Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)N1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:40])[N:18]([CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[CH2:25][CH2:24]3)[C:19]2=[O:22])=[CH:15][C:14]=1[S:41]([NH2:44])(=[O:43])=[O:42].C(O)(=O)C>C(OCC)(=O)C>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:40])[N:18]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=4)[CH2:27][CH2:28]3)[CH:19]2[OH:22])=[CH:15][C:14]=1[S:41]([NH2:44])(=[O:43])=[O:42]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3cccc(C(F)(F)F)c3)CC1)C2=O
Agent: O=C1NC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(O)N(C1CCN(Cc3cccc(C(F)(F)F)c3)CC1)C2=O

Procedure:
A mixture of the 1,3-dioxoisoindole of part (a), (8.1 g., 0.0161 mole), zinc dust (5.78 g., 0.088 mole) and 150 ml. of acetic acid was stirred for 0.5 hr. at 50°-70°, cooled. Residual material, obtained by concentration of the filtrate in vacuo, was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the aqueous layer re-extracted with ethyl acetate. Combined extracts were washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with ethyl acetate provided 6-chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide as a white solid, m.p. 204°-205°.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.[C:12](O)(=O)C.[CH:16]([NH2:18])=[NH:17]>C(O)CCC>[CH3:1][CH:2]([C:3]1[CH:12]=[N:17][CH:16]=[N:18][CH:4]=1)[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CC(C)=CCCC(C)CC=O
Solvent: CCCCO
Product: CC(C)=CCCC(C)c1cncnc1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 3,7-dimethyl-oct-6-enal (Citronellal®) (Commercially available at IFF) (10 g, 0.06 mol), formamidine acetate (31 g, 0.3 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 5-(1,5-dimethyl-hex-4-enyl)-pyrimidine (˜5 g) is obtained.
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[NH:5][C:6]([NH2:8])=[O:7])#[N:2].[CH3:9][Si:10]([CH3:13])([CH3:12])Cl.[Cl-].[Li+]>C[Si](C)(C)N[Si](C)(C)C>[CH3:9][Si:10]([CH3:13])([CH3:12])[N:8]([Si:10]([CH3:13])([CH3:12])[CH3:9])[C:6]([NH:5]/[CH:4]=[CH:3]\[C:1]#[N:2])=[O:7]
Reactant: C[Si](C)(C)Cl
Reactant: N#C/C=C\NC(N)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: C[Si](C)(C)N(C(=O)N/C=C\C#N)[Si](C)(C)C

Procedure:
83 g of cis-2-cyanovinyl urea was dissolved in 200 ml hexamethyldisilazane and 5 ml of trimethylchlorosilane and 1 g of lithium chloride were added. N2 was bubbled and the solution was refluxed until clear. Hexamethyldisilazane was then distilled off and N,N-bistrimethylsilyl-(cis-2-cyanovinylurea) was obtained, which was then dissolved in 200 ml anhydrous dichloromethane. To the solution, 1 g of CdCl2 was added and the solution was stirred with N2 bubbling.
Reaction SMILES: C(O)(=O)C.C(OC([N:12]1[CH2:16][CH2:15][C:14](=O)[CH2:13]1)=O)(C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:18].[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]2[CH2:15][CH2:16][NH:12][CH2:13]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Clc1ccc(Nc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(N(c2ccccc2)C2CCNC2)cc1Cl
Temperature: 25 °C
Yield: 10 %

