Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[CH:12]=3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCn1cc(-c2cccc(Br)n2)nn1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-c4cn(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-[4-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanol (108 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([NH:5][CH2:6][CH2:7]2)[CH2:3]1.F[C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(#N)C.O>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([C:14]4[CH:23]=[CH:24][CH:11]=[CH:12][CH:13]=4)=[O:16])=[CH:18][CH:19]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C[C@H]2CCN(c3ccc(C(=O)c4ccccc4)cc3)[C@H]2C1
Temperature: 80 °C

Procedure:
The product of Example 7B (35 mg, 0.28 mmole), 4-fluorobenzophenone (110 mg, 0.55 mmole) and triethylamine (200 μl, 1.43 mmole) were dissolved in 1 ml of acetonitrile and heated at 80° C. under N2 for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 5% methanol and 0.5% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.93 (d, J=8.82 Hz, 2H) 7.20-7.34 (m, 5H) 6.50 (d, J=9.16 Hz, 2H) 4.31-4.47 (m, 1H) 4.19 (s, 2H) 3.55-3.67 (m, 1H) 3.39-3.52 (m, 1H) 3.09-3.28 (m, 1H) 2.44-2.89 (m, 4H) 2.15-2.27 (m, 1H) 2.09 (s, 3H) 1.94-2.06 (m, 1H); MS (M+H)+=307.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@@H:6]1[C:11](N1CCOC1=O)=[O:12])=[O:4].[CH3:19][O:20][Mg]OC.CO.[Cl-].[NH4+]>CO>[CH3:19][O:20][C:11]([C@@H:6]1[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:12]
Reactant: COC(=O)[C@H]1CC=CC[C@@H]1C(=O)N1CCOC1=O
Reactant: CO[Mg]OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H]1CC=CC[C@@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
In an atmosphere of argon gas, a solution of (4S,5S)-5-methoxycarbonyl-4-(oxazolidin-2-on-3-yl)carbonyl-1-cyclohexene (8.50 g, 33.6 mmoles) disclosed in literature [N. Narasaka et al, J. Am. Chem. Soc., 111, 5340 (1989)] in methanol (50 ml) was added to 1M dimethoxymagnesium/methanol (168 ml, 168 mmoles), and the mixture was stirred at 0° C. for 15 minutes. Saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the resulting mixture was extracted with toluene. The toluene extract solution was washed with saturated aqueous solution of sodium chloride and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9, v/v) to obtain (4S,5S)-4,5-bis(methoxycarbonyl)-1-cyclohexene (1.89 g, Yield 30%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[Cl:26])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=1[CH3:13])=[O:6].[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]([C:7]3[CH:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=3[CH3:13])=[O:6])[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc(Cl)c1Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C1c1cccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 8.4 g of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-chloroethyl ester and 8.8 g of 4-(p-fluorobenzoyl)-piperidine is stirred under argon for 1 hour at a temperature of 145°. After working up, the resulting residue is chromatographed over 500 g of silica gel, yielding 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-[4-(p-fluorobenzoyl)-piperidino]-ethyl ester in amorphous form which exhibits the following characteristic bands in th NMR spectrum: 1H-NMR (CDCl3): 2.3 and 2.4 [2S, 6H, 2 H3C--C (2 and 6)]; 3.6 [s, 3H, H3C--OOC]; 5.4 [s, 1H, H-c (4)], 7.1-8.1 (m, 7H, 7 arom. H). Rf value: 0.40 (hexane/ethyl acetate/methanol=4:2:1).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccccc1O
Product: O=C(NC1CC1)c1ccccc1O
Temperature: 90 °C
Yield: 53.3 %

Procedure:
A mixture of of methyl salicylate (4.36 g, 28.69 mmol) and cyclopropylamine (1.64 g) was heated in a sealed tube at 80-100° C. for 3 h. An additional 0.5 g of cyclopropylamine was added and heated at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography to give the subtitled compound (2.71 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:15][C:16](N)=[O:17]>O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:15][C:16](=[O:17])[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
2-Amino-4-trifluoromethylbenzoic acid (25.0 g, 122 mmol) and urea (75.0 g, 1.2 mol) were combined and heated at 200° C. while stirring. After 1 h, the reaction mixture was allowed to cool to 100° C. and water (100 mL) was added. The reaction mixture was then allowed to cool to room temperature and the solid was isolated by vacuum filtration washing with water (500 mL). The solid was then dried under vacuum (10 mbar, 50° C.). Yield=24 g, 86%; LC-MS: 2.1 min, 230 (M+); 1H NMR (DMSO-d6) δ 7.44 (s, 1 H) 7.47 (d, 1 H), 8.07 (d, 1 H), 11.43 (br s, 1 H), 11.56 (br s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.COC1C=CC=CC=1OC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COc1ccccc1OC
