Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[S:15][CH2:16][C:17](O)([C:19]([F:22])([F:21])[F:20])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A suspension of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 7, 175.8 g, 430 mmol) and triethylamine (295 mL, 2.13 mol) in tetrahydrofuran (3 L) was prepared and stirred at room temperature. Methane sulfonyl chloride (106 mL, 1.36 mol) was added dropwise over the course of an hour. This mixture was stirred at room temperature for 6 hours. The solid was collected by filtration, rinsed with tetrahydrofuran (2×500 mL), and the filtrate was retained while the solid was discarded. The combined tetrahydrofuran layers were concentrated to a viscous, yellow semi-solid which was then washed with water (2×500 mL). This solid was further stirred with water (500 mL) for 18 hours, then filtered and dried in the vacuum oven at 50° C. for 12 hours to give 121.8 g (73%) of 1-(5-bromo-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-2-yl)-3-ethylurea as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C@H:26]1[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][CH2:29][NH:28][CH2:27]1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Clc1ccccc1[C@@H]1CNCC[C@@H]1c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccccc2Cl)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-(2-chloro-phenyl)-4-phenyl-piperidine hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 83.1 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 566 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[NH:17][C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[N:17]([CH3:27])[C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccc2c3c1CCC(c1ccccc1)n3c(=O)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated with cesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μL, 46.5 μmol) and stirred at room temperature for 16 h. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture. 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 3H), 7.03 (d, J=6.9 Hz, 2H), 6.99-6.93 (m, 1H), 6.93-6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H), 2.48-2.11 (m, 7H), 2.09-1.84 (m, 3H); LCMS calculated for C22H22N3O2 (M+H)+: m/z=360.2. found: 360.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCO)c1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Yield: 96.1 %

Procedure:
To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0° C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min. The addition is exothermic and the methanesulfonyl chloride is added at a rate to keep the temperature below 10° C. After the addition is complete, warm the reaction to ambient temperature. Wash the solution with water (2×500 mL), and then brine (750 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction without further purification. An analytical sample is obtained by flash column chromatography eluting with 100% diethyl ether. 1H NMR (300 MHz, CDCl3), δ 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H, J=8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDCl3), δ 158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; 13C NMR (300 MHz, DMSO-d6), 157.58, 136.79, 127.81, 122.91, 122.00, 109.33, 70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm−1; MS (ES+) m/z 257 (M+H)+; Anal. Calc'd. for C13H20O7S2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68; N, 0.13. Rf=0.72 eluting with 95:5 DCM/methanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[NH:16][C:17](C(OC)=O)=[N:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[NH:16][CH:17]=[N:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1nnc(C(=O)CCCCCCc2ccccc2)[nH]1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1nnc[nH]1
Yield: 58.3 %

Procedure:
The title compound was prepared by methyl ester hydrolysis and spontaneous decarboxylation from ketone 14h (9.0 mg, 0.03 mmol) following general procedure A. Preparative thin layer chromatography (SiO2, 100% EtOAc) afforded the title compound (4.5 mg, 52%) as a colorless oil: 1H NMR (CDCl3, 600 MHz) δ 8.47 (br s, 1H), 7.27 (m, 2H), 7.17 (m, 3H), 3.15 (t, 2H, J=7.4 Hz), 2.61 (t, 2H, J=7.7 Hz), 1.78 (m, 2H), 1.64 (m, 2H), 1.42 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 194.3, 157.2, 147.5, 142.8, 128.5, 128.4, 125.8, 39.7, 36.0, 31.4, 29.9, 29.2, 23.7; HRMS-ESI-TOF m/z 258.1599 ([M−H]−, C15H19N3O requires 258.1606).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:24])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21](=O)[CH3:22])=[O:9])[CH3:4].CC(O)=O>CCO.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]([C:7]1[C:8]([OH:9])=[N:10][C:11]2[C:12]([C:21]=1[CH3:22])=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[O:24])[CH3:4]
Reactant: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)ccc1C(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
235 mg (60% in mineral oil, 5.89 mmol) sodium hydride were added to a solution of 1.7 g (5.36 mmol) 3-(2-acetyl-5-(trifluoromethyl)phenylamino)-3-oxopropanoic acid ethyl ester in EtOH (16 ml) and the mixture was refluxed for 3 h and stirred for a further 16 h at RT. Then 1.34 ml (6.70 mmol) AcOH were added and the mixture was diluted with EE (30 ml) and brine (10 ml). The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation (EE) of the residue yielded 920 mg (3.07 mmol, 57%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH2:20]Cl)[CH3:17].[I-].[Na+]>C(C(C)=O)C>[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH2:20][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])[CH3:17]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)Cn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Yield: 30.1 %

