Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:45])[C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=2[NH2:44])=[N:33][CH:34]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][C:14]=1[C:15]([NH:44][C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1[C:36]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=1)=[O:45])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NCCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 70 %

Procedure:
Using a procedure analogous to Example 4-C, 2-[3-(tert-butoxycarbonylamino)-propoxy]-4-(morpholin-4-yl)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide gave the desired product as a solid (2.56 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C=CC(NC2C3C(=CC=CC=3)N=C(C(C3C=CC(F)=CC=3)=O)N=2)=N1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: O=C(c1ccc(F)cc1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Product: COc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3ccccc23)n[nH]1

Procedure:
(4-Fluorophenyl)(4-(5-methoxy-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol is prepared using a procedure analogous to that described in Example 6, substituting (4-fluorophenyl)(4-(5-methoxy-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 75 for the (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone used in Example 6.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][NH:22][CH2:23][CH2:24][OH:25].C(OC)(OC)OC.C([BH3-])#N.C(=O)C1C=CC=CC=1>COCCOC.CC(N(C)C)=O.C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:22]([CH2:23][CH2:24][OH:25])[CH3:21])=[CH:17][CH:18]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Reactant: CNCCO
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CC(=O)N(C)C
Product: CN(CCO)Cc1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
2-[(Aminocarbonyl)amino]-5-[4-formylphenyl]thiophene-3-carboxamide (0.1 g) was stirred in a mixture of DME (10 ml) and DMA(5 ml). 2-(Methylamino)ethanol (0.13 g) was added, followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). The reaction was stirred at 80° C. for 20 min, and then polymer-supported cyanoborohydride (0.45 g) was added. The reaction was stirred at 80° C. for a further 2 h, and then polymer-supported benzaldehyde (0.5 g) was added. The resins were removed by filtration and the filtrate was passed through a 5 g SCX column, washing with methanol (25 ml). The product was eluted using 1M methanolic ammonia (45 ml) and this solution was evaporated to dryness under reduced pressure. Purification by chromatography on silica, eluting with DCM/methanol (9:1), gave the product as an off-white solid (0.072 g). MS (ES) 349 (M+H)+. 1H NMR (DMSO-D6) 2.15 (s, 3H), 2.45 (m, 2H), 3.50 (m, 4H), 4.35 (t, 1H), 6.90 (s, 2H), 7.25-7.40 (m, 3H), 7.50 (d, 2H), 7.70 (s, 1H), 7.75 (s, 1H), 11.00 (s, 11).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:13][C:10]1([CH3:14])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=[C:2]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:3]=[C:4]2[NH:12][CH2:11]1
Reactant: C1COCCN1
Reactant: CC1(C)CNc2nc(Cl)cc(=O)n2C1
Product: CC1(C)CNc2nc(N3CCOCC3)cc(=O)n2C1
Yield: 62 %

Procedure:
0.7 g of 2-chloro-7,7-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 5 mL of morpholine are heated in the microwave oven to 80° C. for 1 h30 mins. The crude is purified by flash chromatography on silica gel SiO2 (100% CH2Cl2 to 92/8 CH2Cl2/MeOH). 0.58 g (yield=62%) of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white solid including the following characteristics:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.O1CC1C[O:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([CH:31]2[CH2:36][CH2:35][CH:34]([O:37][CH2:38][CH:39]3[O:41][CH2:40]3)[CH2:33][CH2:32]2)([CH3:30])[CH3:29])[CH2:24][CH2:23]1>>[OH:21][CH:22]([CH2:27][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:23][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([CH:31]2[CH2:32][CH2:33][CH:34]([O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:6]3[C:5](=[O:10])[C:4]4([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]4)[NH:8][C:7]3=[O:9])[CH2:35][CH2:36]2)([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC1CCC(C(C)(C)C3CCC(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)CC3)CC1)C2=O