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a mixture of 313 mg (purity: 96.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.47 mmol) of 2-cyclopropyl-6-methylphenol were added 1,2-dimethoxybenzene (2.76 g) and 326 mg (5.53 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 189 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 38%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1c2cc(Cc3ccc(N4CCOCC4)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Temperature: 110 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.101 g, 0.248 mmol) in 3 mL of toluene was added morpholine (0.032 g, 0.37 mmol), sodium tert-butoxide (0.60 g, 0.62 mmol), tris[dibenzylideneacetone]dipalladium (0) (0.034 g, 0.037 mmol), and (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.011 g, 0.017 mmol). The mixture was heated at 110° C. for 3 hr, cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (25 mL), and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 458.2 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.10-8.07 (m, 1H), 7.88-7.86 (m, 1H), 7.68 (s, 1H), 7.59-7.56 (m, 2H), 7.28-7.25 (m, 1H), 6.53 (d, J=8.8 Hz, 1H), 4.82-4.69 (m, 2H), 4.33 (s, 2H), 4.20-4.11 (m, 1H), 3.82-3.70 (m, 5H), 3.46-3.41 (m, 4H), 2.23-2.20 (m, 1H), 2.05-1.98 (m, 1H), 1.87-1.64 (m, 4H), 1.51-1.28 (m, 3H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:27])[NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19]1)[C@H:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:7][C@@H:8]([C@H:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:10])[C:16]([NH:17][C:18]1([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:27]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[(1S,2R)-2-tert-butoxy-1-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (0.17 g, 0.45 mmol) was dissolved in DCM (1 mL) and to this was added TFA (0.2 mL). The reaction was allowed to stir at RT for 24 h. The solvent was removed under reduced pressure and the residue triturated with Et2O to give (2S,3R)-2-amino-3-tert-butoxy-N-(1-pyrimidin-2-yl-cyclopropyl)-butyramide trifluoro-acetic acid (0.16 g, 0.45 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]2[C:10]=1[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)=[N:8][NH:7][C:6]2=[O:21].[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[CH2:11][C:9]2[C:10]3[C:5](=[C:4]([CH3:22])[NH:3][C:2]=3[CH3:1])[C:6](=[O:21])[NH:7][N:8]=2)=[O:17])[CH2:28][CH2:27]1)[CH3:24]
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Reactant: CCOC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.1 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.163 g, 0.43 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.091 g, 0.31 mmol), 4-ethoxypiperidine (0.044 g, 0.34 mmol) and triethylamine (0.107 mL, 0.77 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.028 g, 22.5% yield). 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.16-1.95 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 2.99-3.26 (2H, m), 3.33-3.54 (4H, m), 3.85-4.01 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.35 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.53 min (M+H=409.13).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:29]=[CH:28][C:25]=1[CH2:26][OH:27])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C=O)c(OCCCCCCCCCCCCCCCCCCCCCC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(CO)c(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Under an argon atmosphere, 2,4-bis(docosyloxy)benzaldehyde (2.99 g, 3.96 mmol) was dissolved in a mixed solvent of dehydrating tetrahydrofuran (60 mL) and methanol (6.0 mL), sodium borohydride (375 mg, 9.91 mmol) was added, and the mixture was stirred at 40° C. for 2 hr. After completion of the reaction, purified water (2.0 mL) was added dropwise to decompose unreacted sodium borohydride and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, methanol was added, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.77 g, 92.9%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1.Cl>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=2)[CH2:30][CH2:31]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.35 (s, 1H), 7.68–6.82 (m, 11H), 5.58–5.48 (m, 1H), 3.64–3.50 (m, 2H), 3.01–2.94 (m, br, 2H), 2.92–2.54 (m, 4H), 2.48–2.32 (m, br, 2H), 2.20–2.04 (m, 1H), 2.01–1.80 (m, 5H), 1.70–1.54 (m, 1H), 1.54–1.36 (m, 3H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C34H40ClF5N2O2.0.6MeOH: C, 63.12; H, 6.49; N, 4.25; Found: C, 63.38; H, 6.61; N, 3.95. ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([F:16])[C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:26].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:26])[CH:12]=[C:11]([F:16])[C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C1CN(c2c(F)cc(Br)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CN(c2c(F)cc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 140 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-bromo-6-fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.0 g, 2.21 mmol), NaI (1.18 g, 7.87 mmol), CuI (91 mg, 0.48 mmol) and (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (136 mg, 0.96 mmol) in dioxane (15.5 mL) is heated at 140° C. for 1.5 h in a microwave. The reaction mixture is filtered through Celite and washed with additional dioxane. It is then concentrated to a smaller volume and used directly in the next step: MS (M−H)−=461.