Procedure:
An acetic acid solution (15 ml) containing 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (0.67 g) and (3,4-dichlorophenyl)phenylamine (0.94 g) was stirred at room temperature over night. To the mixture was added 1.5 g of sodium triacetoxyborohydride, followed by stirring at room temperature for 8 hours. Dichloromethane was added to the reaction solution and washed with water, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The solvent was distilled off from the purified product under reduced pressure, and the residue was dissolved in 1 N hydrochloric acid-ethanol and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 50 mg of brown amorphous solid (3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.O=C1CCC(=O)N1[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:22][CH:21]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 2-(4-chloro-phenyl)-ethylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (39%, off-white crystals). HPLC-MS m/z=409.2 (M+1), Rt: 4.27 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH:7]([CH2:36][NH2:37])[C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C([N:41](CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:38])[CH:7]([CH2:36][NH:37][NH:41][S:47]([CH3:46])(=[O:49])=[O:48])[C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(CN)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(CNNS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (3R,10S)-2-(aminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo [10.6.1.013,18 ]nonadeca-12 (19),13 (18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (363 mg) and triethylamine (0.54 ml) in dry methylene chloride (20 ml) at 0° C. was added methanesulfonyl chloride (77 μml). The resulting mixture was stirred for 2 hours, allowing the mixture to rise to ambient temperature, then methylene chloride (100 ml) and 0.5N hydrochloric acid (50 ml) added, stirring vigorously. The aqueous layer was further extracted with methylene chloride (2×75 ml), then the combined organic layers washed with brine (100 ml). After drying the organic layer over MgSO4, it was filtered and evaporated to dryness. Purification of the residue by flash column chromatography (20-30% ethyl acetate/methylene chloride) gave (3R,10S)-2-(methylsulfonamidoaminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester as a white solid (211 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:12]([C:11]([F:16])([F:15])[F:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: FC(F)(F)c1nc2ncc(Br)cc2[nH]1

Procedure:
A solution of 5-bromopyridine-2,3-diamine (100 mg, 0.53 mmol) in trifluoroacetic acid (20 mL) and hydrochloric acid (4 mL) was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and dissolved in water (100 ml), adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate (3×80 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to produce 6-bromo-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine as a brown solid (200 mg, crude). To a solution of (4-chlorophenyl)boronic acid (117 mg, 0.75 mmol) in water (5 mL) and dioxane (15 mL) was added 6-bromo-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine (100 mg, crude), Pd(PPh3)4 (43.4 mg, 0.04 mmol) and sodium carbonate (119.5 mg, 1.13 mmol). The resulting solution was stirred overnight at 100° C. with an inert atmosphere of nitrogen and then concentrated under vacuum. The residue was dissolved in water (50 mL), extracted with ethyl acetate (4×50 mL), the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (60 mg) was purified by Prep-HPLC to produce 6-(4-chlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. TFA salt as a white solid (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17](F)[C:16]=3F)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][OH:29].O.CN([CH:34]=[O:35])C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([O:29][CH3:28])[C:16]=3[O:35][CH3:34])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: CN(C)C=O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(F)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1OC
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example No. 15 and sodium hydride (60% dispersion, 160 mg) are dissolved in DMF (10 mL) and to the mixture is added methanol (200 μL). The mixture is heated at 140° C. for 1 h. The reaction mixture is allowed to cool to rt, poured into water (40 mL), acidified with acetic acid (10 mL), and is filtered. The crude product is recrystalized from acetic acid/water and then from toluene to afford 174 mg of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.Cl>CCOCC.CCCCCC>[CH:13]1[C:14]2[CH:15]=[C:2]([B:25]([OH:26])[OH:24])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc2ccccc2c2ccccc12
Temperature: -67 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Under an atmosphere of argon, 9-bromophenanthrene (15 g, 58 mmole) was dissolved into anhydrous ether (150 ml) and the resultant solution was cooled at −35° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 43 ml, 65 mmole) was added dropwise and the resultant mixture was stirred at −20° C. for 1 hour. After the reaction mixture was cooled at −67° C., a solution (30 ml) of triisopropoxyborane (37 ml, 0.16 mole, 2.8 eq) in anhydrous ether was added the resultant mixture was stirred at −65° C. for 1 hour and at the room temperature for 2 hours and left standing for one night. To the obtained reaction mixture, a 10% hydrochloric acid (150 ml) was added. After the resultant mixture was stirred at the room temperature for 1 hour, the formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. The solid obtained after removing the solvent by distillation was washed with hexane and a white solid (10 g, 78%) was obtained.
Reaction SMILES: [Na].[C:2]1([C:8]2[N:9]=[C:10]([SH:19])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[C:27](=O)[CH2:28]Br)([CH3:23])([CH3:22])[CH3:21].C([OH:40])C>>[C:20]([C:24]1[CH:25]=[C:26]([C:27]2[N:9]3[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:11]=[C:10]3[S:19][CH:28]=2)[CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:33]=1[OH:40])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1
Reactant: CCO
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na]
Product: CC(C)(C)c1cc(-c2csc3nc(-c4ccccc4)c(-c4ccccc4)n23)cc(C(C)(C)C)c1O

