Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[C@@H:10]([CH3:22])[CH2:9]2)=[C:4]2[CH:23]=[N:24][CH:25]=[CH:26][C:3]=12.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:22][C@H:10]1[CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[C:3]3[CH:26]=[CH:25][N:24]=[CH:23][C:4]=23)[CH2:13][CH2:12][N:11]1[C:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15]
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1C(=O)N1CCCCC1

Procedure:
Using methods described in Example 1, and starting with (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7 (150 mg, 400 μmol), Pd(PPh3)4 (23 mg, 20 μmol), 4-(trifluoromethyl)phenylboronic acid (106 mg, 560 μmol), and 2 M sodium carbonate (400 μl, 800 μmol), (S)-(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)(piperidin-1-yl)methanone 8 was obtained. MS 484.2 (calc'd) 485.2 (M+H, found).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:18]2[C:23](=[O:24])[N:22]([CH3:25])[C:21](=[O:26])[CH:20]=[N:19]2)=[C:4]([F:27])[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:27])=[C:5]([N:18]3[C:23](=[O:24])[N:22]([CH3:25])[C:21](=[O:26])[CH:20]=[N:19]3)[CH:6]=2)=[CH:10][CH:11]=1
Reactant: Cn1c(=O)cnn(-c2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)cnn(-c2cc(Oc3ccc(N)cc3)c(Cl)cc2F)c1=O

Procedure:
2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reacted with potassium carbonate and 4-fluoronitrobenzene in N,N-dimethylformamide to form 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. 2-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione is reduced with iron powder in acetic acid and water to produce 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. To a mixture of 2-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione in hydrochloric acid is added acetone. The mixture is cooled to about 5° C., and in succession a solution of sodium nitrite in water and methyl acrylate is added. The resultant mixture is stirred for 15-30 minutes. Thereafter, copper (I) chloride is added slowly. This mixture is stirred at room temperature for approximately 30 minutes and then is poured into ice water. Extraction with an organic solvent (e.g., ethyl acetate) and subsequent purification yields methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-(4-methyl-3,5-dioxo-2H,4H-1,2,4-triazin-2-yl)-phenoxy]phenyl]-propionate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11])[CH3:2].[CH3:12]I>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[C:10]#[N:11])[CH3:2]
Reactant: CCc1ccccc1CC#N
Reactant: CI
Product: CCc1ccccc1C(C)C#N

Procedure:
rac-2-(2-Ethyl-phenyl)-propionitrile was prepared from (2-ethyl-phenyl)-acetonitrile and methyl iodide in analogy to Example 65a): light-yellow liquid; MS (EI): 159.1 (M+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10]3=[C:11]([CH2:13][CH2:14][N:9]3[C:8]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:7]2=3)[CH:12]=1)([O-])=O>[Pd].C(O)C>[CH:5]1[C:4]([NH2:1])=[CH:12][C:11]2[CH2:13][CH2:14][N:9]3[C:10]=2[C:6]=1[C:7]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:8]=13
Reactant: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1

Procedure:
Following the procedure of Example 1, Step 3, 2-nitro-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (2.0 g, 7.4 mmol) and 5% palladium on carbon (0.25 g) in ethanol (25 mL) was hydrogenated to provide 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine. MS (ES) m/z 241.2; HRMS: calcd for C16H20N2+H+, 241.16992; found (ESI, [M+H]+), 241.1693.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:27]CS([O-])(=O)=O)[CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:27][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:26][CH2:25][CH2:24]1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: O=S(=O)([O-])CCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C23CCCC=C2C(=O)N(CC2CCC2)C(=O)C3)c1
Reaction time: 10 h

Procedure:
The procedure in Example 9, Part A was followed in which 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (10.74 g) in 135 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (2.15 g) in 90 ml of dimethylformamide at 70° C. Cyclobutylmethylmesylate (9 g) was added and the reaction heated at 80°-90° C. for 6 hours, then at 25° C. for 10 hours. This gave, after chromatography, a crystalline product (6 g), mp 89°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]1)[C:5]([OH:7])=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26]2)=[CH:21][CH:20]=1>>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:2]([F:1])[CH:3]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC1CCN(c2ccc(C(=O)O)cc2F)CC1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CC1CCN(c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)cc2F)CC1

