Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I>CC#N.[Ag]=O>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([O:28][CH3:34])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CC(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(=O)CC(OC)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (E)-6-(1,3-dihydro-4-tert -butyldimethylsilyloxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-4-methyl-4-hexenoate (974 mg) was dissolved in a 6:1 mixture of methyl iodide in CH3CN (25 ml). Silver oxide was then added (5.1 g) and the mixture heated at reflux for 24 hr. The mixture was cooled to room temperature and filtered through a bed of celite. The celite was washed with CH2Cl2 (80 ml) and ethyl acetate (80 ml). The combined organic layers were evaporated to dryness and the residue passed through a flash column (silica gel, hexanes-EtOAc 8:2) to afford 601 mg (60%) of ethyl (E)-6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -3-methoxy-4-methyl-4-hexenoate the product as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24](=[NH:41])[NH2:25])=[CH:22][CH:23]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)C1CCCC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:22]1[CH:23]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)[S:20][CH:21]=1
Reactant: Cc1csc(OB([O-])[O-])c1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
In toluene/ethanol/water (10/1/1) (8.4 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), and to the mixture were added 4-methyl-2-thienyl borate (334 mg) and potassium carbonate (651 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (97 mg). The mixture was stirred at 100° C. for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=8/1) to give methyl 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (432 mg).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31]C(=O)OC(C)(C)C)[CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=3)=[C:3]3[CH2:16][CH2:15][CH2:14][N:4]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCC3)ccn1
Temperature: 150 °C

Procedure:
3-bromo-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (700 mg, 2.5 mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (727 mg, 2.27 mmol, 1.1 eq) are dissolved in 10 mL 1,4-dioxan. To this mixture is added Bis(tricyclohexylphosphine)palladium(II)-dichloride (168 mg, 0.22 mmol, 0.1 eq) and 5.4 mL sodium carbonate solution (2 molar). The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 12 mins at 150° C. in the microwave (Biotage). After cooling, insoluble components are filtered off over Celite and the residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by column chromatography over silica gel using dichloromethane/methanol (95:5) as eluent. After evaporation of the solvents 530 mg (72%) of 4-[2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]pyridin-2-amine are obtained as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:17][C:18]([C:20]([O:22]C)=[O:21])=[CH2:19])(=[O:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:17][C:18]([C:20]([OH:22])=[O:21])=[CH2:19])(=[O:15])[OH:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
To a solution of 341 mg (1 mmol) of [1-(benzyloxycarbonylamino)-ethyl](2-methoxycarbonyl-2-propenyl)phosphinic acid in methanol (20 ml) and H2O (8 ml), was 1N NaOH (2.2 ml, 2.2. mmol) and the mixture was refluxed for 3 hours. After evaporation of methanol, the aqueous layer was washed with chloroform twice and then acidified with 2N HCl. The aqueous solution was extracted with chloroform four times and the combined organic layer was dried over anhydrous magnesium sulfate. Filtration followed by evaporation gave 330 mg (yield 100%) of [1-(benzyloxycarbonylamino)ethyl](2-carboxy-2-propenyl)phosphinic acid. The obtained above phosphinic acid (163 mg, 0.5 mmol) and sodium iodide (300 mg, 2 mmol) were dissolved in acetonitrile (3 ml). Then trimethylsilyl chloride (0.25 ml) was added and the mixture was stirred at room temperature for 6 hours. H2O was added and the mixture was washed with chloroform eight times and adjusted at pH 4 by the addition of saturated sodium carbonate solution. After evaporation to dryness, ethyl acetate (10 ml) was added and the precipitate was filtered. It was dissolved in methanol (10 ml) and the insoluble material was filtered off. Methanol was evaporated and the residue was purified by reversed-phase column chromatography (C-18, eluted with H2O) to give 60 mg (yield 62%) of (1-aminoethyl)(2-carboxy-2-propenyl)phosphinic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)CCc1ccccc1

Procedure:
Following General Procedure A′ above and using 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of from 51°-54° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:31][NH2:32]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2occc2c1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2occc2c1
Temperature: 85 °C
Yield: 49 %