Procedure:
In 20 ml of ethanol was dissolved 0.11 g of metallic sodium and after adding 1 g of 4,5-diphenyl-2-mercaptoimidazole to the solution followed by stirring several minutes, 1 g of 3,5-di-tert-butylphenacyl bromide was added thereto followed by stirring for one hour at room temperature. The reaction mixture was concentrated udner reduced pressure and then water was added to the residue. The crystals thus formed were recovered by filtration, dried, dissolved in 20 ml of phosphorus oxychloride, and the solution was refluxed for 14 hours. The reaction mixture was concentrated under reduced pressure and after adding water to the residue followed by neutralization with potassium carbonate, the product was extracted with chloroform. The extract was dried and concentrated. The residue was subjected to silica gel column chromatography and the product was eluted with chloroform. The crude crystals thus obtained were recrystallized from ethanol to provide 0.8 g of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6-diphenyl imidazo[2,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](SC)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[OH2:10].[NH2:18][CH2:17][CH2:16][NH:19][C:7]1[NH:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: NCCN
Reactant: CSC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Product: NCCNC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Product: O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-chloro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (1 g) in ethylenediamine (2.5 mL) was refluxed for 45 min. Most of the excess of amine was removed by distillation under reduced pressure and the resulting oily residue was dissolved in methanol (10 mL). Addition of diethylether (40 mL) gave rise to the precipitation of an oil which turned to a white solid after a stirring of 30 min. at 0° C. The precipitate was collected by filtration, washed with diethylether and dried. The solid was dissolved in boiling water (40 mL) and traces of insoluble material were removed by filtration. The filtrate was concentrated to the half volume by distillation under reduced pressure and placed at +4° C. for 2 h. The crystalline precipitate of the title compound was cpllected by filtration, washed with a small volume of water and dried to give the title compound (yield: 0.62 g); m.p. 200-204° C.; IR (KBr): 3498, 3372, 2932, 1637, 1560, 1481, 1264, 1163 cm−1; 1H-NMR (DMSO-d6, HMDS; δ ppm): 2.70 (t, 2H, NH—CH2—CH2—NH2), 3.20 (t, 2H, NH—CH2—CH2—NH2), 5.25 (b, 6H, 2×NH+H2O+NH2), 6.95 (d, 1H, 5-H), 7,30 (d, 1H, 6-H), 7.45 (s, 1H, 8-H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:31]1([C:37]2[CH:46]=[CH:45][C:40]([C:41](=[O:44])[CH2:42]Br)=[CH:39][CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:42][C:41]([C:40]3[CH:45]=[CH:46][C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:38][CH:39]=3)=[O:44])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCC(=O)c5ccc(-c6ccccc6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 37.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (398 mg), 4-phenylphenacyl bromide (290 mg) and potassium carbonate (440 mg) in DMF (7 ml) was stirred at room temperature for 72 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: ether =10:1) and recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (217 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25](F)=[C:24]([C:29]#[N:30])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>CC(O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:34][CH:33]([CH3:35])[CH3:32])=[C:24]([C:29]#[N:30])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Temperature: 60 °C
Yield: 42 %

