Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([Si:11]([CH3:14])([Cl:13])[Cl:12])C=C.CC(N=NC(C#N)(C)C)(C#N)C>>[S:7]1[CH:1]=[CH:6][CH:5]=[C:4]1[CH2:3][CH2:2][CH2:8][Si:11]([CH3:14])([Cl:13])[Cl:12]
Reactant: Sc1ccccc1
Reactant: C=CC[Si](C)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C[Si](Cl)(Cl)CCCc1cccs1
Temperature: 60 °C
Yield: 88 %

Procedure:
26.8 g thiophenol, 18.8 g allyl (methyl) dichlorosilane and 0.60 mg azobisisobutylonitrile were put in a 100-mL three-neck flask that had been subjected to nitrogen substitution and the mixture was heated at 60° C. for 5 hours. After the reaction, the product was distilled under reduced pressure, obtaining 3-(thiophenyl) propyl (methyl) dichlorosilane with a 88% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@H:13](O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:54])C(=O)C1>C(Cl)Cl>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@@H:13]([Cl:54])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of mixture of compound 2a (1.0 g, 2.67 mmol) and PPh3 (1.4 g, 5.34 mmol) in CH2Cl2 (15 mL) was added NCS (1.07 g, 8.01 mmol) portionwise at 0° C. Then the resulting mixture was stirred at rt for 1 h and poured into a silica gel column and eluted with EtOAc-hexanes (1:4) using pressure. The collected right fractions were combined, concentrated, and co-evaporated with CH2Cl2 several times and used next step (1.0 g, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl.O>C1COCC1>[Cl:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1nccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
N,N-dimethyl-1H-pyrazole-1-sulfonamide (8.89 g, 50.8 mmol) was dissolved in anhydrous THF (250 mL). The solution was cooled at −78° C., a solution of n-butyl lithium (32.6 mL, 81.4 mmol, 2.5 M in hexane) was added dropwise, and then the mixture was stirred for 45 minutes. A solution of hexachloroethane (18.0 g, 76.3 mmol) in anhydrous THF (20 mL) was added dropwise at −78° C., and the reaction stirred for 1.5 hours. Water was added, and the mixture was extracted 5 times with dichloromethane. The combined organic phases were washed with brine and then dried over magnesium sulfate. After evaporation of the solvent, 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCOc2ccccc21
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Chroman-4-one (46.5 g, 314 mmol) was dissolved in pyridine (160 ml) and hydroxylamine hydrochloride (51 g, 734 mmol) was added to this solution. The solution was refluxed for 8 hours and then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was filtered, washed with diisopropylether, and dried to afford chroman-4-one oxime (22.9 g, 275 mmol, 88%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1/[CH:19]=[CH:20]/[C:21]([NH:23][CH3:24])=[O:22]>CCCCCC.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[CH2:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)/C=C/c1c(O)ccc2cc(-c3cccc(O)c3)ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)CCc1c(O)ccc2cc(-c3cccc(O)c3)ccc12

