Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21][C:22](=[O:30])[CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=O)=[C:4]([F:31])[CH:3]=1.[C:32](O)(=[O:34])[CH3:33].[O-]C#N.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:21]2[C:32](=[O:34])[CH:33]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH2:23][C:22]2=[O:30])=[CH:6][C:7]=1[O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(=O)O
Agent: N#C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(N2C(=O)C=C(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide and 2 ml of acetic acid was added sodium cyanate, and the mixture was stirred at 50° C. for 1 hour and then at 110° C. for 1.5 hours. After cooling, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyridin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1.O>CN(C=O)C>[CH2:1]([S:8][C:12]1[S:13][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)s2)cc1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(SCc3ccccc3)s2)cc1
Temperature: 25 °C

Procedure:
Benzyl mercaptan (1.24 g, 0.01 mol) was added to a stirred mixture of sodium hydride (50% oil dispersion, 0.44 g, 0.11 mol) and degassed DMF (10 mL). The resulting mixture was warmed cautiously until gas evolution ceased. After cooling to 25° C., a solution of 2-bromo-5-(4-methoxybenzoyl)thiophene (2.97 g, 0.01 mol) in DMF (10 mL) was added dropwise. After complete addition, the mixture was heated on the steam bath for 2.5 hours and poured into waTER (200 mL). The aqueous mixture was extracted with ether (2×200 mL) and the extracts were washed with water, saturated NaCl solution and dried (Na2SO4). After evaporation of the solvent, the residue was collected with the aid of hexane and dried, 1.98 g, m.p. 103°-105° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([NH2:44])[CH:42]=[CH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:41]([NH:44][C:38]([C:35]1[CH:36]=[CH:37][N:33]([S:30]([C:28]2[CH:27]=[CH:26][C:17]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[N:15][C:16]=3[CH:29]=2)(=[O:32])=[O:31])[CH:34]=1)=[O:39])[CH:42]=[CH2:43]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: C=CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (0.1 mL, 74 mg, 0.57 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see the step B in example 33 for preparation), allylamine (0.1 mL, 76 mg, 1.33 mmol) and HATU (100 mg, 0.31 mmol) in DMF (5 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 32 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.20-2.41 (m, 1 H), 3.24-3.38 (m, 2 H), 3.84-3.97 (m, 4 H), 4.43 (d, J=7.42 Hz, 2 H), 5.03-5.10 (m, 1 H), 5.10-5.19 (m, 1 H), 5.75-5.94 (m, 1 H), 6.67 (dd, J=3.32, 1.76 Hz, 1 H), 7.30 (dd, J=3.42, 2.25 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.93 (d, J=9.0 Hz, 1H), 7.970 (dd, dd=9.0, 1.8 Hz, 1 H), 8.27 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+0.90 TFA+0.20H2O (590.85): C, 54.48; H, 5.68; N, 9.48. Found: C, 54.53; H, 5.69; N, 9.57.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3)ccc2F)c1
Reaction time: 0.03 h

Procedure:
The phenyl bromide (139)(100 mg, 0.25 mmol) was coupled to 4-fluoro-phenylboronic acid (33 mg, 0.23 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification. For the ester: LC/MS tr 1.62 min; MS(ES+) m/z 412 (M+H)
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of acetic acid (7.5 μL, 0.13 mmol) in DMF (5 mL) was added EDCI (33 mg, 0.17 mmol), HOBt (19.5 mg, 0.14 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-aminopiperidin-1-yl)-1(S)-(4-fluorobenzyl)-2-oxoethyl]amide (EXAMPLE 180, 70 mg, 0.16 mmol) and DIPEA (57 μL, 0.33 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo then crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with NaHCO3 (2×20 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as an off-white powder. m/z (ES+)=486.27 [M+H]+; RT=3.16 min.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,2,2-trifluoroethyl trifluoromethanesulfonate and isolated as light-yellow gum (0.9 mg, 6%). MS(m/e): 365.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9]1.[NH2:25][OH:26].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([CH:13]=[N:25][OH:26])=[CH:9]1
Reactant: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=NO)c3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(3-formylpyrrol-1-yl)phenyl)isoxazoline (Example 15) (329 mg) is suspended in 4 ml 95% ethanol in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with hydroxylamine (80 mg) followed by sodium hydroxide (60 mg) and 0.4 ml water. The reaction is stirred 1 hour at room temperature, the pH is adjusted to 7 with 5% hydrochloric acid, and the white solid is collected. The solid is collected, washed with water, and is dried to give 300 mg (87%) of the title compound as a white solid. The title compound is obtained via chromatography over silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane, mp 216-217° C., [α]25D -67° (c 0.67, DMSO).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:5])[CH3:4].C(N(CC)CC)C>CS(C)=O>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[C:3]([CH3:5])([CH3:4])[CH:2]=[O:1]
Reactant: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
11.9 g of sulfur trioxide pyridine complex dissolved in 75 ml DMSO was added over a period of 20 minutes at room temperature to a solution of 5.48 g of 2-(2-hydroxy-1,1-dimethyl-ethyl)-isoindole-1,3-dione from Step 1 and 7.59 g of triethylamine in 780 ml DMSO. The reaction mixture was stirred at room temperature for 30 minutes, poured onto ice/water and extracted 3 times with tert-butyl methyl ether. The organic was washed with 1N HCl and 2 times H2O, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 4.92 g crystals (mp 80-82° C.), which were used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[CH:5]=[C:6]([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][CH:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:7]=[C:8]([C:11](=[O:25])[NH:12][CH2:13][C:14]2[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=2[CH2:20][CH2:21][CH3:22])[C:9]=1[CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][CH:35]1[CH2:34][CH2:33][N:32]([C:29]2[N:30]=[CH:31][C:26]([C:6]3[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)[C:9]([CH3:10])=[C:8]([CH:7]=3)[C:11]([NH:12][CH2:13][C:14]3[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=3[CH2:20][CH2:21][CH3:22])=[O:25])=[CH:27][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a stirred solution of tert-butyl (1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-(((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)pyridine-2-yl)piperidin-4-yl)carbamate (0.4 g, 0.00051 mol) in DCM (10 mL) at 0° C., TFA (10 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (80 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (60 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.315 g, 92.1%) which was used as such for next reaction.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
4.0 g (16.59 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) of HATU, 10.41 ml (59.74 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 l of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.0 g (85% of theory) of the title compound are isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]([F:27])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:27][C:17]([F:16])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]3)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: OC1CCN(CC(F)(F)F)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Product: CCOC(=O)c1cc2cc(OC3CCN(CC(F)(F)F)CC3)ccc2[nH]1

