Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)=[O:9])[CH2:3][CH2:2]2)=[O:37])[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)CN1CCN(Cc2ccccc2)CC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)CN2CCN(Cc3ccccc3)CC2)CC1

Procedure:
Intermediate 42 (303 mg, 1 mmol) was reacted with carboxylic acid 46 by Method E. Flash chromatography eluted with 9:1 DCM:MeOH afforded compound 50 (379 mg, 73%) as a white solid: Mp 178-183° C. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.34-7.26 (m, 4H), 7.26-7.19 (m, 3H), 6.25 (d, J=7.5 Hz, 1H), 4.14 (d, J=13.4 Hz, 1H), 3.95 (d, J=12.5 Hz, 1H), 3.75-3.66 (m, 1H), 3.45 (s, 2H), 3.23 (d, J=13.2 Hz, 1H), 3.12 (t, J=11.9 Hz, 1H), 3.00 (d, J=13.1 Hz, 1H), 2.78 (t, J=11.6 Hz, 1H), 2.47-2.30 (m, 8H), 1.89-1.76 (m, 2H), 1.40-1.31 (m, 1H), 1.23-1.13 (m, 1H). Purity 90%. HRMS calculated for C20H21F3N4O3−H+ 518.2379. found (ESI(−), [M−H]) 518.2365.
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Yield: 16.1 %

Procedure:
2-Methylsulphinyl-3-nitro-4-phenylpyrrole (2.0g, 0.008 mol) was partially dissolved in ethanol (150 ml) and a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37g, 0.008 mol) in a little ethanol was added to it. The mixture was refluxed for seven days, after which the mixture was stripped and chromatographed on a silica gel column, collecting the required product by elution with ethyl acetate. The crude solid was recrystallised from 2-propanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-phenylpyrrole (0.46g), m.p. 182-184'.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:18][CH2:17]N(C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=C1CC[C:30]2([O:34][CH2:33][CH2:32][O:31]2)CC1>>[C:1]1([C:7]#[C:8][C:9]2[CH2:13][C:12]3([CH2:14][CH2:15][C:30]4([O:34][CH2:33][CH2:32][O:31]4)[CH2:17][CH2:18]3)[O:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Product: C(#Cc1ccccc1)C1=NOC2(CCC3(CC2)OCCO3)C1
Yield: 44.9 %

Procedure:
The title compound was synthesized using the same method described for Compound 1b but using Compound 31a instead of N-Boc-4-methylenepiperidine. After the usual work-up procedure, the title product was purified by automated RP chromatography (Isolera®TM-Biotage; gradient buffer NH4HCO3-MeCN from 40-60 a 20-80. Yield: 44.9%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>S(=O)(=O)(O)O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)cc1
Yield: 80 %

