Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:62][CH2:61]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL) was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.00017 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0334 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0382 g (65%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 438.16 (M+1)+, 98.29%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.1 (s, 1H), 7.78 (d, 2H), 7.44 (m, 2H), 7.38 (m, 1H), 7.26 (d, 2H), 7.1 (m, 2H), 6.84 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.8 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 1.9 (t, 2H), 1.3 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]2[CH2:20][CH2:21][CH2:22][C:23]2=[O:25])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(=O)CCCN
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(OC)c1nc2c(cc1CN1CCCC1=O)CCCN2
Reaction time: 1.5 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 5.0 g, 17.99 mmol), methyl 4-aminobutanoate hydrochloride (4.14 g, 27.0 mmol) and triethylamine (4.24 ml, 30.6 mmol) in 1,2-dichloroethane (85 ml) at room temperature was stirred for 1.5 h and sodium triacetoxyborohydride (5.72 g, 27.0 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and DCM, extracted 2× with DCM, dried over Na2SO4 and evaporated. The residue was triturated with Et2O (20 ml) and filtered washing with Et2O to give the title compound as a pale brown solid.
Reaction SMILES: C([O:4][C:5](=[O:33])[CH2:6][CH2:7][NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[N:24][NH:25][O:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:19][CH:18]=2)[C:13]1=[O:32])=[O:10])CC.[CH3:34][CH:35](C)[CH2:36]OC(=O)CCN>>[CH3:34][CH:35]([O:4][C:5](=[O:33])[CH2:6][CH2:7][NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[N:24][NH:25][O:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:21][CH:22]=2)[C:13]1=[O:32])=[O:10])[CH3:36]
Reactant: CCCOC(=O)CCNC(=O)N[C@H]1CCN(c2ccc(C=NNOC(=O)N(C)C)cc2)C1=O
Reactant: CC(C)COC(=O)CCN
Product: CC(C)OC(=O)CCNC(=O)N[C@H]1CCN(c2ccc(C=NNOC(=O)N(C)C)cc2)C1=O

Procedure:
N-[[[(3S)-1-[4-[[[[(dimethylamino)carbonyl]oxy]amino]iminomethyl]phenyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]-β-alanine propyl ester; N-[[[(3S)- l -[4-[[[[(dimethylamino)carbonyl]oxy]amino]iminomethyl]phenlyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]-β-alanine 2-methylpropyl ester;
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](OC)(=[O:11])[CH3:10].[Na].CC1C=C(C)N=C(O)C=1>CC(N(C)C)=O>[CH2:1]([NH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(C)=O
Agent: Cc1cc(C)nc(O)c1
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CC(=O)NCc1ccccc1
Yield: 84 %

Procedure:
2.1 g. of benzylamine, 7.4 g. of methyl acetate and 1.5 g. of the sodium salt of 4,6-dimethyl-2-hydroxypyridine are dissolved in 30 ml. of dimethyl acetamide and heated at about 78° C. for 4.5 hours. As determined by thin layer chromatography, all but a trace of the benzylamine is consumed. 200 ml. of water and 0.9 ml. of concentrated hydrochloric acid are added to the reaction solution, and the solution is extracted three times with 100 ml. of ethyl acetate. The organic layer is washed with 100 ml. of water, and, after drying with sodium sulfate, concentrated and crystallized. Recrystallization from 300 ml. of ether-petroleum benzin (1:1), 2.5 g. of needle-like crystals of N-benzyl acetamide are obtained (yield: 84 percent). m.p. 60.5° - 62° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([N:26]1[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28]([OH:36])=[N:27]1)[CH3:25].CN(C)C=O.[H-].[Na+]>O>[CH2:24]([N:26]1[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28]([O:36][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=2)=[N:27]1)[CH3:25]
Reactant: CCOC(=O)c1cn(CC)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (3.50 g), ethyl 1-ethyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.36 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.94 g, yield 75%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [Li]CCCC.Br[C:7](Br)=[CH:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1>C1COCC1>[C:27]1([C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]2[CH:13]=[C:9]([C:8]#[CH:7])[N:10]=[CH:11]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrC(Br)=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
n-BuLi (0.192 ml, 0.48 mmol) was added to a solution of 4-(2,2-dibromovinyl)-1-(triphenylmethyl)imidazole (108 mg, 0.22 mmol) in THF (5 ml) at -78° C. under N2. The reaction mixture was quenched by the addition of saturated ammonium chloride (50 ml) and extracted with ethyl acetate (75 ml). The ethyl acetate layer was washed with water (50 ml), separated, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography gave 2[1-triphenylmethyl-1H-imidazol-4yl]ethyne, which was deprotected with 2N HCL to give 18 mg of final product. ##STR77## 4-Ethynylimidazole (46) 1H-NMR (300 MHz, CD3OD): δ8.94 (s, 1H), 7.80 (s, 1H), 4.20 (s,1H); Mass Spectrum (Cl) m/e 93 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:31])=[O:30])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH2:32])(=[O:30])=[O:31])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(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: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(-c2cccc(Cl)c2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol), was added to a solution of 2,3-dichlorophenylboronic acid (57 mg, 0.30 mmol) and 2-[(3-bromophenyl)-sulfonylamino]benzenesulfonamide (97 mg, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at RT under argon for 15 minutes before addition of 2M Na2CO3 (0.5 mL). The reaction was stirred overnight at 90° C., filtered and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (61 mg, 53%) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O=C1C2C(=CC(OCC(OC(C)(C)C)=O)=C(Cl)C=2Cl)CC1C1CCCC1>O.CN(C)C=O>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 1 h