Procedure:
(E)-3-(2-Hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)-N-methylacrylamide is stirred over night with Pd(OH)2 in ethanol/THF 2/1 (1.5 ml) under a hydrogen atmosphere at RT. The reaction mixture is filtered, and the solvent is removed in vacuum on a rotary evaporator. The desired product was obtained in quantitative yield.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])(C)(C)C.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1>[NH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([S:27]([C:25]2[S:26][C:22]([Cl:21])=[CH:23][CH:24]=2)(=[O:29])=[O:28])[C:11]1=[O:19]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCCn1c(=O)n(S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [2-(2-oxo-2,3-dihydrobenzimidazol-1-yl)ethyl]carbamic acid t-butyl ester (27 mg, 0.1 mmol) in THF at room temperature is treated with (5-chlorothien-2-yl)sulfonyl chloride (26 mg, 0.12 mmol) followed by diisopropylethylamine (25 uL, 0.2 mmol) and 4-dimethylaminopyridine (5 mg), stirred at room temperature for 16 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with HCl in dioxane (4 N) (1 mL), stirred for 4 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 10 mg, [M+H] 358, retention time (RT) 2.18 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [Mg].[H-].C([Al+]CC(C)C)C(C)C.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[CH3:23][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:28])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[CH3:26][C:24]([S@@:27]([NH:29][C@H:30]([C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:28])([CH3:23])[CH3:25]
Reactant: Cc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A 250 mL round-bottomed flask containing magnesium turnings (0.685 g, 28.2 mmol) and Et2O (25 mL) was added diisobutylaluminum hydride 1.0 M solution in hexanes (0.18 mL, 0.180 mmol) followed by dropwise addition of 4-bromobenzotrifluoride (2.0 mL, 14.28 mmol). The solution was stirred for 1.5 hours during which it turned from turbid to dark brown in color. The reaction mixture was cooled to −78° C. in a dry ice/acetone bath and then a solution of (S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide (2.15 g, 7.67 mmol) in THF (15 mL) was added dropwise over 5 minutes. The reaction was stirred for 5 hours during which it warmed to rt. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and H2O (25 mL). The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the initial product which was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradient to yield the desired product
Reaction SMILES: Br.[N+:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([Si:30]([CH3:32])([CH3:31])[O:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][N:10]([CH2:9][C:8]2[CH:19]=[CH:20][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(CN2CCN(CCO)CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 94 %

Procedure:
A suspension of 2-[4-(4-nitro-benzyl)-piperazin-1-yl]-ethanol hydrobromide (as prepared in the previous step, 1.00 g, 2.89 mmol) in DMF (3 mL) was treated with imidazole (688 mg, 10.1 mmol) and tert-butyl-chloro-dimethyl-silane (566 mg, 3.76 mmol) at RT for 3 h. The mixture was partitioned between EtOAc (50 mL) and brine (50 mL), and the layers were separated. The organic layer was washed with brine (3×40 mL). The combined aqueous layers were extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 50% EtOAc-hexane afforded the title compound (1.03 g, 94%) as a pale yellow oil which solidified upon standing. Mass spectrum (ESI, m/z): Calcd. for C19H33N3O3Si, 380.2 (M+H). found 380.2.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24]
Reactant: OB(O)c1sccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1sccc1Cl
Yield: 12 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 3-chlorothiophene-2-boronic acid (available from Combi-Blocks Inc.; 81 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(3-Chloro-thiophen-2-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (14 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1H), 8.50 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.74-7.81 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.15 (d, J=5.3 Hz, 1H), 7.15 (d, J=5.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]#[N:14])=[CH:5]2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]([C:13]#[N:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1
Reactant: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cc(Br)ccc2nc1Cl

