Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:16][CH2:15][CH2:14]1.[C:24](=O)([O:27]C)[O:25][CH3:26]>CCOCC>[O:23]=[C:18]1[CH:19]([C:24]([O:25][CH3:26])=[O:27])[CH2:20][CH2:21][CH2:22][C:17]21[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: O=C1CCCCC12CCCC2
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) was cooled to −78° C. and then was treated slowly with n-butyllithium (16.75 mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes, then this solution was transferred via cannula into a −78° C. solution of Example 1A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirred at this temperature for 30 minutes and then was treated with dimethyl carbonate (23.50 mL, 279 mmol). The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was quenched with saturated NH4Cl and diluted with ether (100 mL), then the layers were separated. The aqueous layer was extracted with additional ether, then the organic layers were combined, dried with MgSO4, and concentrated under reduced pressure. The residue was chromatographed on silica gel (100% hexane to 85:15 EtOAc/hexanes, eluant) to provide the title product. 1H NMR (300 MHz, CDCl3) δ 12.40-12.42 (m, 1 H), 3.72-3.76 (m, 3 H), 2.18-2.26 (m, 2 H), 2.00-2.12 (m, 2 H), 1.74-1.86 (m, 2 H), 1.57-1.62 (m, 2 H), 1.54-1.57 (m, 2 H), 1.35-1.48 (m, 4 H). MS (DCI+) m/z 211 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO>[NH2:28][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12]1
Reactant: [BH3-]C#N
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: C[C@]12CC[C@H](N)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3β-Amino-17β-hydroxy-5α-androstane was prepared by the procedure of Boutigue et al. (1973, Bull. Soc. Chim. France 750-753). 17β-Hydroxy-5α-androstan-3-one (403 mg, 1.39 mmol) (Aldrich Chemical Company) was added to 862 mg of ammonium acetate (11.2 mmol, 8.06 equiv.) in 16.0 mL dry methanol (MeOH), followed by 104 mg (1.65 mmol, 1.19 equiv.) of sodium cyanoborohydride. After stirring at room temperature for 15 h, the reaction was concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous 1N sodium hydroxide (NaOH), shaken, and separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.C(=O)(O)[O-].[K+]>CO.O>[OH:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Yield: 71 %

Procedure:
21-Acetoxy-5α-pregnane-3,11,20-trione (4.85 g.) in hot methanol (200 ml.) was treated with potassium bicarbonate solution (10%; 20 ml.) and the stirred solution was refluxed under nitrogen for 15 minutes. The cooled reaction mixture was diluted with water and the oily precipitate was extracted into methylene chloride. The extract was washed with water, dried over sodium sulphate and evaporated to a foam (4.3 g.) which was triturated with ether to give title compound (3.07 g.) as white crystals, m.p. 164°-170°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:5][C:3]1([C:2]([F:7])([F:6])[F:1])[NH:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:4]1
Reactant: CC(=O)C(F)(F)F
Reactant: NC(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l) were admixed with 45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluenesulphonate. The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C., and the solids formed were filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([Cl:8])(Cl)=[O:6].[F:9][CH:10]([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([CH:22]([CH3:24])[CH3:23])C(O)=O)=[CH:14][CH:13]=1>>[F:9][CH:10]([F:25])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([CH:22]([CH3:23])[CH3:24])[C:5]([Cl:8])=[O:6])=[CH:14][CH:13]=1
Reactant: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Reactant: O=C(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(C)[C@H](C(=O)Cl)c1ccc(OC(F)F)cc1
Reaction time: 3 h

Procedure:
Add 1-3 moles of thionyl chloride or phosgene into (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid, and allow the mixture to react at 10° C. to reflux temperature of the solvent for 0.1-100 hours, preferably for 1-5 hours. After the reaction is completed, distill off the unreacted thionyl chloride or phosgene to give the (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][C:4](=[N:6][OH:7])[NH2:5].CCN(CC)CC.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(#N)C>[NH2:5][C:4](=[N:6][O:7][CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][C:2]([F:9])([F:8])[F:1]
Reactant: NC(CC(F)(F)F)=NO
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=CON=C(N)CC(F)(F)F
Temperature: 80 °C

Procedure:
Into a flask containing 3,3,3-trifluoro-N′-hydroxypropanimidamide (21 mmol, 3 g) in ACN (50 ml), Et3N (21 mmol, 3.5 ml) was added at RT. The resulting mixture was heated at 80° C. and a solution of ethyl propiolate (25.1 mmol, 2.5 g) in ACN (20 ml) was added. The reaction mixture was heated at 80° C. for overnight. The solvent was evaporated and the crude was purified by flash-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (t, 3H), 3.18 (q, 2H), 4.09 (q, 2H), 5.44 (d, 1H), 6.78 (bs, 2H), 7.70 (d, 1H). LC-MS: [M−1]=239.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CCl)cn4c3-c3ccccc3)cc2)CCC1
Reactant: COCCN
Solvent: C1CCOC1
Product: COCCNCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C

