Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:28]1[C:29]([N+:35]([O-:37])=[O:36])=[C:30](O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.ClCCl.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.[Cu]I>[CH2:23]1[CH2:22][O:21][C:18]2([CH2:19][CH2:20][C:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)([C:25]#[C:26][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=3)[CH2:16][CH2:17]2)[O:24]1
Reactant: O=[N+]([O-])c1c(O)cccc1I
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3cccc([N+](=O)[O-])c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.14 g, 0.38 mmol) and 3-iodonitrophenol (0.10 g, 0.38 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 70° C. for 0.33 h, the mixture was diluted with dichloromethane, was washed with 1N hydrochloric acid, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 1,1-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-nitrophenylethynyl)cyclohexane as an orange wax. 1H-NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.26 (d, J=2 Hz, 1H), 7.14 (dd, J=8.3, 2 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.82 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 2.18 (m, 4H), 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: Cl[C@H:2]1[C@H:8]2[C:9](=[O:10])[C@H:5]([CH:6]=[CH:7]2)[N:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].Cl[C@@H:21]1[C@H:27]2[C:28](=O)[C@H](C=[CH:26]2)N(OCC2C=CC=CC=2)C1=O.ClC(Cl)C(NOCC1C=CC=CC=1)=O.O1C=CC=C1>CCOC(C)=O>[CH3:26][CH:27]([CH3:28])[CH2:21][C@H:2]1[C@@H:8]2[C:9](=[O:10])[C@H:5]([CH:6]=[CH:7]2)[N:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19]
Reactant: O=C1[C@H]2C=C[C@@H]1N(OCc1ccccc1)C(=O)[C@H]2Cl
Reactant: O=C1[C@H]2C=C[C@@H]1N(OCc1ccccc1)C(=O)[C@@H]2Cl
Agent: O=C(NOCc1ccccc1)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccoc1
Product: CC(C)C[C@@H]1C(=O)N(OCc2ccccc2)[C@H]2C=C[C@H]1C2=O

Procedure:
(±)-(4S,5R,1S) 4-chloro-8-oxo-2-(phenyl methoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (endo-5e) and (±)-(4R,5R,1S) 4-chloro-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (exo-5e):Prepared in 73% yield (72 mg, 0.31 mmol) from the reaction of 2,2-dichloro-N-(phenylmethoxy)acetamide (100.2 mg, 0.43 mmol) with furan via general procedure B. Rf=0.50 (3:1, hexanes:EtOAc) 1H NMR (400 MHz, CDCl3) δ 7.51-7.30 (m, 3H), 6.54 (dd, J=6.0, 1.1 Hz, 1H), 6.51 (dd, J=6.0, 1.7 Hz, 1H), 5.27 (d, J=1.1 Hz, 1H), 5.09 (dd, J=5.1, 1.6 Hz, 1H), 5.00 (d, J=11.0 Hz, 1H), 4.89 (d, J=11.0 Hz, 1H), and 4.76 (d, J=5.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.9, 136.8, 135.3, 133.1, 129.8, 129.2, 128.2, 92.1, 82.1, 78.3, and 56.9; IR (film) 3032, 2950, 2922, 2852, 1712 (s), 1455, 1369, 1213, 1189, 1059, 1023 cm-1. HR-ESIMS calculated for C13H12ClNNaO3 (M+Na)+288.0398, found 288.0391. exo-diastereoisomer: Rf=0.3 (3:1, hexanes:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.48-7.35 (m, 2H), 6.68 (d, J=5.9 Hz, 1H), 6.34 (dd, J=6.0, 1.1 Hz, 1H), 5.28 (s, 1H), 5.02 (d, J=10.9 Hz, 2H), 4.98 (s, 1H), 4.92 (d, J=10.9 Hz, 2H), and 4.09 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 165.5, 138.2, 135.0, 131.4, 129.9, 129.2, 128.8, 91.3, 84.2, 78.4, and 56.1; IR (neat) 3067, 3034, 2946, 2885, 1694, 1046 cm-1; HRMS calculated for C13H12ClNNaO3 (M+Na)+288.0398, observed 288.0399.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccnc1Cl
Yield: 47.5 %

Procedure:
To a solution of (2-chloro-3-pyridyl)methanamine (300 mg, 2.10 mmol) in dichloromethane (2 mL) at room temperature is added acetic acid anhydride (198.88 mL, 2.10 mmol) and triethylamine (293.26 mL, 2.10 mmol). After 1 h the reaction is quenched with saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and the solvent evaporated in vacuo to afford 184 mg of N-[(2-chloro-3-pyridyl)methyl]acetamide. MS (m/z): 185 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.[NH2:23][OH:24].Cl.C([O-])(=O)C.[NH4+]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[N:23][OH:24]
Reactant: NO
Reactant: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To the compound (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OH.HCl (10.1 g) and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 ml). This was followed by washing with water, brine, and drying over magnesium sulfate. The product was concentrated to an oil and purified by column chromatography to yield 12 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([S:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[CH:30]=3)[NH:25][N:24]=2)(=[O:22])=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:25]1[C:26]2[C:31](=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])=[CH:28][CH:27]=2)[C:23]([S:20]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)(=[O:21])=[O:22])=[N:24]1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
3-Chlorobenzylbromide (0.90 mL, 6.8 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (3.24 g, 6.20 mmol) and cesium carbonate (2.21 g, 6.78 mmol) in acetone (80 mL). The mixture was stirred at ambient temperature under nitrogen for 2 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 30-35% ethyl acetate in hexane. Drying at 65° C. in vacuo for 30 minutes gave toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl ester as a dark yellow foam (2.55 g, 63.6%); Mass Spectrum (+EI, [M+H]+) m/z 647. 1HNMR (500 MHz, DMSO-d6): δ8.73-8.75 (m, 1H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.01-8.04 (m, 1H), 7.67-7.75 (m, 4H), 7.56-7.63 (m, 2H), 7.17-7.27 (m, 5H), 7.05-7.07 (m, 2H), 6.98 (dd, 1H, J=9.28 Hz and 2.32 Hz), 5.71 (s, 2H), 4.31-4.33 (m, 2H), 4.15-4.17 (m, 2H), 2.17 ppm (s, 3H). Elemental Analysis for C33H27ClN2O6S2: Calcd: C, 61.25; H, 4.21; N, 4.33; Found: C, 60.93; H, 4.22; N, 4.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3×10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4) The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.25 (1H, d, J~1.8 Hz), 7.30 (1H, d, J~8.2 Hz). MS exact mass, m/1 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:38](O)=O)[CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:38]2[NH:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=3[N:24]=2)[CH2:37][CH2:36][O:35][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOC1
Reactant: Nc1ccc(Cl)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (1.75 g, 8.5 mmol) is added portionwise at 0° C. to 4-chloro-o-phenylenediamine (1.21 g, 8.5 mmol) and 3-tert-Butoxycarbonylamino-tetrahydro-furan-3-carboxylic acid (1.97 g, 8.5 mmol) in THF (50 mL). After stirring overnight at rt, the reaction mixture was filtered and evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 0-5% EtOH/DCM) to furnish [3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (2.35 g, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:9]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: OO
Reactant: N#Cc1cccnc1
Solvent: CC(=O)O
Product: N#Cc1ccc[n+]([O-])c1
Yield: 58.3 %

Procedure:
5.21 g of 3-cyanopyridine are completely dissolved in 50 ml of glacial acetic acid at 40° C., with stirring. Then 9.8 ml of a 30% aqueous solution of H2O2 are added and the mixture is heated, with stirring, to 100° C. for 2 hours. Thin-layer chromatography shows that the reaction is complete. The solvent is cautiously removed by evaporation and the beige solid is treated with 25 ml of ethanol, cooled and and filtered. The residue is dried at 35° C. under vacuum, affording 3.5 g (58.3% of theory) of 3-cyanopyridine-N-oxide as a white solid with a melting point of 172°-174° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([CH3:28])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[C:1]([NH:5][C:6]([C:17]1[N:18]([CH3:28])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Product: Cn1c(C(=O)NC(C)(C)C)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl

Procedure:
Using essentially the same procedure as Example 33, but using t-butyl isocyanate (0.040 mL, 0.30 mmol), 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][N:15]1[S:19](=[O:21])(=[O:20])[N:18]2[CH2:22][CH2:23][CH2:24][CH:17]2[C:16]1=[O:25]>CN(C=O)C>[C:1]1([N:7]2[C:11]([S:12][CH2:14][N:15]3[S:19](=[O:21])(=[O:20])[N:18]4[CH2:22][CH2:23][CH2:24][CH:17]4[C:16]3=[O:25])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=C1C2CCCN2S(=O)(=O)N1CCl
Solvent: CN(C)C=O
Product: O=C1C2CCCN2S(=O)(=O)N1CSc1nnnn1-c1ccccc1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
The Na salt of 1-phenyl-5-mercapto-1H-tetrazole (0.57 g) was added to a solution of 2-chloromethyl-tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (0.5 g) in DMF (10 ml) at room temperature, and the mixture was allowed to react at 60° C. for 6 hours and then cooled. The mixture was poured into ice/water containing saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried over sodium sulfate. The solvent was concentrated in vacuo and the residue was purified by silica gel flash chromatography (40% ethyl acetate/hexane) to afford 0.69 g of 2-(1-phenyl-1H-tetrazol-5-yl-thiomethyl)tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (Formula I: R4 =1-phenyl-1H-tetrazol-5-yl; X=S; R1 =H; R2 and R3 together=--(CH2)3 --) as a solid, m.p.99.5°-100.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([CH3:36])[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: Cc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(C)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 90.5 mg (0.61 mmol) of 4-chloromethyl-2-methyl-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction and dried at 40° C. under reduced pressure. This gives 88.8 mg (66.2% of theory) of product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cncc(Br)c1
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: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(-c2cncc(Br)c2)cc1
Temperature: 150 °C
Yield: 9.3 %

Procedure:
3,5-Dibromopyridine (4.4 mmol), 4-trifluoromethoxyphenyl boronic acid (5.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 mmol), 2 M potassium carbonate (8.44 mmol) and dioxane (21 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The ether layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. The crude mixture was purified by silica gel chromatography to yield 130 mg of 3-bromo-5-(4-trifluoromethoxy-phenyl)-pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (m, 2H), 8.00 (t, J=2.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H); EIMS 317 m/z (M+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:22])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C@H:8]([CH2:10][C:11](=[O:13])[OH:12])[NH2:9].[CH:23](N[C@@H]1C(=O)OC(=O)C1)=[O:24].N[C@H](C(O)=O)CC1C=CC=CC=1>O.CO>[CH:23]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH2:10][C:11](=[O:13])[OH:12])=[O:24]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
This invention relates to a preparation process of α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. More specifically, this invention provides a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required. Further, this invention provides another process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water containing methanol in an amount of 6 moles or less per mol of the L-phenylalanine at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:23]([CH2:25][NH2:26])O>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:26]3[CH2:25][CH2:23][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Yield: 74.8 %

Procedure:
To a solution of 3.77 g of 2-trichloroacetamido-5-chlorobenzophenone in 100 ml of ethanol was added 3.05 g of monoethanolamine, and the resulting mixture was refluxed for 2 hours. Then, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 2.25 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 216° - 217°C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[S:30]1[CH:34]=[C:33]([CH2:35]O)[N:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][C:33]5[N:32]=[CH:31][S:30][CH:34]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OCc1cscn1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1cscn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1,3-thiazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and thiazol-4-yl-methanol following General Procedure J.
Reaction SMILES: C(O[C:5](=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:13][C:14](=[O:32])[NH:15][C:16]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27]C=[C:25]([CH2:29][F:30])[CH:24]=4)[C:20](C)=[CH:19][C:17]=3[N:18]=2)[CH:7]=1)C=C.O.[NH2:35][NH2:36]>CO.O>[F:30][C:29]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:12]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([NH:35][NH2:36])=[O:33])[CH2:13][C:14](=[O:32])[NH:15][C:16]=3[CH:22]=2)=[CH:24][CH:25]=1
Reactant: C=CCOC(=O)c1cccc(C2=Nc3cc(C)c(-c4cccc(CF)c4)cc3NC(=O)C2)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
To a suspension of 3-[7-(3-fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid allyl ester (Starting material 8a-1) (207 mg, 0.5 mmol) in MeOH (3.5 mL) was added hydrazine hydrate (0.25 mL, 5 mmol). The mixture was stirred at 60° C. for 15 h, then cooled to 23° C. and diluted with H2O (35 mL). The precipitate was collected by filtration and dried, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (64 mg).