Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:17][C:16]4[C@@H:18]([CH3:22])[NH:19][C:20](=[O:21])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[OH:44][C:38]([C:40]([F:43])([F:42])[F:41])=[O:39].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:3]2[N:2]([CH3:1])[C:11](=[O:12])[C:10]3[C:5](=[C:6]([C:13]4[NH:17][C:16]5[C@@H:18]([CH3:22])[NH:19][C:20](=[O:21])[C:15]=5[CH:14]=4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH2:25]1
Reactant: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@@H]5CCC[C@H](NC(=O)OC(C)(C)C)C5)nc34)[nH]c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@H]5CCC[C@@H](N)C5)nc34)[nH]c21
Yield: 98.9 %

Procedure:
A solution of (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, see below) (47 mg, 0.093 mmol) and TFA (71.5 pt, 0.928 mmol) in DCM (928 pt) was stirred at RT for 1.5 h when mostly product was observed via LCMS. The reaction mixture was concentrated to give (rac)-2-(((cis)-3-aminocyclohexyl)amino)-3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one TFA salt (506, 48 mg, 0.092 mmol, 99% yield) as an off-white solid and a 2.6:1 ratio of diastereomers via LCMS and 1.3:1 via 1H NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.33 (m, 1H) 1.33-1.46 (m, 5H) 1.46-1.56 (m, 1H) 1.89 (d, J=12.72 Hz, 1H) 1.98 (d, J=11.74 Hz, 1H) 2.06 (d, J=10.56 Hz, 1H) 2.30-2.39 (m, 1H) 3.05-3.17 (m, 1H) 3.45 (s, 3H) 4.01-4.15 (m, 1H) 4.50-4.61 (m, 1H) 6.93-7.01 (m, 1H) 7.06 (d, J=4.11 Hz, 1H) 7.17 (t, J=7.63 Hz, 1H) 7.62 (s, 0.42H) 7.66 (s, 0.58; H) 7.84 (d, J=7.63 Hz, 1H) 7.88-8.00 (m, 3H) 11.78 (s, 0.42; H) 11.91 (s, 0.58; H). 19F NMR (376 MHz, DMSO-d6) δ ppm −73.81 (s, 3F). MS (ESI, pos. ion) m/z: 407.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cnc(C)c(C)c3)c(=O)c3cc(F)ccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.24 mmol) 3-(5,6-dimethyl-pyridine-3-carbonyl)-6-fluoro-1H-quinolin-4-one, 12 mg (0.29 mmol) of 60% sodium hydride, 53 mg (0.29 mmol) of 2-bromomethyl-6-methyl-pyridine and 1 mL of N,N-dimethylformamide. Yield: 67 mg of a white solid: LC-MSD, m/z for C24H20FN3O2 [M+H]+=402.1; HPLC retention time: 0.7 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:13][C:14](=O)[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([CH3:15])[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1ccc(Br)cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1.2 (5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and 1-Chloro-propane-2-one (1 eq.) in DMF (2 ml) is added and stirred 2 h at 70° C. After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. (5-Bromo-pyridine-2-yl)-(4-methyl-thiazole-2-yl)-amine is obtained as a colourless powder in a yield of 86%; mp. 241.5-242.6° C.; HPLC (method C): 1.55 min, 269.95 (M+H+); LC-MS (method A): 1.432 min; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 11.314 (s, 1H), 8.363 (d, 1H, J=2.9 Hz), 7.865 (dd, 1H, J=2.9 Hz, J=8.9 Hz), 7.037 (d, 1H, J=8.9 Hz), 6.578 (s, 1H), 2.242 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15]>>[CH3:11][O:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[CH:3][CH:4]=1
Reactant: COC=Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Product: COC=Cc1ccc(C=O)cc1

