Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.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>[CH3:27][C:16]1[CH:15]=[C:14]([O:13][CH:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1
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+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C
Yield: 61.7 %

Procedure:
Ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) was dissolved in dry THF (3 mL), and treated with 4-(trifluoromethyl)benzeneboronic acid (104 mg, 0.55 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol) and sodium carbonate (146 mg, 1.38 mmol) in water (2 mL). The mixture was then heated at 70° C. for 3 hours, cooled to rt and partitioned between EtOAc and water. The layers were separated and the organic layer washed with brine, dried (Na2SO4) and concentrated to give a brown oil. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60° C.:EtOAc (19:1) afforded the title compound as a colourless gum (142 mg).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=C(/C(O)=O)\C)[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:35]=[O+][O-].CSC>CO>[CH:26]([CH:25]([N:23]([CH3:24])[C:21]([CH:16]([NH:15][C:13](=[O:14])[CH:3]([NH:2][CH3:1])[C:4]([CH3:12])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:11])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH:32]([CH3:33])[CH3:34])=[O:35]
Reactant: O=[O+][O-]
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Solvent: CO
Solvent: CSC
Product: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (1.0 g) in methanol (20 mL) is added to 100 mL of methanol at −78° C. which had been treated with ozone until the solution is blue. The resulting colorless reaction mixture is treated with ozone at −78° C. until the blue color remained. After 5 min dimethylsulfide (2 mL) is added. The reaction mixture is allowed to warm to room temperature and then concentrated in vacuo to give the title compound as an oil. MS (ES): m/z 418.4 (M+H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1-(ethylsulfonyl)-4-fluorobenzene (1.36 mmol, 0.257 g) in sulfuric acid (1.32 ml) was added potassium nitrate (0.243 g) at 80° C. The mixture was stirred at 90° C. for 2 hours. Ice water (5 ml) was added and the mixture was extracted with ethyl acetate (25 ml) and washed with water (20 ml) and brine (10 ml). The organic extracts were combined and dried over sodium sulfate and concentrated. The residue was purified by column chromatography (hexane/ethylacetate 1:3) to give a light yellow solid which was crystallized from methanol. HPLC indicated 98% purity, mp 128-131° C., (0.21 g, 66% yield). 1H NMR (CDCl3): 1.35 (t, 3H, CH3), 3.21 (q, 2H, CH2), 7.55 (t, 1H, Ar—H), 8.21 (m, 1H, Ar—H), 8.64 (d, 1H, Ar—H); MS: 229 M−. Elemental Analysis (C, H, N, F, S) for C8H8FNO4S; calculated C, 41.20; H, 3.46; N, 6.01; F, 8.15; S, 13.75. found C, 41.31; H, 3.35; N, 5.85; F, 8.17; S, 13.53.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FCBr
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=NOCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
Potassium carbonate (110.6 g, 0.8 ml) was added to ethyl 2-hydroxyimino-cyanoacetate (56.8 g, 0.4 mol) in dimethylsulfoxide (200 ml) under ice-cooling, and the mixture was stirred for 10 mins, and then Fluoromethyl bromide (48.8 g, 0.4 mol) in N,N-dimethylformamide (40 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred at an internal temperature of 20° to 30° C. for 2.5 hrs. The reaction solution was dispersed in ice water (1 L), and it was extracted with ethyl acetate (800 ml, 500 ml, and 500 ml). The combined extracts were washed twice with saturated brine (300 ml) and dried over sodium sulfate, and then concentrated to give a concentrate (66.4 g) which was purified by column chromatography using silica gel (60 g) to give ethyl 2-fluoromethoxyimino-cyanoacetate (46.6 g, yield: 66.9%) as an oily substance.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:12].O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[NH:13][C:11](=[O:12])[CH2:10][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: O=C1CCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCCC1=O
Reaction time: 2 h
Yield: 90.4 %

Procedure:
In 300 ml of toluene was suspended 9.2 g of 60% sodium hydride in a nitrogen stream, and 21.3 g of 2pyrrolidinone was slowly added dropwise to the suspension at an inner temperature controlled at 40° C. or lower. After stirring the mixture for 2 hours, 19.7 g of 2-chloro-N(2,6-dimethylphenyl)acetamide was added thereto, and the mixture was allowed to react at 60° to 70° C. for 2 hours. To the reaction mixture was added 50 ml of hot water of about 70° to 85° C., followed by allowing to cool with stirring. The precipitated crystals in the aqueous layer were collected by filtration and dried under reduced pressure to obtain 22.2 g (90%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[N:4][C:3]=1[NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccccc1
Temperature: 50 °C
Yield: 80 %