Procedure:
6-Bromo-3-cyano-2-[1H]-quinolone (142 g) was heated under reflux in phosphorus oxychloride (500 cm3) for 1.5 hours. Volatile material was removed in vacuo and the solid residue was taken into chloroform (400 cm3) and the resulting slurry was poured onto ice. The mixture was neutralised with aqueous ammonia solution (S.G. 0.880) and the aqueous phase was extracted further with chloroform (2×150 cm3). The dried (MgSO4) organic extracts were concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with toluene to give a solid which was recrystallised from ethyl acetate to afford 2-chloro-6-bromo-3-cyano-quinoline, m.p. 228°-230°, (80 g).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].[NH2:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[N:14]=1>C(O)C.Cl>[ClH:19].[NH2:12][C:13]1[N:18]=[C:17]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=2)[CH:16]=[C:15]([CH3:20])[N:14]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 4-aminoacetanilide 14 (3.55 g, 23.64 mmol) and 2-amino-4-chloro-6-methylpyrimidine 15 (3.73 g, 26 mmol) in ethanol (50 mL) was added. C.HCl (2 drops). The reaction mixture was stirred under reflux conditions for 2 h, cooled to 20° C. and the product was filtered washed with more ethanol and dried to give essentially pure 16 (6.38 g, 92%); mp (EtOH) 203-207° C.; 1H NMR [(CD3)2SO] δ 12.60 (br, 1 H, N+H), 10.50 (br 1 H, NH), 10.02 (s, 1 H, NH), 7.60-7.58 (br m, 6 H, NH2 & ArH), 6.13 (s, 1 H, H-5″), 2.26 (s, 3 H, CH3), 2.04 (s, 3 H, CH3); HRMS (FAB+), calc. for C13H16N5O (M+1) m/z 258.1355, found 258.1346.
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:4][CH2:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(COC2CC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of 2.0 g of tert-butyl 4-[(cyclopropyloxy)methyl]piperidine-1-carboxylate in 20 mL of dichloromethane was added 3.0 mL of trifluoroacetic acid, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and then the aqueous layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/methanol) to obtain 756 mg of 4-[(cyclopropyloxy)methyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[CH2:12][C@H:13]4[NH:17][C@@H:16]([C:10]3=[N:9][N:8]=2)[CH2:15][CH2:14]4)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([C:28]([F:31])([F:30])[F:29])=[N:21][CH:22]=[CH:23][C:24]=1[C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]3[CH2:12][C@H:13]4[N:17]([C:25]([C:24]5[CH:23]=[CH:22][N:21]=[C:20]([C:28]([F:31])([F:29])[F:30])[C:19]=5[Cl:18])=[O:26])[C@@H:16]([C:10]3=[N:9][N:8]=2)[CH2:15][CH2:14]4)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nnc3n2C[C@@H]2CC[C@H]3N2)s1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(c1ccnc(C(F)(F)F)c1Cl)N1[C@H]2CC[C@@H]1c1nnc(-c3ccc(Cl)s3)n1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of (6S,9R)-3-(5-chlorothiophen-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine (Example 55, step b) (35 mg, 0.132 mmol) in DCM (2 mL) was added 3-chloro-2-(trifluoromethyl)-4-pyridinecarboxylic acid (30 mg, 0.132 mmol) followed by HOBt (12 mg, 0.09 mmol), EDCl (38 mg, 0.197 mmol) and TEA (0.04 mL, 0.263 mmol). The reaction was stirred at room temperature overnight and then loaded directly on a SiO2 column eluting with IPA/EtOAc to afford the title compound (53 mg, 85%). MS (ESI): mass calcd. C18H12Cl2F3N5OS, 473.01; m/z found, 473.8 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.75-8.59 (m, 1H), 7.68-7.30 (m, 1H), 7.26-7.13 (m, 1H), 7.03-6.92 (m, 1H), 5.46-5.31 (m, 1H), 4.98-4.87 (m, 1H), 4.65-4.50 (m, 1H), 4.25-3.94 (m, 1H), 2.63-2.23 (m, 3H), 2.00-1.86 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])(=[O:35])=[O:34]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1ccc2cc(-c3nc(C(C)(C)CNS(=O)(=O)CCCCl)[nH]c3-c3ccncc3)ccc2c1
Yield: 40 %

Procedure:
The title compound (11 mg, 40%) was prepared starting from the product of Example 2 and 3-chloro-propanesulfonyl chloride using the method described in Example 4; MS(ES) m/e 514 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>C(#N)C>[Br:49][CH2:18][C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(CO)cc2N1c1c(Cl)cccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1NCc2c(-c3ccccc3Cl)cc(CBr)cc2N1c1c(Cl)cccc1Cl

