Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=1>O1CCOCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:18]([F:21])=[N:19][CH:20]=1
Reactant: Brc1ncccn1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ncc(Br)cc1-c1ncccn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Bromopyrimidine (5.42 g, 34.1 mmol), sodium carbonate (22.75 mL, 45.5 mmol), 5-bromo-2-fluoropyridine-3-boronic acid (5 g, 22.75 mmol, commercially available from Frontier Scientific, Inc., Logan Utah), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (1.858 g, 2.275 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (32.5 mL) and stirred at 100° C. overnight. LC-MS indicated good conversion to desired product. The material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide 2-(5-bromo-2-fluoropyridin-3-yl)pyrimidine (4.37 g, 17.20 mmol, 76% yield) as yellow solid. m/z (ESI) 253.8.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([O:25]CC)=O.[NH2-:28].[Li+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([NH2:28])=[O:25]
Reactant: CCOC(=O)c1c(SC(C)C)c2cc(OCc3ccccc3)ccc2n1C
Reactant: [NH2-]
Agent: [Li+]
Product: CC(C)Sc1c(C(N)=O)n(C)c2ccc(OCc3ccccc3)cc12
Yield: 78 %

Procedure:
Prepared from ethyl 1-methyl-3-[(1-methylethyl)thio]-5-(phenylmethoxy)-1H-indole-2-carboxylate and lithium amide as described in Example 18. After evaporation of excess ammonia, the residue is treated with ice water. The insoluble material is filtered and washed with water, then recrystallized from ethyl acetate-hexane. Yield 78%; mp 151°-154° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:18])=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:8][CH:7]=[N:6]2.[N:19]1([CH2:25][CH2:26][CH2:27]O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[C:3]([O:18][CH2:27][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:8][CH:7]=[N:6]2
Reactant: Cc1c(O)cn2ncnc(Oc3ccccc3)c12
Reactant: OCCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCCCN2CCCCC2)cn2ncnc(Oc3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a mixture of 5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-ol (1.47 g, 6.1 mmol, for preparation see WO 0071129), 1-piperidinepropanol (1.74 g, 12.2 mmol) and triphenylphosphine (3.2 g, 12.2 mmol) in tetrahydrofuran (20 mL) at 0° C. under argon, was added DEAD (1.9 mL, 12.2 mmol). The resulting mixture was stirred at 0° C. for 30 min, and then at RT for 1 hr. The volatiles were removed in vacuo. The residue was purified by silica gel flash column chromatography using 5% (2M NH3 in MeOH)/20% ethyl acetate /CH2Cl2 to afford the desired product as beige solid (1.6 g, 72% yield). MS: (M+H)+=367.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1>CN(C=O)C>[C:18]1([C:10]2[N:9]=[C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(N3CCNCC3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.7 %

Procedure:
Piperazine (3.22 g) was dissolved in DMF (830 mL), and 4-chloro-2-phenylquinazoline (3 g) was added thereto. The mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue and an insoluble material was filtered off. The organic layer of the filtrate was separated and extracted with 1 mol/L hydrochloric acid. The aqueous layer was basified with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure to give 1-(2-phenyl-4-quinazolinyl)piperazine (2.27 g) as a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.O.[O:20]1[CH2:24][CH2:23][CH2:22]C1>>[CH3:22][CH:23]([CH3:1])[C:24]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:20]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Solvent: O
Product: CC(C)C(=O)c1ccc(N2CCOCC2)cc1
Reaction time: 0.33 h
Yield: 67 %

