Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: Fc1ccccn1
Product: O=C(OCc1ccccc1)N1CC[C@H](CNc2ccccn2)[C@H](O)C1
Temperature: 120 °C

Procedure:
A mixture of (cis)-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (0.1 g, 378 mmol) and 2-fluoropyridine (0.25 mL) was heated to 120° C. for 24 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a (cis)-3-hydroxy-4-(pyridin-2-ylaminomethyl)-piperidine-1-carboxylic acid benzyl ester crude product, which was purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc). M.S (M+1): 342
Reaction SMILES: [CH2:1]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Br[CH2:22][CH2:23]CCCCCCCCCCCCC>>[CH2:1]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCc1ccco1
Product: CCCCCCCCCCCCCCCCCc1ccco1

Procedure:
2-(heptadecyl)furan (4) was prepared exactly as described above for 2-(pentadecyl)furan, substituting 1-bromo heptadecane for 1-bromopentadecane. The chromatographed product was recrystallized from methanol as described above to afford of 2-(heptadecyl)furan (4) in 48% yield.
Reaction SMILES: BrCC1N=C([C:8](OCC)=[O:9])SC=1.BrCCC1ON=C(C(OCC)=O)C=1.BrCC1N=C(C(OCC)=O)OC=1.[CH2:38]([N:40]([CH2:51][C:52]1[N:53]=[C:54]([CH2:57][OH:58])SC=1)[CH2:41]/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]([O:49][CH3:50])([CH3:48])[CH3:47])[CH3:39].C(N(CC1ON=C(CO)C=1)C/C=C/C#CC(OC)(C)C)C>>[CH2:38]([N:40]([CH2:51][C:52]1[O:58][C:57]([CH2:8][OH:9])=[CH:54][N:53]=1)[CH2:41]/[CH:42]=[CH:43]/[C:44]#[C:45][C:46]([O:49][CH3:50])([CH3:48])[CH3:47])[CH3:39]
Reactant: CCOC(=O)c1nc(CBr)cs1
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1csc(CO)n1
Agent: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)no1
Agent: CCOC(=O)c1cc(CCBr)on1
Agent: CCOC(=O)c1nc(CBr)co1
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1ncc(CO)o1

Procedure:
When the same reactions as in Referential Example 49 are carried out using ethyl 4-bromomethylthiazol-2-carboxylate [see Ann., 1981, 623] or ethyl 5-bromoethylisoxazol-3-carboxylate [synthesized by brominating ethyl 5-methylisoxazole-5-carboxylate [see J. Heterocyclic Chem., 19, 557(1982)] with N-bromosuccimide in carbon tetrachloride] insted of the starting ethyl 4-bromomethyloxazol-2-carboxylate, (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-2 -hydroxymethyl-4-thiazolylmethylamine and (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxymethyl-5-isoxazolylmethylamine are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[C:16]([OH:18])=O.CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>O.CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH:11]2[C:16]([NH:21][CH:25]2[CH2:27][CH2:26]2)=[O:18])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: O=C(O)C1COCCN1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC1CC1)C1COCCN1c1nc(Cl)ncc1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added 2,4-dichloro-5-fluoropyrimidine (0.835 g, 5 mmol), DMSO (1 ml), morpholine-3-carboxylic acid (0.656 g, 5.00 mmol) and DIPEA (3.49 ml, 20.00 mmol). The reaction was stirred at 80° C. for 10 minutes then cooled to ambient temperature, HATU (2.85 g, 7.50 mmol) was added followed by cyclopropanamine (0.526 ml, 7.50 mmol) and the reaction mixture was again heated at 80° C. for 2 hours. Upon completion the reaction was suspended in water and filtered. The collected solid was washed successively with water, small amount of ethanol and diethyl ether. The solid was dried in vacuo for 16 hours to afford 4-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopropylmorpholine-3-carboxamide (0.325 g, 1.081 mmol, 21.62% yield) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[CH3:10][C@@H:11]([CH2:30][CH3:31])[C@H:12]([NH:17][C:18]([O:20]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:10][C@@H:11]([CH2:30][CH3:31])[C@H:12]([NH:17][C:18]([N:2]([CH3:1])[CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1)=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: CNCc1csc(C)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)OC
Yield: 0.1 %

