Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:46])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ccncc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (1.5 g, 2.92 mmol) (Intermediate 45) and N-methoxy-N-methylisonicotinamide.
Reaction SMILES: N1C=CN=C1.C1CCN2C(=NCCC2)CC1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29]=1[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][N:41]=1>C1COCC1>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[C:29]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][N:41]=3)=[C:28]([NH:27][C:24](=[O:25])[CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:32][N:31]=2)=[CH:34][CH:35]=1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Reactant: O=C(Cl)Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Imidazole 0.43 g and DBU 1.9 g were dissolved in 40 mL of THF. Under cooling with ice, 0.97 g of phenylacetyl chloride was dropped into the solution, followed by 20 minutes' stirring at room temperature. Then 40 mL of a THF solution containing 0.8 g of 5-amino-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole was dropped into the system and stirred at room temperature for 6 hours. From the reaction solution the solvent was distilled off under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. Thus obtained residue was purified on 40 g silica gel column chromatography (eluent, chloroform:methanol=100:1) and washed with ether to provide 0.77 g of the title compound (yield: 66%) in the form of colorless crystal.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([S:12][CH3:13])=S.[O:14]1[CH:19]=CSC=[N:15]1.Cl.NO>C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:12][CH2:13][CH2:19][O:14][N:15]=1
Reactant: CSC(=S)c1nc2ccccc2s1
Reactant: C1=CSC=NO1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Product: c1ccc2sc(C3=NOCCS3)nc2c1

Procedure:
Methyl 2-benzothiazolecarbodithioate (37 g, 0.16 mol) was converted to 1,4,2-oxathiazine using hydroxylamine hydrochloride (13.2 g) and triethylamine (33 ml) as described in Example 4. The ethyl acetate extract of the product was washed successively with diluted hydrochloric acid (2N), water, 5% sodium hydroxide and water. Evaporation of the solvent left a solid residue which was recrystallized from ethanol/ethyl acetate to 5,6-dihydro-3-(2-benzothiazolyl)-1,4,2-oxathiazine (18.0 g, mp 150°-151° C.) Found C 50.68, H 3.27, N 11.78, C10 H8N2OS2 requires C 50.85, H 3.39, N 11.80.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:43])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:42])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:42])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:43])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.29 mmol) was added to a stirred solution of {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.043 g, 0.074 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.035 g, 84%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s., 1 H) 8.71 (s, 2 H) 8.58 (s, 1 H) 8.34 (d, J=7.82 Hz, 2 H) 8.00 (dd, J=8.60, 6.20 Hz, 1 H) 7.90 (s, 1 H) 7.56 (d, J=7.82 Hz, 2 H) 7.37 (br. t, J=8.80, 8.80 Hz, 1 H) 6.64 (d, J=10.27 Hz, 1 H) 3.83 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C27H16F7O4S [(M−H)−] 569, obsd. 569.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[Na].BrC1[S:25][CH:26]=[CH:27]N=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[S:25][CH:26]=[CH:27][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: Brc1nccs1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2nccs2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 2.37 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide, there is added under nitrogen at less than 30°C., 0.38 g. of sodium borohydrode. The mixture is stirred at 20°-30°C. for 1 hour, then 3.2 ml. of 2-bromothiazole is added. The mixture is heated to 130°-135°C. for 1 hour, then cooled and diluted with water. The crude product is filtered off and recrystallized from methanol yielding 1-acetamido-2-nitro-4-(thiazol-2-ylthio)benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc2c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(OC)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-methoxybenzoxazole (674 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [O:1]1[CH2:11][CH:2]1[CH2:3][C:4]12O[CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9]2.[CH2:12]([CH2:14][NH2:15])[OH:13]>O>[OH:13][CH2:12][CH2:14][NH:15][CH2:11][CH:2]([OH:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCCO
Reactant: C1=CC2OC2(CC2CO2)C=C1
Solvent: O
Product: OCCNCC(O)Cc1ccccc1

Procedure:
The above compound could be made in the same manner as Example 1 using the appropriate epoxide. 1 equivalent of (2,3-Epoxypropyl)benzene oxide and 4 eq. ethanol amine could be stirred at room temperature overnight. The solution could be poured into water and the water is extracted with dichloromethane. The combined dichloromethane layers could be washed with brine and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: Oc1cc(F)cc(Br)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Fc1cc(Br)cc(OC2CCCCO2)c1
Yield: 94.8 %

