Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO.C(O)C>[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:1][C:3]3[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)(=[O:12])=[O:11])=[CH:5][CH:4]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of toluene-4-sulfonic acid 4-formyl-phenyl ester (3.28 g, 11.88 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.45 g, 11.88 mol) in 40 mL of methanol was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. A portion of the crude residue (1.36 g, ˜2.92 mmol) was dissolved in 35 mL of ethanol and was treated with sodium borohydride (0.687 g, 18.16 mmol), which was added in portions over a period of about 3 hr. The reaction was stirred at room temperature overnight at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL of water and 25 mL of saturated sodium bicarbonate. The mixture was extracted three times with methylene chloride and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (2% methanol/methylene chloride to 10% methanol/methylene chloride) afforded 1.06 g (80%) of the title compound. MS 467.1 (M+1)+
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:5].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=CC=1>>[CH-:9]1[CH:10]=[CH:11][CH:6]=[CH:12]1.[CH-:9]1[CH:10]=[CH:11][CH:6]=[CH:12]1.[Zr+2:5]
Reactant: Cc1ccccc1
Reactant: [Zr+4]
Agent: [Cl-]
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
1H NMR (d8-THF): δ 1.4 (d, 12H, Me), 3.22 (s, 4H, bridge CH2), 3.4 (septet, 2H, CHMe2), 5.93 (s, 2H, CH), 6.28 (m, 4H, aromatic CH), 7.08 (t, 2H, aromatic CH), 7.22 (t, 2H, aromatic CH), 7.28 (t, 4H, aromatic CH), 7.66 (d, 4H, aromatic CH) ppm. The dianion was suspended in toluene and cooled to −30° C.; 0.15 g of ZrCl4 (0.64 mmol) were added and the reaction mixture was stirred for 4 hours at 20° C. and then centrifuged. Toluene was discarded and the remaining powder was extracted with CH2Cl2. Centrifugation afforded a mixture of the two isomers rec/meso-1,2-ethylene-bis(1-isopropyl4-phenyl-2-indenyl)zirconium dichloride, about in a 1:1 ratio.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](=O)[NH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1C=CC=C[CH:24]=1>O=P(Cl)(Cl)Cl>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([NH:23][CH3:24])=[N:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: CSc1nn2c(=O)[nH]c(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nc(C)nc2c(S(=O)(=O)c3ccccc3)c(SC)nn12
Temperature: 110 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A suspension of 0.36 g (1 mmol) of 8-benzenesulphonyl-2-methyl-7-methylsulphanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one in 20 ml of POCl3 was treated with 0.12 ml (1.5 mmol) of pyridine and heated 110° C. for 3 hrs. The reaction solution was cooled to RT and evaporated. The residue was dried azeotropically twice with 50 ml of toluene each time. The thus-obtained residue was taken in 10 ml of 2N methylamine in tetrahydrofuran and stirred at room temperature for 4 hrs. The reaction solution was evaporated and partitioned between H2O and AcOEt. The organic phase was washed with H2O and sat. NaCl solution, dried (MgSO4), filtered and evaporated. Chromatography (SiO2, AcOEt/hexane 1:1) yielded 0.28 g (80%) of (8-benzenesulphonyl-2-methyl-7-methylsulphanyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl)-methylamine as white crystals, m.p. 285° (dec).
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([OH:18])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CC(C)=O>[Cl:1][C:2]([F:19])([F:20])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:28]([CH3:30])[CH3:29])[CH:4]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC(C)C)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 88.9 %

Procedure:
A mixture of 15.0 g (0.047 mol) of product of Example 3, 6.5 g (0.047 mol) of K2CO3 and 5.2 ml (0.052 mol) of 2-iodopropane in 100 ml of acetone was stirred at reflux for 64 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in ether, washed with H2O, dried (MgSO4), and concentrated in vacuo to a brown oil which was kugelrohr distilled at 68 Pa, pot temperature 90° C., affording 15.11 g (88.9%) of product as a clear oil, nD25 1.4405.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH2:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]>CO>[Br-:1].[Br-:1].[CH2:9]([N+:12]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:12]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH3:11])[CH2:10][CH3:11]
Reactant: CCCN(CCC)CCC
Reactant: BrCCCCCCBr
Solvent: CO
Product: CCC[N+](CCC)(CCC)CCCCCC[N+](CCC)(CCC)CCC
Product: [Br-]
Reaction time: 24 h

