Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH3:17]>CC(C)=O>[CH2:14]([N:13]([CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)[CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(CBr)s1
Reactant: CCCCNC
Solvent: CC(C)=O
Product: CCCCN(C)Cc1ccc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(bromomethyl)thiophene-2-carboxylate (350 mg, 1.49 mmol) in dry acetone (6.0 mL) is added N-methylbutylamine (533 μL, 4.47 mmol) and the solution stirred at room temperature overnight. The reaction is then concentrated under reduced pressure, redissolved in methylene chloride, washed with saturated sodium bicarbonate, water, and brine. The organic layer is then dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=3 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 3.86 (s, 3H), 3.69 (s, 2H), 2.41–2.36 (m, 2H), 2.25 (s, 3H), 1.53–1.43 (m, 2H), 1.34–1.25 (m, 2H), 0.91 (t, J=7 Hz, 3H)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:28]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:28]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(Br)c1ccccc1C#N
Product: CC(Sc1c(Cl)ccc2c1CCNCC2)c1ccccc1C#N
Product: Cl

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (±)-2-(1-bromoethyl)benzonitrile to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[CH:8]([S:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:18][C:17]1[C:12]([S:11][CH:8]([CH3:10])[CH3:9])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:5]
Reactant: CC(C)Sc1ncccc1O
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1cccnc1SC(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
12.3 ml of 2-bromopropionic acid methyl ester are added dropwise at room temperature to a mixture of 16.9 g of 2-isopropylthio-3-hydroxypyridine and 15.2 g of potassium carbonate in 250 ml of dimethylformamide and the batch is stirred for 75 minutes. The suspension is introduced into a mixture of ice-water (300 ml), 50 ml of 2N hydrochloric acid and 300 ml of ethyl acetate, washed four times with 120 mi of water and 120 mi of ethyl acetate each time, and the organic phase is dried over sodium sulfate and concentrated by evaporation. 25.4 g of the desired intermediate are obtained in the form of a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH2:14]([S:16][C:17]1[C:22]([C:23]([NH:1][C:2]2[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=2)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:15]
Reactant: Nc1cc(C(F)(F)F)cnc1S
Reactant: CCSc1ccncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A mixture of 450 mg of 3-amino-5-trifluoromethylpyridine-2-thiol, 637 mg of 4-ethylsulfanylnicotinic acid hydrochloride, 532 mg of EDCI hydrochloride, 31 mg of HOBt and 5 ml of pyridine was stirred at room temperature for 2 hours and then stirred at 60° C. for 30 minutes. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 494 mg of 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide. 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:38]=[CH:37][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=4)=[CH:37][CH:38]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of methyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]benzyl}amino)phenyl]propanoate (100 mg, 0.20 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (75 mg, yield 77%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C@H:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[F:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][C:34]=1[C@@H:41]([OH:46])[C:42]([CH3:45])([CH3:44])[CH3:43].C(Cl)Cl.[Si:50](Cl)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>CN(C1C=CN=CC=1)C>[CH3:54][C:53]([Si:50]([CH3:52])([CH3:51])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C@@H:18]([OH:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=1)([CH3:56])[CH3:55].[CH3:54][C:53]([Si:50]([CH3:52])([CH3:51])[O:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:26]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=2[F:24])=[C:34]([C@H:41]([OH:46])[C:42]([CH3:43])([CH3:45])[CH3:44])[CH:35]=1)([CH3:56])[CH3:55]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2[C@H](O)C(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2[C@@H](O)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2[C@@H](O)C(C)(C)C)c1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2[C@H](O)C(C)(C)C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of (1R)-1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol or (1S)-1-(2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol (T9.8 or T9.9) (0.300 g, 0.9 mmol) in DCM (10.00 mL, 155 mmol) at 23° C. was added tert-butyldimethylsilyl chloride (0.2 mL, 1 mmol), followed by TEA (0.2 mL, 1 mmol) and DMAP (0.01 g, 0.09 mmol). Stirring was continued for 16 hours. The mixture was then concentrated in vacuo to give the residue. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (1S)-1-(4-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol or (1R)-1-(4-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-2-yl)-2,2-dimethyl-1-propanol T9.10 or T9.11 (0.375 g, 92% yield). MS ESI (pos.) m/e: 450.2 (M+H2O)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([C:27]([OH:29])=O)[O:25][CH3:26])[C:16]=2[F:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([C:27](=[O:29])[NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([C:32]#[N:31])=[CH:34][CH:35]=3)[O:25][CH3:26])[C:16]=2[F:30])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c(C(OC)C(=O)O)c1