Procedure:
To a stirred solution of 4-(2-(benzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl) but-1-enyl)phenol (480 mg, 1.0 eq) in 15 mL MeOH was added 5 mL CH3NH2 (aq) and the mixture was heated at 85° C. for 48 h. The organic solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (230 mg, 49%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 4.11 (t, J=4.8 Hz, 1H), 3.92 (t, J=4.8 Hz, 1H), 3.01 (t, J=5.2 Hz, 1H), 2.89 (t, J=5.2 Hz, 1H), 2.45-2.54 (m, 5H), 0.89-0.94 (m, 3H); m/z=414[M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([F:10])[C:7]3[O:11][C:12]4[C:17]([C@@:18]5([CH2:23][CH2:22][O:21][C:20]([NH2:24])=[N:19]5)[C:6]=3[CH:5]=2)=[CH:16][C:15]([NH2:25])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.C(N(CC)CC)C.CCCP(=O)=O>CCOC(C)=O>[NH2:24][C:20]1[O:21][CH2:22][CH2:23][C@:18]2([C:6]3[CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:9]=[C:8]([F:10])[C:7]=3[O:11][C:12]3[C:17]2=[CH:16][C:15]([NH:25][C:33](=[O:34])[C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][N:31]=2)=[CH:14][CH:13]=3)[N:19]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2CC2)nc1F
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(C2CC2)nc1F
Reaction time: 0.02 h
Yield: 12.2 %

Procedure:
To a solution of (S)-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.0864 g, 0.254 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.044 g, 0.279 mmol) in EtOAc (2 mL) was added triethylamine (0.106 ml, 0.762 mmol). The mixture was stirred for one minute and propylphosphonic anhydride solution, 50 wt. % in ethyl acetate (0.302 ml, 0.508 mmol) was added. Stirring continued for 1 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.015 g, 0.031 mmol, 12.31% yield). MS m/z=480.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>CO>[C:29]([NH:33][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)(C)C)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (2.1 g, 5.47 mmol) and tert-butyl amine (1.75 mL, 16.4 mmol) in dry methanol (130 mL) were reacted in a similar manner to that described under 34 to afford 40. Yield 2.1 g (84%); mp 119-120° C.; MS (FAB) 458 (M++1); IR (KBr) 3403, 1631; 1H NMR (200 MHz, CDCl3) δ 8.11 (d, J=9.5 Hz, 1H), 7.10 (s, 2H), 7.02-6.99 (m, 2H), 6.70 (s, 1H), 4.14-4.11 (m, 3H), 3.96 (s, 6H), 3.93 (s, 3H), 2.86-2.81 (m, 2H), 1.14 (s, 9H). Analysis Calcd for C25H31NO7: C, 65.63; H, 6.83; N, 3.06. Found: C, 65.47; H, 6.77; N, 3.12.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:38]=[CH:37][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(OCCN2CCNCC2)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCNCC4)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (80 mg, 0.15 mmol), 1-(2-(4-bromophenoxy)ethyl)piperazine (86 mg, 0.30 mmol), 2.0M aqueous potassium carbonate (0.50 mL, 1.0 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue, which was purified by preparative TLC to give the title compound (40 mg, 40% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ8.50 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.00 (m, 2H), 4.20 (m, 2H), 3.90 (s, 3H), 2.99 (m, 4H), 2.85 (m, 2H), 2.60 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17]1
Reactant: CC1CCCNC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 13.9 %

Procedure:
6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 14%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 3-methylpiperidine (0.21 g, 1.92 mmol) according to the general procedure of Example 2.
Reaction SMILES: S(C1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.CC([O-])(C)C.[K+].O.[CH3:19][CH2:20][O:21][C:22]([CH3:24])=O>C1COCC1>[CH:10]([C:8]1[C:9]2[CH2:19][CH2:20][O:21][C:22]=2[CH:24]=[CH:6][CH:7]=1)=[CH2:11]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc2c1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The Part C tosylate (100 g, 314 mmol) was dissolved in THF (1200 mL) in a 2000 mL three-neck round bottomed flask equipped with a mechanical stirrer, a digital thermometer, and a pressure equalizing addition funnel at room temperature. The reaction mixture was cooled to 0° C. by an ice-water bath. To this was added a solution of t-BuOK (1 M, 345.5 mL) in THF dropwise at 0° C. over a period of 110 min. The reaction mixture was warmed to ambient temperature and stirred for additional 2 hr. Water (350 mL) and EtOAc (600 mL) were added and the two layers were separated. The aqueous layer was further extracted with EtOAc (2×150 mL). The combined EtOAc layers were washed with brine (2×150 mL) dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give 46 g of the title styrene in 100% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1
Reactant: CN(C)[C@H]1CC[C@H](CN)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)[C@H]1CC[C@H](CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (537 mg, 1.73 mmol) was reacted with trans-4-(aminomethyl)-N,N-dimethylcyclohexanamine (595 mg, 2.60 mmol) to afford the desired product (440 mg, 59%) as a white solid: 1H NMR (300 MHz, CH3OD) δ 9.13 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.83 (dd, J=9.0, 2.0 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 3.65 (d, J=6.4 Hz, 2H), 2.91-2.67 (m, 1H), 2.41-2.18 (m, 7H), 1.99 (d, J=10.1 Hz, 4H), 1.67 (d, J=3.3 Hz, 1H), 1.43-0.99 (m, 8H).
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C(OC)=O.CO>O>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:18]=[N+:19]=[N-:20])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)COc1ccc(-c2ccccc2)cc1
Yield: 86.5 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 3.00 g of 4-phenylphenoxymethyloxirane (prepared as described in Preparation 82), 4.23 g of sodium azide, 15 ml of methyl formate and 90 ml of an 8:1 by volume mixture of methanol and water were used, to give 3.09 g of the title compound, melting at 72.2° to 73.9° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]>CO.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[C:1]([O:5][C:6](=[O:15])[CH2:7][C@H:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(=O)CC(=O)OC(C)(C)C
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: CCCCC[C@@H](O)CC(=O)OC(C)(C)C
Reaction time: 42 h
Yield: 90.5 %