Procedure:
N,N,N,N',N',N'-Hexapropylhexamethylenediammonium dibromide was synthesized by refluxing 100 grams (0.4 mole) of 1,6-dibromohexane with 140 grams (0.98 mole) of tripropylamine in 200 cc of methanol. The reaction took 24 hours and an oil was precipitated by addition of ether. The oil was redissolved in dimethylformamide. Addition of ether precipitated a white solid, which was separated from the liquid by filtration. It was washed with ether and dried at 50° C. in a vacuum. The composition of the product included:
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([C:12]3[N:13]4[CH2:19][CH2:18][N:17]=[C:14]4[S:15][CH:16]=3)=[CH:9][CH:10]=[CH:11][C:4]1=2>ClCCl>[BrH:1].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([C:12]3[N:13]4[CH2:19][CH2:18][N:17]=[C:14]4[S:15][C:16]=3[Br:1])=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: C1=C(c2cccc3sccc23)N2CCN=C2S1
Reactant: BrBr
Solvent: ClCCl
Product: Br
Product: BrC1=C(c2cccc3sccc23)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (0.30 ml) in dichloromethane (15 ml) was added dropwise under nitrogen at 0-5° C. to a stirred solution of 3-(benzo[b]thiophen-4-yl)-5,6-dihydroimidazo[-2,1-b]thiazole (1.45 g) in dichloromethane (40 ml), then the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration, washed with dichloromethane (20 ml) and dried in vacuo at 40-50° C. to give 3-(benzo[b]thiophen-4-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (2.3 g) as a pale yellow solid, m.p. 229-235° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2C(SC)=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])[N:10]=2)=[C:5]([CH3:24])[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:3]1=[O:35].[Na].[CH3:37][S:38]([OH:40])=[O:39].[CH3:41]N(C)CCN>CS(C)=O.C(OCC)(=O)C.C1C=CC=CC=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+].[Cu+]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:37]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])[N:10]=2)=[C:5]([CH3:24])[N:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[C:3]1=[O:35]
Reactant: CSc1cn(-c2cccc(C#N)c2)nc1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Reactant: CN(C)CCN
Reactant: CS(=O)O
Agent: [Cu+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1c(-c2nn(-c3cccc(C#N)c3)cc2S(C)(=O)=O)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 41.4 %