Procedure:
A solution of 15 gm (0.1 mole) of 4-hydroxyphenylacetic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3 A molecular sieves. The solution was heated to reflux for 72 hours, and the sieves were exchanged at 24-hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 mL toluene and extracted with 3×100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 13 gm (80% yield) of a yellow oil. The NMR spectrum was consistent with the assigned structure and this material was used in the next reaction step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1)=[O:36]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccco2)C[C@@H]1C(=O)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
Compound 2 (51 mg, 0.13 mmol) obtained in Example 2 was dissolved in dichloromethane (0.65 mL), and furan-2-carboxylic acid chloride (0.025 mL, 0.26 mmol) and pyridine (0.041 mL, 0.51 mmol) were added thereto, followed by stirring at 0° C. for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A residue obtained by concentrating the organic layer under reduced pressure was purified by preparative thin layer chromatography to obtain the title compound (65 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])=[CH:21][CH:20]=1.Cl>ClCCCl>[OH:33][C:26]1([C:9]2[C:8]([OH:11])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:36][CH:35]=2)[C:25]1=[O:34]
Reactant: Cc1noc2ccc(O)cc12
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a stirred solution of 3-methyl-1,2-benzisoxazol-5-ol (Lindemann, et al Justus Liebigs Annalen der Chemie 1927, 456:308) (3.10 g, 20.8 mmol) in 1,2-dichloroethane (200 mL) was added isopropylmagnesium chloride (10.4 mL, 2.0 M solution in tetrahydrofuran, 20.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (5.3 g, 19.8 mmol) was added and the reaction mixture was stirred at reflux for 120 h. The mixture was cooled to 0° C. and 5% w/v hydrochloric acid was added. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluted with ethyl acetate/hexanes (1/1) to afford 3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (0.87 g, 10%): 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.01 (s, 1H), 7.37-6.76 (m, 10H), 4.83 (ABq, 2H), 3.70 (s, 3H), 2.46 (s, 3H); MS (ES+) m/z 415.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:28])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([F:27])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:13]([F:28])[F:12])=[N:15][CH:16]=1)[CH2:23][C:24]1([F:27])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.89. [α]D20=+21.70 (c=3.00 mg/mL,CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.CCN(CC)CC.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:30](=[O:31])[CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCNC1CCc2cccc(OC)c2C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 60 mg (0.27 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) and 0.11 mL Et3N (0.79 mmol) in 5 mL dry CHCl3 was cooled in an ice bath. After adding 0.05 ml (0.41 mmol) 2-thienylacetic acid chloride (A3-1: W=Cl, Cy=2-thienyl) to the mixture the ice bath was removed and the reaction was stirred for 2 hrs at room temperature. In a second step further 0.05 mL (0.41 mmol) of 2-thienylacetic acid chloride (A3-1) were added and the reaction stirred for 20 hrs. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and finally extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 40/1 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[O:22][C:21]([F:20])([F:32])[F:33])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccccc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (0.022 mmol) were suspended in pyridine (2 mL), and 2-(trifluoromethoxy)benzoyl chloride (202 mg, 0.900 mmol) was added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 475 (111 mg, 53 as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]1[CH2:16][O:15][CH2:14][CH2:13][NH:12][CH2:11]1.Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[CH2:11][CH2:10][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1CNCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Brc1ccc(CN2CCCOCC2)cc1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 4-bromobenzaldehyde (616 mg, 3.3 mmol) in dichloroethane (50 mL) was added homomorpholine hydrochloride (548 mg, 4 mmol) and acetic acid (0.1 mL). Sodium triacetoxyborohydride (3.4 g, 16 mmol) was added and the reaction was stirred overnight. The reaction was quenched with sat. NH4Cl (30 mL). Ethyl acetate (250 mL) was added and the solution was washed with sat. NaHCO3 (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was flushed through a silica plug with (5% MeOH/CH2Cl2) to give a white solid (850 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.3 Hz, 2H), 7.10 (d, J=7.3 Hz, 2H), 3.66-3.57 (m, 2H), 3.55-3.50 (m, 2H), 3.46-3.42 (m, 2H), 3.16-3.10 (m, 2H), 2.55-2.45 (m, 4H), 1.75-1.65 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=O)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C(C)([O-])C.[K+]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=[CH2:17])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by combining (3aR,6aS)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (100 mg, 0.464 mmol) [prepared as described by Santora, V. J., et. al. Bioorganic & Medicinal Chemistry Letters 2008, 18(4), 1490-1494] in 2 mL of tetrahydrofuran with methyltriphenylphosphonium bromide (249 mg, 0.697 mmol) and potassium tert-butoxide (78 mg, 0.697 mmol). The reaction was stirred at room temperature overnight, concentrated, and the crude material was purified by silica gel chromatography using 1-100% ethyl acetate/hexanes to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.47-7.41 (m, 2H), 7.40-7.33 (m, 2H), 7.31-7.25 (m, 1H), 4.93-4.89 (m, 1H), 4.80-4.76 (m, 1H), 3.55 (d, J=13.1, 1H), 3.47 (d, J=13.1, 1H), 2.96-2.87 (m, 1H), 2.63-2.41 (m, 5H), 2.33 (dd, J=8.9, 3.9, 1H), 2.17 (dddt, J=14.9, 7.4, 5.8, 1.6, 1H), 1.68 (ddd, J=16.0, 12.4, 8.1, 1H), 1.51-1.39 (m, 1H); MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C@H:7]([OH:16])[C@@H:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:2]1>C(Cl)Cl>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:10][C@@H:9]3[C@@H:5]([CH2:6][C:7](=[O:16])[CH:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:17]1
Reactant: CCOC(=O)[C@@H]1[C@@H]2CC3(C[C@@H]2C[C@@H]1O)OCCO3
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)C[C@H]2CC3(C[C@@H]12)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.5 %

Procedure:
A solution of 294 mg of (1S,5R,6R,7S)-3,3-ethylenedioxy-7-hydroxy-6-ethoxycarbonylbicyclo [3.3.0]octane (III)' in methylene chloride (2 ml) as prepared in Example 1 was added to a solution of a chromic anhydride-pyridine complex in methylene chloride [prepared from chromic anhydride (688 mg), pyridine (1088 mg) and methylene chloride (18 ml)], and the mixture was stirred at room temperature for 10 minutes. The supernatant was separated, the residue was washed with ether, and the combined organic layer was extracted with 5% aqueous sodium hydroxide solution. The aqueous layer was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was successively washed with saturated aqueous copper sulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, and concentrated to obtain 92 mg of (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one. To the thus obtained (1R,5S)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo [3,3,0]octan-3-one were added 20 mg of sodium hydroxide and 0.9 ml of water-ethanol mixed solution (4:1), and the mixture was stirred at 90° C. for 4 hours. After cooling, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ether. The organic layer was then washed with saturated brine, dried over sodium sulfate, and concentrated to give 42 mg of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[C].[Pd].C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH:14]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the obtained tert-butyl 4-((E)-2-(4-(acetamido)phenyl)vinyl)-2-(4-fluoroanilino)benzoate were added acetic acid 2.0 mL,dioxane 2.0 mL and 10% palladium-carbon 30 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 3 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated. Trifluoroacetic acid 10 mL was added to the obtained residue, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(2-(4-(acetamido)phenyl)ethyl)-2-(4-fluoroanilino)benzoic acid 60 mg of a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[S:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C:15](=[O:23])[N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(-c2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(-c3ccccc3)n2)sc2ccccc12
Yield: 57.7 %