Procedure:
n-Butyllithium (1.6 M, 25.8 mL, 41.3 mmol) was added to a solution of 1-bromo-4-(4-morpholinyl)benzene (10.0 g, 41.3 mmol) in tetrahydrofuran (100 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added N-isobutyrylpropyleneimine (5.77 g, 45.4 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (40 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain the title compound (6.50 g, yield 67%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH2:26][NH2:27]>CO.CCOC(C)=O>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:27][NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: NN
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1 equivalent) in MeOH is added hydrazine (1.10 equivalents). After stirring for 2 hours at room temperature, the reaction mixture is heated to 40° C. for 8 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: Cl[C:2]1[N:3]([C@H:24]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>CS(C)=O>[CH3:33][C@H:34]1[NH:35][C@@H:36]([CH3:40])[CH2:37][N:38]([C:2]2[N:3]([C@H:24]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:39]1
Reactant: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2[C@H]2CCN(S(C)(=O)=O)C2)C[C@H](C)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to 5-{8-chloro-9-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (100 mg, 0.21 mmol) and cis-2,6-dimethylpiperazine (119 mg, 1.04 mmol) and the resulting mixture was stirred at 140° C. for 1 hour. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (95 mg, 82%) as a light brown solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:22][CH:23]=[CH2:24])[CH2:20][OH:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:22][CH:23]=[CH2:24])[CH:20]=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](C=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
To a solution of oxalyl chloride (0.713 mL, 8.24 mmol) at −78° C. in dry methylene chloride (100 mL) under nitrogen in a three necked flask was added dropwise a solution of DMSO (1.37 mL, 19.8 mmol) in methylene chloride (4 mL) with stirring at −78° C. for an additional 20 min. A solution of (2S)-2-(3,4-dichlorophenyl)pent-4-en-1-ol (1.26 g, 5.45 mmol) in methylene chloride (50 mL) was added dropwise (45 min) while maintaining the reaction temperature below −60° C. After stirring at −60° C. for an additional 2 h, triethylamine (4.6 mL, 33.3 mmol) was added dropwise. The stirred reaction mixture was allowed to warm to ambient temperature for 2 h, cooled in ice, quenched by addition of water (80 mL), and stirred for an additional 30 min. The organic layer was washed with water and brine, dried (Na2SO4), and evaporated to give 1.25 g of the title compound which was used without further purification. This material was determined to be about 72% pure by HPLC.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[CH:15]=1)[CH2:9][CH2:10][CH3:11].[C:28](Cl)([CH3:30])=[O:29]>C(Cl)Cl>[C:28]([N:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:29])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCNCc1cc(OC)c(OC)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(Cc1cc(OC)c(OC)c2ccccc12)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
Triethylamine (350 μL, 2.5 mmol) was added to a solution of aminonaphthalene 19 (250 mg, 0.9 mmol) and AcCl (90 μL, 1.27 mmol) in CH2Cl2 (5 mL) at 0° C. The cooling bath was removed after 10 min, the reaction mixture was stirred for 1 h at room temperature, diluted fivefold with CH2Cl2, washed with an aqueous solution of NaHCO3 followed by 3% HCl, brine and dried (MgSO4). The crude product (315 mg, 100%) obtained after evaporation of the solvent was used in the following step without further purification. 1H NMR (CDCl3) 8.19, 8.15 (2d, J=7.6, 8.4 Hz, 1H), 8.97, 7.80 (2d, J=7.9, 8.2 Hz, 1H), 7.35-7.58 (m, 2H), 7.16, 7.04 (2s, 1H), 5.05, 4.95 (2s, 2H), 4.01, 3.99 (2s, 3H), 3.99, 3.96 (2s, 3H), 3.47, 3.13 (2t, J=7.4, 7.8 Hz, 2H), 2.20, 2.09 (2s, 3H), 1.15-1.70 (m, 4H), 0.91, 0.87 (2t, J=7.2, 7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=1.C(OCCCC)CCC>>[F:15][C:13]1[CH:12]=[C:11]([O:16][CH3:17])[N:10]=[C:9]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:14]=1
Reactant: CCCCCCN
Reactant: COc1cc(F)nc(F)n1
Solvent: CCCCOCCCC
Product: CCCCCCNc1nc(F)cc(OC)n1
Reaction time: 1 h

Procedure:
15.6 g (0.154 mol) of n-hexylamine were added at 0° to 2° C. to a stirred mixture of 10.4 g (0.071 mol) of 2,4-difluoro-6-methoxypyrimidine in 60 ml of methyl t.-butyl ether within 15 minutes. After 1 hour at 0° C., 4 hours at 25° C. and working up as in B 2-3, 9.6 g (60% of theory) of the title compound of nD23 =1.4938 were obtained.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH3:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])=[O:12])[CH2:6][CH2:5]1)=[S:3].Cl[CH:22]([C:30]#[N:31])[C:23]([O:25][C:26](C)(C)C)=O>CO>[Cl:18][C:17]1[C:16]([Cl:19])=[C:15]([CH3:20])[NH:14][C:13]=1[C:11]([NH:10][CH:7]1[CH2:8][CH2:9][N:4]([C:2]2[S:3][C:22]([C:30]#[N:31])=[C:23]([O:25][CH3:26])[N:1]=2)[CH2:5][CH2:6]1)=[O:12]
Reactant: CC(C)(C)OC(=O)C(Cl)C#N
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(N)=S)CC2)c(Cl)c1Cl
Solvent: CO
Product: COc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C#N
Temperature: 80 °C