Procedure:
The procedure is as in Example 21, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g), N,N-diethylchloroacetamide (12 g) and sodium iodide (13.5 g) in methyl ethyl ketone (30 cc). The mixture is heated for 16 hours to boiling and then cooled to a temperature in the region of 20° C. The reaction medium is added to distilled water (100 cc), treated with IN sodium hydroxide (50 cc) and then extracted with ethyl acetate (150 cc). After drying over magnesium sulphate and then concentrating to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is purified by chromatography on a silica column with ethyl acetate as eluent. N,N-Diethyl-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)acetamide (4.2 g) is obtained, which product is converted to a hydrochloride, m.p. 223° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:33])=[C:30]([CH3:32])[CH:31]=2)=[CH:20][N:19]=1)([O-])=O>C1(OC)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:33])=[C:30]([CH3:32])[CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: COc1ccccc1
Product: Cc1cc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cnc1C
Yield: 47 %

Procedure:
A mixture of 5-bromo-2-(4-aminobutyl)-3-methyl pyridine, (0.68 g) and 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.83 g) in anisole (25 ml) were refluxed for 4 hrs. Excess petroleum ether was added to precipitate the product which was then chromatographed on a silica gel column in CHCl3. The product crystallised under ether to give 2-[4-(5-bromo-3-methyl-pyrid-2-yl)-butylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.6 g) m.p. 126°14 8° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]([F:19])([F:18])[F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[CH:5]2.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([C:16]([F:18])([F:17])[F:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)c(F)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(C(F)(F)F)c(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of 2.24 g of ethyl 5-fluoro-4-trifluoromethylindole-2-carboxylate in 80 ml of ethanol was treated with 40 ml of 2N sodium hydroxide solution and stirred at room temperature for 1 hour. The alcohol was evaporated and the solution was adjusted to pH 1 with 2N hydrochloric acid. The separated crystals were isolated, washed with water and dried. There were obtained 1.17 g (85%) of 5-fluoro-4-trifluoromethylindole-2-carboxylic acid as beige crystals with m.p. 204°-210°.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([NH:20][CH2:21][CH2:22][OH:23])=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][CH2:21][CH2:22][OH:23])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCCO
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)NCCO

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-N-(2-hydroxy-ethyl)-3-phenyl-propionamide [JACS 1969, 91, 2684-2691.] in DMSO to provide the title compound in good yield.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[O:26]=[S:19]1(=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[N:18]1[CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2Cc2cccc(C(F)(F)F)c2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 3-trifluoromethyl-benzyl bromide. MS: ESI (negative): 513 (M−H).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=O)C>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(O)cc1
Yield: 98.3 %

Procedure:
Methyl 2-(4-acetoxyphenoxy)propanoate (1.0 g, 4.2 mmol) is hydrolyzed by refluxing for 2 hours at 80° C. with methanol (10 mL) and concentrated HCL (36%, 2 drops). The reaction product is concentrated under reduced pressure to obtain methyl 2-(4-hydroxyphenoxy)propanoate (0.81 g). Conversion 99%, selectivity 99%, yield 97%; IR (neat) 1757 (vs) 1H NMR (CDC13) delta 1.60 (d, J=7.0 Hz, 3H), 3.80 (s, 3H), 4.85 (q, J=7.0 Hz, 1H), 6.82 (s, 4H).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](OC)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].CO.[Cl-].[Na+]>O1CCCC1>[OH:18][CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: COC(=O)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of methyl 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylate (0.126 g) in tetrahydrofuran (5 ml) were successively added lithium borohydride (0.035 g) and methanol (1 ml), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0), and recrystallized from hexane-ethyl acetate to give the title compound (0.105 g, yield 89%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:35]=[C:23]2[N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:35]=[C:23]2[NH:24][CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:36])[N:20]=1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCn2c1cc(Cl)nc2=O
Product: O=c1nc(OCc2ccc(Oc3cccc(F)c3)c(F)c2)cc2n1CCCN2