Procedure:
By the method of example 28, 1-bromo-4-(2-methoxyethenyl)benzene is prepared, lithiated, and reacted with dimethylformamide to provide 4-(2-methoxyethenyl) benzaldehyde as a yellow oil after chromatography. This material is converted to 1-(2-phenylethenyl)-4-(2-methoxyethenyl)benzene by Wittig reaction with benzyl triphenylphosphonium chloride, using the conditions described in example 1 (A). The material is obtained as a mixture of all four possible (E) and (Z) stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21](O)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-].O>CS(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([NH2:32])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylic acid (40 mg, 0.09 mmol) in 1 mL of anhydrous DMSO, CDI (22 mg, 0.14 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 50° C. for 3 h. After cooling down to rt, NH4Cl (11 mg, 0.14 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at it overnight. The reaction mixture was poured into water. The yellow precipitate was collected as the desired product by filtration, followed by washed with water in 96% yield. 1HNMR (in DMSO): 4.90 (d, J=5.5 Hz, 2H), 7.66-7.72 (m, 2H), 7.93 (s, 1H), 8.19 (d, J=3.3 Hz, 1H), 8.72 (s, 1H), 9.17 (d, J=2.6 Hz, 1H), 9.53 (d, J=2.6 Hz, 1H), 9.87 (t, J=5.8 Hz, 1H), 10.22 (d, J=3.3 Hz, 1H). Mass: M+H+: 426.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])=[O:19].CC1C=CC(S(O)(=O)=O)=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCN(CC)CC>[N:8]1([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])=[O:19])=[O:12]
Reactant: NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of Boc-L-Proline (1.43 g, 6.7 mmol) and Gly-Gly-Gly-OCH2Ph.TsOH (3.0 g, 6.7 mmol) in CH2Cl2 (40 mL) and Et3N (2.80 mL) was cooled to 5° C. and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.34 g, 7.0 mmol) was added. The reaction was stirred at ambient temperature for 3 days and then the solvent was evaporated. The crude material was dissolved in ethyl acetate (50 mL) and washed with saturated aqueous NH4Cl (25 mL), brine (25 mL), dried over MgSO4, and then evaporated to dryness. The product was purified by column chromatography (SiO2, CH2Cl2-MeOH 95:5) to give Boc-Pro-Gly-Gly-Gly-OCH2Ph (SEQ ID NO.: 1) (2.25 g, 71%) as colorless crystals, mp 54–55° C. 1H-NMR (300 MHz, δ, CDCl3): 1.42 (9H, s), 1.80–2.20 (4H, m), 3.35–3.55 (2H, m), 3.85–4.20 (7H, m), 5.15 (2H, s), 7.05 (2H, bs), 7.30–7.35 (5H, m), 7.80 (1H, bs). 13C-NMR (75 MHz, δ, CDCl3): 24.6, 28.3, 29.4, 41.1, 43.0, 43.3, 47.2, 60.7, 66.9, 80.9, 128.4, 128.5, 128.7, 135.4, 155.8, 169.6, 170.0, 173.9. IR (KBr, cm−1):, 1753(CO), 1667(CO).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br.O>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8][C:6]2=[S:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(N(CC2CC2)C(N)=S)cc1
Reactant: O=Cc1ccccc1
Agent: Br
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=S)N2CC1CC1
Yield: 71.8 %

Procedure:
To a suspension of 2.36 g (0.01 mole) of N-cyclopropylmethyl-N-(p-methoxyphenyl) thiourea in 30 ml of toluene were added 1.21 g (0.011 mole) of benzaldehyde and 0.84 g (0.005 mole) of 48% hydrobromic acid. The resulting mixture was heated under reflux for 6 hours using a water separator. After cooling, the reaction mixture was washed with dilute hydrochloric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from isopropyl alcohol to give 2.33 g (72%) of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinethione, m.p. 146°-147° C.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To an ice cooled solution of 2.04 g (10 mmol) of Boc-homopiperazine, 1.32 g (10 mmol) of DIPEA in 80 ml of methylene chloride was added a solution of 2.18 g (10 mmol) of 2-chlorophenylsulfonyl chloride in 40 ml of methylene chloride. Then the reaction mixture was stirred at RT overnight. The organic phase washed with HCl aq, water, dried over sodium sulphate and evaporated to dryness to give 3.7 g of compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH:16]3[CH:14]([CH:15]3[NH:18][C:19]([O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[CH:24]=3)=[O:20])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH:16]3[CH:14]([CH:15]3[NH:18][C:19](=[O:20])[O:21][CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28](=[O:29])[NH:34][CH3:33])[CH:24]=3)[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1cc(COC(=O)NC2C3CN(c4ccc5cc(F)ccc5n4)CC32)on1
Yield: 60 %