Procedure:
A suspension of N-[1-(aminocarbonothioyl)piperidin-4-yl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 95, 0.22 g, 0.7 mmol) and tert-butyl chloro(cyano)acetate (0.12 g, 0.7 mmol) in MeOH was heated to 80° C. in the microwave reactor for 40 minutes. The product precipitated and was filtered off.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]1[C:23]2[N:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]5[C:48]6[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=6[C:42]6[C:37]5=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[CH2:49]([OH:51])C.ClCCl>O>[CH:49]([C:13]1[CH:12]=[CH:11][C:23]2[N:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[CH:32][C:33]([N:36]5[C:48]6[CH:47]=[CH:46][C:45]([CH:8]=[O:9])=[CH:44][C:43]=6[C:42]6[C:37]5=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:21]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:51]
Reactant: CCO
Reactant: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4cc(C=O)ccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87 %

Procedure:
Phosphorus oxychloride (13 ml, 21.5 g, 140 mmol) was added dropwise to a stirring mixture of N,N-dimethylformamide (5.40 ml, 5.10 g, 69.7 mmol) and 4,4′-bis(carbazol-9-yl)biphenyl (7.72 g, 16.0 mmol) and the resulting mixture was stirred at room temperature for 5 minutes then heated to 90° C. for 24 h. (nb reaction mixture was followed by TLC using 5% ethanol/dichloromethane as the eluent). The reaction mixture was poured into water (800 ml) and this beaker was placed in the ultrasonic bath for 2 hours to break up the material. The mixture was stirred for a further 2 hours then filtered. The residue was washed with water and then hexane and dried in vacuo for 2 hours. The crude product was heated with acetone (3×400 ml) and filtered. The product was insoluble in most organic solvent. The impurities were removed by washing with acetone. The product, 4,4′-bis(3-formyl-carbazol-9-yl)biphenyl, (7.92 g, 87%) was obtained with melting point 295° C. (dec.). Found: C, 81.74; H, 4.71; and N, 4.45. C38H28N2O2.(CH3)2CO requires C, 82.25; H, 5.05; N, 4.68%. 1H n.m.r. (300 MHz, Me2SO): δ 10.09 (2 H, s, CHO); 8.88 (2 H, d, J 0.88 Hz, aromatic H); 8.41 (2 H, d, J 7.61 Hz, aromatic H); 8.41 (4 H, d, J 8.49 Hz, aromatic H); 8.00 (2 H, dd, J 8.49, 1.46 Hz, aromatic H); 7.83 (4 H, d, J 8.49 Hz, aromatic H); 7.38-7.61 (8 H, m, aromatic H). λmax(CH2Cl2): 215 nm (ε/Lmol−1cm−1 9163), 241 (68 488), 272 (65 928), 294 (67 194) 328 (42 620). FT-IR (solid): 3045, 2825, 2730, 1682, 1623, 1591, 1505, 1456, 1438, 1365, 1319, 1275, 1230, 1180, 802, 745 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=S)[C:10]2([F:24])[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:11][C:10]2([F:24])[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)C2(F)F)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)CC2(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
4-(S)-(1Ethoxycarbonylcyclopropyl)-3,3-difluoro-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (2.883 g, 8.157 mmol) was dissolved in anhydrous ethanol (80 ml), and the solution was mixed with Raney nickel (8 ml) and stirred at room temperature for 30 minutes. After removing the catalyst by celite filtration (ethanol washing), the resulting filtrate was concentrated under reduced-pressure. The thus obtained residue was dissolved in diethyl ether (150 ml), washed with 10% ammonia water (100 ml×4) and saturated brine (100 ml) in that order and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 2.540 g (96.3%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=O.O.NN.[OH-].[K+]>C(O)CO>[CH3:1][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1
Reactant: O=CC1(c2ccccc2)CCC(=O)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(c2ccccc2)CCC(=O)CC1
Reaction time: 5 h
Yield: 67 %

