Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[NH2:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH2:12])[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(N)cc1N
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
A solution of 4-tert-butylbenzene-1,3-diamine (D-9) (657 mg, 4 mmol) and pyridine (0.39 mL, 4.8 mmol) in CH2Cl2/MeOH (12/1.8 mL) was cooled to 0° C., and a solution of benzyl chloroformate (0.51 mL, 3.6 mmol) in CH2Cl2 (8 mL) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min, then warmed to room temperature. After 1 h, the mixture was washed with 1M citric acid (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the crude (3-amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester as a brown viscous gum (0.97 g), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 6H,), 7.12 (d, J=8.5 Hz, 1H), 6.89 (br s, 1H), 6.57 (dd, J=2.3, 8.5 Hz, 1H), 5.17 (s, 2H), 3.85 (br s, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3, rotameric) δ 153.3 (br), 145.3, 136.56, 136.18, 129.2, 128.73, 128.59, 128.29, 128.25, 127.14, 108.63 (br), 107.61 (br), 66.86, 33.9, 29.7; ESI-MS 299.1 m/z (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenylboronic acid to give (6-methoxy-1-phenyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([NH2:36])=O)[O:33][C:29]=2[C:28]([F:37])=[C:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]=1[CH3:44])#[N:24]>C1(C)C=CC=CC=1>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34](=[S:10])[NH2:36])[O:33][C:29]=2[C:28]([F:37])=[C:27]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:26]=1[CH3:44])#[N:24]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=O)nc2c1C#N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=S)nc2c1C#N
Temperature: 125 °C
Yield: 41.8 %

Procedure:
Lawesson's reagent (458 mg, 1.13 mmol) was added to a toluene solution of 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-196) (304 mg, 1.03 mmol), followed by heating under reflux in an oil bath at 125° C. for 10 minutes. After cooling to room temperature, the reaction liquid was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=20:1→10:1) to obtain the entitled compound (134 mg, 41.8%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].[C:22]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CSc1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc(C(=O)O)cc1
Yield: 96.8 %

Procedure:
To a mixture of 2-bromothioanisole (4.8 g, 23.6 mmol), 4-carboxybenzeneboronic acid (3.92 g, 23.6 mmol) and 2M K2CO3 (35.5 mmol, 71 mmol) in dioxane (20 ml) was added dichlorobis(triphenylphosphine)palladium (II) (415 mg, 0.6 mmol) under Ar. It was refluxed for 2 hrs. After the removal of the solvent, the residue was neutralized by 1 N HCl and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo to give 4-[(2-ethylthio)phenyl]benzoic acid (5.9 g, 100%). ES-MS (M+H)+=245.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:39]=1[C:40](Cl)=[O:41]>O>[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:40](=[O:41])[C:39]3[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:38]=3[Cl:37])=[CH:20][C:19]=2[N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(-n2cccc2)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(-n2cccc2)c1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 320 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-(1-pyrrolyl)aniline and 110 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 200 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 260 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-(1-pyrrolyl)phenyl)-2-chloro-5-nitrobenzamide (Compound No. 127) having a melting point of from 165 to 167° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]2([CH3:35])[CH2:34][CH2:33]2)[CH:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:25]([NH:26][C:27]3[N:28]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[N:29]=[C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)[CH:31]=3)=[O:24])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C