Procedure:
The procedure described in Example 6, step 6.4. is followed. Starting from 0.30 g (0.68 mmol) of ethyl 5-[({[3-(6-fluoro-quinolin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamoyl}oxy)-methyl]isoxazole-3-carboxylate and 8.50 ml of an 8M solution of methylamine in ethanol, and after high-temperature crystallization in diethyl ether, 0.17 g (60%) of product is obtained in the form of a white solid.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N:9]([C@H:12]1[C@@H:15]([CH2:16][OH:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])=[N+:10]=[N-:11]>CN(C)C=O>[N:9]([C@H:12]1[C@@H:15]([CH2:16][O:17][CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])=[N+:10]=[N-:11]
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2CO)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC[C@@H]1[C@H](N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Temperature: -20 °C

Procedure:
A suspension of 60% sodium hydride (749 mg, 18.72 mmole) was washed under argon with hexane (9 ml). The sodium hydride was then cooled to -20° C. and dimethylformamide (20 ml) was added. The mixture was then cooled to -50° C. and methyl bromoacetate (1.77 ml, 18.72 mmole) was added via syringe. Next, a solution of (±)-(cis)-3-azido-4-hydroxymethyl-1-(4-methoxyphenyl)-2-oxoazetidine (3.303 g, 13.37 mmole) in dimethylformamide (25 ml) was added dropwise. The reaction was stirred at -50° C. for ten minutes, warmed to -20° C. over 40 minutes, stirred at this temperature for thirty minutes, and then stirred at -5° C. overnight (ca. sixteen hours). The solvent was mostly removed in vacuo (30° C.). The residue was treated with ether, then pH 4.5 monobasic potassium phosphate buffer. The aqueous layer was extracted with additional ether. The organic extracts were washed with cold 0.5 N hydrochloric acid, water, brine, dried (sodium sulfate), and filtered and concentrated to 4.2 g of an orange oil. The crude product was chromatographed on silica gel (180 g, 230-400 mesh) eluting with 60% hexane-ethyl acetate. Combination of fractions 35-46 (20 ml fractions), concentration and drying in vacuo produced 2.46 g of the title compond as an oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[C:4]([OH:26])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid ethyl ester (707 mg, 1.80 mmol in tetrahydrofuran/water (24 mL, 3:1) was treated with lithium hydroxide (166 mg, 3.97 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction concentrated in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (1×15 mL). The aqueous layer was acidified to pH=1 with a 2N aqueous hydrochloric acid solution, and extracted with chloroform (3×25 mL). The combined organic layers were washed with water (1×25 mL) and a saturated aqueous sodium chloride solution (3×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (426.7 mg, 65%) as a white solid: mp 122–123° C.; EI-HRMS m/e calcd for C16H19F3O4S (M+) 364.0956 found 364.0956.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:16]1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:14])[F:13])=[O:41])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:31])([F:32])[CH:24]([F:30])[O:25][C:26]([F:28])([F:29])[F:27])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 1 h
Yield: 96.9 %

Procedure:
0.2 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxy-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 92 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.20 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methoxy-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.O>C(O)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=CC=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=CC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 94.9 %

Procedure:
Ethyl 5,5-diphenylpenta-2,4-dienoate (3.70 g) was dissolved in ethanol (68 mL), and 1N sodium hydroxide solution (22 mL) was added thereto, followed by stirring at room temperature for 28.5 hours. Subsequently, while the mixture was stirred under ice-cooling, 1N hydrochloric acid was added thereto, and pH of the resultant mixture was adjusted to about 2. The mixture was condensed to a certain volume under reduced pressure. Water was added to the condensed product, and the thus-obtained solid was collected through filtration and washed several times with water, followed by air-drying, to thereby yield 3.16 g of the product of interest (yield 94.9%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:26][O:27][C:28]([N:30]1[C@@H:38]2[C@@H:33]([C@@:34](O)([C:39]#[C:40][C:41]3[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1)=[O:29]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][O:27][C:28]([N:30]1[C@H:38]2[C@H:33]([C@:34]([O:9][C:8](=[O:10])[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)([C:39]#[C:40][C:41]3[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1)=[O:29]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCN1CCCC1
Temperature: 22 °C
Reaction time: 50 h
Yield: 35 %