Procedure:
Prepared using General Procedure 2. To a solution of (S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (2.5 g 5.7 mmol) in IPA (30 mL) was added sodium isopropoxide (0.61 g, 7.4 mmol). The reaction mixture was heated at 60° C. for 4 h. Upon cooling, the mixture was concentrated to 50% volume and the suspension was cooled to 0° C. The resulting solid was filtered and dried under high vacuum to afford 1.14 g (42%) of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as off-white solid. LCMS-ESI (m/z) calculated for C26H28N4O3S: 476.2; found 477.2 (M+H). tR=4.12 min. 1H NMR (400 MHz, CDCl3) δ 8.26-8.04 (m, 2H), 7.82 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.38-5.08 (m, 1H), 4.94-4.62 (m, 1H), 3.54-3.32 (m, 1H), 3.21 (s, 1H), 2.80-2.59 (m, 1H), 1.97-1.74 (m, 1H), 1.52-1.35 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 166.93, 165.54, 161.59, 155.65, 145.84, 142.05, 133.28, 128.71, 127.59, 126.64, 126.33, 122.72, 115.54, 113.86, 103.69, 79.59, 72.50, 60.35, 55.73, 33.78, 31.27, 28.39, 21.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3S[CH2:7][C:6]2=1.O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:26])[C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:22](=[O:24])(=[O:21])[CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)c1c(n2C)-c2ccccc2S(=O)(=O)C1
Reaction time: 6 h

Procedure:
8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (257 mg, 0.915 mmoL) in MeOH (3 mL) and water (3 mL) was treated with OXONE (2.744 mmoL, 1.68 g) at room temperature. The reaction mixture was stirred for 6 hours. The solvent was removed and the residue was partitioned between EtOAc and saturated NaHCO3. The aqueous phase was extracted two times with EtOAc. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown solid. The crude material (the oil) was then purified by column chromatography (silica gel, 1:1 hexanes:EtOAc as eluent) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][NH:20][C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1.Cl[C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C1(N)C=CC=CC=1.ClC1C(Cl)=CC=CN=1>>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:16]4[O:17][CH2:18][CH2:19][N:20]([C:25]5[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=5)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:21]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4)[nH]c2c1
Agent: Clc1cccnc1Cl
Solvent: Nc1ccccc1
Product: FC(F)(F)c1ccc2nc(-c3cccc4c3OCCN4c3ncccc3C(F)(F)F)[nH]c2c1
Yield: 91 %

Procedure:
The procedure of Example 6 was repeated except for using 8-(6-(trifloromethyl)-1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine and 2-chloro-3-trifluoromethylpyridine instead of 445-tert-butyl-1H-benzo[d]imidazol-2-yl)benzenamine and 2,3-dichloropyridine in Example 6 respectively to obtain the title compound (4.2 g, yield: 91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.P(OCC)(OCC)[O:30]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC)(C)(C)C.Cl>C1COCC1>[CH:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[CH:25]([OH:30])[C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:19][C:18]3=[O:28])[CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Buspirone (8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4.5)-decane-7,9-dione) (246.5 g, 639.6 mmol) was charged to a 12 L flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (4.383 kg, 60.8 mol, 4.930 L, 20 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (371.9 g, 2.238 mol, 383.8 mL, 3.5 eq) was added and the mixture was cooled to −68 to −75° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (600.4 g, 664.1 mmol, 664.1 mL, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of buspirone. Additional buspirone in THF (10-20 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 0.5% to 5% excess of buspirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (384.8 g, 4.365 mol, 520.0 mL) was added followed by 1M hydrochloric acid (1350.8 g, 1.328 mmol, 1328 mL) and the solution was warmed to ambient temperature. The pH was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4. The phases were separated and the organic phase was washed twice with brine (542.3 g, 493 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to crystallize the reaction product. There is an option to seed with 0.01 to 5% buspirone at approximately 54 to 56° C. The crystalline slurry was then filtered and the wet cake was washed with isopropyl alcohol and dried to provide 6-hydroxybuspirone (220.0 g, 82%), mp 109.5° C.