Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH2:27][CH3:28])[CH3:26]>CN(C)C=O>[CH:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH2:27][CH3:28])[CH3:26]
Reactant: CCC(C)Br
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 80.9 %

Procedure:
12 g of 7-hydroxy-isoflavone are boiled for 2 hours under reflux condenser with 10 g of potassium carbonate and 9 g of sec-butyl bromide in 40 ml of dimethyl formamide. On pouring the reaction mixture on water, the separated product is recrystallized from acetone, yielding 12 g of 7-sec-butyloxy-isoflavone, m.p. 87°-89° C. In a similar way, also 7-sec-butyloxy-2-methyl-isoflavone, m.p. 107°-109° C., and all the other isoflavone derivatives described in Example 7 can be prepared.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([C:44]([C:40]4[N:39]([CH3:38])[CH:43]=[CH:42][CH:41]=4)=[O:45])[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: Cn1cccc1C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2cccn2C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (1-methyl-1H-pyrrol-2-yl)-piperazin-1-yl-methanone (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C39H45Cl2N6O3 [(M+H)+] 715.2925, observed 715.2926.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH:43]([Mg]Br)([CH3:45])[CH3:44].C(OCC)(=O)C>O1CCCC1>[OH:37][CH:36]([CH:43]([CH3:45])[CH3:44])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(C)C)CC2)c2ccnn12
Reaction time: 1.5 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.57 g) in tetrahydrofuran (5 mL) was added dropwise isopropylmagnesium bromide (1 M tetrahydrofuran solution, 2 mL) at 0° C., and the mixture was stirred for 1.5 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL), sodium borohydride (0.04 g) was added, and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.31 g, 56%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([C:7]1[N:8]=[C:9]([NH:21][CH:22]([CH3:24])[CH3:23])[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5]>O1CCOCC1.[OH-].[Na+]>[C:16]([N:14]1[C:13](=[O:20])[N:11]2[CH:12]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:25])=[O:2])[N:8]=[C:9]([NH:21][CH:22]([CH3:23])[CH3:24])[C:10]2=[N:15]1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1nc(C(C)(C)C(=O)O)cn2c(=O)n(C(C)(C)C)nc12
Reaction time: 72 h

Procedure:
A solution of 160 mg of the product of Step A in 1,4-dioxane (5.0 mL) and 6N NaOH (1.0 mL) was warmed to 50° C. After three days, the solvents were removed and the residue was dissolved in water and extracted with chloroform. The pH of the aqueous layer was adjusted to 3 with 2N HCl and then extracted with 9:1 chloroform/IPA (3×). The organic extracts were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to afford 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid as a white solid. MS (M+H+)=336.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(F)c2[nH]1
Product: CCOC(=O)c1cc2c(Cl)ccc(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+) and αD20=−54.7, was prepared in accordance with the general method of example 12b) from 4-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([CH:12]([OH:24])[C:13]#[C:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:4][CH2:3]1>CCCCC.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:32])[C:11]2[CH:10]=[C:9]([C:12](=[O:24])[C:13]#[C:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:4][CH2:3]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCC
Solvent: ClCCl
Product: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1
Temperature: 37 °C
Yield: 20 %

Procedure:
0.1 g (0.237 mmol) of 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthyl)-3-hydroxyprop-1-ynyl]benzoic acid (described in Example 15d) is dissolved in 2 ml of pentane and 2 ml of dichloromethane, 0.31 g (3.55 mmol) of manganese dioxide is then added and the medium is heated at 37° C. for 24 hours. The medium is filtered and concentrated, and the residue obtained is purified by chromatography (eluent: 85/15 heptane/ethyl acetate). A white solid is obtained (0.02 g; yield=20%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl>CN(C)C=O.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[C:8]([NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:21]=[CH:20][CH:19]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cccc(C(=O)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Dimethylcarbamoyl chloride (7.5 grams, 0.07 mole) was added to a solution of 3-aminobenzophenone (10 grams, 0.05 mole) in dimethylformamide (150 ml.), triethylamine (10 ml.) at 10° C. with stirring and ice cooling. The reaction temperature was next raised to 60° C. for 20 hours, then cooled and poured onto ice water (500 grams) containing dilute hydrochloric acid. A tarry solid was obtained by decanting off the aqueous organic solution. Purification was effected by dissolving the tarry solid in methylene chloride and passing through a silica gel dry column eluant methylene chloride. On elution with dichloromethane, the product, 3-(m-benzoylphenyl)-1,1-dimethyl urea, is obtained. Melting point was 104° -105° C. Crystallization from benzene-hexane (9:1) mixture gave solid 109° - 110° C., which on benzene-hexane crystallizations afforded a melting point of from 121° to 122° C. identified as the desired urea by comparison with the sample prepared from phosgene and dimethylamine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ncnc(F)c1F
Reactant: CC#CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of tetrahydrofuran, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.52 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15]I.[CH3:17][CH2:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][CH3:23].[Li]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:20]([C:19](=[O:25])[CH2:18][CH3:17])[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)CC(=O)CC
Reactant: COc1cc(Cl)ccc1C=CCCCCI
Agent: [Li]
Product: CCC(=O)C(CCCCC=Cc1ccc(Cl)cc1OC)C(=O)CC