Procedure:
Heat a solution of 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Preparation 4, 1.05 equiv, 0.5845 g), [5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl ester (Preparation 39, 1.0 equiv, 0.8054 g) and diisopropylethylamine (2 equiv, 0.7 mL) in DMSO (0.25 M, 8 mL) to 60° C. for 6 hours. Cool the resulting mixture to ambient temperature, and add water (20 mL). Extract with EtOAc (2×25 mL), then wash the combined organic phases with water (10 mL) and saturated aq. sodium chloride solution (10 mL). Dry over MgSO4, then subject residue to silica gel chromatography eluting with a gradient 2 M ammonia-methanol in dichloromethane. LCMS(ES+): m/z=532.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH2:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]=[CH:10][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: C=CS(=O)(=O)CC
Solvent: ClCCl
Product: CCS(=O)(=O)C=CSc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
4-chlorophenylsulfenyl chloride, 7.5 g was added to 5.0 g of ethyl vinyl sulfone in 20 ml of dichloromethane. There was no exotherm and the system was refluxed for 3 hours. The dichloromethane was removed by stripping and the residue was dissolved in 50 ml of benzene. Triethylamine, 4.2 g, was added dropwise with cooling and after standing for 1 hour, the triethylamine hydrochloride was removed by filtration and the benzene stripped to give a crude product. Purification was carried out by chromatography on a silica gel column. The product, ethyl 2-(4-chlorophenylthio)vinyl sulfone, 4.2 g, was obtained as a clear oil showing one spot by thin-layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(N[O:31]C)C.[O:33]1[CH2:37][C@@H:36]([OH:38])[CH2:35][NH:34]1.O1C[C@H](O)CN1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[C:6]([OH:16])[C:7]=1[S:8]([N:11]1[CH2:12][C@H:13]([OH:31])[CH2:15][O:14]1)(=[O:10])=[O:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[C:6]([OH:16])[C:7]=1[S:8]([N:34]1[CH2:35][C@@H:36]([OH:38])[CH2:37][O:33]1)(=[O:10])=[O:9]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Reactant: CCNOC
Reactant: O[C@H]1CNOC1
Agent: Cl
Agent: O[C@@H]1CNOC1
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3C[C@@H](O)CO3)c2O)c(=O)c1=O
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3C[C@H](O)CO3)c2O)c(=O)c1=O

Procedure:
These compounds namely, 3-[4-chloro-2-hydroxy-3-((S)-4-hydroxy-isoxazolidine-2-sulfonyl)-phenylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione (Intermediate FC) and 3-[4-chloro-2-hydroxy-3-((R)-4-hydroxy-isoxazolidine-2-sulfonyl)-phenylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione (Intermediate FD) are prepared analogously to 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) by replacing N-ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) with hydrochloride salts of either (S)-isoxazolidin-4-ol (Intermediate I) or (R)-isoxazolidin-4-ol (Intermediate J). [M+H]+ 418.9 and [M+H]+ 418.9.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([C:35]3[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]([CH3:43])[CH:36]=3)[C@H:32]([OH:44])[C@@H:31]2[OH:45])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:48](Cl)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([C:35]3[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]([CH3:43])[CH:36]=3)[C@H:32]([O:44][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:31]2[OH:45])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[CH3:7][O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([C:35]3[C:41](=[O:42])[NH:40][C:38](=[O:39])[N:37]([CH3:43])[CH:36]=3)[C@H:32]([OH:44])[C@@H:31]2[O:45][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](c3cn(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](c3cn(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2O[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](c3cn(C)c(=O)[nH]c3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25 %
Yield: 25 %

Procedure:
Anhydrous pyridine (3.64 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-1-N-methylpseudouridine (2.67 g, 4.48 mmol) and AgNO3 (934 mg, 5.69 mmol) in dry THF (32 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (934 mg, 5.87 mmol) in dry THF (3 mL) and stirred at the same temperature for 3-4 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel which was saturated with 2% triethylamine in hexanes, and eluted with hexane-ethyl acetate (1:1) to give a pure title compound (780 mg, 25%), and 5′-O-(4,4′-dimethoxitrityl)-3′-O-(tert-butyldimethylsilyl)-1-methylpseudouridine (800 mg, 25%) as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37]OC([Si](C)(C)C)C.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>FC(F)(F)C(O)=O>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:37].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: C1CCNC1
Reactant: Cc1ccc(F)cc1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1N(CCCN2CCCC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 26.9 %

Procedure:
In a manner similar to the method described in example 60b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 60a (91 mg, 0.134 mmol) was reacted with pyrrolidine (2 mL), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-pyrrolidin-1-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (21 mg, 26.9%).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(F)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (0.217 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.49 g) and diethyl [(3S,8aR)-3-(3-fluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.9 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[O:14][C:13]([C:15]2[O:19][C:18]([SH:20])=[N:17][N:16]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[CH2:1]([S:20][C:18]1[O:19][C:15]([C:13]2[O:14][C:10]([Br:9])=[CH:11][CH:12]=2)=[N:16][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccc(Br)o2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Brc1ccc(-c2nnc(SCc3ccccc3)o2)o1
Reaction time: 2 h

