Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[Cl:25][C:26]1[CH:31]=[N:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:25][C:26]1[N:27]=[C:28]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[CH:29]=[N:30][CH:31]=1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Temperature: 105 °C
Yield: 97.7 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 14 (1.00 g, 2.272 mmol) and 2-chloro-6-(tributylstannyl)pyrazine 1b (1.375 g, 3.41 mmol) in DMF (9 mL) followed by Pd(PPh3)4 (0.131 g, 0.114 mmol) and CuI (7.70 μL, 0.227 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 1 h. The resulting mixture was diluted with DCM. The organic layer was separated, washed with water, dried, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in Hexanes) to give 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.95 g, 2.22 mmol, 98% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 427.0 (M+1).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:39][CH2:40][CH:41](CO)[OH:42]>>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:41]([OH:42])[CH2:40][OH:39])=[O:23])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 180 °C

Procedure:
A mixture of 2.25 g of methyl 4-(n-hexadecylamino)benzoate, 280 mg of glycerol, and 1.37 g of p-toluenesulfonic acid is heated at 180° C for 18 hours and then is partitioned between ether and 3% aqueous carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH2:29][CH2:30][NH:31][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: Cn1cc(CCN)c2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(CCNC(=O)c2ccc(Cc3cccc(F)c3)cc2)c2cc(Cl)ccc21
Yield: 23.3 %

Procedure:
N-(2-(5-Chloro-1-methyl-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-1-methyl-1H-indol-3-yl)ethanamine (0.080 g; 0.382 mmol), HATU (0.145 g; 0.382 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.034 g (23%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[C:6]1=[O:24].[Cl:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:24])[CH:5]([CH2:4][CH:3]=[O:2])[CH2:14][CH2:13]2
Reactant: CCOC(C)=O
Reactant: COC(CC1CCc2cc(Cl)ccc2C1=NN(C)C)OC
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1CCc2cc(Cl)ccc2C1=O)OC
Product: O=CCC1CCc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %
Yield: 43 %

Procedure:
6-Chloro-1-(dimethylhydrazono)-1,2,3,4-tetrahydro-2-naphthaleneacetaldehyde dimethyl acetal (10.3 g) was dissolved under argon in a mixture of 500 ml of tetrahydrofuran and 265 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 8.7 g of copper(II) chloride dihydrate and stirred at room temperature for 18 hours. 400 ml of ethyl acetate were added to the reaction mixture and it was washed twice with 500 ml of a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) each time. The aqueous wash phases were extracted three times with 200 ml of ethyl acetate each time, the organic phases were combined, dried over MgSO4 and freed from solvent. The crude product, 8.2 g of brown oil, was chromatographed on 330 g of silica gel with ethyl acetate/hexane mixtures (1:6 to 1:4) as the eluent. There were obtained 2.1 g (24%) of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal besides 3.2 g (43%) of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](O)=[O:22])=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[CH2:48]([O:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1)[CH3:49]>C(Cl)Cl>[CH2:48]([O:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:21]([C:7]2[CH:8]=[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])[C:4]3[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=3)[CH:6]=2)=[O:22])=[CH:53][CH:52]=1)[CH3:49]
Reactant: CCOc1ccc(N)cc1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)c2cc(NCc3c(C)cccc3CC)c3nc(C)c(C)n3c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). 4-ethoxyanilin(0.19 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was added to a column with silica gel and was purified by chromatography using methylene chloride:methanol (95:5) as eluent. The residue was treated with a hot mixture of hexane:ethyl acetate (2:1) and the product was filtered off and dried to obtain 0.14 g (74%) of the desired compound as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4].[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1>>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[CH3:13])=[O:4])[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1c(F)cccc1NC(=O)CCl
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
The subtitle compound was prepared from the product of Example 36 step (i) (14.5 g) and cis-2,6-dimethylpiperazine (9.0 g) by the method of Example 58 step (i) as cream solid. Yield: 11.48 g
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1Br)=[O:4].[Cu](C#N)[C:13]#[N:14]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[C:13]#[N:14])=[O:4]
Reactant: COC(=O)c1sc(C)cc1Br
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc(C)cc1C#N
Temperature: 220 °C
Yield: 74.4 %

