Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1.[O-]O.S(=O)(O)[O-:32].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]3)[N:13]=2)=[CH:9][CH:8]=1)=[O:32]
Reactant: CSCCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [O-]O
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound of Step C (650 mg, 1.55 mmol) was dissolved in 5 ml TFA and 3 ml DCM. At room temperature 79 mg (2.3 mmol) hydroperoxide 30% were added. This mixture was stirred at room temperature for 2 hours. Afterwards 10 ml 10% sodium bisulfite solution was added and stirring continued for 15 minutes. The solution was basified with 40% NaOH and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 0.35 g (50%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH:26]=O)=[C:19]([CH:25]=1)[C:20]([N:22]([CH3:24])[CH3:23])=[O:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:26][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[C:19]([C:20](=[O:21])[N:22]([CH3:24])[CH3:23])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)c1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)c1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (86.0 mg, 0.460 mmol, 1.00 equiv), 5-bromo-2-formyl-N,N-dimethylbenzamide (130 mg, 0.510 mmol, 1.10 equiv), dichloromethane (10 mL). Triethylamine (139 mg, 1.37 mmol, 3.00 equiv) was added. The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (293 mg, 1.38 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (15 mL), extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50/50) to provide 170 mg (87% yield) of tert-butyl 4-[[4-bromo-2-(dimethylcarbamoyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 426 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][NH:8][CH3:9])=[CH:5][S:4][C:3]=1[C:10]([NH:12][C@@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:15][C@@H:14]1[NH:24][C:25](=[O:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])=[O:11].C(N(CC)CC)C.Br[CH2:45][CH2:46][N:47]=[C:48]=[O:49]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:6]([CH2:7][N:8]([C:48]2[O:49][CH2:45][CH2:46][N:47]=2)[CH3:9])=[CH:5][S:4][C:3]=1[C:10]([NH:12][C@@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]([CH3:22])[CH3:23])=[O:20])[CH2:16][CH2:15][C@@H:14]1[NH:24][C:25](=[O:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])=[O:11]
Reactant: O=C=NCCBr
Reactant: CNCc1csc(C(=O)N[C@@H]2C[C@@H](C(=O)N(C)C)CC[C@@H]2NC(=O)C(=O)Nc2ccc(Cl)cn2)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)c2scc(CN(C)C3=NCCO3)c2Cl)C1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of the compound obtained in Example 331 (590 mg) in methylene chloride (20 mL) were added triethylamine (0.735 mL) and 2-bromoethylisocyanate (0.106 mL), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with methylene chloride, and the diluted solution was washed sequentially with water, 0.5N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine. The resultant organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel flash column chromatography (methylene chloride:methanol=20:1), and the solvent was removed under reduced pressure. The crude product was dissolved in methylene chloride (2 mL) and ethanol (3 mL), and 1N HCl in ethanol (0.5 mL) was added thereto, followed by stirring for 30 minutes at room temperature and concentration under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected through filtration and washed, to thereby yield the title compound (197 mg) as a colorless powder.
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]2[C:22](=[O:37])[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=3)([CH3:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:37][C:22]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([OH:5])[CH:7]=2)[C:21]2[CH:38]=[CH:39][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=2[O:25][CH2:24][C:23]1([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=1)[CH3:26]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
Under argon atmosphere 3-bromomagnesium phenyl trimethylsilyl ether was prepared from 3-bromophenyl trimethylsilyl ether (3 g, 12.24 mmol) and magnesium turning (300 mg, 12.34 mmol) in dry tetrahydrofuran (10 ml) and cooled to 0° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran-4-one (900 mg, 2.51 mmol) dissolved in dry tetrahydrofuran (5 ml) was slowly added dropwise thereto and then refluxed for 12 hours. The reaction mixture was cooled to room temperature, quenched with water and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=2:1) to obtain 760 mg (yield: 67%) of the title compound as a foam.