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E111 starting from (3-fluoro-4-(3-fluorophenoxyl)phenyl)methanol and tert-butyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidine-1-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:28])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6]([Cl:28])=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 3-cyano-4-methoxy-5-trifluoromethoxybenzoic acid (500 mg), toluene (10 mL), N,N-dimethylformamide (3 droplets) and thionyl chloride (0.28 mL) were added, and then the mixture was stirred at 60° C. for 6 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (i).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Cl:13])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1)(O)(=O)=O.N1C2C(=CC=CC=2)C=CC=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([Cl:13])[CH:6]=1)[N:3]=[C:2]([N:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[CH3:26])[CH:11]=[CH:10]2
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1cc(Cl)c2nc(Cl)ccc2c1
Solvent: c1ccc2ncccc2c1
Product: CN(c1ccc(O)cc1)c1ccc2cc(Cl)cc(Cl)c2n1

Procedure:
4-[N-(6,8-dichloro-2-quinolinyl)-N-methylamino]-phenol was prepared from 2,6,8-trichloroquinoline and 4-(N-methylamino)phenol sulfate following essentially the same procedure as that described in Example 19, Part a). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.0-6.6 and 7.1 (9H, m, and d of d, quinoline, OH and phenyl protons; 3.6 (3H, s, N--CH3).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24]>C(O)C.O.[Pd]>[ClH:24].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]2=[O:23])=[CH:19][CH:18]=1
Reactant: O=c1n(Cc2ccccc2)ccn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(CN2CCN(Cc3ccccc3)C2=O)cc1
Reaction time: 24 h

Procedure:
A mixture of the product from step (a) (3.0 g), 10% Pd/C (750 mg) and 2N aqu. HCl (4.7 ml) in ethanol/water (55 ml, 3:2 v/v) was hydrogenated at room temperature and atmospheric pressure for 24 hours (uptake 1100 ml). The mixture was filtered through celite, the residue washed with hot water and the filtrate evaporated in vacuo to give the desired product as a yellow oil (2.9 g). The 200 MHz 1H NMR and MS were consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:11]([CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(Oc2ccc(N)cc2)cc(C(=O)OC)c1
Yield: 92.9 %

Procedure:
Into a 1 liter egg plant-shaped flask, 66.24 g (0.2 moles) of dimethyl 5-(4-nitrophenoxy)isophthalate of the first intermediate compound, 6.39 g of a 10% palladium-active charcoal, 440 ml of tetrahydrofuran and 220 ml of ethanol were placed, and the resultant mixture was stirred for 24 hours under the atmosphere of hydrogen. The reaction fluid was filtered with Celite, and the filtrate was concentrated under a reduced pressure. Hexane was added to the concentrated fluid, and formed precipitates were separated by filtration. The obtained white solid substance was dried at 50° C. for 1 day under a reduced pressure, and 55.96 g of the second intermediate compound was obtained (the yield: 93%).
Reaction SMILES: [C:1]([O:12][C@H:13]([CH2:39][O:40][C:41](=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:14][S:15][CH2:16][C@@H:17]([C:36]([OH:38])=O)[NH:18]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][P:64](=[O:71])([O:68]CC)[O:65]CC>>[NH2:18][C@@H:17]([CH2:16][S:15][CH2:14][C@H:13]([O:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:39][O:40][C:41](=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:36](=[O:38])[NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][P:64](=[O:65])([OH:71])[OH:68]
Reactant: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Product: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCCCC

Procedure:
The title product was prepared from (5R,9R)-9-(decanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azahenicosane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (CDCl3): δ 8.67 (br s, 1H), 5.07-5.16 (m, 1H), 3.29 (dd, 1H), 4.08 (dd, 1H), 3.40-3.73 (m, 13H), 3.26-3.38 (m, 2H), 3.02 (dd, 1H), 2.87-2.97 (m, 1H), 2.78 (dd, 1H), 2.68 (dd, 1H), 2.18-2.29 (m, 4H), 1.75-1.89 (m, 2H), 1.46-1.59 (m, 4H), 1.10-1.31 (m, 24H), 0.81 (t, 6H). LRMS [M+H]=743.5.