Product: CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-4-[3-(Carboxy-methoxy-methyl)-5-ethoxy-2-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester was coupled with 4-aminomethyl benzonitrile to give (RS)-4-{3-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester according to general procedure B. Yellow oil. MS 564.4 ([M+Na]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[CH3:33])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.S(Cl)(Cl)=O.[CH3:40]OC(=O)C1C=CC(N)=C(C)C=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:40][O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:34][CH3:35])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[C:25]([CH3:33])[CH:26]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3C)cc21
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)c(C)c1

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoic acid, MS (ISP): m/e=515.3 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using thionyl chloride in toluene and dimethyl-formamide for the formation of the acyl chloride, and 4-amino-3-methyl-benzoic acid methyl ester was used for the coupling, yielding 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:9]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH3:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:39]=[CH:38][S:37][CH:36]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)=[CH:3][CH:4]=2)[CH:9]([N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])[CH3:10])=[CH:24][CH:25]=1
Reactant: CC(C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C(Cc1ccc(Cl)cc1)c1ccc(-c2ccsc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
113 mg of N-{(1RS,2RS)-2-(4-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl}phthalimide prepared in the same manner as in Example 114, was dissolved in 3 ml of toluene, and 99 mg of tributyl(3-thienyl)tin and 14 mg of tetrakis(triphenylphosphine)palladium (O) were added thereto. The mixture was refluxed under heating for 3 hours in a light-shielding nitrogen atmosphere. The reaction solution was left to cool to room temperature. Then, 2 ml of a 5% potassium fluoride aqueous solution was added thereto, and the mixture was stirred for 30 minutes. Insoluble matters were separated by filtration. Then, ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=100/1→30/1) to obtain 83 mg of N-[(1RS,2RS)-3-(4-chlorophenyl)-1-methyl-2-{4-(3-thienyl)phenyl}propyl]phthalimide.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH3:26]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:26])=[O:24])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: N
Product: CC(C)n1nccc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2

Procedure:
Following the procedure in Example 51, 2-(1-Isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid was coupled with ammonia to give 115. MS(ESI+): 338.1. 1H NMR (400 MHz, DMSO) δ 8.94 (d, J=2.2, 1H), 7.94 (s, 1H), 7.77 (dd, J=8.5, 2.2, 1H), 7.69 (s, 1H), 7.44 (d, J=1.4, 1H), 7.25 (s, 1H), 7.08 (d, J=8.5, 1H), 6.40 (d, J=1.7, 1H), 5.34 (dt, J=13.0, 6.4, 1H), 4.52 (dd, J=11.0, 5.6, 4H), 1.44 (d, J=6.6, 6H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[CH3:24][S:25][C:26]1[S:30][C:29]([C:31]([NH2:33])=O)=[CH:28][C:27]=1[C:34]1[S:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1.[Na+].[Cl-]>ClC(Cl)C>[CH3:24][S:25][C:26]1[S:30][C:29]([C:31]#[N:33])=[CH:28][C:27]=1[C:34]1[S:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1
Reactant: CSc1sc(C(N)=O)cc1-c1nc(-c2ccccc2)cs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: CC(Cl)Cl
Product: CSc1sc(C#N)cc1-c1nc(-c2ccccc2)cs1
Temperature: 40 °C
Yield: 58.9 %

Procedure:
A slurry of P2O5 (2.7 g, 19 mmol) and hexamethyldisiloxane (6.7 mL) in dichloroethane (13 mL) was heated to 90° C., while stirring under a N2 atmosphere. After stirring for 2 h, the resulting clear solution was allowed to cool to 40° C. 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide (0.9 g, 2.7 mmol) as prepared in previous step was added to this solution and the mixture was heated at 75° C. for 5 h. This solution was cooled to room temperature and stirred with aqueous NaCl (6 M, 100 mL) for 10 min. As the aqueous solution is added a yellow solid precipitated. After 10 min this solid was separated by filtration, and dried under vacuum to give (0.5 g, 59%) of 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile as a yellow solid. 1H-NMR (DMSO-d6; 300 MHz) δ2.76 (s, 3H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 2H), 8.05-8.08 (m, 2H), 8.22 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[C:8]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Yield: 71 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid (150 mg, 0.47 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.20 mL, 1.41 mmol) and 2-aminothiazole (75 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h. At this time, the reaction was diluted with water (10 mL). The organic phase was separated and washed with a 1N aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The aqueous layers were each back-extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide (134 mg, 71%) as a pale yellow solid: mp 185-187° C.; EI-HRMS m/e calcd for C24H23N3OS (M+) 401.1561, found 401.1555.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.O>C(#N)C>[NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Solvent: CC#N