Procedure:
The 3-oxooctanoic acid t-butyl ester (4.50 g, 21.0 mmol) obtained in Production Example A-1 and dichloro [(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium (II) (hereunder abbreviated as (R)-BINAP-RuCl2) (40 mg, 50.3 μmol) were dissolved in methanol (10 ml) freeze-degassed with liquid nitrogen. The obtained methanol solution was stirred for 42 hours using an autoclave (SUS-316; Taiatsu) at room temperature under 60 atm of hydrogen. The reaction solution was then condensed, and purified using column chromatography (silica gel: 150 g, n-hexane/ethyl acetate=10/1) to produce the target compound (4.11 g, 89%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH2:23][C:24]1[N:28]([CH3:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=1)[C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.Cl>O1CCCC1>[CH3:29][N:28]1[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[C:24]1[CH2:23][N:5]([CH2:4][CH:3]=[O:2])[C:6](=[O:22])[O:7][CH2:8][CH:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: COC(CN(Cc1nc2ccccc2n1C)C(=O)OCC1c2ccccc2-c2ccccc21)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(CN(CC=O)C(=O)OCC2c3ccccc3-c3ccccc32)nc2ccccc21
Temperature: 75 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of the product of Example 148B (0.2 g) in tetrahydrofuran (0.2 mL) was treated with 30% HCl (0.2 mL), stirred at 75° C. for 6 hours, cooled to 25° C. and concentrated. The residue was partitioned between 10% NaHCO3 and ethyl acetate, the organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (175 mg).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([CH3:39])[C:34]([O:36]CC)=[O:35])[CH:27]=[C:28]([F:31])[C:29]=1O>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:29]3[C:28]([F:31])=[CH:27][C:26]([CH2:32][CH:33]([CH3:39])[C:34]([OH:36])=[O:35])=[CH:25][C:24]=3[F:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CC(Cc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1)C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (prepared according to PCT Application WO2010/048207A2) followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.81 (d, J=9.6 Hz, 2H), 5.18 (s, 2H), 2.88-2.93 (m, 1H), 2.51-2.59 (m, 2H), 1.11 (d, J=6.3 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for: C21H15ClF5NO3S: 492.0 (M+H). found 492.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[N:23]([CH3:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5cccc(C)c5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5c(C)cccc5n(C)c4=O)CC3)c2cc1OC
Yield: 73 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline (Compound 100) obtained in Reference Example 11 was used in place of Compound 24. As a result, 226.8 mg (yield: 73%) of Compound 57 was obtained as white crystals.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:22])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:22])=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCCCCc1cccnc1)c1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NCCCCc1cccnc1)c1ccc(-c2cccc(O)c2)cc1
Yield: 58.2 %

Procedure:
A solution of 7.8 g of 3'-(phenylmethoxy)-N-[4-(3-pyridinyl)butyl][1,1'-biphenyl]-4-carboxamide in 150 mL of ethanol was hydrogenated over 0.8 g of 10% palladium on carbon. The product was crystallized from acetonitrile to give 3.6 g of 3'-hydroxy-N-[4-(3-pyridinyl)butyl][1,1'-biphenyl]-4-carboxamide mp 150°-151.5° C. The analytical sample was obtained from acetonitrile, mp 151.5°-152.5° C.