Procedure:
A mixture of 8 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 5 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane was heated at 180°-200° C. for 5 hours. The reaction mixture was then purified by column chromatography through silica gel eluted with a 60:10:1 by volume mixture of ethyl acetate, ethanol and triethylamine and then by recrystallisation from ethyl acetate, giving the desired compound in the form of white crystals melting at 130°-133° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20]C(C)(C)C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of Compound 46d (1.1 g, 3.2 mmol) in MeOH (20 mL) and THF (20 mL) was added 7 N NaOH (4.0 mL, 28 mmol) and the solution stirred at 50° C. for 3 h. The reaction mixture was cooled in an ice bath then acidified by the addition of 1 N HCl (20 mL). The resulting precipitate was filtered, rinsed with water then dried under vacuum to give Compound 46a (790 mg, 89% yield) as a white solid. LCMS ESI 277.0 (M+H), RT=1.41 min (Method Q). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (br. s., 1H), 12.91 (br. s., 1H), 7.90-6.67 (m, 5H), 5.01 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1

Procedure:
This compound was prepared from 3-chloro-4-fluoronitrobenzene and 3-fluorobenzyl alcohol using the method described above in Example 13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([Mg]Br)[CH:10]([CH3:12])[CH3:11].CCOCC>O1CCCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.[Fe]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)C[Mg]Br
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2,5-dibromopyridine (4.5 g, 19 mmol) in tetrahydrofuran (50 ml) was added [1,1′-bis (diphenylphosphino)ferrocene]dichloronickel (II) (103 mg, 0.19 mmol) and the resulting mixture was cooled to −10° C. A 2M solution of isobutylmagnesium bromide in ether (12.4 ml, 24.7 mmol) was added slowly and the mixture was stirred at −10 to 10° C. for 3.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in pentane to afford the 5-Bromo-2-(2-methylpropyl)pyridine compound as a volatile oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][S:11][C:12]([F:25])([F:24])[C:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])([OH:15])[CH2:14][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(C(F)(F)SCCOCc3ccccc3)CO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCOCc1ccccc1
Yield: 17.6 %

Procedure:
Using 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (3.0 g, 0.008 mol), DMSO (30 ml), 1,2,4-triazole (1.4 g, 0.02 mol) and potassium carbonate (2.8 g, 0.02 mol), 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyi)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.62 g, yield: 17.4%) was obtained as a colorless oil by similar procedures to Example 14.
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[CH:9][C:8]=1[NH:15][C:16]([O:18]C(C)(C)C)=O)(C)(C)C.[O:24]([C:31]1[CH:39]=[CH:38][C:34](C(Cl)=O)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1>[Cl:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:6]([OH:5])=[O:23])=[C:8]([NH:15][C:16](=[O:18])[C:34]2[CH:38]=[CH:39][C:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)c(F)cc1C(=O)O)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h
Yield: 4 %

Procedure:
Under an atmosphere of Argon, 2-tert-butoxycarbonylamino-4-chloro-5-fluoro-benzoic acid tert-butyl ester (200 mg) and 4-phenoxy-benzoyl chloride ([1623-95-6], 269 mg) were dissolved in THF (5 mL). Triethylamine (0.24 ml) was added, and the mixture was heated to reflux overnight. The solvent was evaporated, and the residue was purified by column chromatography (silica gel/methanol/dichloromethane). The eluate, which contained two UV-absorbing components, was evaporated, and the residue was dissolved in a mixture of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml). After 2 h, the volatiles were evaporated, and the title compound (9 mg, 0.4%) was isolated from the mixture by preparative, reversed-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 4.5 min, flow rate 30 ml/min). MS: m/e=384.1 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:35]=[CH:34][C:33]([S:36][CH2:37][C@@H:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)=[CH:32][CH:31]=1.[I-].[Li+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[CH2:37][S:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([F:44])([F:28])[F:43])=[CH:31][CH:32]=1
Reactant: FC(F)(F)c1ccc(SC[C@@H]2CCCN2)cc1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CCC2=O
Yield: 57.2 %