Procedure:
Part A. A solution of 5-amino-4,6-dichloropyrimidine (10.0 g, 61.0 mmol) and triethylamine (12.8 mL, 91.5 mmol) in ethanol (100 mL) was treated with benzylamine (7.30 mL, 67.1 mmol), and heated to 50° C. overnight. The resulting mixture was cooled, and the resulting crystalline solid was collected by filtration. The solid was triturated with hexane, refiltered and dried under vacuum. A second crop was collected from the mother liquor and purified like the first crop to afford in total 12.67 g (48.8 mmol, 80%) of 5-amino-6-benzylamino-4-chloropyrimidine. TLC RF 0.10 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.62 (1H, s), 7.13-6.97 (SH, m), 6.61 (1H, br t, J=5 Hz), 4.43 (2H, d, J=5.5 Hz), 4.24 (2H, br s). MS (NH3—CI): m/e 238 (4), 237 (33), 236 (15), 235 (100).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:38][C@H:37]([CH3:39])[O:36][C@H:35]([CH3:40])[CH2:34]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([OH:29])=O)[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:43].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC>C1COCC1.CN(C=O)C.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:33]2[CH2:38][C@H:37]([CH3:39])[O:36][C@H:35]([CH3:40])[CH2:34]2)=[C:22]([F:32])[C:23]([F:31])=[C:24]([C:26](=[O:30])[C:27]([N:42]([CH3:43])[CH3:41])=[O:29])[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)O)c(F)c2F)C[C@H](C)O1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(=O)N(C)C)c(F)c2F)C[C@H](C)O1
Yield: 74.5 %

Procedure:
2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-oxoacetic acid (Intermediate 118, 250 mg, 0.44 mmol), HATU (335 mg, 0.88 mmol), triethylamine (0.184 ml, 1.32 mmol) and 2.0M dimethylamine (0.440 ml, 0.88 mmol) in THF were stirred in DMF (5 ml) in a closed vial for 16 hours. The reaction was diluted with water and extracted 3× with ethyl acetate. The organic layers were washed 3× with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound (195 mg, 0.328 mmol, 74.5%)
Reaction SMILES: [C:1]([N:11]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)N)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].N#N.S([O-])([O-])=O.[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([CH3:34])=O>O>[C:1]([N:11]1[C:13]2[C:18](=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:31]([CH2:30][C:29]([OH:36])=[O:35])=[C:32]1[CH3:34])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCC(=O)O
Reactant: NN(C(=O)C=Cc1ccccc1)c1ccc2c(c1)OCO2
Agent: N#N
Agent: O=S([O-])[O-]
Agent: [Na]
Solvent: O
Product: Cc1c(CC(=O)O)c2cc3c(cc2n1C(=O)C=Cc1ccccc1)OCO3
Temperature: 25 °C

Procedure:
A mixture of 8 g of sodium N1 -cinnamoyl-3,4-methylenedioxyphenylhydrazine-N2 -sulfite, ##EQU11## and 45 ml of levulinic acid was heated in the presence of small amount of surfuric acid at 80° - 85°C for 3 hours. The reaction mixture was cooled to a room temperature and poured into water to give 1-cinnamoyl-2-methyl-5,6-methylenedioxy-3-indolylacetic acid. The crystals obtained by twice recrystallizing from acetone-water (5 : 1) showed a melting point of 190° - 192°C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[C:20]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[N:19][CH:18]=1>O1CCOCC1.CN(C=O)C.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>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:20]3[C:21]4[N:22]([CH:23]=[CH:24][N:25]=4)[C:17]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:18][N:19]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
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+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1[nH]ncc1-c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)c2nccn12

