Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O-:3])=[O:2].[BH4-].[Na+].C(O)(=O)C.O>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1[nH]ccc1-c1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])CCc1[nH]ccc1-c1ccc(I)cc1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Following the procedure for a β-unsubstituted pyrrole (Strachan, J. P. et al., J. Org. Chem. 2000, 65, 3160-3172), a sample of 18 (1.36 g, 4.00 mmol) was dissolved in anhydrous THF/MeOH (40 mL, 9:1) under argon at 0° C. NaBH4 (605 mg, 16.00 mmol) was added in portions and stirring was continued for 1 h at 0° C. Then the mixture was stirred for 2 h at room temperature. The reaction mixture was neutralized with acetic acid (pH=7), then water (50 mL) was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (Na2SO4), concentrated, and purified by passage through a short column [silica, hexanes/ethyl acetate (3:1)] to give a pale white solid (1.2 g, 88%): mp 88-89° C.; 1H NMR δ 3.41 (t, J=6.6 Hz, 2H), 4.52 (t, J=6.6 Hz, 2H), 6.26 (s, 1H), 6.74 (s, 1H), 7.07 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 8.33 (br, 1H); 13C NMR δ24.0, 75.0, 91.1, 109.3, 117.8, 122.1, 122.2, 129.8, 135.7, 137.7; FAB-MS obsd 341.9877, calcd 341.9865; Anal. Calcd for Cl2H11IN2O2: C, 42.1; H, 3.2; N, 8.2. Found: C, 42.3; H, 3.3; N, 8.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>C1COCC1.CN(C=O)C.C1COCC1.CCOC(C)=O>[CH:39]1([C:44]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CCCC4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.241 mmol) in THF/DMF (20 mL/1 mL) was added Et3N (0.06 mL, 0.481 mmol). The suspension was cooled to 0° C., a solution of cyclopentanecarbonyl chloride (64.0 mg, 0.481 mmol) in THF (5 mL) was added to the reaction mixture drop wise over 2 hours. The reaction was stirred at rt for 1.5 hours, then diluted with EtOAc (25 mL). The resulted mixture was washed with water (25 mL×3), followed by washing with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v)=80/15/1) to give the title compound as a white solid (39 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH2:27][CH2:26][CH2:25]2.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH2:27][CH2:26][CH2:25]2
Reactant: COc1ccc(CN2CCCc3cc(Cc4cc([C@]5(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)ccc4Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(CN2CCCc3cc(Cc4cc([C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)ccc4Cl)ccc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
To a stirred solution of (2S,3R,4S,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (325 mg, 0.6 mmol) in acetonitrile-dichloromethane mixture (1:1 mixture, 14 mL) was added triethylsilane (0.4 mL, 2.2 mmol) and boron trifluoride diethyletharate complex (0.15 mL, 1.1 mmol) at −20° C. After stirring for 4 h at 0° C., reaction was quenched with aq. saturated NaHCO3 solution (8 mL). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (5 mL), dried over sodium sulphate, concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (160 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([CH2:10][CH2:11][CH3:12])[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:10][CH2:11][CH3:12])[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(O)nc(SC)n1
Product: CCCc1cc(Cl)nc(SC)n1
Yield: 100 %

Procedure:
A suspension of 2-methylsulfanyl-6-propyl-pyrimidin-4-ol (15.5 g) in phosphorous oxychloride (160 mL) was refluxed for 6 hours. The solvent was distilled off under reduced pressure. The residue was diluted with dichloromethane and poured in ice. The layers were separated, then the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford 4-chloro-2-methylsulfanyl-6-propyl-pyrimidine (17.5 g, 100%) as an orange oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]3[NH:18][CH:19]=[CH:20][C:10]=23)[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>ClCCl.C(Cl)(Cl)Cl>[CH3:28][S:29]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]3[NH:18][CH:19]=[CH:20][C:10]=23)[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1cnc2[nH]ccc2c1N[C@@H]1CCCNC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC[C@@H](Nc2c(C(N)=O)cnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[(3R)-3-piperidinylamino]-1H-pyrrolo[2,3-b]-pyridine-5-carboxamide hydrochloride (50 mg) in dichloromethane (1.0 mL) were added triethylamine (0.014 mL) and methanesulfonyl chloride (0.094 mL) at 4° C. The mixture was stirred at ambient temperature for 5 hours. To the mixture was added water and chloroform and the organic layer was extracted with chloroform. The extract was washed with saturated aqueous sodium hydrogencarbonate, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol to give 4-{[(3R)-1-(methylsulfonyl)-3-piperidinyl]-amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (7 mg) as a white powder.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 4-(5-hydroxypentyl)-1-piperidinecarboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].CCCCCC.[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1[CH:37]=[O:38])=[O:23])([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1[CH:37]([OH:38])[C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C#CCOC1CCCCO1
Temperature: -78 °C
Yield: 90.2 %