Procedure:
A solution containing the product from Example 109B (0.200 g, 1.4 mmol) in THF (6 mL) was treated with the product from Example 109C (0.415 g, 1.4 mmol), triethylamine (0.196 mL, 1.4 mmol), and DMAP (0.020 g, 0.16 mmol) at 25° C., stirred at reflux for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and 5% K2CO3. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated to give the title compound (0.38 mg, 86% yield).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]2[N:12]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:23]([CH3:24])[C:14]2=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]2[N:12]=1)=[O:33])[CH3:2]
Reactant: CCSc1cc(F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cc(F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.85 g) and chloroform (12 ml), 3-chloroperbenzoic acid (purity: not less than 65%, 0.81) was added under ice-cooling, heated to room temperature, and stirred for 30 minutes. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of 2-(2-ethylsulfinyl-4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 117) and 0.52 g of 2-(2-ethylsulfonyl4-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 118).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc(C(C)(C)C)cc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.070 g, 0.253 mmol) was reacted with N-(2-azidoethyl)-4-tert-butylbenzamide (0.062 g, 0.253 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-tert-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H), δ 7.64 (t, 1H), δ 7.36 (d, 2H), δ 7.27 (s, 1H), δ 6.42 (s, 1H), δ 5.99 (s, 2H), δ 4.51 (t, 2H), δ 3.88 (q, 2H), δ 2.58 (t, 2H), δ 2.22 (t, 2H), δ 1.52 (m, 13H), δ 1.21 (m, 11H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.3, 150.4, 149.6, 148.3, 138.9, 131.2, 127.3, 125.6, 122.2, 106.5, 84.8, 49.4, 40.2, 35.1, 31.3, 31.1, 29.3, 28.9, 28.3, 28.2, 28.1, 25.6 ppm; HRMS (ESI) calcd for C28H41N7O3 (M+) 523.3271, found 523.3270, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-tert-butylbenzamide hydrochloride (0.105 g, 90% yield). 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), δ 7.76 (d, 2H), δ 7.48 (d, 2H), δ 6.50 (s, 1H), δ 4.84 (s, 2H), δ 3.95 (s, 2H), δ 2.85 (s, 2H), δ 2.46 (t, 2H), δ 1.73 (s, 2H), δ 1.57 (m, 2H), δ 1.39 (s, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 155.6, 147.3, 130.8, 129.9, 127.6, 127.2, 127.1, 126.7, 125.4, 125.3, 119.5, 108.6, 108.5, 52.3, 39.4, 34.6, 30.4, 27.9, 27.8, 27.6, 24.1, 23.2, 22.2 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747, found 423.2741.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1.C=O.[C:31]([BH3-])#N.[Na+].O>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:21][CH2:20][N:19]([CH3:31])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2c(Br)n[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3,5-Dibromo-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (77 mg, 0.15 mmol) was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) and sodium cyanoborohydride (9.5 mg, 0.15 mmol) and one drop of acetic acid. The reaction was stirred at room temperature for 1 h. The reaction was poured into water and extracted with diethyl ether. The aqueous was made basic by addition of 4 M sodium hydroxide and extracted with diethyl ether. The ethereal was combined, washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in 20% trifluoroacetic acid in dichloromethane and stirred at room temperature for 5 min. The solution was concentrated, loaded onto a strong cation exchange cartridge in methanol, and the cartridge washed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 41 mg (52%). 1H-NMR (CDCl3, 500 MHz) δ 10.09 (bs, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.24 (dd, J=8.9 Hz, 5.2, 2H), 7.13 (d, J=1.5 Hz, 1H), 7.05 (dd, J=8.9, 8.5 Hz, 2H), 4.49 (q, J=6.7 Hz, 1H), 3.39 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.59 (m, 2H), 1.85-2.30 (m, 9H), 1.40 (d, J=6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.6 (d, J=246 Hz), 137.2, 128.7, 128.63, 128.57, 127.68, 125.3, 121.7, 121.6, 115.7, 115.5, 114.3, 78.9, 77.9, 51.9, 51.7, 46.1, 40.3, 32.6, 32.3, 22.1.
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[O:19]=[C:20]1[NH:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O-:30])=[O:29]>>[O:19]=[C:20]1[N:24]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:23][CH2:22][N:21]1[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28]([O:30][CH3:2])=[O:29]
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: Fc1ccc(CBr)cc1
Reactant: BrCc1ccccn1
Agent: Br
Product: COC(=O)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Yield: 66 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with 2-(bromomethyl)pyridine hydrobromide to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 66% yield: mp 100-102° C.; 1H NMR (300 MHz, CDCl3) δ 8.88 (d, J=0.9 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.70-7.64 (m, 1H), 7.46-7.44 (m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.22-7.18 (m, 1H), 4.62 (s, 2H), 4.07 (t, J=8.1 Hz, 2H), 3.90 (s, 3H), 3.54 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.9, 157.0, 156.6, 153.4, 149.3, 148.0, 138.7, 137.2, 122.7, 122.4, 116.7, 112.5, 52.6, 49.6, 41.9, 41.5; MS (ES+) m/z 312.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([Cl:18])[C:3]=1[CH2:4][CH:5]([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 96.3 %