Procedure:
A mixture of 3-Bromo-5-methyl-thiophene-2-carboxylic acid methyl ester (0.54 g, 2.3 mmol), and Copper cyanide (0.27 g, 2.99 mmol) in NMP (3 ml) was heated in a microwave at 220° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with aqueous NH4OH, and brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-20% EtOAc in hexane) to give 0.31 g (74%) white solid.
Reaction SMILES: [Br:1]Br.[C:3]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[C:3]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[CH:18]([Br:1])[CH2:17]2)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Oc1cccc2c1C(=O)CC2)c1ccccc1
Reactant: BrBr
Solvent: C1CCOC1
Product: O=C(Oc1cccc2c1C(=O)C(Br)C2)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.1 ml of bromine was added dropwise to a solution of 0.47 g of 7-benzoyloxy-1-indanone in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 30 minutes. To 7-benzoyloxy-2-bromo-1-indanone obtained by evaporation of the solvent was added 15 ml of 2-propanol and 0.33 g of 4-imidazolylthioacetamide hydrochloride, followed by 2.5 hours of heating under reflux. After cooling and evaporation of the solvent, the residue was mixed with ethyl acetate, and extracted with 1N hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residual 4-benzoyloxy-2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole was dissolved in 10 ml of methanol, to the solution was added 1 ml of 5N aqueous sodium hydroxide solution and then stirred at room temperature for 15 minutes. After acidifying with 1N hydrochloric acid, the reaction solution was neutralized with sodium bicarbonate, and extracted with chloroform-methanol, and then the extract was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resultant crude crystals were recrystallized from ethanol to obtain 55 mg of 4-hydroxy-2-(4-imidazolylmethyl)-8H-indeno[1,2-d]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:17])[CH:5]=[N:4]1.[CH3:24]N(C)C=O.[H-].[Na+].CI>C(OCC)C.O>[CH3:1][O:2][C:3]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]([CH3:24])[C:6](=[O:17])[CH:5]=[N:4]1
Reactant: COC1(c2ccccc2)N=CC(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Solvent: O
Product: COC1(c2ccccc2)N=CC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-methoxy-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (920 mg) and dry dimethylformamide (8 ml), sodium hydride (50% suspension in a mineral oil; 156 mg) is added under cooling at -30° C. for 15 minutes. Methyl iodide (842 mg) is added to the mixture, which is stirred at room temperature for 10 minutes. The reaction mixture is poured into icy water, and shaken with diethyl ether. The organic layer is dried over sodium sulfate and evaporated to remove the solvent. The residue is recrystallized from methylene chloride/isopropyl ether to give 5-methoxy-1methyl-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (708 mg) as fine prisms melting at 163 to 164° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>ClCCl.O>[CH3:39][S:36]([O:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COS(C)(=O)=O)COC2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(2-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one (4 g, 10.41 mmol) in dichloromethane (70 mL) at 0° C., were added triethylamine (3.15 g, 31.25 mmol) and mesyl chloride (1.78 g, 15.614 mmol), the resultant reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (3-((2,3-dimethoxy-6-(1-oxo-2,3-dihydro-1H-inden-4-yl)phenoxy)methyl)oxetan-3-yl)methyl methanesulfonate as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CSc1nc(F)cc(F)n1
Solvent: O
Solvent: CCO
Product: CSc1nc(F)cc(NN)n1
Yield: 94.7 %

Procedure:
A solution of 15.8 g (0.097 mol) of 4,6-di-fluoro-2-methylthiopyrimidine in 50 ml of ethanol was added slowly with stirring to a solution of 11.6 ml (12.0 g, 0.214 mol) of hydrazine monohydrate in 100 ml of ethanol, keeping the temperature below 0° C. by external cooling. The mixture was allowed to react for an additional 30 min and the volatiles were then removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate and the resulting solution extracted with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.0 g of the title compound as a white powder melting at 153°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12](O)(=[O:14])[CH3:13].C(OC(=O)C)(=O)C>O>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reaction time: 1 h