Procedure:
To a solution of propargyl 2-tetrahydropyranyl ether (15.2 g, 109 mmol) in tetrahydrofuran (165 ml), 1.6 N n-butyllithium in hexane (68.1 ml, 109 mmol) was added in a nitrogen stream under cooling with ice, and the mixture was stirred under cooling with ice for 1 hour. The mixture was cooled to -78° C. and added to a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyl-dimethylsiloxy-2-formylpyrrolidine (31.7 g, 90.2 mmol in tetrahydrofuran (150 ml) obtained by Reference Example 1-3) in a nitrogen stream at -78° C. and the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was raised to -20° C. and stirred at the same temperature for 1.5 hours, a saturated ammonium chloride aqueous solution (150 ml) was added thereto and stirred. Ethyl acetate was added hereto and the organic layer was washed with water a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, hexane-ethyl acetate 1:1) to obtain (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[1-hydroxy-4-(2-tetrahydropyranyloxy)-2-butynyl]pyrrolidine (38.2 g, yield: 90%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:30][OH:31].C(N(CC)CC)C>O1CCCC1.CO>[OH:31][NH:30][C:23](=[NH:24])[C:22]1[CH:21]=[CH:20][C:19]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)c1ccc(N2CCCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 107 %

Procedure:
305 mg 4-[6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 1.19 g hydroxylamine hydrochloride were added followed by the addition of 2.42 ml triethylamine. The reaction mixture was stirred at 90° C. for four hours. The solvents were removed in vacuo and the resulting residue poured into 50 ml water and extracted five times with portions of 50 ml ethylacetate. The combined organic extracts were washed with 100 ml brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 355 mg crude N-Hydroxy-4-[6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-benzamidine. This material was used without further purification.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:16]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1>>[N:13]1[CH:14]=[CH:15][N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:29]4[CH:28]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:37])([F:38])[F:39])=[O:33])[CH:26]=[CH:25][CH:30]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[N:12]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Ic1cnc2cc(-c3nccnn3)ccn12
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nccnn4)ccn23)c1

Procedure:
3-Iodo-7-[1,2,4]triazin-3-yl-imidazo[1,2-a]pyridine (96 mg, 0.3 mmol) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea were coupled according to procedure D4 to furnish the title compound as a yellow solid (39 mg). 1H NMR (400 MHz, Me-d3-OD & CDCl3): 9.26 (1H, d), 8.91-8.80 (2H, m), 8.67 (1H, d), 8.16-8.04 (2H, m), 7.85 (2H, d), 7.48 (1H, t), 7.39 (1H, d), 7.30 (1H, d), 3.91 (2H, q). MS: [M+H]+414
Reaction SMILES: B(F)(F)F.CCOCC.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:19]2([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[CH2:21][O:20]2)[CH:16]=[CH:17][CH:18]=1.[CH3:35][O:36][CH2:37][CH2:38][OH:39]>>[Cl:12][C:13]1[CH:14]=[C:15]([C@:19]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23]2)([OH:20])[CH2:21][O:39][CH2:38][CH2:37][O:36][CH3:35])[CH:16]=[CH:17][CH:18]=1
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C2(c3cccc(Cl)c3)CO2)C1
Agent: FB(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A stirred solution of BF3.Et2O (12.9 mg, 0.0592 mmol) and NaH (22.6 mg, 0.296 mmol) in 2-methoxyethanol (10 mL) was warmed to 55-60° C. and (3R)-tert-butyl 3-(2-(3-chlorophenyl)oxiran-2-yl)piperidine-1-carboxylate (100 mg, 0.296 mmol) was added dropwise. After addition, the reaction mixture was stirred at the same temperature overnight. The reaction mixture was concentrated and the residue was partitioned between H2O and EtOAc. The organic layer washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. LC-MS analysis of the crude product indicated the presence of two isomers. The crude product was purified by preparative HPLC to give the major isomer (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)ethyl)piperidine-1-carboxylate (30 mg, 0.073 mmol); 1H NMR (400 MHz, CDCl3): 1.33 (s, 9H), 1.65 (m, 1H), 1.74 (m, 1H), 1.96 (m, 1H), 2.47 (m, 2H), 3.26 (m, 2H), 3.33 (s, 3H), 3.46 (m, 2H), 3.61 (m, 2H), 3.79 (m, 1H), 3.84 (m, 1H), 3.99 (m, 1H), (m, 1H), 7.22 (m, 3H), 7.42 (s, 1H); MS (E/Z): 414 (M+H+)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OCC3C=CC=CC=3)[CH2:9][CH2:8]2)[CH2:3]1>CO>[NH2:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH2:12][CH2:11]1
Reactant: O=C(NC1CCC(N2CC[C@H](O)C2)CC1)OCc1ccccc1
Solvent: CO
Product: NC1CCC(N2CC[C@H](O)C2)CC1
Temperature: 27.5 °C
Reaction time: 15 h
Yield: 54265.7 %