Procedure:
A solution of 3-bromo-5-fluorophenol (1.64 g, 8.59 mmol), 3,4-dihydro-2H-pyran (1.56 mL, 17.2 mmol) and PPTS (0.216 g, 0.859 mmol) in DCM (10 mL) was stirred for 16 h at rt. The reaction was concentrated in vacuo. The residual crude oil was purified by chromatography (SiO2) using a 0% to 20% EtOAc/hexane over 15 min to give the title compound (2.24 g, 8.14 mmol, 95% yield) as a clear oil. 1H NMR (CDCl3) δ: 7.05 (dd, J=2.8, 2.1 Hz, 1H), 6.90 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 6.77 (dt, J=10.6, 2.2 Hz, 1H), 5.41 (t, J=3.1 Hz, 1H), 3.91-3.81 (m, 1H), 3.72-3.58 (m, 1H), 2.05-1.92 (m, 1H), 1.92-1.82 (m, 2H), 1.81-1.58 (m, 3H); 19F NMR (CDCl3) δ: −110.28 (s); 13C NMR (CDCl3) δ: 164.22 (s), 162.24 (s), 158.78 (d, J=11.8 Hz), 122.41 (d, J=12.5 Hz), 115.88 (d, J=3.3 Hz), 112.33 (s), 112.13 (s), 103.42 (s), 103.22 (s), 96.67 (s), 61.97 (s), 30.05 (s), 25.01 (s), 18.39 (s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:33][CH2:34][N:35]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:2]=3[OH:1])[CH2:36][CH2:37]1)(=[O:30])=[O:31])[CH:23]=[CH:22]2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: O=C(c1ccc(-c2ccncc2)cc1O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In the same manner as in Example A-4, a reaction was conducted using 2-(hydroxy-4-(4-pyridyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])#[CH:9].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:5]([NH:13][C:12]1[CH:11]=[C:10]([C:8]#[CH:9])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[CH3:6]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Acetic anhydride (13.8 mL, 144 mmol) was added dropwise to a solution of 3-ethynylaniline (14.0 g, 120 mmol) and 4-(Dimethylamino-)pyridine (DMAP) (1.5 g, 12 mmol) in tetrahydrofuran (300 mL). The mixture was stirred at room temperature for 2 hours, water (100 mL) was added to the mixture and the whole was extracted with dichloromethane (2×250 mL). The combined organics was washed with 10% citric acid (100 mL) followed by saturated sodium bicarbonate solution (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 3-(acetylamino)phenylacetylene as a yellow solid (18.3 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[NH:13][C:14]([C:16]1[C:17](=[O:27])[CH:18]=[C:19]([CH3:26])[N:20]2[C:25]=1[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:15])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:18]1[C:17](=[O:27])[C:16]([C:14]([NH:13][C:6]2[C:7]([CH2:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:3][CH3:4])=[O:15])=[C:25]2[N:20]([C:19]=1[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24]2
Reactant: CCc1cccc(CC)c1NC(=O)c1c2n(c(C)cc1=O)CCCC2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1c2n(c(C)c(Br)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A mixture of 0.11 ml of bromine and 8 ml of methylene chloride was dropwise added to a mixture of 0.70 g of N-(2,6-diethylphenyl)-6,7,8,9-tetrahydro-4-methyl-2-oxo-2H-quinolizine-1-carboxamide, 1.27 g of sodium carbonate and 12 ml of methylene chloride at room temperature taking 30 minutes and further stirred for 5 hours at room temperature. After filtering the insoluble material off, the solution was concentrated and the resulting crystalline residue was recrystallized from a mixture of ethyl acetate and methanol to afford 0.64 g (Yield 75%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(OCC)(=O)C.[N:15]#[C:16]Br.[OH-].[Na+]>O>[NH2:15][C:16]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2o1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
A mixture of 2.5 g 2-aminophenol (7-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (7-2).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=5)=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=CC=1.[OH:36]S(O)(=O)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:32]([NH2:33])=[O:36])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(C(F)(F)F)cc5)ccc4c23)cc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3ccc(C(F)(F)F)cc3)ccc12