Procedure:
A solution of 0.5 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one in 4 ml of dimethylformamide is stirred with 0.55 g of (2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidine and 0.32 g of lithium iodide for 2 hours at a bath temperature of 100° C. Then, it is added to sodium bicarbonate solution, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/acetone. 0.45 g of 11β-fluoro-3-hydroxy-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one with [α]D22 =+32.7°(c=0.51% in chloroform) is obtained.
Reaction SMILES: N1CCCC(=O)[C:2]1=O.F[C:10]([C:13]1[C:14](=[O:20])[C:15](=[O:19])[N:16]=[CH:17][CH:18]=1)(F)F.FC(F)(S(F)(=O)=O)C(OC)=O.[OH-].[OH-].[Li+].[OH-].[Na+]>[Cu]I.CO.O1CCCC1.CN(C=O)C>[CH3:2][C:18]1[CH:17]=[N:16][C:15](=[O:19])[C:14](=[O:20])[C:13]=1[CH3:10]
Reactant: O=C1CCCNC1=O
Reactant: O=C1N=CC=C(C(F)(F)F)C1=O
Agent: [Cu]I
Agent: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=C(C)C(=O)C(=O)N=C1

Procedure:
The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:19]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cc(C(=O)O)ncn1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncn1)c1ccc(OCC(F)(F)F)nc1
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (175 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (148 mg, 0.58 mmol, Amine-1, single enantiomer) and 6-aminopyrimidine-4-carboxylic acid (80 mg, 0.58 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[NH:7][CH:6]=[C:5]2[CH:13]=O.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:11]([C:10]1[CH:9]=[C:8]2[C:4]([C:5](/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:6][NH:7]2)=[CH:3][C:2]=1[F:1])#[N:12]
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2cc(C#N)c(F)cc12
Temperature: 90 °C

Procedure:
To a solution of 5-fluoro-3-formyl-1H-indole-6-carbonitrile (D152) (250 mg) in acetonitrile (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (926 mg). The reaction mixture was refluxed at 90° C. for 24 hours. The solvent was then evaporated and the residue was chromatographed on silica gel eluting with EA and PA (3:7-7:3) to generate ethyl (2E)-3-(6-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D153) (275 mg). MS (ES): C14H11FN2O2 requires 258.1; found 259.1 (M+H+).
Reaction SMILES: CP([CH:5]1[S:10][CH2:9][S:8][CH2:7][S:6]1)(C)=O.C([Li])CCC.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[O:16]([C:23]1[CH:24]=[CH:25][C:26]([C:29](=[C:5]2[S:10][CH2:9][S:8][CH2:7][S:6]2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CP(C)(=O)C1SCSCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=C1SCSCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran was dissolved 1.58 g of 2-dimethylphosphoryl-1,3,5-trithiane, and 4 ml of 1.6M n-butyl lithium was added dropwise under an argon atmosphere at a temperature of about -70° C. After completion of the dropwise addition, the resulting mixture was stirred for 1 hour. Next, a solution of 1.41 g of ethyl 4-phenoxyphenylglyoxylate dissolved in 5 ml of tetrahydrofuran was dropped thereinto. After completion of the dropping, the reaction temperature was slowly raised to room temperature and the mixture thus obtained was stirred overnight. Thereafter, the same treatment as in Example 1 was carried out to give a crude product, which was then purified by a silica gel column chromatography (chloroform:hexane=2:1) to obtain 1.63 g of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]2[CH:10]=[CH:9][NH:8][CH:4]2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:3]2[CH:10]=[CH:9][NH:8][CH:4]2[N:5]=[CH:6][N:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: ClC1=NC=NC2NC=CC12
Product: O=[N+]([O-])c1ccc(OC2=NC=NC3NC=CC23)cc1[N+](=O)[O-]