Procedure:
A mixture of 9.3 g. (0.038 mole) of 4-formyl-4-phenyl cyclohexanone, ethylene ketal (prepared in Example 30), 5 ml. of hydrazine hydrate and 6.4 g. of potassium hydroxide in 120 ml. of ethylene glycol is heated at reflux for about 1 hour. The solvent is then allowed to distill until the pot temperature comes to about 200°C. After about 5 hours the mixture is allowed to cool and then diluted with water and brine and evaporated to dryness. The residue is chromatographed on 750 ml. of Florisil (magnesium silicate) with elution by 1% ethyl acetate in Skellysolve B. The crystalline fractions are combined and recrystallized from a mixture of methanol and water to give 5.92 g. (67% yield) of 4-methyl-4-phenylcyclohexanone, ethylene ketal, having a melting point of 48° to 50°C.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.CC(C)=O.Cl[CH2:25][C:26]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[O:28][N:27]=1>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([O:18][CH2:25][C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)[O:28][N:27]=4)=[CH:13][CH:14]=3)[O:9][CH:8]=2)=[CH:1][CH:2]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Solvent: CC(C)=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(OCc3noc(-c4cccc(C(F)(F)F)c4)n3)ccc12

Procedure:
To a suspension of daidzein (2.0 g, 7.87 mmol) in acetone (80 ml) 2 N aqueous potassium hydroxide (3.94 ml, 7.87 mmol) was added, and the mixture was sonicated for a few minutes. To this mixture was added 3-chloromethyl-5-(3-trifluoromethylphenyl)-[1,2,4]oxadiazole (2.17 g, 8.26 mmol), and the reaction mixture was refluxed for 3 days. The mixture was concentrated under reduced pressure, and the residue dissolved in methanol, mixed with silica gel, and the solvent removed under reduced pressure. Purification by flash column chromatography, eluting with methylene chloride/methanol (95/5 to 90/10) provided pure 3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methoxy)chromen-4-one as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][C@H:13]([OH:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](CCOCc2ccccc2)C1
Temperature: -78 °C

Procedure:
In a 100 mL flask with 3-(benzyloxyethyl)cyclobutanone (2.5 g, 12.2 mmol) inside, dry THF 30 mL was added under argon to give a light yellow solution. This was cooled to −78° C., after a while, L-selectride (1.0 M in THF, 14.7 mL, 14.6 mmol) was added drop by drop and this was allowed to warm up to room temperature, after which the reaction was quenched with saturated NaHCO3. Then the mixture was cooled to 0° C. and 30% H2O2 was added drop by drop, followed by the addition of H2O and EtOAc. The organic phase was separated, washed with H2O twice and brine once, dried over MgSO4 and solvent evaporation gave the crude product, which was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give a colorless oil (2.0 g, 79.4%, Rf=0.2 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 300 MHz): δ 1.40-1.60 (m, 2H), 1.60-1.90 (m, 3H), 2.05-2.21 (bs, 1H), 2.38-2.50 (m, 2H), 3.32-3.44 (t, J=, 2H), 4.52 (s, 2H), 7.20-7.40 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 22.90, 37.08, 37.85, 39.91, 64.14, 68.78, 73.04, 127.62, 127.68, 128.45, 138.59. MS (FAB): expected for C13H18O2 (M+H)+ 207.28. Found 207.13801.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH:19]=O)=[CH:14][N:13]=1>>[C:2]1([CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[C:5]([NH2:6])=[N:18][C:16]2[N:17]=[C:12]([NH2:11])[N:13]=[CH:14][C:15]=2[CH:19]=1
Reactant: Cc1ccccc1CC#N
Reactant: Nc1ncc(C=O)c(N)n1
Product: Cc1ccccc1-c1cc2cnc(N)nc2nc1N

Procedure:
The title compound was prepared according to Example 1, starting from 2-methylbenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 300-302° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:9][C:8]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(F)c1
Product: CC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
m-Fluoroacetophenone (20.0 g, 0.14 mol) was cooled to below -5° C. and fuming nitric acid (100 cm3) added dropwise at such a rate that the temperature of the reaction mixture never exceeded -5° C. When the addition was complete the mixture was poured into ice/water. The precipitated yellow solid was filtered, washed with water and dried to give 5-fluoro-2-nitroacetophenone (21.4 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH:18]1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][CH:18]3[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][CH:17]3[CH3:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1CCCC(C)C1O
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: CC1CCCC(C)C1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 72, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-dimethyl-cyclohexanol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,6-dimethyl-cyclohexyloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.5 g, 86% for the final step); LC-MS: 363 (M+1)+, tR=5.03 min. Purity on HPLC: tR=10.3 min, 99.3% (214 nm), 99.0% (254 nm). 1H NMR (300 MHz, DMSO-d6): δ 12.89 (s, 1H), 7.79-7.77 (m, 1H), 6.96-6.82 (m, 1H), 5.36 (dd, 1H, J=10.8 Hz, J=3.9 Hz), 4.58-4.15 (m, 1H), 2.20-0.76 (m, 25H).