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11](=O)[NH:10][C:9](=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9](=[O:14])[NH:10][C:11]1=[O:12]
Reactant: O=c1cc(-c2ccccc2)oc(=O)[nH]1
Reactant: CN
Product: Cn1c(-c2ccccc2)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To 189 mg (1 mM) of 6-phenyl-1,3-oxazine-2,4-dione from Preparation Ia(1) is added 10 ml of a 40 percent aqueous CH3NH2 solution. The reaction mixture is allowed to heat at reflux for 18 hours. The resulting solution is cooled to room temperature and the precipitate filtered, washed well with water, and dried at 60° C. under vacuum. The yield is 146 mg (72 percent) (m.p. 183°-185° C.) of 1-N-methyl-6-phenyl-2,4-pyrimidine-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17](=O)[CH2:18][C@H:19]2[N:22]([C:23](=O)[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C:21](=[O:38])[C@@H:20]2[C@H:39]([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH3:40])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH2:18][C@H:19]3[N:22]([C:21](=[O:38])[C@@H:20]3[C@H:39]([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH3:40])[C:23]=2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N(C(=O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1
Agent: CCOP(OCC)OCC
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C3=CCN(C(=O)OCc4ccccc4)CC3)C[C@H]12
Reaction time: 6 h
Yield: 83.8 %

Procedure:
To a solution of 4-nitrobenzyl 2-[(3S,4R)-4-{2-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl}-3-{(1R)-1-trimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-oxoacetate (4.73 g) and triethyl phosphite (6.2 ml) in toluene (70 ml) was heated under reflux for 2 hours under nitrogen atmosphere. To this solution was added hydroquinone (800 mg), and the reflux was continued for additional 6 hours. The solvent was removed in vacuo to give a residue, which was chromatographed on silica gel (400 ml) eluting with a mixture of hexane and ethyl acetate (4:1 v/v) to give 4-nitrobenzyl (5R,6S)-3-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-trimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (3.77 g).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[C:14](=[O:17])([O-])[O-].[K+].[K+].Cl.[C:21]1(C)[CH:26]=CC=[CH:23][CH:22]=1>>[O:17]=[C:14]1[C:26]2[CH:21]=[CH:22][CH:23]=[CH:7][C:6]=2[O:5][CH:3]=[CH:2]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: Cl
Agent: [K+]
Product: O=c1ccoc2ccccc12
Temperature: 25 °C
Reaction time: 36 h
Yield: 56 %

Procedure:
The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added to trifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassium carbonate (44 g, 318 mmol) and toluene (400 mL). This suspension was stirred at room temperature for 36 hours, then heated to reflux for 4 hours. After cooling to room temperature, the suspension was poured over rapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCl (12 N, 50 mL). The resulting organic phase was separated from the clear mixture, was washed with water (5×500 mL), brine (1×500 mL), dried over MgSO4, filtered and concentrated in vacuo yielding tan solid which was dried under high vacuum. This sample was partially dissolved in heptane (100 mL) and ethyl acetate (12 mL) with heating on a steam bath, was filtered to remove insoluble material. The filtrate was allowed to cool to room temperature yielding the desired 4-oxo-4H-1-benzopyran as a fluffy tan solid (14.17 g, 56%): mp 106.7-108.6° C. This material was of suitable purity to use in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:38])(=[O:7])=[O:6].[H-].[Na+].C(OCC)(=O)C.O>C1COCC1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:24]1[CH:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH2:21]2)[C:16](=[O:38])[N:15]1[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:8]1[CH2:2][CH2:3][CH2:4][S:5]1(=[O:6])=[O:7]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(=O)(=O)CCCCl)C1c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1C2CC=CC=C2C(=O)N(C2CCCCC2N2CCCS2(=O)=O)C1c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of 1.63 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chloropropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of THF was added 142 mg of sodium hydride, followed by stirring at 50° C. overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 466 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl]-1-oxo-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl(O)(=O)=O.[CH3:25][S:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:34][CH2:33][C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:36][CH:35]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [O-][Cl+2]([O-])O