Procedure:
Using 1.0 g of (2,6-dichloro-4-(trifluoromethyl)benzyliden)malononitrile, 20 ml of ethanol and 0.03 g of sodium borohydride, and according to the process described in the REFERENCE PRODUCTION EXAMPLE 3, there was obtained 0.97 g of (2,6-dichloro-4-(trifluoromethyl)benzyl)malononitrile (the intermediate (32)).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:33]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:32][CH3:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCOc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: CCOc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-ethoxybenzenesulfonamide [Chem. Ber., 1982, 25, 1838]: 1H-NMR (CDCl3) δ 7.74 (2H, d, J=8.9 Hz), 7.47-7.24 (9H, m), 6.95-6.92 (21H, in), 6.40 (1H, br.s), 4.07 (2H, q, J=7.1 Hz), 3.53-3.46 (2H, m), 2.86 (2H, t, J=6.8 Hz), 2.33 (3H, s), 2.26 (3H, s), 1.42 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 29.5 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and thiomorpholine (0.030 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (26 mg, 0.059 mmol, yield 29%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][CH:17]([OH:28])[CH2:18][N:19]([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:27][N:19]([CH2:18][CH:17]([OH:28])[CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: CN(Cc1ccccc1)CC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 3 h
Yield: 22.6 %

Procedure:
To a solution of 6-hydroxycarbostyril (1.6 g) and sodium hydride (50% oily) (1 g) in dimethylformamide (30 ml), 1-chloro-2-hydroxy-3-(N-methyl-N-benzylamino)propane (2.2 g) is added dropwise at room temperature. After the addition, the mixture is heated with stirring at 70°-80° C. for 3 hours. The reaction mixture is poured into water and extracted with chloroform, and the extract is dried over magnesium sulfate. Chloroform is distilled off and the resulting residue is purified by silica gel column chromatography (solvent; methanol:chloroform=1:100-1:25) and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (0.76 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.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.O[C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1.Cl>C(Cl)Cl>[CH3:13][C:7]1([CH3:14])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][C@H:49]3[CH2:53][CH2:52][O:51][CH2:50]3)=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8]1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2C1
Reactant: O[C@@H]1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O[C@H]3CCOC3)ccc2C1