Procedure:
A solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (500 mg, 1.15 mmol), triphenyl phosphine (363 mg, 1.38 mmol) and carbon tetrabromide (459 mg, 1.38 mmol) in acetonitrile (34 mL) was stirred at rt for 24 h. Removal of the solvent and subsequent purification by flash chromatography using 22% acetone/hexane as eluent provided 7-(bromomethyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 4.26 (d, 1H, J=14.7 Hz), 4.35 (abq, 2H, J=10.5 Hz), 4.44 (d, 1H, J=14.6 Hz), 5.01 (s, 1H), 6.18 (s, 1H), 6.96 (s, 1H), 7.30-7.60 (m, 7H). MS (API-ES+): 497 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:23]=[CH:22][C:10]2[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:16])[NH:14][CH2:15][C:9]=2[CH:8]=1.C(S)C>C(Cl)Cl>[OH:6][C:7]1[CH:23]=[CH:22][C:10]2[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:16])[NH:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2CNC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Anhydrous aluminum chloride (7.6 g, 57 mmol) was added portionwise to a stirred solution of methyl (±)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (3.0 g, 11 mmol) and ethanethiol (4.2 mL, 57 mmol) in methylene chloride (100 mL) at 0° C. under argon. The resulting mixture was allowed to warm to room temperature and stir overnight, then was concentrated. The residue was triturated with ice-water, and the resulting solid was collected by filtration and dried to give the title compound (2.64 g, 91%) as an off-white solid: MS (ES) m/e 250.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]([N:5]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]1=[O:18])[CH3:4].[CH2:19]([C:22]1([CH2:26][CH2:27][CH3:28])[CH2:25][NH:24][CH2:23]1)[CH2:20][CH3:21]>C1C=CC=CC=1>[Cl:17][C:13]1[CH:12]=[C:11]([N:7]2[CH2:8][CH:9]([CH3:10])[N:5]([CH:3]([CH3:4])[CH2:2][N:24]3[CH2:25][C:22]([CH2:26][CH2:27][CH3:28])([CH2:19][CH2:20][CH3:21])[CH2:23]3)[C:6]2=[O:18])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(CCl)N1C(=O)N(c2cccc(Cl)c2)CC1C
Reactant: CCCC1(CCC)CNC1
Solvent: c1ccccc1
Product: CCCC1(CCC)CN(CC(C)N2C(=O)N(c3cccc(Cl)c3)CC2C)C1

Procedure:
A mixture of 7 g. of 3-(2-chloro-1-methylethyl)-1-(m-chlorophenyl)-4-methyl-2-imidazolidinone and 10 g. of 3,3-dipropylazetidine in 100 ml. of anhydrous benzene is heated in a bomb at 150°-160° C. for 8 hours. The solvent is evaporated under vacuum and the residue is taken up with water, alkalinized with aqueous sodium carbonate and extracted with diethyl ether. The residue obtained by evaporation of the organic layer is purified by column chromatography through silica gel, using as the eluent chloroform containing 8% of methanol. Yield 8.6 g., b.p. 220° C./0.5 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17](C=O)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: O=Cc1ccc2c(c1)CCC2
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCC3)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.3 mg (0.29 mmol) of 5-indancarboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C17H19NO2S2, 334.09 (M+H), found 332.3 (imine), 333.4.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42](OC)=[O:43].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>>[CH:46]1([N:49]2[CH2:2][C:3]3[C:12]4[CH:11]=[CH:10][C:9]([C:13]([OH:41])([C:17]5[N:18]=[CH:19][NH:20][CH:21]=5)[CH:14]([CH3:16])[CH3:15])=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[C:42]2=[O:43])[CH2:48][CH2:47]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C1CC1)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (1.32 g) and cyclopropylamine (3.0 ml), the title compound (0.58 g) was obtained as a colorless amorphous solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([SH:28])[S:26][CH:27]=2)[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]1>>[OH:14][C:15]1([C:23]2[CH:24]=[C:25]([S:28][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:26][CH:27]=2)[CH2:16][CH:17]([CH3:22])[O:18][CH:19]([CH3:21])[CH2:20]1
Reactant: CC1CC(O)(c2csc(S)c2)CC(C)O1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Product: CC1CC(O)(c2csc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CC(C)O1
Yield: 28 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-hydroxy-4-(2-mercaptothien-4-yl)-2,6-dimethyltetrahydropyran to give 4-hydroxy-2,6-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 28% yield;