Reaction SMILES: Br[C:2]1([CH3:19])[O:6][C:5]([CH3:17])([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[O:4][C:3]1=[O:18].C1CCN2C(=NCCC2)CC1>C(OC(C)C)(C)C>[CH2:19]=[C:2]1[O:6][C:5]([C:7]23[CH2:14][CH:13]4[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]4)[CH2:16]2)[CH2:8]3)([CH3:17])[O:4][C:3]1=[O:18]
Reactant: CC1(Br)OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Solvent: CC(C)OC(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
16.5 g (0.05 mol) of 5-bromo-2,5-dimethyl-2-(1-adamantyl)-1,3-dioxolan-4-one was placed in a 500 ml egg-plant type flask, and 200 g of isopropyl ether was added thereto and dissolved therein. While cooling with a refrigerant of −10° C., 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 g of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.7 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 14%) and that 80% of the raw materials was decomposed into adamantyl methyl ketone.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]([O:19]C(C)(C)C)=[O:18]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1cn2c(Cl)c(C(=O)OC(C)(C)C)c(C)cc2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c(Cl)c(C(=O)O)c(C)cc2n1
Reaction time: 2 h
Yield: 140.5 %

Procedure:
6-tert-butyl 2-ethyl 5-chloro-7-methylimidazo[1,2-a]pyridine-2,6-dicarboxylate (11.4 g, 27.2 mmol, 1 equiv) was treated with TFA (100 mL) and stirred for 2 h. Upon completion, the reaction was concentrated in vacuo. The crude product was triturated in ether and filtered to provide the product (10.8 g, 100%) as a cream colored solid. LCMS (ESI, M+1): 283.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([O:18][C:16]([NH:15][C@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)SCC[C@H]2NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(N[C@@H]1CCSc2cc(C(=O)O)ccc21)OCc1ccccc1
Yield: 97.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (R)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (3.35 g) and potassium carbonate (2.59 g), the objective (R)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid (3.13 g) was obtained as colorless crystals.
Reaction SMILES: ClCl.[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:15]=[C:14](S)[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[N+:17]([O-:19])=[O:18].C(O)(=O)C.[S:25]([Cl:29])(Cl)(=[O:27])=[O:26]>O>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:14]([S:25]([Cl:29])(=[O:27])=[O:26])[CH:15]=[C:6]([C:5]([O:4][CH3:3])=[O:20])[C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)c1cc(S)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Agent: ClCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Chlorine gas is passed into a stirred slurry of 6.4 g. of dimethyl-2-nitro-5-mercaptoisophthalate in a mixture of 50 ml. of acetic acid and 15 ml. of water. The temperature of the reaction rises to 70° C. as all the solid goes into solution. Introduction of chlorine is continued as a heavy precipitate forms. Stirring is continued for 15 min.; then the mixture is diluted with 300 ml. of water. The solid is collected, washed with water and dried, giving 7.5 g. of the sulfonyl chloride, m.p. 124°-125° C.
Reaction SMILES: Cl[O-].[Na+].[OH-].[NH4+:5].[NH2:6][C:7]1[NH:12][C:11](=[S:13])[C:10]2[N:14]=[CH:15][N:16]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:9]=2[CH:8]=1>[OH-].[K+]>[NH2:6][C:7]1[N:12]=[C:11]([S:13][NH2:5])[C:10]2[N:14]=[CH:15][N:16]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:9]=2[CH:8]=1
Reactant: [NH4+]
Reactant: Nc1cc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Product: NSc1nc(N)cc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Aqueous sodium hypochlorite (5.25%, 4.6 mL, 3.2 mmol) was cooled to 0° C. Twelve mL of 1.4N ammonium hydroxide was added and stirred for 10 min at 0° C. A suspension of 6-amino-1-β-D-ribofuranosylimidazo [4,5-c]pyridine-4(5H)-thione 34, prepared as per P. D. Cook and R. K. Robins, J. Oro. Chem., 43, 189 (1978), (900 mg, 3 mmol) in 2N potassium hydroxide (1.5 mL) was added and stirred for 1.5 h at 0° C. The precipitate was collected by filtration, washed with water, EtOH, and acetone and dried at room temperature over P2O5 to yield 660 mg of desired compound 35: m.p. 134°-137° C. (dec): UV: λmax (pH 1) 374 nm (ε7,000): 264 (5,400), 230 (21,400) λmax (pH 7) 322 nm (ε5,500), 261 (5,800) 223 (24,000): λmax (pH 11) 319 nm (ε8,500), 223 (24,100): 1H NMR (DMSO-d6): δ3.70 (s, 2, exchangeable in D20, SNH2), 5.61 (d, 1, J =6.4 Hz, C1'H), 5.63 (s, 2, exchangeable in D2O, NH2), 6.25 (s, 1, C7H), 8.12 (s, 1, C2H). Anal. Calcd for C11H15N5O4S.1/2H2O: C, 40.99: H, 5.00: N, 21.73: S, 9.95. Found: C, 41.12: H, 4.81: N, 21.43: S, 10.23.