Procedure:
A mixture of {1-[4-(6-chloromethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (103 mg) and 2-methoxyethylamine (31 mg, 0.035 mL) in THF (1.1 mL) was heated at 110° C. under microwave irradiation for 1 hour. On cooling, the reaction mixture was concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ncccn2)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-(2-pyrimidinyloxy)benzenecarbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B64 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:18]=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: COc1cccnc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C=O)ccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-chloro-3-methoxypyridine (1.55 g, 10.8 mmol, prepared as described in WO2007/123995) in dry THF (30 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (4.75 mL, 11.9 mmol). After 1 hour, a solution of DMF (2.5 mL, 32.4 mmol) in THF (5 mL) was added. After a further 2.5 hours, a saturated aqueous ammonium chloride solution was added and the reaction mixture was allowed to warm to RT. The resultant biphasic mixture was separated and extracted twice with diethyl ether. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 20 to 25% ethyl acetate in cyclohexane) to afford the title compound (1.42 g, 77%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 10.44 (d, J=0.8 Hz, 1H), 8.34 (dd, J=4.9 and 0.8 Hz, 1H), 7.60 (d, J=4.9 Hz, 1H), 4.08 (s, 3H). LCMS (Method A): RT=2.84 min, [M+H]+=172/174.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(C=O)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CO)cc12
Reaction time: 0.5 h
Yield: 85 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-formylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (553 mg, 1.24 mmol) was dissolved in ethanol (12 mL). Thereafter, sodium borohydride (76.0 mg, 2.01 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 30 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(hydroxymethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (473 mg, 85%) in the form of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].CCN=C=NCCCN(C)C.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH:14]1[C:10]2[C:11](=[O:12])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Nc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-((2-aminophenyl)thio)benzoic acid, prepared as described in the previous step, (30 g, 0.122 mol) in dichloromethane (300 mL) was added EDCI (35.2 g, 0.183 mol), triethylamine (51 mL, 0.366 mol) and HOBT (24.7 g, 0.183 mol). The reaction mixture was stirred at room temperature for 12 hours, washed with 1M aq.HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over MgSO4. The solution was filtered, concentrated, and purified by column chromatography to provide the title compound. ESI-MS (M+1): 228 calc. for C13H9NOS 227. 1H NMR: (CDCl3, 400 MHz): δ (ppm) 7.70-7.67 (m, 1H), 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.35 (m, 1H), 7.24-7.22 (m, 1H), 7.17-7.13 (m, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[Cl:14]Cl.[OH-].[Na+]>O>[Cl:14][C:8]1[C:9]([OH:10])=[CH:11][CH:12]=[CH:13][C:6]=1[OH:7]
Reactant: Oc1cccc(O)c1
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(O)c1Cl
Temperature: 110 °C
Yield: 42.1 %

Procedure:
Into a 500 mL flask containing 156 mL of 96% (w/w) sulfuric acid are added 52.5 g of resorcinol. Before the resorcinol completely dissolves, another 156 mL of 96% (w/w) sulfuric acid and another 52.5 g of resorcinol are added. The resulting exotherm causes the temperature of the mixture to increase to as much as 90° C. When this the temperature is reached, or when the temperature of the mixture no longer increases, the mixture is heated to 110° C. for two hours. Then, the mixture is cooled to 15° C., after which time 120 g of chlorine are added at such a rate to maintain a temperature of 15° C. The mixture is then poured into a 2 liter flask containing 450 g of ice and 400 mL of water. To the resulting aqueous phase is added aqueous sodium hydroxide (prepared by dissolving 76 g of sodium hydroxide into 150 mL of water) followed by a 24-hour reflux of the mixture. The temperature of the solution is reduced to room temperature, and after extraction by ethyl ether and ether evaporation, the residual mixture, which contains resorcinol and 2-chlororesorcinol, is subjected to flash column chromatography, using CH2Cl2 as eluent. This affords 29 g (21% yield) of the pure 2-chlororesorcinol (M.P. 97° C.).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=O)C>[OH-].[K+]>[NH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c(Cl)cc1N
Reaction time: 1 h