Procedure:
4-[6-(2-Methoxy-4-chlorophenyl)-5-hexenyl] -3,5-heptanedione was prepared from 84 g. of 6-(2-methoxy-4-chlorophenyl)-5-hexenyl iodide and lithium 3,5-heptanedione (from 42 g. of 3,5-heptanedione and 2.6 g. of lithium hydride in 400 ml. of dimethylformamide). The product was chromatographed on silica gel and eluted with ethyl acetate-hexane 1:4 to give 56 g. of oil used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3S[CH2:22][CH2:21][C:16]=3[N:17]=[C:18]([Cl:20])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>C1COCC1.C(N(CC)CC)C.[Pd].[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH2:21][CH3:22])[N:17]=[C:18]([Cl:20])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Agent: [Ni]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
200 mg palladium charcoal was added to 200 mg 4-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL THF and 0.08 mL triethylamine. Raney-nickel and 5 mL ethanol was added and the reaction was stirred 24 h at 50° C. and 3 bar hydrogen. The mixture was filtered. The filtrate was evaporated and the residue was purified by HPLC to give 20 mg desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:22][CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Reactant: O=C(O)CCI
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC(=O)O)[C@H]1OC(C)=O
Reaction time: 16 h
Yield: 87 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (1.49 g, 4.87 mmol) and freshly crystallized 3-iodopropionic acid (0.97 g, 4.86 mmol) in dichloromethane (20 ml) containing triethylamine (1.35 ml) is kept for 16 hours at room temperature. Hydrochloric acid (2.5 N, 20 ml) and dichloromethane (10 ml) are added and the solution is washed with water, dried, and evaporated in vacuo to a residue that is put on a column of silica gel and eluted with chloroform-methanol-water, 92.5:7.5:0.75 (v/v/v). Compound 23 is isolated in 87% yield (1.6 g), and used, without further purification, for the preparation of 24.
Reaction SMILES: [Br:1]Br.[S:3]1[C:11]2[C:6](=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:5]1[C:6]2=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[S:3][CH:4]=1
Reactant: BrBr
Reactant: COC(=O)c1cc2sccc2nc1C(=O)OC
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2scc(Br)c2nc1C(=O)OC
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of bromine (20 g, 0.125 mol) in acetic acid (50 mL) is added dropwise over three hours to a solution of dimethyl thieno[3,2-b]pyridine-5,6-dicarboxylate, (26.3 g, 0.104 mol), containing sodium acetate (17.2 g, 0.2 mol) in acetic acid (300 mL) at 85° C. Additional sodium acetate (18 g) and bromine (20 g) in acetic acid (50 mL) is added over an hour and the mixture stirred at 85° C. overnight. Bromine (10 g) is added in one portion then left at 85° C. for four hours. The mixture is cooled and treated with aqueous sodium bisulfite, diluted with ethyl acetate and concentrated. The reaction product is partitioned between water and methylene chloride and the organic layer washed with aqueous sodium chloride and the solvent removed. The residue is washed with ether to give 25 g of crude product, mp 165°-168° C. Recrystallization from methanol gave needles of dimethyl 3-bromothieno[ 3,2-b]pyridine-5,6-dicarboxylate, mp 168°-169° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[N:23]=[C:22]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][CH:19]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:23]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1Nc1cccc(CN2CCOCC2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (Example 1, Step 1) (83 mg, 0.33 mmol), 4-[(6-bromopyridin-2-yl)methyl]morpholine (84 mg, 0.33 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), X-PHOS (23 mg, 0.05 mmol), and potassium carbonate (50 mg, 0.36 mmol). The tube was evacuated, and backfilled with argon three times. Fully degassed tert-amyl alcohol (0.8 mL) was added to the reaction vessel, which was sealed and left to stir at 100° C. overnight. The reaction vessel was cooled to room temperature, taken up in ethyl acetate and washed with 100 mL saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated into a sealed tube. To the tube was charged Pd2(dba)3 (18 mg, 0.02 mmol), X-PHOS (46 mg, 0.1 mmol), and potassium carbonate (100 mg, 0.72 mmol). The tube was evacuated, and backfilled with argon three times. Fully degassed tert-amyl alcohol (0.8 mL) was added to the reaction vessel, which was sealed and left to stir at 100° C. overnight. The reaction vessel was cooled to room temperature, taken up in ethyl acetate and washed with 100 mL saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. To the filtrate was added 1.0 g of silica gel and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound. 1H NMR (500 MHz, d6-DMSO): δ 11.29 (s, 1H), 7.96 (d, 2H), 7.79 (s, 1H), 7.70 (t, 1H), 7.60 (s, 1H), 7.53 (d, 2H), 7.07 (d, 1H), 7.02 (d, 1H), 3.67 (s, 2H), 3.59 (m, 4H), 2.46 (m, 4H). LRMS (APCI) calc'd for C20H21ClN5O2S [M+H]+: 430.1, found 430.0.
Reaction SMILES: N[C@H](C(O)=O)C(C)(C)C.[BH4-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:26](=[O:27])[C:25](=[O:28])[NH:24][C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=3[S:21]2)=[CH:16][CH:15]=1>O1CCCC1>[OH:27][C@H:26]1[C:25](=[O:28])[NH:24][C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[S:21][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2=O)cc1
Agent: CC(C)(C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A reducing agent is prepared in the same manner as in Example 9 from a mixture of L-tert-leucine (721 mg), sodium borohydride (189 mg) and tetrahydrofuran (50 ml), and the reaction mixture is cooled to -15° C. To the mixture is added 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (997 mg), and the acid listed in the following Table 1 is added thereto at 30 minutes and 2 hours thereafter (totality: 3.33 mmole), and the reaction is carried out at the same temperature. After confirming by HPLC that the starting compound is completely consumed, the mixture is treated in the same manner as in Example 9 to give (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. The yield, optical purity of the cis-compound and content of the trans-compound are as shown in the following Table 1.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>CO>[O:4]=[C:3]1[NH:18][C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:17]=[C:2]1[CH2:1][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1N
Solvent: CO
Product: COC(=O)Cc1nc2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl acetylenedicarboxylate (31.2 g., 0.22 mol.) was added slowly to a solution of o-phenylenediamine (21.6 g., 0.2 mol.) in methanol (400 ml.). The reaction mixture was stirred at room temperature for three hours and then cooled in an ice bath. The yellow solid was collected and washed with cold methanol. The solid was recrystallized from tetrahydrofuran (27.7 g., m.p. 230-232° dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=C[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.NN.[CH2:21](O)[CH3:22]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:17]=[CH:18][C:13]3[N:12]([C:21]([CH3:22])=[N:15][N:14]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc(-c2nnc3cccnn23)c1
Agent: [Pd]
Agent: NN
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Temperature: 20 °C