Procedure:
1-[(4-Methoxybenzyl)amino]-7-[4-(trifluoromethyl)phenyl][1]benzothieno[3,2-c]pyridine-4-carbonitrile was placed in a flask cooled to 0° C. before conc. H2SO4 (excess) was added dropwise under vigorous stirring. The final mixture was warmed to room temperature and, after 1 h, poured into THF/EtOAc and aqueous NaHCO3 previously saturated with NaCl solid. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were dried over MgSO4 and filtered. After evaporation of the organic solvents, the crude material was purified by a wash with Et2O to provide the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[S:21])[CH2:12]1)[CH2:18]2)C1C=CC=CC=1.Br>CCOCC>[NH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[S:21])[CH2:12]1)[CH2:18]2
Reactant: O=C(NC12CC3CC(C1)C(=S)C(C3)C2)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Product: NC12CC3CC(C1)C(=S)C(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
To 10B (30 mg, 0.10 mmol) was added HBr (33% in HOAc) 2 mL and the mixture was stirred at rt for 1 h. Ether (10 mL×2) was added and the resulting precipitate was collected and dried under vacuum to give the title compound as hydrogen bromide salts (10) (20 mg). LC-MS (ESR): m/z=182 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[O:1][CH2:6][CH2:5][S:4][CH:3]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)C1=CSCCO1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CSCCO1
Yield: 47.8 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5,6-dihydro-1,4-oxathiin-2-carboxylic acid (7.3 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-chloro-1,8-naphthyridine (7.2 g). The product obtained by precipitation in water is purified by recrystallization in dimethylformamide (60 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5,6-dihydro-1,4-oxathiin-2-carboxamide (5.9 g), m.p. 270° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1

Procedure:
The product from Example 33B and 2-methoxybenzylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 453 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:7]1[C:2]([CH:9]=[CH2:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncccc1Br
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 2,3-dibromopyridine (2.0 g, 8.44 mmol) in DMF (10 mL) was treated with tributyl(vinyl)tin (2.94 g, 9.29 mmol), LiCl (1.07 g, 25.32 mmol), and PdCl2(PPh3)2 (0.296 g, 0.422 mmol). The reaction mixture was heated at 100° C. for 18 hours. The mixture was extracted with hexanes (3×50 mL). The combined hexane layers were extracted with 1N HCl. The aqueous layer was neutralized with 1N NaOH, extracted with hexanes, and the extracts were dried (MgSO4), filtered, and concentrated to provide the desired product as a yellowish oil (0.83 g, 53% yield). MS m/z 184(MH+); 1H NMR (300 MHz, CD3OD) δ 5.53 (dd, J=10.80, 2.01 Hz, 1H), 6.33 (dd, J=16.83, 1.83 Hz, 1H), 7.08-7.26 (m, 2H), 7.96 (dd J=8.05, 1.46 Hz, 1H), 8.44 (dd, J=4.76, 1.46 Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 121.9, 122.4, 125.7, 134.9, 142.8, 149.5, 154.5.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH2:20][CH2:21][CH3:22])[CH2:15]1)[CH2:5][OH:6]
Reactant: CCC[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of 23.0 g of (3R,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-propyldihydrofuran-2-one obtained in Example (116e) (75.9 mmol), 40.0 ml of a solution of 4 N hydrochloric acid in dioxane (160 mmol) and 5.20 g of 10% palladium-carbon (50% wet) in ethanol (400 ml) was stirred under a hydrogen atmosphere at room temperature for seven hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 200 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain crude (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-propyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:6].N[C@@H](C(O)=O)C[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)[N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccccc2)cc1)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
A solution of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-tyrosine methyl ester (253 mg, 0.74 mmol) (prepared from (D)-tyrosine following the procedure described in example 55), Ph3Bi(OAc)2 [triphenylbismuth diacetate] (895 mg, 1.6 mmol) (prepared according to the literature procedure; H. Brunner, U. Obermann, and P. Winner, Organometallics 1989, 8, 821-826), and Cu powder (43 mg, 0.68 mmol) in methylene chloride (15 ml) is stirred at room temperature under nitrogen atmosphere overnight. This reaction mixture is concentrated in vacuo and the crude material is chromatographed on silica with hexane/ethylacetate (3:1) to give N-(3,5-dimethylbenzoyl)-N-methyl-O-phenyl-(D)-tyrosine methyl ester as a colorless oil. Hydrolysis of the methyl ester obtained above (294 mg, 0.70 mol) by lithium hydroxide hydrate (31 mg, 0.74 mol) gives a corresponding acid.