Procedure:
7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.95 g, 4.99 mmol) was dissolved in 30 ml DCM and triphenylphosphine (1.96 g, 7.49 mmol) and diisopropyl azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(−)-3-hydroxytetrahydrofuran (0.600 ml, 7.49 mmol) was added. The mixture was stirred over night. 0.5M HCl (aq.) was added and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30% EtOAc in Hex.) provided (S)-3,3-dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-dihydronaphthalen-1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[F:5][C:6]([F:19])([F:18])[C:7]1[CH:8]=[C:9]([OH:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>C(O)(=O)C>[N+:1]([C:8]1[C:7]([C:6]([F:5])([F:18])[F:19])=[CH:12][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:10][C:9]=1[OH:17])([O-:4])=[O:2].[N+:1]([C:12]1[C:7]([C:6]([F:18])([F:19])[F:5])=[CH:8][C:9]([OH:17])=[CH:10][C:11]=1[C:13]([F:15])([F:14])[F:16])([O-:3])=[O:2]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(C(F)(F)F)cc(O)cc1C(F)(F)F
Product: O=[N+]([O-])c1c(O)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 43 h
Yield: 59.3 %

Procedure:
Fuming nitric acid (8.22 mL, 198.2 mmol) was added dropwise to a solution of 3,5-bis(trifluoromethyl)phenol (28.5 g, 123.9 mmol) in acetic acid (300 mL) at about 10° C. After being elevated to room temperature, the mixture was stirred for 43 hours. The reaction mixture was poured into ice water and the resulting solution was extracted with ethyl acetate. The organic layers were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (developing solvent; hexane:acetone=15:1→10:1) to yield a crude product. The crude product thus obtained was subjected to sublimation separation under reduced pressure (3 mmHg) at 80° C. by using an evaporator to distill off the isomer, that is, 2-nitro-3,5-bis(trifluoromethyl)phenol, whereby 10.1 g (yield: 29.7%) of 4-nitro-3,5-bis(trifluoromethyl)phenol was obtained as yellow needle-like crystals.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:34])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=3)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=2)[N:8]=1)(=[O:3])[CH3:2].[P:35](Cl)([O:39][CH3:40])([O:37][CH3:38])=[O:36].CCOC(C)=O.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:35]([O:39][CH3:40])([O:37][CH3:38])([O:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:30])[CH3:31])=[C:24]([Cl:32])[CH:23]=1)=[O:33])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]([CH3:34])[CH:6]=2)=[CH:10][CH:11]=1)=[O:36]
Reactant: COP(=O)(Cl)OC
Reactant: CC(=O)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COP(=O)(OC)OCC[C@H](Cc1ccc(-c2cn(C)c(C(C)=O)n2)cc1)NC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of N-((1S)-1-{[4-(2-acetyl-1-methyl-1H-imidazol-4-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (500 mg, 1.04 mmol) in dry CH2Cl2 (10 mL) under N2, was added dimethyl chlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed ˜50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 and the combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) m/e 592.4 (M+H)+. Note that the product was contaminated with ˜1 eq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:60]=[CH:59]3)[C@@H:52]([NH2:54])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]>CN1C(=O)CCC1>[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[N:60]=[CH:59]3)[C@@H:52]([NH:54][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:9])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]
Reactant: Cc1cnc(C(=O)O)s1
Reactant: Cc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2ccc(C)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-methyl-1,3-thiazole-2-carboxylic acid (29 mg, 0.2 mmol) was dissolved in NMP (1 mL) together with HATU (76 mg, 0.2 mmol) and DIEA (133 uL, 0.8 mmol). The mixture was stirred in r.t. for 5 min before (1R,2S)-1-(3,4-dimethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (58 mg, 0.15 mmol, prepared analogously to Example 6a with corresponding starting material) was added. The reaction mixture was stirred in r.t. overnight before it was evaporated under reduced pressure and purified by semi-prep. HPLC.