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-methylsulfonyl-benzylamine hydrogen chloric acid salt (59 mg, 0.32 mmol). The title compound was obtained as a yellow solid (54 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.51 (1H, m), 8.99 (2H, s), 8.48 (1H, s), 7.89 (2H, dd), 7.55 (2H, dd), 4.51 (2H, m), 3.18 (3H, s). MS m/z: 515.97, 517.99 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[N:10][CH:11]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)nc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
To an acetic acid (20.0 mL) solution of 4-(5-methyl-pyridin-2-yloxymethyl)-benzaldehyde (2.93 g, 12.9 mmol) described in Manufacturing Example 44-1-2 were added nitromethane (3.94 g, 64.5 mmol) and ammonium acetate (1.99 g, 25.8 mmol under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.50 g) as a crude product.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH3:11])[CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([O-:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ncccc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc([N+](=O)[O-])cc2)c2ncccc21
Temperature: 100 °C
Yield: 37.1 %

Procedure:
A mixture of 3-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (200 mg), (4-nitrophenyl)boronic acid (175 mg), Pd(PPh3)4 (95 mg) and Na2CO3 (201 mg) in DME (4 mL) and water (2 mL) was heated at 100° C. for 19 h. After this time, the reaction was cooled to room temperature, diluted with AcOEt (100 mL), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (heptane to 1:1 AcOEt/heptane) to give the title compound (89 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.C(O)(=O)C>C1COCC1>[C:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[B:31]([OH:36])[OH:32])=[N:8][N:9]=[N:10]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 5-phenyl-1-trityl-1H-tetrazole (70.0 g, 180.20 mmol, 1.00 equiv) in THF (dried) (560 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to −25° C. Butyllithium was added to quench the trace of water in the reaction mixture until the color of the mixture remained red for at least 5 minutes. Butyllithium (80.0 mL, 2.5 mol/L) was then added dropwise to the mixture over a period of about 40 minutes at a temperature below −25° C. The temperature of the mixture was raised to −5° C., and the mixture was stirred at −5° C. for 3 hours. The mixture was then cooled to −25° C. and triisopropyl borate (50.8 g, 270.11 mmol, 1.50 equiv) was added dropwise. The mixture was warmed to temperature in the range of 25-35° C. and stirred for 2 hours. The mixture was cooled again in the range of 0-5° C., and 3% aqueous acetic acid (470 mL) was slowly added over 30-40 minutes. The mixture was stirred for 30-40 minutes and then filtered. The crude product was washed with water (2×300 mL) and dried over reduced pressure. The crude product was then purified by re-crystallization from EtOAc (1 g/15 ml) to yield 54 g (69%) of the title compound as a white solid. ES m/z: [M+H]+ calcd for C26H21BN4O2 433.1, found 433.1.
Reaction SMILES: O.[CH3:2][CH:3]([CH3:5])[O-:4].[CH3:6][CH:7](C)[O-:8].C[CH:11](C)[O-:12].CC(C)[O-].[Ti+4:18].CC(O)(CC(O)C)C>CC(O)C>[CH3:2][CH:3]([O:4][C:7]([CH3:6])=[O:8])[CH2:5][O:12][CH3:11].[Ti:18]
Reactant: CC(C)[O-]
Reactant: [Ti+4]
Agent: CC(O)CC(C)(C)O
Solvent: O
Solvent: CC(C)O
Product: COCC(C)OC(C)=O
Product: [Ti]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
IPA solution (500 g) of deionized water (27 g) was agitated with IPA solution (500 g) of a titanium tetraisopropoxide (284 g) and dropped at room temperature for 2 hours. 2-methyl-2,4-pentanediol (120 g) was added to a solution obtained and agitated at room temperature for 30 minutes. After the solution was concentrated under reduced pressure at 30° C., it was heated to 60° C. and heating was continued under reduced pressure to generate no distillate. Then, PGMEA (1,200 g) was added thereto and heated under reduced pressure at 40° C. until no BOH was distilled to obtain a PGMEA solution of a titanium-containing compound [B-II] (1,000 g) (compound concentration: 20%). The molecular weight (Mw) of the compound measured in terms of polystyrene was 1,100.