Procedure:
4-Chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine (1.66 g, 10.8 mmol), 3,4-dinitrophenol (2.4 g, 13 mmol) and TFA/TEA were heated at 150° C. for 2 h. The resulting green solid was purified on silica gel using a Hexane/EtOAc gradient (100/0 to 50/50) to give 4-(3,4-dinitro-phenoxy)-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH2:28][C:29]#[N:30])[CH:26]([CH2:31][CH3:32])[C:25]([C:33]([F:36])([F:35])[F:34])=[N:24]4)=[CH:19][CH:18]=3)[CH:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(C1C(CC#N)N(C2C=CC(O)=CC=2)N=C1C(F)(F)F)C.ClC1C(N2CC[C@H](O)[C@H](C)C2)=CC(OC)=NC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]#[N:30])[C@H:26]([CH2:31][CH3:32])[C:25]([C:33]([F:36])([F:34])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[CH:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCC1C(C(F)(F)F)=NN(c2ccc(OC3CCN(c4cc(OC)ncc4Cl)CC3C)cc2)C1CC#N
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCC1C(C(F)(F)F)=NN(c2ccc(O)cc2)C1CC#N
Agent: COc1cc(N2CC[C@H](O)[C@H](C)C2)c(Cl)cn1
Solvent: C1CCOC1
Product: CC[C@@H]1C(C(F)(F)F)=NN(c2ccc(OC3CCN(c4cc(OC)ncc4Cl)CC3C)cc2)[C@H]1CC#N
Yield: 26 %

Procedure:
2-(1-(4-((1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile: To a solution of 2-(4-ethyl-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (174 mg, 0.58 mmol) and (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (150 mg, 0.58 mmol) in THF (195 μl) was added triphenylphosphine (215 mg, 0.82 mmol). The reaction vessel was then lowered into a sonication bath and sonicated for several minutes (to allow for mixing) giving a clear and highly viscous solution. While sonicating, (E)-di-tert-butyl diazene-1,2-dicarboxylate (161 mg, 0.70 mmol) was added dropwise to the reaction mixture, and the reaction mixture was sonicated for 120 min. LCMS showed the desired mass of product. Then, sat. aq. NaHCO3 (10 mL) was added slowly to the reaction mixture. The mixture was then extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried (Na2SO4), filtered, and concentrated. Purification by chromatography gave 2-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (80 mg, 0.15 mmol, 26% yield) an oil. LC-MS Anal. Calc'd for C26H29ClF3N5O2 535.20. found [M+H] 536.0.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13]([CH3:15])C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26]C=1N>C1C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[F:20])[N:13]([C:15]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[F:22])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1Br
Reactant: COc1ccc(N)c(F)c1
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-dimethylaminoacrylate (1.09 g) and 2-fluoro-4-methoxyaniline (0.51 g) are dissolved in benzene (10 ml), and the mixture is allowed to stand at room temperature for 2 hours. The reaction mixture is washed with diluted hydrochloric acid and saturated aqueous sodium chloride, and dried over sodium sulfate. After distilling off the solvent, the residue is dissolved in anhydrous dioxane (20 ml) and thereto is added 60% sodium hydride (0.14 g). The mixture is stirred at room temperature for one hour and further refluxed for one hour. After cooling, the reaction mixture is poured into saturated aqueous ammonium chloride under ice-cooling. The precipitated crystals are separated by filtration, washed with water, purified by silica gel column chromatography (solvent, dichloromethane:methanol=80:1), and then recrystallized from ethanol to give ethyl 6,7-difluoro-1-(2-fluoro-4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.59 g) as pale yellow needles, m.p. 170°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=O.P(Br)(Br)[Br:21].C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:21][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1c[nH]c2c(F)cc(OC)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(F)cc(OC)cc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 8-fluoro-6-(methoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (12 g, 45 mmol) in DMF (56 ml) was added dropwise phosphorus tribromide (4.5 ml, 47 mmol) over fifteen minutes (slightly exothermic). The reaction was held at 0° C., with an ice bath, for one hour and allowed to warm to room temperature then stirred for a further 2 hours. The mixture was then diluted with water (400 mL). A solution of sodium bicarbonate was added to reach pH 7. The reaction mixture was stirred for one hour at 0° C. then filtered. The precipitate was washed with water and dried in vacuo to afford the product as a yellow solid (12.2 g, 82%).