Procedure:
A 103.0 g portion of 3-methyl-6-(3-nitrophenyl-1,2,4-triazolo[4,3-b-]pyridazine and 1.0 g of 10% palladium on carbon were suspended in 2 liters of ethanol. The mixture was heated to reflux and 140 ml of anhydrous hydrazine added via a syringe pump over 24 hours. The solution was cooled to 20° C., filtered and the filtrate concentrated in vacuo. The residue was dissolved in 3 liters of hot dichloromethane and passed through a short column (200 g) of hydrous magnesium silicate with dichloromethane as the eluent. The fractions containing product were combined and evaporated, giving 83 g of the desired compound as yellow needles, mp 206°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:18]=[CH2:19])=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl[Pd+]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [CH2-]c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=Cc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.21 g) was suspended in toluene (5 mL) and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (45 mg) was added, followed by tributylvinyltin (0.23 mL). The resulting mixture was stirred at reflux for 17 hours, cooled to room temperature, poured into saturated aqueous ethylenediaminetetraacetic acid (10 mL), and extracted with tetrahydrofuran:ether (1:1). The combined extracts were dried and evaporated to yield a yellow powder. Chromatography, with chloroform as the eluent, yielded the title compound as a white powder (80 mg); mp 212°-214° C. (dec); NMR: 11.44 (s,1), 7.55 (m,1), 7.30 (m,2), 6.69 (dd,1, J=17.7, 11.6), 5.90 (dd,1, J=17.7, 1.8), 5.52 (dd,1, J=11.5, 1.8), 3.8 (s,3). Analysis for C13H10ClNO3.0.2 H2O: Calculated: C, 58.42; H, 3.92; N, 5.24: Found: C, 58.48; H, 3.87; N, 5.06.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:21])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:20].O.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[CH3:21][N:7]([CH3:6])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][C:17]([CH:27]=[O:28])=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A stirred solution of N,N-dimethylformamide (2 ml) was added dropwise slowly with phosphorus oxychloride (104 μl, 1.1 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (221 mg, 1 mmol) in 1.2 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (15 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (105 mg, 38%) as a pink oil which was used as such.