-amyl nitrite (70 ml, 474.4 mmoles), together with n-heptane (150 ml) and N-methylpyrrolidone (50 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 10.1 ml/min (0.45 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was effected at 90° C. for 5 hours. The reaction product was analyzed by gas chromatography, revealing that di-n-amyl malonate (82.3 mmoles, 60.7%) and n-amyl acetate (25.5 mmoles, 18.8%) were obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.Cl[CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]=1[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][O:14][C:15]1[CH2:20][CH2:19][CH:18]([CH2:23][C:24]2[N:25]=[CH:26][N:27]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:28]=2[CH3:29])[C:17](=[O:21])[CH:16]=1
Reactant: COC1=CC(=O)CCC1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC1=CC(=O)C(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
n-Butyllithium (1.58 M in hexane; 21 ml) was added at -78° under nitrogen to a stirred solution of diisopropylamine (4.6 ml) in dry THF (75 ml) and the solution was stirred at 0° for 30 min. The solution was cooled to -78° and added to a solution of 3-methoxy-2-cyclohexen-1 one (3.4 g) in dry THF (25 ml) at -78° under nitrogen with stirring. After stirring for 1 h at -78° and for 30 min. at 0° the solution was cooled to -78° and a solution of 4-(chloromethyl)-5-methyl-1 -(triphenylmethyl)-1H-imidazole (10 g) in dry THF (100 ml) was added dropwise with stirring under nitrogen. The solution was stirred at -78° for 3 h and at 0° for 30 min., treated with 8% aqueous sodium bicarbonate (400 ml) and extracted with ethyl acetate (2×300 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 13 g) which was purified by SPCC eluting with System A (967:30:3) to give the title compound (3.28 g), m.p. 145°-148°.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH:8]=1.CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:27][C:24]1([CH3:28])[O:23][CH:22]([CH2:21][O:6][C:7]2[CH:15]=[CH:14][C:10]3[CH:11]=[CH:12][S:13][C:9]=3[CH:8]=2)[CH2:26][O:25]1
Reactant: Oc1ccc2ccsc2c1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(COc2ccc3ccsc3c2)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Dimethylformamide (10 mL) was added to a reactor containing 6-hydroxybenzothiophene (22, 619 mg, 4.12 mmol), (R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate ((R/S)-18a, 1.04 g, 4.95 mmol) and Cs2CO3(1.61 g, 4.95 mmol). The reaction mixture was agitated at 100° C. for 6 hours and then cooled to room temperature. After adding water, extracting with ethyl acetate, washing with saturated ammonium chloride aqueous solution, and removing water using sodium sulfate, column chromatography yielded 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene ((R/S)-25, 1.08 g, 99%) as a liquid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:34][CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=4)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Product: COc1cccc(CNC(=O)CC2NC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 50 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and (3-methoxyphenyl)methanamine. Yield: 50%. LC/MS; expected 453; found 453.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.7 μM.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)C(C)=O.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([NH2:1])=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20])#[N:18]
Reactant: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1ccccc1-c1ccc(N)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4'-Acetamino-2-cyanobiphenyl (0.265 moles, 62.47 g.) was added at -15° to -20° C. to 600 ml of concentrated sulfuric acid. While maintaining the temperature below -15° C., nitric acid (0.278 moles, 17.5 g of 90%) in 200 ml of concentrated sulfuric acid was added dropwise. The reaction was stirred for 30 minutes following the addition and then for 3 hours at room temperature. The reaction was poured onto ice with vigorous stirring. The precipitate was filtered and dried. The solid was stirred in methanol (6 liters) and 2N sodium hydroxide (11 liters) for 6 hours, filtered and dried. The reaction produced 60 g of 4-(2-Cyanophenyl)-3-nitroaniline. (MS)
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:33]([O:35]C(C)(C)C)=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28]C(C)(C)C)=[O:27])=O)(C)(C)C.O>C(O)(=O)C>[NH2:8][C@@:9]1([C:33]([OH:35])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 97.3 %

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (5.30 g, 9.01 mmol) is added to water (30.02 mL) and acetic acid (30.02 mL). Heat the reaction at reflux until the complete consumption of the starting material. Cool and concentrate on a rotary evaporator. Triturate the concentrate with diethyl ether, collect the precipitate, then dry in a vacuum oven to give the title compound (3.30 g, 8.77 mmol, 97%). MS (m/z): 376/378 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]5)=[CH:36][CH:37]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:14]1=[O:23]
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c2)c2ccccc21
Reaction time: 2 h
Yield: 11 %

Procedure:
The title compound was synthesized according to the method of Example A45, except substituting (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (35 mg, 0.084 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (42 mg, 0.109 mmol). The solvent was removed and the Boc-protected amine purified by column chromatography (silica gel, CH2Cl2/MeOH, 95:5) to give an impure product which dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. The reaction was stirred for 2 h, the solvent removed and the residue purified by prep-HPLC to give the title compound as a white powder (4.0 mg, 11%); 1H NMR (400 MHz, CD3OD) δ 7.88-7.85 (m, 3H), 7.46 (s, 1H), 7.18-7.12 (m, 3H), 7.03-6.97 (m, 2H), 6.65 (t, J=7.7 Hz, 1H), 6.04 (d, J=7.5 Hz, 1H), 3.51-3.48 (m, 4H), 3.42-3.39 (m, 4H), 3.35 (s, 3H), 2.29-2.25 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 450.2, calcd for [C28H27N5O+H]+ 450.23.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]#[N:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][C:16]1OC(=O)[S:18][N:17]=1.O>CCCCCCCCCCCC>[CH3:13][O:14][CH2:15][C:16]1[N:12]=[C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[S:18][N:17]=1
Reactant: COCc1nsc(=O)o1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: O
Solvent: CCCCCCCCCCCC
Product: COCc1nsc(S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 150 °C

Procedure:
4-Methylbenzenesulfonyl cyanide (16.26 g) was added to an emulsion of 5-methoxymethyl-1,3,4-oxathiazol-2-one (6.6 g) in dodecane (60 cm3). The reaction mixture was stirred and heated at 150° C. for 18 hours, then cooled. Water was added and the product extracted into ethyl acetate. The combined organic phases were dried (MgSO4) and ethyl acetate was removed by evaporation under reduced pressure. The residue separated into a brown liquid and a clear dodecane layer which was removed and discarded. Chromatography of the brown liquid on silica gel (Sorbsil C30) using 3:7 ethyl acetate:hexane as eluant give a pale orange oil which solidified on standing (6.94 g). M+ =284; 1H NMR: δ 2.40(3H,s); 3.45(3H,s); 4.7(2H,s); 7.4(2H,d); 8.0(2H,d); (mp 43.4-45-4° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:7]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (200 mg, 0.82 mmol), 6-chloronicotinonitrile (75 mg, 0.54 mmol) and diisopropylethylamine (140 μl, 0.82 mmol) in DMF (5 mL) at room temperature overnight. Concentrate and chromatograph on silica gel to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (300 MHz, MeOH-d4) δ 8.44 (1H, d, J=1.51 Hz), 7.95 (1H, dd, J=9.23, 2.07 Hz), 7.56-7.68 (2H, m), 7.40 (1H, dd, J=8.38, 2.17 Hz), 6.97 (1H, d, J=9.42 Hz), 4.42 (2H, d, J=3.01 Hz), 4.16-4.25 (1H, m), 4.04-4.13 (1H, m), 3.82-3.96 (2H, m), 3.63-3.77 (1H, m), 2.56-2.69 (1H, m), 2.43 (1H, m), MS (ES): 347 [M+].