Procedure:
0.5 mol (99.5 g) of 2-acetamido-4-chloro-5-nitroanisole and 125 ml of a solution of potassium hydroxide (140 g of KOH/100 ml of water) are introduced into a 500 ml flask; the mixture is brought to between 100° and 110° C. for one hour and three quarters; the product is dried without heating and washed with water.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([NH:23][C:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCNc1nc[nH]c1C(N)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CCCCCN(C(=S)NC(=O)c1ccccc1)c1nc[nH]c1C(N)=O
Reaction time: 8 h
Yield: 139.1 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carboxamide (4.0 g, 0.020 mol) in DCM (50 mL) was added benzoyl isothiocyanate (3.3 mL, 0.024 mol). After being stirred overnight, the solid formed was filtered to give the crude product (10 g, ca 60% purity, 80% yield). This product was used for next step without further purification. LCMS calculated for C17H22N5O2S (M+H): 360.1. found: 360.1.
Reaction SMILES: Cl[CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].[SH-:18].[Na+].Cl>>[SH:18][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(S)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
A mixture of 0.05 moles of α-chloro-6-methoxy-2-naphthylacetic acid and 5 g. of sodium hydrosulfide in 100 ml. of absolute ehtanol and under a nitrogen atmosphere is stirred for 15 hours. The mixture is then acidified with 6 N hydrochloric acid. The solvent is removed in vacuo and the residue is extracted into ether, washed with water, saturated sodium chloride solution, dried and evaporated to dryness to obtain α-mercapto-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: C(OC([N:8]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][S:18][C:17]1=[N:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[O:36][CH3:37])[CH2:9][C:10]([OH:12])=[O:11])=O)(C)(C)C.Cl>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:28]=[C:17]2[N:16]([CH2:15][CH2:14][CH2:13][NH:8][CH2:9][C:10]([OH:12])=[O:11])[C:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[CH:19][S:18]2)=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCC(=O)O

Procedure:
The compound (665 mg) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (577 mg) as hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=3[OH:24])=[C:11]([F:25])[CH:10]=2)[CH2:4]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl.O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:26](=[O:28])[CH3:27])[O:7][C:6]3=[O:8])=[CH:10][C:11]=2[F:25])=[C:17]([OH:24])[CH:18]=1)[CH3:23]
Reactant: CCc1ccc(Oc2ccc(N3CC(CN)OC3=O)cc2F)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(Oc2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of 5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-oxazolidin-2-one (10 mg, 0.028 mmol) in 2 ml of dry dichloromethane, cooled to 0° C., was added acetic anhydride (3 mg, 0.028 mmol) taken in 0.2 ml of dichloromethane. The reaction mixture was warmed to rt and stirred for 5 minutes until reaction was complete on TLC. The reaction mixture was diluted with 3 ml of water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic fraction was dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was purified by preparative HPLC (Column: C18 Symmetry (300×19 mm), 7μ, Mobile phase A: 20 mM ammonium acetate, Mobile phase B: Acetonitrile) to get 6 mg, 55.2% of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)=[CH:5][CH:4]=1.[Br:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52](Br)[CH:53]=2)[CH:48]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[CH:53]=[C:52]([C:14]1[CH:15]=[C:10]([N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:11]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=1)[CH:51]=[CH:50]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(c2ccccc2)c2cc(-c3ccc4cc(Br)ccc4c3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1

Procedure:
13.42 g of a product (yield: 66%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(4-methoxyphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.76 g, 30 mmol), 2,6-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])OC(=O)[CH:4]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([C:11]([O:19][CH3:20])=[O:18])=[C:7]([CH3:9])[CH:8]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(C)oc(=O)c1
Product: COC(=O)c1cc(OC)cc(C)c1C(=O)OC
Temperature: 180 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of compound K (41.4 g, 295 mmol) and dimethyl but-2-ynedioate (47.2 mL, 384 mmol) was stirred at 180° C. for 1 hour, then at 210° C. for 30 minutes. The mixture was cooled to room temperature and purified by silica gel chromatography (ethyl acetate:hexane=20:1-4:1) to give compound L (53.4 g, 76%) as a pale-yellow oil. 1H NMR (CDCl3, 400 MHz): δ 2.34 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 6.91 (1H, d, J=2.4 Hz), 7.29 (1H, d, J=2.4 Hz). EIMS (+): 238 [M]+
Reaction SMILES: [C:1]([C@@H:3]([NH:18][C:19]([C:21]1([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:27][C:21]1([C:19]([NH:18][C@H:3]([C:1]#[N:2])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:7][CH:6]=2)=[O:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(F)cc3)cc2)CCOCC1
Solvent: O=CO
Product: N#C[C@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)C1(N)CCOCC1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
To (S)-tert-butyl 4-(1-cyano-2-(4′-fluorobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 4, step (ii(i)), 218 mg) was added formic acid (4 mL) and the mixture heated to 50° C. for 20 min. The mixture was evaporated to dryness, dissolved in methanol (10 mL), re-evaporated to dryness, dissolved in methanol (6 mL) and purified on reverse phase HPLC eluting with 25% to 95% methanol in 0.1% aqueous TFA on a Waters SunFire column. The material was converted to free base by evaporating the relevant fractions, dissolving in dichloromethane (20 mL) and shaking with saturated sodium bicarbonate solution (20 mL). The dichloromethane was separated, dried and evaporated to afford the titled compound (100 mg).