Procedure:
3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid was reacted with [1-(4-aminophenyl)-pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 424.00 (C25H33FN4O); MS (ESI): 425 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:17]12([NH2:27])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[C:17]12([NH:27][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of 2-chloronitrobenzene (10 g), potassium carbonate (17.5 g) copper (I) iodide (609 mg) and 1-adamantanamine (19.2 g) was heated at 180° under nitrogen for 6 h. The mixture was allowed to cool to room temperature and was adsorbed onto silica. This was chromatographed with hexane-EA (9:1) as eluent to give the title compound (10.86 g) as an orange/brown crystalline solid containing 29% 2-chloronitrobenzene. T.l.c. (99:1 hexane-EA) Rf 0.23
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:21].Br[CH2:23][CH2:24][C:25]([N:27]([O:29][CH3:30])[CH3:28])=[O:26]>CN(C)C=O>[CH3:30][O:29][N:27]([CH3:28])[C:25](=[O:26])[CH2:24][CH2:23][N:6]1[CH2:7][CH2:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:4]([CH3:3])[C:5]1=[O:21]
Reactant: CON(C)C(=O)CCBr
Reactant: CC1C(=O)NCCN1c1cccc(OC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCN1CCN(c2cccc(OC(F)(F)F)c2)C(C)C1=O
Reaction time: 1 h
Yield: 105.5 %

Procedure:
NaH (55% dispersion in mineral oil, 24 mg, 0.56 mmol) was added at 0° C. to a solution of 3-methyl-4-(3-trifluoromethoxy-phenyl)-piperazin-2-one (example 41D; 127 mg, 0.46 mmol) in N,N-dimethylformamide (3 mL), then after 5 min a solution of 3-bromo-N-methoxy-N-methyl-propionamide (Patent Application US 2007249589; 100 mg, 0.51 mmol) was added. After 30 min the ice bath was removed and the reaction mixture was allowed to reach RT over 1 h, then partitioned between EtOAc and 10% aq. KHSO4 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (189 mg) which was directly used in the next step. Light yellow oil, MS: 390.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([CH:4]1[N:8]([C:18](=[O:21])[CH:19]=[CH2:20])[C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=CCC1CCC(C)(C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1CCC(C)(C)N1C(=O)C=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-allyl-2,2-dimethylpyrrolidine (1.5 g, 10.5 mmol) in 50 ml of anhydrous CH2Cl2, triethylamine (3 ml, 21 mmol) and acryloyl chloride (0.94 ml, 11.6 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for overnight. Analysis of the reaction mixture by LCMS indicated the completion of the reaction. Saturated aqueous NaHCO3 was added to the reaction mixture and the layers were separated. Aqueous layer was worked up twice with CH2Cl2 and the combined organic layers were dried over Na2SO4. Removal of the volatiles and purification of the crude by column chromatography gave the product in 80% yield (1.60 g) as colorless oil.
Reaction SMILES: CS[C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.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>[CH2:13]([N:20]1[CH:24]=[C:23]([C:3]2[N:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:7]3[CH:6]=[CH:5][N:4]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1nccc2nc(N)nn12
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2ccnc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 130 °C

Procedure:
A microwave vial containing 5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.05 g, 0.276 mmol), 1-benzyl-1H-pyrazole-4-boronic acid (123 mg, 0.607 mmol), copper(1)thiophene carboxylate (116 mg, 0.607 mmol) and tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) in THF (1.2 mL) was heated under microwave irradiation (130° C., 15 min). The reaction mixture was filtered through celite and the cake washed with dichloromethane. The filtrate was washed with water followed by brine, dried over magnesium sulfate and concentrated under vacuum. Trituration with diethyl ether provided a yellow solid that did not require further purification. Yield: 0.05 g, 63%; LCMS method: 2, RT: 3.18 min, MI: 292 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([NH2:27])[CH:26]=1)=[O:21].[Br:28]N1C(=O)CCC1=O.O>O1CCCC1>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20]([C:22]1[S:23][C:24]([Br:28])=[C:25]([NH2:27])[CH:26]=1)=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cs1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)c(Br)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (360 mg, 0.87 mmol) (Example I3) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (NBS) (155 mg, 0.87 mmol). The mixture was stirred at room temperature for 1.5 hours. Water (50 ml) was added and the organic phase was extracted twice with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane) to give 5-bromo-4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (343 mg; 80% yield); 1H-NMR (CDCl3, 400 MHz): 7.26 (s, 2H), 7.10 (s, 1H), 3.8 (s, 2H), 2.24 (s, 6H) ppm.
Reaction SMILES: [CH3:1][P:2](=[O:19])([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:4]=1>C(O)C.[Pd]>[CH3:18][P:2]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:4]=1)([CH3:1])=[O:19]
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1N
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of dimethyl[4-nitro-3-(propan-2-ylsulfonyl)phenyl]phosphane oxide (0.24 g, 0.88 mmol) in Ethanol was added Pd on carbon (10% w/w, 24 mg) and stirred under hydrogen overnight. The reaction mixture was filtered and the organic solvent was removed under reduced pressure. The residue was purified by prep-HPLC to yield 100 mg of desired product (50% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[CH3:14][N:15]([CH3:28])[CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:28][N:15]([CH3:14])[CH2:16][CH2:17][C@@H:18]([NH:27][C:7]1[C:6]([F:9])=[CH:5][C:4]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:3][C:2]=1[F:1])[CH2:19][S:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Reactant: NS(=O)(=O)c1cc(F)c(F)c(F)c1
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1c(F)cc(S(N)(=O)=O)cc1F

