Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[C:12]([NH:14]C(=O)C(F)(F)F)[CH:11]=[CH:10][C:9]=2[S:21](Cl)(=[O:23])=[O:22])=[N:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>C(#N)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([S:21]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)(=[O:22])=[O:23])=[C:8]([CH2:7][C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:13]=1
Reactant: Cc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a stirred solution of 2-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (300 mg, 0.78 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (194 mg, 1.3 mmol) in 5 mL of ACN was added pyridine (1.26 mL, 9.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (318 mg, yield 82%). MS calcd for (C19H16BN4O6F3S): 496.2, MS found (ESI negative): (M−H)−=495.1. 1H NMR (DMSO-d6) δ (ppm): 11.5 (s, 1H), 10.5 (s, 1H), 9.20 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (s, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.86 (s, 2H), 4.59 (s, 2H), 2.40 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Cl:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CC#N>[C:33]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Cl:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1)(=[O:35])[CH3:34]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(C)=O)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (0.100 g, 0.221 mmol) was suspended in acetic anhydride (5 mL, 53.0 mmol) and stirred with gradual heating to 110° C. After 5 h, the mixture was cooled to RT and diluted with MeCN (15 mL). The solids were collected by filtration, rinsed with MeCN and dried to afford 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (107 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.13 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.57 (d, J=4.0 Hz, 1H) 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 494.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:28]>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin4-ol (which was obtained in Intermediate 7) and 4-cyanobenzyl bromide according to Method A; LC retention time 3.01 min; MS: m/z (ESI) 501 (M+H).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[CH2:17]([O:25][C:26](=[O:30])[CH2:27][C:28]#[N:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OC(=O)C)(=O)C>>[CH2:17]([O:25][C:26]([C:27]([C:28]#[N:29])=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1)=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCOC(=O)CC#N
Reactant: O=C(O)c1ccc(-n2ccc(=O)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCOC(=O)C(C#N)=C1C=CN(c2ccc(C(=O)O)cc2)C=C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 4-(4-oxo-4H-pyridin-1-yl)benzoic acid (814 mg, 3.5 mmol), octylcyanoacetate (3.44 g, 17.5 mmol) and acetic anhydride (45 ml) was heated at 130° C. for 3 hours. More octylcyanoacetate (3.44 g, 17.5 mmol) was added and the mixture heated for 3 hours more. The mixture was then filtered hot, and the filtrate was diluted with acetic acid (15 ml) and water (15 ml). Upon standing overnight in the refrigerator the product crystallized out and was isolated by suction filtration as a yellow solid (1.16 g, 85%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:8][CH:9]([C:31](=[O:34])[NH:32][OH:33])[CH:10]([OH:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([NH:7][CH2:8][CH:9]([CH:10]([OH:30])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)[C:31]([NH:32][OH:33])=[O:34])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(COc2ccc(C(O)C(CN(Cc3ccccc3)C(=O)OC(C)(C)C)C(=O)NO)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(O)C(CNCc3ccccc3)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 2 h
Yield: 154.8 %

Procedure:
Benzyl-{3-hydroxy-2-hydroxycarbamoyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propyl}-carbamic acid tert-butyl ester (0.07 g, 0.10 mmol) from Example 21 was taken up in methylene chloride (3 mL) and TFA (2 mL) under nitrogen atmosphere at room temperature. The reaction was complete after 2 h, was concentrated, taken up in water (5 mL), and freeze-dried to give the title compound (0.073 g, 100%) as a white solid. MS found: (M+H)+=472.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[CH:1]1[C:6]2[C:7]3[N:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH:19]=3)[CH2:9][C:10](=[S:21])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: S=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Temperature: 100 °C
Yield: 767.4 %

Procedure:
A mixture of 15 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 3.09 g phosphorus pentasulfide and 11.46 g sodium bicarbonate in 300 ml diglyme was heated at 100° C. for two hours. The resulting mixture was cooled and poured into 3 L water to precipitate a solid. The solid was collected, triturated successively with cyclohexane, ether and hexane and dried (P2O5) to give 14.1 g solid. Recrystallization of 4.0 g from n-propanol gave 3.0 g solid, m.p. 259°-261° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.C(Cl)Cl>C(O)(=O)C.C(O)=O>[Br:20][C:6]1[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[N:8][O:9][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)Nc1noc(C(C)(C)C)c1Br
Temperature: 70 °C
Yield: 99.1 %