Procedure:
In the same way as described for Compound 127, step 4, using 5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (75 mg, 0.36 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (70 mg, 0.18 mmol) and Pd(PPh3)4 (52 mg, 0.045 mmol) in dioxane (0.6 mL), DMF (1.33 mL) and 1.5M Na2CO3 (0.97 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.62 min (98.2%); m/z (APCI) 389 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C/C1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of tert-butyl 4-((E)-2-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}vinyl)piperidine-1-carboxylate (0.0693 g, 0.138 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(E)-2-(piperidin-4-yl)vinyl]benzofuran-3(2H)-one (0.0473 g, 85%).
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH2:11]([C:16]1[CH2:30][C@@H:29]([O:31][Si](C(C)(C)C)(C)C)[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([O:49][Si](C(C)(C)C)(C)C)[CH2:42][C@H:43]([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[C:17]=1[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1>[CH2:11]([C:16]1[CH2:30][C@@H:29]([OH:31])[C@H:28](/[CH:39]=[CH:40]/[C@@H:41]([OH:49])[CH2:42][C@H:43]([CH3:48])[CH2:44][CH2:45][CH2:46][CH3:47])[C:17]=1[S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@H](C[C@H](C)CCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@@H](O)C[C@H](C)CCCC)[C@H](O)C1
Reaction time: 15 h
Yield: 51.2 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (0.1 mL) was added hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-pentyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (71 mg, 0.10 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromotography (30 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (24 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (227 mg, 0.75 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (127 mg).
Reaction SMILES: [F:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=1>C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:5]([C:2]2([F:1])[CH2:4][CH2:3]2)=[O:7])=[CH:26][N:25]=1
Reactant: O=C(O)C1(F)CC1
Reactant: COc1ccc(N)cn1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2(F)CC2)cn1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
1-Fluorocyclopropanecarboxylic acid (crude) (0.84 g, 0.0081 moles) was added in two portions to a solution of methylene chloride (50 ml ) and carbonyl di-imidazole (1.31 g, 0.0081 moles). The reaction was allowed to stand for 1 hour and then 5-amino-2-methoxypyridine (0.83 ml , 0.0081 moles) was added to it in one portion. The reaction mixture was allowed to stand at room temperature for 1 hour. The reaction mixture was then washed with saturated sodium bicarbonate (50 ml ), 5% hydrochloric acid (20 ml ) and saturated sodium bicarbonate solution (25 ml ); dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 0.5 g of crude N-(2-methoxy-5-pyridyl)-1-fluorocyclopropanecarboxamide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2([C:32]#[N:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:32]([C:26]1([C:22]2[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:28][CH2:27]1)#[N:33]
Reactant: Cc1ccnc(C2(C#N)CCNCC2)c1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CN2CCC(C#N)(c3cc(C)ccn3)CC2)c2ccccn2c1=O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A mixture of the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (2.60 g, 10.6 mmol), 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile (1.78 g, 8.83 mmol), and 36.8 mL of anhydrous THF was cooled to 10° C. and stirred vigorously. To the stirring mixture was added sodium triacetoxyborohydride (2.62 g, 12.4 mmol), portionwise over a period of 1 hour. The mixture was heated to 50° C. for 18 hours. The reaction was quenched with a 10% sodium bicarbonate solution and extracted with EtOAc (3×50 mL). The organic layers were combined, acidified with 1 N HCl, and extracted with DCM (8×150 mL). In a 500 mL Erlenmeyer flask, the aqueous layer was neutralized slowly with solid sodium carbonate under continuous stirring until pH ˜7-8 and then extracted with DCM (3×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to afford the ethyl 1-{[4-cyano-4-(4-methylpyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectrum consistent with theory and a mass spectrum (ES+) m/z of 431.0 calculated for M+H+: 1H NMR (400 MHz, CDCl3) δ 9.51 (d, J=7.1 Hz, 1H), 8.43 (d, J=4.95 Hz, 1H), 8.32 (s, 1H), 8.14 (d, J=8.9 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.26 (m, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.75 (s, 2H), 3.01 (d, J=12.0 Hz, 2H), 2.56 (t, J=11.3 Hz, 2H), 2.39 (s, 3H), 2.29 (t, J=12.9 Hz, 2H), 2.05 (d, J=12.4 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]([O:13]CC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C([O-])=O.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]([NH2+:37][NH2:38])[CH3:36])=[CH:31][CH:30]=1)=[O:28])[CH3:25]>C(#N)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH2:10][C:11](=[O:13])[N:37]([C@H:35]([C:32]3[CH:33]=[CH:34][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][CH:31]=3)[CH3:36])[N:38]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1ccc([C@H](C)[NH2+]N)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc([C@H](C)N2N=C(c3cc(Cl)cc(Cl)c3)CC2=O)cc1

Procedure:
Ethyl 3-(3,5-dichlorophenyl)-3-oxopropanoate (4.2 g, 16.1 mmol) and {(1S)-1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinium trifluoroacetate (5.2 g, 16.1 mmol) were heated in dry acetonitrile (100 ml) to 85° C. for 1 hr. The solvent was removed under reduced pressure, and the residue purified by column chromatography (SiO2, 20% ethyl acetate in hexanes) to give ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]ethyl}benzoate as a white solid. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.78 (d, J=7.0 Hz, 3H); 3.55 (d, J 22.6 Hz, 1H); 3.60 (d, J=22.6 Hz, 1H); 4.36 (q, J=7.1 Hz, 2H); 5.57 (q, J=7.0 Hz, 1H); 7.39 (t, J=1.9 Hz, 1H); 7.50 (d, J=8.4 Hz, 2H). 7.52 (d, J=1.9 Hz, 2H); 8.02 (d, J=8.4 Hz, 2H). MS C20H18Cl2N2O3 Cald: 404.07; Obsd (M+1): 405.20.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH:10]([OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[N:12]=1)([CH3:4])[CH3:3].[Cl:21][C:22]1[C:29]([F:30])=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>>[CH3:4][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH:10]([O:19][C:24]1[CH:23]=[C:22]([Cl:21])[C:29]([F:30])=[CH:28][C:25]=1[C:26]#[N:27])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[N:12]=1)([CH3:1])[CH3:3]
Reactant: COc1cccc(C(O)CCNC(=O)OC(C)(C)C)n1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Product: COc1cccc(C(CCNC(=O)OC(C)(C)C)Oc2cc(Cl)c(F)cc2C#N)n1

Procedure:
The sub-title compound was prepared by the method of Example 58 (c) using [3-hydroxy-3-(6-methoxy-2-pyridinyl)propyl]carbamic acid 1,1-dimethylethyl ester (Example 61 (b)) and 4-chloro-2,5-difluorobenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1OC

Procedure:
3,4-Dimethoxybenzaldehyde (5 g), malonic acid (4.7 g), piperidine (0.5 ml) and pyridine (15 ml) were refluxed for six hours. The reaction mixture was poured into ice-cold water and acidified with 6M hydrochloric acid. The resultant solid was filtered, washed with water and dried under vacuum.