Procedure:
The title compound was prepared from 3,4,5-trifluorobenzenesulfonamide and (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine using the procedure described for Intermediate 4.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C@@H:14]1[CH2:19][C@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:17][CH2:16][C@@H:15]1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Si:21]([O:20][C@@H:18]1[CH2:17][CH2:16][C@H:15]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:14]([C:11]([CH3:12])=[CH2:1])[CH2:19]1)([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (1.2 g) was suspended in toluene (16 mL) prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (5.8 mL) in toluene. After 1 h, this solution was cooled to 0° C. prior to the addition of benzyl (1S,2R,4R)-2-acetyl-4-(tert-butyldimethylsilyloxy)cyclohexylcarbamate (660 mg) in toluene (5.4 mL). After 20 min at 0° C., the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS found: (M+H)+=404.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:44]/[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=4)[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2cc(/C=C/c3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (0.70 g), [(2-pyridyl)methyl]triphenylphosphonium chloride (0.82 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, 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 subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethenyl)pyridine as colorless crystals (0.65 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:32]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33].C(N(CC)CC)C>C1C=CC=CC=1>[C:32]([C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[N:8]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:12])=[CH:4][CH:3]=2)=[O:43])=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc(N)ccc2CC1c1ccc(C#N)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2ccc(C#N)cc2)C3)cc1
Temperature: 100 °C

Procedure:
To a solution of Intermediate 13 (100 mg, 0.24 mmol) and 10 mL of anhydrous benzene under argon at 25° C. was added 4-acetylphenyl isocyanate (43 mg, 0.26 mmol) and triethylamine (50 mg, 0.48 mmol). The resulting mixture was heated to 100° C. for 12 hours and the reaction was quenched with water. The product was extracted with EtOAc, the layers were separated, and the organic layer was washed with brine, and dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (85:15) to yield Intermediate 23 as a light yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3([CH:14]([NH2:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][CH2:12][CH2:13]3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N#CC1(N2CCN(C3CC3)CC2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCN(C3CC3)CC2)CCC1

Procedure:
The title compound, yellow liquid, MS: m/e=286.2 [(M+H)+], was prepared in accordance with the general method or intermediate B from 1-(4-cyclopropyl-piperazin-1-yl)-cyclobutanecarbonitrile (intermediate V) and phenyllithium.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:29][CH2:28][C:23]4([O:24][CH2:25][CH2:26][O:27]4)[CH2:22][CH2:21]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (7.35 g, 42.1 mmol) in ethanol (76.6 mL), triethylamine (5.87 mL, 42.1 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one (Reference Example 15) (11.5 g, 38.3 mmol) in ethanol (76.6 mL) was added dropwise, and the obtained solution was stirred at room temperature for 15 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (14.7 g, 35.0 mmol, 91%) as an amorphous product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O.OS(O)(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: COC(=O)Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 107.8 %

Procedure:
To a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) in dichloroethane (100 ml) was added MeOH (15:6 ml, 383 mmol) and H2SO4 (1 ml) at room temperature. After 20 minutes stirring, the mixture was heated at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq. NaHCO3 and brine. After dried over Na2SO4, the extract was concentrated in vacuo to give methyl 3-chlorophenylacetate (25.4 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ 3.60 (s, 2H), 3.70 (s, 3H), 7.15–7.26 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[C:5]([N+:11]([O-])=O)[CH:6]=[C:7]([F:10])[C:8]=1[Cl:9])#[N:2].[H][H]>[Pd].C(O)C>[C:1]([C:3]1[C:4]([Cl:14])=[C:5]([CH:6]=[C:7]([F:10])[C:8]=1[Cl:9])[NH2:11])#[N:2]
Reactant: N#Cc1c(Cl)c(F)cc([N+](=O)[O-])c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1c(Cl)c(N)cc(F)c1Cl
Temperature: 25 °C

Procedure:
27.0 g of 3-cyano-2,4-dichloro-5-fluoronitrobenzene (0.247 mol), 500 ml of ethanol and 2.18 g of Pd/C were heated to 60° C. and hydrogenated under 3 Mpa of hydrogen pressure for 3 hours. The reaction mixture was cooled to room temperature. The catalyst was filtered off. After removing the solvent, 48.0 g of 3-cyano-2,4-dichloro-5-fluoroaniline were given in 94.7 yield.