Solvent: CO
Product: N[C@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Example 1 was repeated with the difference that the sample to be tested was a tyrosine of unknown enantiomer composition, the comparison samples were (RS)-, (R)-, and (S)-tyrosine, and the mobile phase was a mixture of methanol, water, and acetonitrile in a 1:1:0.6 ratio by volume. In this case, the (R)-tyrosine gave a spot with an Rf -value of 0.34 and the (S)-tyrosine gave a spot with an Rf value of 0.26.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.CS(C)=O.[B-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [B-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
While cooling using a water bath, to a mixture of 1-benzyloxy-4-((E)-2-nitro-vinyl)-benzene described in Manufacturing Example 229-1-1 (60 g, 0.23 mol), acetic acid (27 mL) and dimethyl sulfoxide (400 mL) was added sodium borohydrate (8.9 g, 0.23 mol), which was stirred for 20 minutes at room temperature. Water (2.5 L) was added dropwise to the reaction mixture, and the deposited solids were filtered. Diethyl ether (300 mL) was added to the obtained solids to dissolve the title compound, and separation into filtrate and solids was carried out by filtration. The filtrate was concentrated under a reduced pressure to obtain the title compound (39 g). On the other hand, diethyl ether (300 mL) was added to the previously separated solid to dissolve the title compound, and separation into filtrate and solids was carried out by filtration. The filtrate was concentrated under a reduced pressure to obtain the title compound (12 g). This was combined with the previously obtained solids to obtain the title compound (51 g) as a crude product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.B.O1CCCC1.FC(F)(F)C(O)=O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cn1ccc2c([N+](=O)[O-])cccc21
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of 1-methyl-4-nitro-1H-indole (3.8 g, Organic Process Research and Development 2001 5 (6) 604) and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 86.3 ml) at 0° C. under an atmosphere of nitrogen was added, dropwise, trifluoroacetic acid (88 ml). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 90 min. The mixture was cautiously added to 2M sodium carbonate solution (750 ml) over 20 min and then stirred for 30 min. The mixture was extracted with ethyl acetate (2×300 ml), the combined organic extracts were dried over sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting with hexane:ethyl acetate (9:1) gave the title compound as a red solid (1.97 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]([OH:41])([CH3:40])[CH3:39]>>[CH:38]([O:41][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)([CH3:40])[CH3:39]
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)O
Agent: [Li]CCCC
Product: CC(C)Oc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (200 mg, 0.4 mmol) with 2 equivalents each of n-butyl lithium and isopropanol by the procedure described in Reference Examples 6 and 7 to afford the title compound: HPLC/MS: m/e=486 (M++1); Rt=4.11 min. 1H-NMR 400 MD (CDCl3): δ 1.32 (d, J=6 Hz, 6H), 5.01-5.06 (m, 1H), 7.17-7.30 (m, 6H), 7.36-7.37 (d, J=2 Hz, 1H), 7.36-7.41 (m, 1H), 7.56-7.59 (m, 1H), 8.53-8.55 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34]CCOO1.[Cl-].[NH4+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([CH2:34][OH:29])[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COOOC1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
Titanium tetrachloride (18 ml) was added dropwise to a solution of 4-(R)-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (41.5 g) in dichloromethane (300 ml) at 0° C. Diisopropylethylamine (28 ml) was added dropwise and the resulting purple suspension was stirred for 30 min, then a solution of trioxane (11.2 g) was added, followed by titanium tetrachloride (18 ml) and the mixture was stirred for two hours, during which time the solution changed in colour from purple to amber. Ammonium chloride (400 ml saturated aqueous solution) was added and the mixture was stirred for 10 min, then the phases separated and the organic layer washed with water and saturated brine, dried (Na2SO4) and evaporated to give the title compound as a colourless solid (45 g).