Procedure:
A mixture of 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.98 g., 0.01 mole), tert.-butylbromoacetate (2.15 g., 0.011 mole), potassium carbonate (2.76 g., 0.02 mole) and dimethylformamide (15 ml.) is stirred at 25° for 1 hour then poured into water (50 ml.) the tert.-butyl (1-oxo-2-cyclopentyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COCCO
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(COCCOC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(bromomethyl)acrylate (2.0 g, 9.0 mmol) in 2-methoxyethanol (30 ml) at 0° C. was added, in one portion, potassium carbonate (2.5 g, 18 mmol) and the mixture stirred at 0° C. for 1 hour. The reaction was diluted with distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2×50 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (2:1) to give, after combination and evaporation of appropriate fractions, the title compound as a yellow oil, (1.6 g, 82%). Rf. 0.32 (silica, hexane/ethyl acetate, 2:1). 1H-NMR (300 MHz, CDCl3) 1.50 (s, 9H), 3.42 (s, 3H) , 3.56-3.63 (m, 2H), 3.65-3.74 (m, 2H), 4.25 (s, 2H), 5.84 (s, 1 H), 6.25 (s, 1H) ppm.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]2[C:16]=1[CH2:17][CH:18]([C:27]([O:29][CH3:30])=[O:28])[O:19][CH2:20]2.CI.[NH4+].[Cl-]>C1COCC1.O>[CH3:30][O:29][C:27]([C:18]1([CH3:1])[CH2:17][C:16]2[C:21](=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[CH2:20][O:19]1)=[O:28]
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2CO1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)Cc2c(OC)ccc(OC)c2CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of di-isopropylamine (616.8 μl, 4.37 mmol) in THF (10 ml) was cooled to 0° C. and degassed briefly. n-Butyl lithium (1.6M in hexane, 2.60 ml, 4.17 mmol) was added. After stirred for 30 minutes at 0° C., the solution was further cooled to -78° C. A solution of 5,8-dimethoxy-3-methoxycarbonylisochroman (1.0 g, 3.97 mmol) in THF (10 ml), pre-degassed, was added slowly. The resulting yellow solution was stirred for 1 hour at -78° C. before the addition of methyliodide (1.01 ml, 16 mmol). After stirred further for 45 minutes, sat. NH4Cl solution was added. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product which was chromatographed (hexane:EtOAc=3:1) to give the desired product as a solid (650 mg, m p. 73.0°-74.5° C.) and another fraction (192 mg) which contained 66% of titled product and 34% of the starting material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](#N)C.C(N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: CC#N
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g) in methanol (1.32 ml)/acetonitrile (40 ml) was treated with N,N-diisopropylethylamine (1.78 ml). Trimethylsilyldiazomethane (2M, 8.73 ml) was added dropwise and the resulting mixture was stirred at room temperature, under argon for 24 h. The mixture was diluted with ethyl acetate, washed with 2M HCl, saturated aqueous sodium hydrogen carbonate, brine then dried (magnesium sulfate). The solvent was removed under reduced pressure to afford the title compound (2.10 g)
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C.CN(C)C=O>C(OC(=O)C)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([CH:35]1[CH2:36][NH:37][CH2:38][CH2:39][N:34]1[CH3:33])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCNCC1C1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Reaction time: 8 h

Procedure:
A mixture of benzyl 6-azido-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (0.1 mmol), N-methylpiperazine (0.11 mmol), triethylamine (1 mmol) and anhydrous dimethylformamide (1 ml) is allowed to stand at room temperature overnight. The mixture is diluted with ethylacetate, washed thoroughly with water and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent under vacuum provides benzyl 6-azido-3-(N-methylpiperazinyl)1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClC1C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=Cc1ccccc1
Reactant: ClCC=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Clc1ccccc1
Product: C(C=Cc1ccccc1)=Cc1ccccc1
Yield: 27.7 %

Procedure:
The procedure described in Example 1 is followed, except that 16.7 g (0.1 mol) of cinnamyl chloride, 13.0 g (0.125 mol) of styrene, 23.3 g (0.125 mol) of tri-n-butylamine, 100 ml of chlorobenzene and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 5 hours at a bath temperature of 140° C., 5.7 g (0.0277 mol) of 1,4-diphenyl-1,3-butadiene, corresponding to a yield of 27.7% of theory, are obtained; melting point 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15](O)=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazoleproponic acid (1.5 g) in THF (20 ml) was added lithium aluminum hydride (0.27 g), followed by stirring for 3 hours at room temperature. Water (3 ml) was added to the reaction mixture. The resultant was extracted with ethyl acetate. The ethyl acetate layer was washed with 2N-HCl and water, dried over MgSO4, and distilled to remove the solvent. The oily residue was subjected to a silica gel chromatography. Crystals of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanol (1.11 g, 78%) were obtained from the fraction eluted with ethyl acetate-hexane (2:1, V/V). Recrystallization from ether-hexane gave colorless prism crystals of mp 43°-44° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].Cl>O1CCCC1.O>[S:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:11][S:12](=[O:15])(=[O:14])[NH2:13])(=[O:15])(=[O:14])[NH2:13]
Reactant: OCCCCCCCO
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 63.1 %

Procedure:
A 57% oil dispersion of sodium hydride (11.8 g, 0.28 mole NaH) was added to 150 ml of tetrahydrofuran. The suspension was stirred and gently heated, and 15.84 g (0.12 mole) of 1,7-heptanediol in 75 ml of tetrahydrofuran was added gradually over a period of 90 minutes. An additional 25 ml of tetrahydrofuran was then added, and the reaction mixture was stirred at reflux for five hours. An additional 150 ml of tetrahydrofuran was added, and to the stirred warm mixture there was added dropwise a solution of 28.9 g (0.25 mole) of sulfamoyl chloride in 150 ml of tetrahydrofuran over a two hour period. The reaction mixture was stirred at reflux for five hours, then cooled and treaated dropwise with 125 ml of water. The mixture was acidified with 2N hydrochloric acid, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give a yellow solid which was recrystallized from an ethyl acetate--hexane mixture to give 22.0 g of 1,7-heptanediol disulfamate as colorless granules, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([O:10][CH2:11][CH3:12])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Br)cnc1N
Yield: 87.4 %

Procedure:
A solution of 2-amino-3,5-dibromopyrazine (obtained as described in Gazz. Chim. Ital., 1960, 90, 1807) (1.26 g) and sodium ethoxide (0.4 g) in ethanol (50 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was partitioned between water (20 ml) and ethyl acetate (50 ml). The organic layer was separated and dried (MgSO4). Volatile material was removed by evaporation to give 2-amino-5-bromo-3-ethoxypyrazine (0.95 g); 1H NMR (d6 -DMSO): 1.4 (t, 3H), 4.3 (q, 2H), 6.4 (br s, 2H), 7.6 (s, 2H); mass spectrum (+ve CI): 218 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C=CC=CC=1>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 90 °C
Yield: 96.6 %

Procedure:
A flask similar to that used in Example A was charged with 156.22 g of styrene, 147.09 g of maleic anhydride, 3.0 g of azobisisobutyronitrile and 2,400 ml of toluene. The mixture was heated at 90° C. for 1.5 hours while agitated under a nitrogen atmosphere so as to carry out the required reaction. After the reaction, the reaction mixture was condensed and petroleum ether about 10 times as much as the condensed mixture by volume was added to the condensed reaction mixture so as to precipitate the resultant cooligomer. The cooligomer thus obtained was washed with 500 g of petroleum ether three times, thereby obtaining 290 g of styrene-maleic anhydride cooligomer (F) having a number average molecular weight of 7,000.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][N:20]=4)=[CH:31][N:30]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(C(F)F)c2)cc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (70 mg, 0.27 mmol), 5-(pyrazin-2-yl)pyridin-2-amine (55 mg, 0.32 mmol), N,N-diisopropylethylamine (139 μL, 0.80 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (152 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 203. MS m/z 418.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.99(d, 1H), 8.90(dd, 1H), 8.70(d, 1H), 8.63(dd, 1H), 8.53(d, 1H), 8.40-8.33(m, 2H), 8.30(s, 1H), 7.84(s, 1H), 7.70-7.68(m, 2H), 7.62-7.60(m, 1H), 7.50-7.49(m, 2H), 6.70(t, 1H), 3.87(s, 2H).