Procedure:
The title compound was prepared in analogy to example 40d), from ethyl 5-hydroxyindole-2-carboxylate and 1-(2,2,2-trifluoro-ethyl)piperidin-4-ol, using diisopropyl azodicarboxylate instead of diethyl azodicarboxylate. Off-white solid. MS (m/z): 371.2 (M+H)+.
Reaction SMILES: [S:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)[C:2]#[N:3].[N+:21]([O-])([OH:23])=[O:22].O>C(O)(=O)C>[N+:21]([C:6]1[CH:5]=[C:4]([S:1][C:2]#[N:3])[CH:20]=[CH:19][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
4′-Thiocyano-p-toluenesulfonanilide (19.2 g (63.2 mmol)) was dissolved in acetic acid (60 ml). To this, fuming nitric acid (3.04 ml (75.9 mmol)) was added dropwise with stirring at room temperature. Then, the mixture was stirred at 50° C. for 4 hours, poured into water, and the crystals separated were filtered and washed with water. The resulting crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 21.8 g (99%) of 2′-nitro-4′-thiocyano-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(O)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:18]([CH3:24])([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:29])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CCOC(=O)C(C)(C)Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 0.75 h
Yield: 52 %

Procedure:
3.0 g (8.0 mmole) of ethyl 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio]-2-methylpropionate was combined in a flask with 0.91 g (1 eq.) of a 30% H2O2 solution, 10 ml of formic acid and 50 ml of dichloromethane. The mixture was briskly stirred and the reaction monitored by TLC. After 45 minutes, 1 ml more of a 30% H2O2 solution was added to consume the remaining starting material. The reaction was stopped when the TLC showed the starting material was consumed (at which point oxidation of the product to the sulfone will begin) and the reaction mixture was diluted with 3N HCl. The dichloromethane layer was separated, washed with 3N HCl, water, and a saturated salt solution, dried over sodium sulfate and evaporated to an oil. The oil was crystallized by adding methanol and the resulting solid was collected and recrystallized from methanol to yield 1.6 g (52%) of ethyl 2-[ [3-(4-chlorophenyl)-1,2-benzisoxazol-6yl-]sulfinyl]-2-methylpropionate, m.p. 89° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[N:3][CH:2]=1
Reactant: Nc1ccncn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of pyrimidine-4-amine (1.00 g, 10.5 mmol) and pyridine (2.55 ml, 31.5 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (2.55 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.97 g, 69.4%) as a solid was collected by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][NH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:7]1[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:10][CH2:11]2)[CH2:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccc2c(c1)NCC1(CC1)O2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2
Temperature: 60 °C
Yield: 26.5 %

Procedure:
To a stirred solution of 6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (3.11 g, 12.9 mmol) in DMF (20 mL) was added potassium carbonate (3.6 g, 26.0 mmol) and benzyl bromide (1.61 mL, 13.6 mmol). The reaction mixture was heated at 60° C. for 6 h then cooled to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethylacetate (2×50 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL), then dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to furnish 4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1-cyclopropane] (1.13 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: CCc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 79.5 %

Procedure:
The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-ethylphenylboronic acid (99 mg, 0.6 mmol) as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(C(F)(F)F)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-(trifluoromethyl)benzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Yield: 80.8 %

Procedure:
A mixture of 1-benzyl-4-(4-trifluoromethylphenyl)piperidin-4-ol (692 mg, 2.06 mmol) prepared in Reference Example 95, concentrated hydrochloric acid (4.5 ml) and acetic acid (10 ml) was heated under reflux overnight. The reaction mixture was allowed to return to room temperature, and diluted with methylene chloride. The mixture was washed with water, 10% sodium hydroxide aqueous solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=4/1) to afford 1-benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (528 mg, yield 80%) as a pale yellow crystalline powder.
Reaction SMILES: CC1N([CH2:7][CH:8]2[C:21](=[O:22])[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[N:19]([CH3:20])[C:11]=3[CH2:10][CH2:9]2)C=CN=1.CN1C2CCCC(=O)C=2C2C1=CC=CC=2.C=O.N1CCOCC1>C(O)(=O)C>[CH3:20][N:19]1[C:11]2[CH2:10][CH2:9][C:8](=[CH2:7])[C:21](=[O:22])[C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Agent: C=O
Agent: Cn1c2c(c3ccccc31)C(=O)CCC2
Solvent: CC(=O)O
Solvent: C1COCCN1
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Kim et al. (Heterocycles 1997, 45, 2041) disclose a two-step synthesis of ondansetron. In the first step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (compound of formula 1, Scheme 1) is reacted with a source of formaldehyde and morpholine in boiling glacial acetic acid to provide 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (compound of formula 2, Scheme 1). In the second step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one is reacted with 2-methylimidazole in the presence of alumina (Al2O3) to provide ondansetron (See, Scheme 1).