Procedure:
To 400 g of 2-amino-5-nitrophenol in a 5-L multi-necked flask equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, 500-mL addition funnel, heating mantle, and a thermocouple attached to a temperature controller was added 1.6 L of acetic acid. The mixture was stirred at 60° C. as 398 g of acetic anhydride was added over 1.5 hours. After 1 hour, another 37 g of acetic anhydride was added. After another 1 hour, the mixture was cooled and diluted with 2 L of water. Solid was collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give 509 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH2:18][CH2:19][CH2:20]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
A mixture of 4-chlorophenylboronic acid (167 mg), 4-(2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (100 mg), pyridine (0.087 mL), diacetoxycopper (130 mg), and cesium carbonate (116 mg) in DMSO (3.0 mL) was stirred at room temperature for 24 hr. The mixture was diluted with water, and extracted with EtOAc (40 mL). The organic layer was washed with 0.1N NaOH aq. (2×40 mL) and then brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give the title compound (23.0 mg) as a white solid.
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[CH:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Li]C1C=CC=CC=1.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[Cl:30][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]=[O:22]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(C=O)c1
Agent: CNCCN(C)C
Agent: [Li]CCCC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(C=O)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a sol. of N,N′,N′-trimethylethylendiamine (2.77 g, 21.4 mmol) in toluene (50 mL) was added BuLi (13.0 mL, 20.8 mmol) dropwise at 0° C. After stirring for 15 min at 0° C., m-anisaldehyde (2.44 g, 20 mmol) was added, and the mixture was stirred 30 min at 0° C. PhLi (30 mL, 60 mmol) was then added at 0° C., and the mixture was stirred at rt for 4 h. The mixture was cooled to −30° C., and 25 mL THF were added followed by hexachloroethane (14.2 g, 60 mmol) in THF (25 mL). The cooling bath was removed and the mixture was stirred for 3 h. Then it was poured with stirring onto aq. 5M HCl (20 mL). The aq. layer was extracted with EtOAc (2×). The combined org. extracts were washed successively with aq. 1M NaOH, aq. 1M HCl, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 5:95→1:9) afforded the desired aldehyde, which was further purified by crystallization (EtOAc/heptane, 0° C.) to give 1.50 g of pure title product. LC-MS: tR=0.88 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:10])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(Br)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.06 g, 5 mmol) in dry N,N-dimethylformamide (10 mL) was charged with sodium hydride (240 mg, 10 mmol) and the mixture was stirred at room temperature for 30 minutes, then methyl 2-bromoacetate (0.84 g, 5.5 mmol) was added and the mixture was stirred at room temperature for 12 hours. After completed (40 mL) of methanol was added followed by concentrating under vacuum to give methyl 2-(2-acetyl-5-bromophenoxy)acetate (1.38 g, 90%) as colorless oil. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 4.73 (s, 2H), 3.81 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[NH:17][C:18](=[O:31])[C:19](=[O:30])[CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:21][C:15]=2[CH:14]=1.C(O)(=O)C.O1CCCC1>O1CCCC1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[NH:17][C:18](=[O:31])[C@H:19]([OH:30])[C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[S:21][C:15]=2[CH:14]=1
Reactant: COc1ccc(C2Sc3cc(Cl)ccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A mixture of L-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (50 ml) is refluxed under nitrogen atmosphere for three hours. The mixture is cooled to -15° C., and thereto is added 8-chloro-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (1113 mg). Each 0.38 ml of 25% acetic acid/tetrahydrofuran solution (1.67 mole as acetic acid) is added thereto at 20 minutes, and 2 hours 20 minutes after the beginning of the reaction, and the reaction solution is stirred at the same temperature for 19 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added 1N hydrochloric acid (70 ml). The precipitated crystal is collected by filtration, washed with water, and dried. The collected crystal is suspended in chloroform (50 ml), and the mixture is heated with stirring at 65° C. The mixture is cooled to 5° C., and allowed to stand overnight. The precipitated crystal is collected by filtration, and dried to give (2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (896 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.ClC1(N)C=CN=CC1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[Br:17][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[NH2:8].[Br:17][C:5]1[C:6]([NH2:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccnc(Cl)c1
Agent: NC1(Cl)C=CN=CC1
Solvent: CC#N
Product: Nc1cc(Cl)ncc1Br
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Chloro-4-amino-pyridine was brominated according to the method described in Synthesis 2001, 14, 2175-2179: a solution of 4-chloro-4-amino-pyridine (12.3 g) in acetonitrile (500 ml) was treated with N-bromosuccinimide (17.8 g) and the resulting solution was stirred at room temperature for 24 hours. The solution was then concentrated in vacuo and the residue subjected to silica gel chromatography (cyclohexane:ethyl acetate 8:2) to afford 3-bromo-2-chloro-4-aminopyridine (12.2 g, m.p. 146° C. (hexane/ether)) and 5-bromo-2-chloro-4-aminopyridine (2.9 g, m. p. 117-119° C.).