Procedure:
To a solution of the compound prepared in Example 269 (2.84 g) in dimethyl sulfoxide (9.8 ml) were added methanesulfinic acid sodium (2.00 g), copper trifluoromethanesulfonate benzene complex (1.24 g), N,N-dimethylethylenediamine (529 mg) and the resulting mixture was stirred at 110° C. for seven hours. The reaction mixture was diluted with ethyl acetate (300 ml), and the organic layer was washed with 10% ammonia water (50 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile (1.25 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([F:31])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonyltryptophan (1.2 g, 4 mmol) and pyridine (0.35 ml, 4 mmol) in methylene chloride (10 ml) is dropped cyanuric fluoride (0.72 ml, 36 mmol) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonyltryptophan fluoride.
Reaction SMILES: C1C=CC(COC([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1.[H][H]>CO.[Pd]>[CH:16]1[CH:15]=[CH:14][C:13]([C@@H:12]([NH2:11])[C:19]([OH:21])=[O:20])=[CH:18][CH:17]=1.[CH3:22][N:23]1[CH2:24][CH2:25][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:28]1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CN1CCC(C2CCN(C(N)=O)CC2)CC1
Solvent: CO
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
A vigorously stirred solution of CBz-D-phenylglycine-4-(1-methylpiperidin-4-yl)piperidinamide (1.1 g, 2.45 mmol) in methanol (120 ml), containing Palladium on carbon (200 mg ) was treated with hydrogen gas (balloon) at atmospheric pressure overnight. The reaction mixture was filtered through celite and concentrated to yield the title compound as a colourless oil (585 mg, 76%).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C(Cl)(=O)C>N1C=CC=CC=1>[CH3:19][O:18][C:16]1[N:17]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=2)[CH:13]=[C:14]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:15]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNc2cc(-c3cccc(NC(C)=O)c3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine acetate [156 mg, 0.38 mmol, Example 2] in pyridine (1.3 mL) is added acetyl chloride (32 μL, 0.45 mmol). The reaction mixture is stirred for 3 hours at ambient temperature, quenched with the addition of water (20 mL), and extracted three times with EtOAc (20 mL). The combined extracts are washed four times with aqueous copper sulfate solution (10 mL), with water (10 mL), with brine (10 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica gel (4.5 g) eluting with 3% MeOH in DCM to afford N-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetamide [51 mg, 34%, Example 6(b)]. LCMS: RT=2.3 minutes, MS: 393 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([CH3:17])=[CH:10][C:9]2[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-dimethylamino-4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M87) (0.32 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (140 mg, 57%).
Reaction SMILES: C[O:2][C:3]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:4]=1[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=O.[OH:27]O.O>C(O)(=O)C>[CH3:23][O:22][C:21]1[C:3](=[O:2])[C:4]([CH2:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:18]([CH3:26])[C:19](=[O:27])[C:20]=1[O:24][CH3:25]
Reactant: OO
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
9-(2',3',4'-Trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=Y=H3CO, X=H, n=8, in the free form) (0.09 part) was reduced with zinc amalgam (0.2 part) by a procedure similar to that described in Example 10 and oxidized with 30% hydrogen peroxide (10 volume parts) in acetic acid. Following the addition of water, the reaction mixture was extracted with diethyl ether (500 volume parts) and the extract was washed with water and dried. The ether was then removed by distillation. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13].[C:25](Cl)(=[O:27])[CH3:26].O>ClCCl>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:25](=[O:27])[CH3:26])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COCCOCC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a suspension of NaHCO3 (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5° C. The mixture was stirred overnight at 15° C. and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5.0 g, 87%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH2:14][CH3:15].C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[OH:3][C:4]1[C:9]([CH:10]=[CH:11][CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:16])[CH:14]=[CH:15][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC=Cc1cccc(C(=O)CC)c1O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=Cc1cccc(C(=O)C=Cc2ccccc2)c1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
60 ml of 50% (w/v) sodium hydroxide was added dropwise during 30 minutes to a solution of 17.6 g of a 7:3 E-Z mixture of 2'-hydroxy-3'-(1-propenyl)propiophenone (prepared as described in R. E. Ford. et al., J. Med. Chem., 29,538, (1986)) and 10.82 g of benzaldehyde in 73 ml of ethanol stirred at 0° C. The temperature of the reaction mixture was raised to 25° C. and stirring was continued for 4 hours. After standing at room temperature overnight, 150 ml of water was added, followed by dropwise addition of 95 ml of 37% hydrochloric acid under stirring at O° C. The precipitated solid was filtered by suction, washed with water and desiccated, yielding 26.8 g of 1-[2-hydroxy-3-(1-propenyl)phenyl]-3-phenyl-2-propen-1-one. This material was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:48]=[CH:49][CH:50]=1)[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[S:37][C:33]=2[C:32]=1[C:46]#[N:47]>O1CCCC1.C(OCC)(=O)C>[C:46]([C:32]1[C:33]2[S:37][C:36]([NH:38][C:39]([CH:41]3[CH2:42][CH2:43]3)=[O:40])=[N:35][C:34]=2[CH:44]=[CH:45][C:31]=1[O:30][C:29]1[CH:28]=[C:27]([NH:26][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=2)[CH:50]=[CH:49][CH:48]=1)#[N:47]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1c(Oc2cccc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzoic acid (70 mg, 0.339 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (90 mg, 59%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1)#[N:2].[C:12](=[O:22])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13].[C:23]1([O:29][P:30]([O:38]C2C=CC=CC=2)[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([NH:13][CH:10]([P:30]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:38])[O:29][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(CC=O)cc1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
This compound was synthesized from crude 4-cyanophenylacetaldehyde, benzyl carbamate, and triphenylphosphite using a modification of the previously described amidoalkylation procedure.9Benzyl carbamate (6.1 g, 40 mmole) and 4-cyanophenylacetaldehyde (4.7 g, 32 mmole) were dissolved in 50 mL toluene and refluxed for 1 h. The toluene was evaporated, glacial acetic acid (10 mL) and triphenyl phosphite (8.5 mL, 32 mmole) were added to the residue, and the mixture was heated at 80 ° C. for 2 h. The volatile materials were removed by evaporation in vacuo and the resulting oil was dissolved in 50 mL methanol. The solution was refrigerated overnight and the white precipitate was filtered, dried, and recrystallized from 50 mL hot methanol. The undissolved product was discarded, and the filtrate was cooled down to give white crystals, yield 25-35%; mp 136°-137° C.; 1H NMR (DMSO) δ8.20 (d, 1H), 7.75 (d, 2H), 7.54 (d, 2H), 7.35 (m, 5H), 7.3-7.1 (m, 10H), 4.95 (q, 2H), 4.60 (m, 1H), 3.4-3.0 (m, 2H); MS (FAB+) m/e 513 (m+1). Anal. (C29H25N2O5P) C, H, N.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)[CH3:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].[ClH:29]>CO.O.CS(C)=O>[OH2:15].[ClH:29].[ClH:29].[CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCN(CC)CCC(=O)Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 165 °C

Procedure:
A mixture of 50.0 g (0.211 mol) 4-(diethylamino)-1-(4-fluorophenyl)butanone, 29.0 g (0.42 mol) imidazole, 58.24 g (0.42 mol) anhydrous potassium carbonate and 50 mL dimethylsulfoxide is heated to 150° C. for 18 hr and to 165° C. for 3 hr. After this time, the mixture is treated with 500 mL H2O and is extracted with 2×400 mL methylene chloride. The organic layers are washed with 5×300 mL water. The organic layer is dried over sodium sulfate, filtered and the solvent evaporated to provide crude title compound as free base. This material is dissolved in 200 mL methanol, acidified to pH=1 with hydrochloric acid (gas) and the solvent removed in vacuo. The residue is recrystallized from methanol-isopropanol (2/3) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[OH:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]2=[O:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reaction time: 15 h

Procedure:
tert-Butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate obtained in Example (77b) (300 mg, 0.80 mmol) was dissolved in DMSO (3 mL). Triethylamine (1.2 mL, 8.61 mmol) and sulfur trioxide-pyridine complex (737 mg, 4.63 mmol) were added, and the mixture was stirred for 15 hours. Ethyl acetate was added, to the reaction solution. This was washed with 5% saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.