Procedure:
10% vPd/C (40 mg) was added to a solution of (S)-benzyl (4-(3-hydroxypyrrolidin-1-yl)cyclohexyl)carbamate (400 mg, 1.2 mmol) in MeOH (8 mL) and the mixture was stirred continuously under hydrogen atmosphere at 20-35° C. for 15 h. The reaction mixture was filtered over a celite bed and the filtrate was concentrated under reduced pressure to afford 120 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[O:10])#[N:2].[OH:26]S(O)(=O)=O>>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:3]=1[C:1]([NH2:2])=[O:26])=[O:10]
Reactant: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Reactant: O=S(=O)(O)O
Product: COCCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 45 °C

Procedure:
A mixture of 1-(4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)-3-(3-methoxypropyl)urea (12 mg, 0.032 mmol) in 0.8 mL conc. H2SO4 was heated at 45° C. After 1.5 hours the reaction was quenched into 25 mL water containing brine. The aqueous solution was adjusted to pH=1 using saturated NaHCO3 and then extracted with EtOAc, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was recrystallized from acetonitrile giving the title compound as a white solid (4 mg, 29%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirring mixture of methyl 1-(6-hydroxy-2-naphthoyl)piperidine-4-carboxylate (500 mg, 1.59 mmol), cis-4-(t-butyl)cyclohexanol (487 mg, 3.18 mmol, 2 equiv) and PPh3 (833 mg, 3.18 mmol, 2 eq) in THF (5 mL) was added DIAD (642 g, 3.18 mmol, 2 eq) at room temperate under N2 atmosphere, then the mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylate (230 mg, yield: 32%) as a yellow solid. ESI-MS (M+1)+: 453.2. 1HNMR (400 MHz, CDCl3) δ: 7.76-7.70 (m, 3H), 7.43 (d, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 4.32-4.26 (m, 1H), 3.71 (s, 3H), 3.08-3.06 (m, 2H), 2.60-2.58 (m, 1H), 2.28-2.26 (m, 2H), 1.91-1.88 (m, 4H), 1.67-1.65 (m, 4H), 1.29-1.26 (m, 2H), 1.12-1.11 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:23]([N:17]1[CH2:16][CH:3]([CH3:4])[CH:2]([C:1]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C/C=C/C(=O)OCc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccccc2)CC1C(=O)OCc1ccccc1
Yield: 105.9 %

Procedure:
Benzyl (2E)-but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane (5 ml), and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 μl, 3.47 mmol) was added, and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (33.1 g, 139 mmol) was added dropwise to the reaction liquid over 15 minutes so that the internal temperature did not exceed 62° C., while washing with dichloromethane (25 ml). The reaction liquid was left to stand until it reached mom temperature and was stirred for 15 hours. The reaction liquid was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (38 g).
Reaction SMILES: [C:1]([O:6][CH:7]([O:10][C:11](=[O:27])[CH2:12][CH:13]([CH2:18][NH:19]C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[C:1]([O:6][CH:7]([O:10][C:11](=[O:27])[CH2:12][CH:13]([CH2:18][NH2:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C)OC(=O)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(OC(=O)CC(CN)CC(C)C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Compound 24 (0.3 g, 0.77 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (4.5 mL) was added and maintained in an ice water bath for 30 minutes. The solution was then warmed to room temperature and stirred for 5 hours. After concentrating and drying, 0.25 g of 3-aminomethyl-5-methyl-hexanoic acid 1-isobutyryloxy-propyl ester TFA salt 25 was obtained (Yield: 80%). 1HNMR (CDCl3, 500 MHz) δ0.87-0.95 (m, 6H), 1.15-1.65 (m, 4H), 1.18-1.28 (m, 2H), 1.52-1.67 (m, 1H), 1.71-1.82 (m, 2H), 2.18-2.31 (m, 1H), 2.39-2.46 (m, 1H), 2.51-2.62 (m, 2H), 3.02 (br s, 1H), 3.19 (br s, 1H), 6.89 (t, J=5.5 Hz, 1H), 7.48 (br s, 2H); 13CNMR (CDCl3, 125 MHz) δ 7.29, 7.35, 14.69, 18.39, 18.42, 18.48, 18.52, 21.70, 21.73, 22.43, 24.90, 26.18, 31.05, 31.13, 33.93, 36.92, 37.08, 41.26, 41.47, 44.73, 44.79, 66.05, 91.73, 91.83, 172.58, 172.69, 176.43.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:20].CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[N:7]([CH3:28])[C:6]1=[O:20]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)n(C)c2c1
Yield: 94.3 %

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-7-(methoxycarbonyl)-2,4-(1H,3H)-quinazolinedione (2.30 g), methyl iodide (2.13 g) and potassium carbonate (2.07 g) in acetone (30 ml) was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated, and the residue was washed with water (60 ml) and methyl t-butyl ether (20 ml) and dried to give the objective compound (2.25 g) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (5-chloro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).