Procedure:
Benzylbromide (6.18 g, 36.1 mmol) was added over 5 minutes time-period to a mixture of 5-(5-bromo-furan-2-yl)-[1,3,4]oxadiazole-2-thiol (8.5 g, 36.1 mmol), trietylamine (6.96 g, 68.8 mmol) and ethanol (100 ml, 99%). The reaction mixture was stirred at room-temperature for 2 hours. Aqueous sodium hydroxide (50 ml, 1 M) and water (100 ml) was added followed by extraction with diethylether (3×50 ml). The organic phase was washed with water (3×50 ml), dried and evaporated. The product was isolated as a red solid. Yield 10.7 g (92%).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.C1CCCCC1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41]O)[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[S:28][C:27]3=[CH:29][N:30]([CH2:41][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]([CH3:8])[CH3:7])[C:31](=[O:40])[C:32]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[C:26]3[NH:25][C:24]=2[CH:43]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Reactant: CC(C)C(C)C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: CC(C)C(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Yield: 11 %

Procedure:
A mixture of 1.0 g. of 2,3-dimethylbutyric acid (8.6 mmol.) and 2.5 ml. of thionyl chloride (34.3 mmol.) in 10 ml. of cyclohexane was refluxed on a steam bath for 1.5 hours. The resulting solution was then concentrated under reduced pressure and the residue azeotroped with cyclohexane to yield a colorless oil. The oil was then added dropwise to a cold, stirred suspension containing 0.8 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.0 mmol.) in 15 ml. of pyridine. After stirring for 35 minutes, the mixture was poured onto ice-water, resulting in the formation of a yellow precipitate which was filtered, washed with water and air-dried, then purified using flash chromatography on silica gel, employing a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2,3-dimethyl-1-oxobutoxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow crystalline solid (110 mg; 11% yield) having the structural formula, ##STR20## a melting point in the range of 204°-205° C. and the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[OH:21])[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(O)CN2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)piperazin-1-yl)-1-(4-methoxyphenyl)ethanone (75 mg, 175 μmol) and NaBH4 (10 mg, 264 μmol) in THF (5 mL) and MeOH (1 mL) was stirred at RT. Water (5 mL) and 10% aq.Na2CO3 (5 mL) was added and stirred for 10 min. The mixture was extracted with EtOAc; the organic layers were washed with brine (20 mL), dried over Na2SO4, filtered off and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[C:14](Cl)(=[O:18])C(Cl)=O.[CH3:20][N:21](C=O)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:18][N:21]([CH3:20])[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(OC)c(C(=O)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2,5-dimethoxybenzoic acid (6.00 g, 33.0 mmol) in DCM (100 mL) was added oxalyl chloride (3.6 mL, 41.3 mmol) and then DMF (0.2 mL). The solution was stirred at room temperature for 2 h, and the solvent was removed under reduced pressure. The crude material was placed under vacuum for 30 min to remove all of the oxalyl chloride. To a mixture of the residue and N, O-dimethylhydroxylamine hydrochloride (4.03 g, 41.32 mmol) in DCM (100 mL) at 0° C., triethylamine (6.8 mL, 48.78 mmol) was added dropwise. The solution was stirred at 0° C. for 30 min and then at room temperature for additional 30 min. The reaction was diluted with DCM (50 mL), washed (2×100 mL H2O, 100 mL brine), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified on a silica gel column to yield N,2,5-trimethoxy-N-methylbenzamide (7.32 g, 99%) as clear oil which solidified over time. 1H NMR (CDCl3): δ 7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][CH:13]=[N:14][C:7]=12.C(O[C@@H:19]1[O:31][C@H:30]([CH2:32][O:33]C(=O)C)[C@@H:25]([O:26]C(=O)C)[C@H:20]1[O:21]C(=O)C)(=O)C.ClCC(O)=O>N>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:19]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:25]([OH:26])[C@H:20]3[OH:21])[CH:13]=[N:14][C:7]=12
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1csc(-c2ccnc3[nH]cnc23)c1
Agent: N
Agent: O=C(O)CCl
Product: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)[C@H](O)[C@@H]1O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
A mixture of Compound 4 (80 mg, 0.4 mmol), tetra-O-acetyl-β-D-ribofuranose (130 mg, 0.4 mmol) and chloroacetic acid (2 mg) was heated at 200° C. for 5 minutes. The resulting dark syrup was treated with methanolic ammonia (40 ml) at room temperature for 18 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with 30% aqueous CH3CN, and the product was purified by reversed-phase HPLC to give Compound 11 (39 mg, 29%, 2 steps).