Procedure:
6-Phenyl-2-pyridinecarbonitrile (0.72 g, 4.0 mmol) and methyl thiosalicylate (1.20 g, 7.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.73 g, 57%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])=[N:10]1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+].Cl>C(Cl)(=O)C.CO>[Cl:1][C:2]1([CH3:39])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([N:15]([C:16]2[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:20])[C:40](=[O:42])[CH3:41])=[N:10]1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(NC2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC)c(N(C(C)=O)C2=NN(C3C=CC(C)=CC3(C)Cl)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dodecyl 3-{N-[1-(2-chloro-2,4-dimethylphenyl)-4,5-dihydro-5-oxo-1H-pyrazol-3-yl]-amino}-4-methoxy-benzoate (10.5 g, 18.9 mmol) was dissolved in acetyl chloride (50 ml) and acetic anhydride (35 ml) and the solution was heated under reflux for 1.5 hrs. The solution was cooled, then it was slowly poured into ice/water (750 ml) and the resulting sticky solid was extracted with ethyl acetate (2×100 ml). The combined extracts were dried (MgSO4) and evaporated to give an oil. Sodium hydroxide (0.8 g, 18.9 mmol) was added to a solution of the oil in methanol (80 ml) and the mixture was stirred at room temperature for 4 hrs. The solution was poured slowly into 3N hydrochloric acid (500 ml), the aqueous liquor was decanted off and the residue was dissolved in ethyl acetate (100 ml). The organic solution was dried (MgSO4) and evaporated to give a glass. The crude material was recrystallized from methanol (50 ml) to give pure product as a white solid, 5.8 g, 51%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:17][CH2:16]1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: BrCC1CC1
Product: NC(=O)c1ccnc(-c2cn(CC3CC3)cn2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7) and cyclopropylmethyl bromide according to the procedure for the preparation of Example 124, part A. [M+H] Calc'd for C13H14N4O, 327. Found, 327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a 100 mL round-bottomed flask was added 4-aminobenzenethiol (4.9 g, 39.1 mmol) and potassium carbonate (9.72 g, 70.3 mmol) in dimethylformamide (20 ml). tert-Butyl 4-(tosyloxy)piperidine-1-carboxylate (5 g, 14.07 mmol) was added and the reaction was stirred in a sealed flask at 70° C. for 20 hours. The mixture was cooled and filtered through a plug of silica gel with dichloromethane. The filtrate was concentrated under vacuum and chromatographed to give the title compound.
Reaction SMILES: [Mg].[CH2:2]([Br:4])[CH3:3].[CH3:5][O:6][N:7]=[C:8]1[C:17]2[C:12](=[CH:13]C=[C:15](C3C=NN(CC)C=3OS(CCC)(=O)=O)[C:16]=2C)[S:11](=O)(=O)[C:10](=C=O)[CH2:9]1>C1COCC1>[CH3:5][O:6][N:7]=[C:8]1[C:17]2[C:12](=[CH:13][CH:3]=[C:2]([Br:4])[C:16]=2[CH3:15])[S:11][CH2:10][CH2:9]1
Reactant: CCBr
Reactant: CCCS(=O)(=O)Oc1c(-c2ccc3c(c2C)C(=NOC)CC(=C=O)S3(=O)=O)cnn1CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CON=C1CCSc2ccc(Br)c(C)c21

Procedure:
1.1 Grams (46 mmol) of magnesium was dispersed in 10 ml of THF, and 2.2 g (20 mmol) of ethyl bromide was dropwise added under nitrogen current. The mixture was allowed to react for 10 minutes, and then a THF solution of 2.9 g (10 mmol) of the 4-methoxyimino-5-methyl-6-bromothiochroman obtained in the above (1) was gradually added at room temperature. The mixture was refluxed for 3 hours and then cooled to room temperature, and carbon dioxide gas was bubbled in for 1 hour. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ether. An ether layer was extracted with a 5% potassium carbonate aqueous solution, and an aqueous layer was neutralized with concentrated hydrochloric acid. The neutralization product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. The washed extract was dried over sodium sulfate, and then the solvent was distilled off to give 1.6 g (yield 63%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid.