Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-])=O.Cl.C(O)(C)C.[H][H]>CO.[Pd]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[O:8][C:7]3[C:2]([NH2:1])=[C:3]([NH2:24])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(N)c3O2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(N)c(N)c3O2)cc1

Procedure:
Toluene-4-sulfonic acid (2R)-8-amino-7-nitro-2,3-dihydro-benzo(1,4)-dioxin-2-ylmethyl ester (4.1 g, 11 mmole) was dissolved in 200 mL of methanol to which 0.50 g of 10% palladium on carbon had been added. 4 N isopropanol HCl (10 mL) was then added and the mixture treated with 60 psi of hydrogen on a Parr apparatus overnight. The mixture was filtered through celite and concentrated in vacuum to give 4.6 g of the (R)-enantiomer of the title compound as a pink solid (m.p. 178-180° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1

Procedure:
A solution of {4-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-thiazol-2-yl]-phenyl}-carbamic acid tert-butyl ester (Example 97, 70 mg, 0.17 mmol) in 0.8 mL of CH2Cl2 and 0.8 mL of TFA was stirred at RT for 1 h. Solvents were removed under vacuum and the residue was azeotroped twice with toluene. To the flask, 4.0 mL of aqueous HCl (1 M) was added and solids formed. The solvent was removed again and the solid was azeotroped with toluene twice. The solid was dried under vacuum overnight to afford the title compound as a light yellow solid. MS m/z: 320.2 (M+1). Anal. Calc'd for C18H13N3OS.0.8H2O.1.6HBr: C, 55.13; H, 4.16; N, 10.72; O, 7.34; S, 8.18. Found: C, 55.24; H, 4.15; N, 10.66; O, 7.45; S, 8.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[O:9][C:5]=2[CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=3[C:7]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCCc1c(/C=C/C(=O)O)oc2cc(OC)ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)oc2cc(OC)ccc12
Yield: 86.2 %

Procedure:
As in Example 113, (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid (3.35 g) was reacted with 4-nitrophenol (1.8 g) in dichloromethane (35 mL) in the presence of 1,3-dicyclohexylcarbodiimide (2.42 g). The crude product was crystallized from 2-propanol to afford 4.1 g of (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid 4-nitrophenyl ester, mp 120°-121.5° C. Anal. Calcd for C23H23NO6 : C, 67.47; H, 5.66; N, 3.42 Found: C, 67.29; H, 5.89; N, 3.43
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(NCCCCOc2ccc3ccccc3c2)cc1
Temperature: 130 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.4 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 130° C. for 7 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get as oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[4-(naphthalen-2-yloxy)butyl]amine, yellow solid, m.p 95° C., (yield 0.67 gm, 97.8%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20].[BH4-].[Na+]>CO>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCNCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2)CC1
Yield: 35.4 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.304 g, 1.26 mmol), 1-isopropyl-piperazine (0.161 g, 1.26 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.158 g (32%) of the title compound as a white solid (chromatography solvent: ethyl acetate→7:3 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C20H27N4O2 355.2134, found 355.2140; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3 Hz), 3.56 (s, 2H), 2.79-2.52 (m, 9H), 1.13 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1(O)[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:10]1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]([OH:21])[CH2:19][NH:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1)(=[O:12])[NH2:13]
Reactant: NC(=O)C1C=C(C(=O)CBr)C=CC1(O)OCc1ccccc1
Reactant: NCCCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(O)CNCCCn2nnc3ccccc32)ccc1OCc1ccccc1

Procedure:
A mixture of 17.5 gm of 2-benzyloxy-5-bromoacetyl salicylamide, 17.6 gm of 1-(3-aminopropyl)-1H-benzotriazole, 6 gm of sodium carbonate and 150 ml of ethyl acetate was refluxed for 1.5 hours. After separation of the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in a 100 ml of acetonitrile, and the solution was acidified with 5 gm of oxalic acid. The precipitated 1-[3-(3-carbamoyl-4-benzyloxy-β-oxophenethylamino)-propyl]-1-H-benzotriazole oxalate was collected by suction of filtration converted with aqueous ammonia into the base (m.p. 186°-188° C.) and reduced in 100 ml of ethanol with sodium borohydride to form 1-[3-(3-carbamoyl-4-benzyloxy-β-hydroxyphenethylamino)-propyl]-1-H-benzotriazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:31]3[C:26](=[CH:27][N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[CH:30]=3)[CH2:25][O:24][C:21]=2[C:22]=1[CH3:23]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:31]3[C:26](=[CH:27][N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[CH:30]=3)[CH2:25][O:24][C:21]=2[C:22]=1[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(Cl)c1C
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1C
Yield: 11 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl(1-((2-acetamido-7-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (168 mg, 0.037 mmol, 11% yield) as a brown oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.96 min.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].[OH-].[Na+].[C:18](OC(=O)C)(=[O:20])[CH3:19]>O>[CH3:8][CH:7]([NH:6][C:18](=[O:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C)Cc1ccccc1

Procedure:
Seventy three and six tenths g (0.2 moles) of rac. amphetamine sulfate was suspended in 150 ml of water and to the stirred suspension, a solution of twenty g (0.5 moles) of sodium hydroxide in 200 ml of water was added. The liberated oil was collected by three extractions with 200-ml portions of toluene. The combined extracts were dried over anhydrous K2CO3, then the drying agent removed by filtration. To the filtrate, 100 ml of acetic anhydride (1.0 mole) was added in portions and the resulting solution refluxed for two hours. The toluene, excess anhydride and acetic acid were distilled in the rotary evaporator and the residual oil distilled in a simple Claisen still collecting the fractions that boiled at 120°-126°/7 mm, yield 63.3 g (89%) of a colorless oil that spontaneously set to a mass of crystals, mp 91°-93°.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:28]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[CH3:36]O>>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27][CH3:36])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH2:28])[CH2:16][CH2:15]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)Cn2c(C(C)(C)O)cnc21
Agent: O=S(=O)(O)O
Product: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Sulfuric acid (0.15 mL, 2.85 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (120 mg, 0.285 mmol) in methanol (1.5 mL). The reaction mixture was heated to 60° C. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 336.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:29](O)=[O:30]>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][N:5]=[N:6]2)=[CH:13][C:12]=1[CH:29]=[O:30]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O

Procedure:
A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45 mmol) in trifluoroacetic acid (200 ml) and hexamethylenetetramine (186.9 mmol) was heated at 100°, under nitrogen for 16 h. The reaction mixture was quenched with 2N sulphuric acid (250 ml) and extracted with ether (3×250 ml)). The combined organics were dried (Na2SO4) and evaporated to give a dark yellow oil. Purification by FCC (hexane/ether (2:1)) afforded the title compound (8.8 g) as a pale yellow solid. T.I.c. (hexane/ether (2:1)) Rf 0.36
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:52])([F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:51])([F:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 5552820; 13.9 mg, 0.0188 mmol) was dissolved in dichloromethane (2.1 mL), and trifluoroacetic acid (TFA, 0.7 mL) was added to the solution. The mixture was stirred at room temperature for 16 hours, and the solvent was distilled off. To the residue was added dichloromethane, and the solvent was again distilled off. This operation was repeated twice. Subsequently, HPLC purification (water with 0.05% TFA-acetonitrile with 0.05% TFA) was performed to obtain (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514403; 5.6 mg, 44% yield, white powder).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([NH:13][NH2:14])=[O:9]
Reactant: CCOC(=O)c1cn[nH]c1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1[nH]ncc1C(=O)NN
Temperature: 120 °C

Procedure:
In a 25 mL sealed tube, ethyl 5-methyl-1H-pyrazole-4-carboxylate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (1 mL, 5 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 5-methyl-1H-pyrazole-4-carbohydrazide (0.24 g) which was used without further purification in the following step.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH3:29])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][O:31]CC(O)=O>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH2:25][O:31][CH3:30])=[CH:19][C:18]=4[O:27][CH3:28])=[N:11][C:10]=3[N:9]([CH3:29])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(NC(C)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: COCC(=O)O
Product: COCC(=O)Nc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Yield: 96 %

Procedure:
The same reaction procedure as in Example 12 was performed, except that the compound obtained in Example 45 was used in place of the compound obtained in Example 6, and methoxyacetic acid was used in place of 4-(4-methyl-1-piperazinyl)benzoic acid. In this manner, 82 g (96%) of the captioned compound was obtained.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10]C1CCCCO1.CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>C(OCC)C.O>[OH:10][C:9]1[C:8]([C:7]([F:6])([F:21])[F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:33]=[O:34]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccccc1OC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1cccc(C(F)(F)F)c1O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 192.1 %

Procedure:
A n-butyl lithium-1.58M n-hexane solution (65.9 ml, 104 mmol) was added dropwise to a solution of 2-[2-(trifluoromethyl)phenoxy]tetrahydro-2H-pyrane (21.4 g, 86.8 mmol) which was synthesized according to the method described in literature (Miller, J. A. et al., J. Org. Chem. 1993, vol. 58, pp. 2637-2639) and N,N,N′,N′-tetramethylethylenediamine (15.7 ml, 104 mmol) in diethyl ether (230 ml) at −20° C. over 10 minutes. After the reaction mixture was stirred at −20° C. for 30 minutes, it was further stirred at room temperature for 40 minutes. After the reaction mixture was cooled to −30° C. and N,N-dimethylformamide (13.5 ml, 174 mmol) was added thereto, the mixture was further stirred at room temperature for 1 hour. After the reaction mixture was carefully poured into cooled water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with 1N hydrochloric acid, a 5% aqueous sodium hydrogencarbonate solution, water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1-10/1). The obtained 2-(tetrahydro-2H-pyran-2-yloxy)-3-(trifluoromethyl)benzaldehyde as a pale yellow oil was left to stand at room temperature overnight to give 2-hydroxy-3-(trifluoromethyl)benzaldehyde as a pale yellow solid (31.7 g, yield: 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:15](O)=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[Br:1][C:2]1[C:3]([O:18][CH:19]([CH3:21])[CH3:20])=[C:4]([C:15]([NH:34][C:35]2[NH:39][N:38]=[N:37][N:36]=2)=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CC(C)Oc1c(Br)c(Br)n(Cc2ccccc2)c1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)Oc1c(Br)c(Br)n(Cc2ccccc2)c1C(=O)Nc1nnn[nH]1
Yield: 49.6 %

Procedure:
Prepared by the method described in Example 115 from 4,5-dibromo-3-(1-methylethoxy)-1-(phenylmethyl)-1H-pyrrole-2-carboxylic acid (2.1 g, 0.005 moles), 1,1'-carbonyldiimidazole (0.9 g, 0.0055 moles), and 5-aminotetrazole (0.43 g, 0.005 moles). Recrystallization from acetonitrile gave the product (1.2 g); mp 199°-205° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (422 mg, 55%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:16]1[C:17]2[C:22](=[C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2ccc(C(N)=O)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Add drop wise via an addition funnel a solution of trifluoroacetic acid (5.7 mL) in dichloromethane (25 mL) to a stirred solution of 5-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.1 g, 5.7 mmol) in dichloromethane (75 mL) at 0° C. Warm to room temperature and stir for 18 hours. Evaporate on a rotary evaporator, dissolve the residue in methanol (50 mL) and dichloromethane (50 mL), and then add MP-carbonate resin (7.9 g A 2.87 eq/g). Agitate for 2 hours, filter, concentrate on a rotary evaporator, and dry under vacuum to yield 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (1.5 g, 5.6 mmol): HPLC=85% (50/50 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm). 1H NMR (DMSO-d6, 300.00 MHz): 8.55 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 6.95 (m, 5H), 3.90 (s, 2H), 2.85 (m, 2H), 2.38 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][OH:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCO)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)[nH]c2c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (11.00 g, 25.1 mmol) and triethylamine (5.25 ml, 37.7 mmol) in chloroform (77 ml) was added dropwise methanesulfonyl chloride (2.33 ml, 30.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]1H-indole-6-carboxylate (12.60 g, yield 97%).