Procedure:
3-Pyrrolidin-1-yl-propionic acid (143 mg, 1.0 mmol) and dicyclohexylcarbodiimide (247 mg, 1.2 mmol) were dissolved in dichloromethane (5 mL). Subsequently, 4-dimethylaminopyridine (97 mg, 0.8 mmol) and (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (250 mg, 0.8 mmol) were added. The resulting suspension was stirred at room temperature (22° C.) for 50 h. The precipitation was then removed by filtration and the clear filtrate was subjected to silica gel flash chromatography [ISCO CombiFlash Companion; 40 g silica gel; methylenechloride/methanol; methanol 0% (4 min), 1% (4 min), 2% (4 min), 2-5% (2 min), 5% (5 min) and 10% (8 min)]. Then, the solvents were evaporated to yield (3aR,4S,7aR)-4-(3-pyrrolidin-1-yl-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (123 mg, 0.28 mmol, 35% yield). MS [M+H]=439; RT=6.122 min (LC-MS Method III). 1H-NMR (600 MHz; DMSO-d6) ppm 1.23 (m, 1H), 1.65 (broad s, 4H), 1.80 to 2.10 (m, 5H), 2.30 (s, 3H), 2.46 (m, 4H), 2.49 (m, 4H), 2.67 (m, 2H), 3.13 (m, 1H), 3.30 (m, 1H), 3.42 (q, 1H), 3.55 (s, 3H), 3.88 (m, 1H), 7.22 (broad s, 2H) and 7.27 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1([CH2:11]O)[CH2:10][CH2:9]1.[N+:13]([C:16]1[CH:20]=[CH:19][NH:18][N:17]=1)([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:13]([C:16]1[CH:20]=[CH:19][N:18]([CH2:11][C:8]2([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][CH2:10]2)[N:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: OCC1(OC2CCCCO2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccn(CC2(OC3CCCCO3)CC2)n1
Temperature: 0 °C
Yield: 21 %

Procedure:
[1-(Tetrahydro-pyran-2-yloxy)-cyclopropyl]-methanol (1.00 g, 5.81 mmol), 3-nitro-1H-pyrazole (prepared in example 3, 656 mg, 5.81 mmol), and triphenylphosphine (1.52 g, 5.81 mmol) were combined and dissolved in anhydrous tetrahydrofuran (30 mL). The reaction was chilled to 0° C. under nitrogen. While stirring, diisopropyl azodicarboxylate (1.72 mL, 8.72 mmol) was added dropwise over a period of 2 min. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes) afforded 3-nitro-1-[1-(tetrahydro-pyran-2-yloxy)-cyclopropylmethyl]-1H-pyrazole (326 mg, 21%) as a white powder: H1-NMR (400 MHz, CDCl3) δ 0.74-0.82 (1H, m), 0.86-0.94 (1H, m), 0.95-1.02 (1H, m), 1.05-1.03 (1H, m), 1.40-1.70 (5H, m), 1.74-1.84 (1H, m), 3.46-3.54 (1H, m), 3.83-3.90 (1H, m), 3.94 (1H, d, J=14.4 Hz), 4.66-4.72 (1H, m), 4.87-4.94 (1H, m), 6.88 (1H, d, J=2.8 Hz), 7.84 (1H, d, J=2.4 Hz).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[F:7][C:8]([F:36])([F:35])[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=1)[CH2:12][NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:4][CH:2]([CH3:3])[CH3:1])[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])[CH:16]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of propan-2-ol (2 mL) in N,N-dimethylformamide (5 mL), sodium hydride (72 mg, 3.00 mmol, 5.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (250 mg, 0.58 mmol, 1.00 equiv, 98%). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate and washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 280 mg (99%) of product as a brown oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C(=O)[C@@H]1CCCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2S)—N,N-Dimethyl-2-piperidinecarboxamide hydrochloride (880 mg, 4.567 mmol) was dissolved in a mixture of CH2Cl2 (15 mL) and water (15 mL), and then solid sodium bicarbonate (1.534 g, 18.268 mmol) was added, followed by benzoyl chloride (0.556 mL, 4.795 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-10% methanol/dichloromethane) to provide (2S)—N,N-dimethyl-1-(phenylcarbonyl)-2-piperidinecarboxamide (883 mg, 74%). LCMS: (M+H)+: not detected.