Reaction SMILES: [P:1]([O:10][CH2:11][CH2:12][Cl:13])([O:6][CH2:7][CH2:8][Cl:9])[O:2]CCCl.[C:14]([C:18]1[C:19]([OH:28])=[C:20]([CH3:27])[C:21]([CH3:26])=[C:22]([CH:25]=1)[CH2:23]Cl)([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([C:18]1[C:19]([OH:28])=[C:20]([CH3:27])[C:21]([CH3:26])=[C:22]([CH:25]=1)[CH2:23][P:1](=[O:2])([O:6][CH2:7][CH2:8][Cl:9])[O:10][CH2:11][CH2:12][Cl:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: Cc1c(CCl)cc(C(C)(C)C)c(O)c1C
Solvent: Cc1ccccc1C
Product: Cc1c(CP(=O)(OCCCl)OCCCl)cc(C(C)(C)C)c(O)c1C

Procedure:
13.45 tris-(2-chloroethyl) phosphite and 11.55 grams of the compound of Example 9 dissolved in 50 ml of dry xylene were mixed together and heated at 65° for 3 hours and then at 110° to 115°C for 21/2 hours during which 1,2-dichloroethane distilled out of the reaction mixture and was collected in a trap. The reaction mixture was free of solvent at reduced pressure, the resulting solid was triturated with petroleum ether and then recrystallized successively from a solvent mixture of benzene-hexane and then from toluene, yielding the desired product as white crystals melting at 133° to 135°C (Compound 9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[CH2:33]([SH:37])[CH2:34][CH2:35][SH:36].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=3)[S:37][CH2:33][CH2:34][CH2:35][S:36]2)[CH:8]=1)[CH3:2]
Reactant: SCCCS
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Cc1cccc(C2(c3cccc(CC(C)(C)C(=O)OCC)c3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (6.2 g, 14 mmol) in dichloromethane (100 mL) was added 1,3-propanedithiol (1.9 g, 17.5 mmol) and borontrifluoride etherate (0.52 mL) solution was stirred at room temperature overnight and 5% sodium hydroxide solution (17.5 mL) was added. The organic layer was separated, washed with water (50 mL), dried over sodium sulfate, and evaporated to afford 3-(3-{2-[3-(2-ethoxycarbonyl-2-methyl-propyl)-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethyl-propanoic acid ethyl ester (6.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3): δ (ppm): 7.58-6.96 (m, 8H), 4.10 (q, J=7.2 Hz, 4H), 2.85 (s, 4H), 2.76 (t, J=5.6 Hz, 4H), 1.98 (m, 2H), 1.25-1.14 (m, 18H). 13C NMR (75 MHz, CDCl3): δ (ppm): 177.2, 142.2, 138.1, 131.1, 129.3, 127.8, 127.3, 60.4, 46.2, 43.5, 29.4, 24.9, 24.5, 14.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11].[H-].[Na+].[C:20]1([Se:26]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[C:10]([Se:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11]
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Reactant: Cl[Se]c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC([Se]c1ccccc1)(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Yield: 47 %

Procedure:
To a solution of 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (3 g, 11 mMole) in tetrahydrofuran (60 ml) cooled to 5° was added sodium hydride as a 50% by weight dispersion in oil (0.68 g of said dispersion which contained 14 mMole of sodium hydride). Thirty minutes later phenylselenenyl chloride was added in four equal portions over five minutes (2.95 g, 15.4 mMole). Fifteen minutes later glacial acetic acid was added (1.5 ml) and the mixture was poured into water (100 ml). Excess solid sodium bicarbonate was added to basify the solution, which was then extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with saturated saline solution (3×50 ml) and dried over anhydrous magnesium sulphate. Evaporation gave an impure oil, weight 5.4 g. Purification was carried out by `flash` column chromatography under slight pressure (2 p.s.i.) on a `Merck Kieselgel 60` (trade mark) 230-400 mesh silica-packed column, eluting with ether and 40°-60° petrol (1:1). The appropriate fractions after collection and evaporation gave a solid which was recrystallized from cyclohexane to give the pure title compound, 2.57 g, m.p. 84°-86° (47% yield).