Procedure:
To a solution of methyl 5-t-butyl-3-isoxazolylcarbamate (2.00 g) and anhydrous sodium acetate (1.1 mol equivalent) in glacial acetic acid (5 ml), bromine (1.0 mol equivalent) is added. The resultant mixture is heated at 50° C for 53 hours and mixed with glacial acetic acid (5 ml), anhydrous sodium acetate (0.91 g) and bromine (0.81 g). The mixture is heated at 70° C for 31 hours, mixed with several drops of formic acid, poured onto ice water (50 ml) and shaken with methylene chloride. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and water in order and evaporated under reduced pressure to remove the solvent, whereby methyl 4-bromo-5-t-butyl-3-isoxazolylcarbamate (2.77 g) is obtained as an oil. I.R.: 1774, 1203 cm-1 (CCl4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:19]([NH:20][C:21](=[O:42])[C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:24][C:23]=4[NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCCC1.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:19]([NH:20][C:21](=[O:42])[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][C:23]=3[NH:35][CH:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[N:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(C#Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(CCc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
10 mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N-(5-((3,5-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in solution in a mixture of 10 ml of tetrahydrofuran and 5 ml of methanol before placing the reaction medium under an atmosphere of hydrogen. The reaction mixture is stirred for 12 hours at room temperature and then filtered on Celite and concentrated. 62 mg (yield=60%) of N-(5-(3,5-difluorophenethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide are isolated in the form of a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH2:12]1.Cl>ClC=CCl>[C:5]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[S:13][CH2:12][CH:11]([CH3:10])[CH2:20]2)(=[O:8])[CH2:6][CH3:7]
Reactant: CC1CSc2ccccc2C1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CC(C)CS2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.13M of AlCl3, 0.12M of propionyl chloride in 150 ml of 1,2-dichloroethylene, 0.1M (16.4 gr.) de 3-methyl-thiochromane are dropwise added at a temperature of ±5° C. After agitating the mixture for 3 hours at room temperature, a mixture of ice and HCl is added and extraction is made with CHCl3. The organic phase is dried on MgSO4, filtered and evaporated. 17.3 gr. of 6-propionyl-3-methyl thiochromane are so obtained, the homogeneity of which is verified by TLC and the structure of which is verified by NMR spectrum.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[CH:6]1[C:11](O)=[CH:10]C=[C:8](C)[CH:7]=1.CI.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>[Pd](Cl)Cl.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(O)cc1
Reactant: COC(C)=O
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CI
Product: CC(=O)Oc1ccccc1

Procedure:
A 300-ml autoclave equipped with an agitator was charged with 59.2 g of methyl acetate, 104 g of p-cresol, 1.8 g of palladium chloride, 31.5 g of methyl iodide and 5.8 g of triphenylphosphine, and the reaction was carried out at 195° C. and a carbon monoxide pressure of 28 kg/cm2 gauge (total pressure of 38 kg/cm2 gauge). The yields of acetic acid and phenyl acetate were 95.8% and 95.6%, respectively. The reaction was repeated several times, and the resulting reaction product liquids were collected and used in Example 13.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5[nH]ccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-formylindole to the procedure of step 1, Example 66. MS (ESI) m/z 508.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NCCc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: N#Cc1c(NCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and phenylethylamine in ethanol. ES-MS rn/e (%): 306 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1)[CH2:5][C:4]([OH:36])=[O:3])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OCCc2ccccc2)c1)C(OCC)OCC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OCCc2ccccc2)c1
Yield: 51.4 %

Procedure:
Using the same procedure as in Example 1 (3), 4,4-diethoxy-2-ethoxycarbonyl-3-(4-methoxy-3-phenethyloxyphenyl)butyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonyl butyric acid ethyl ester, was used to obtain a light yellow solid of above-described compound (51.4%) via 4,4-diethoxy-3-(4-methoxy-3-phenethyloxyphenyl)butyric acid (yield 51.4%).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:40][S:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:31])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccs1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccs2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.CN(C)C1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:43](=[O:44])[CH2:42][C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)[C@H:5]2[S:4]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: -15 °C
Yield: 86.8 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylaniline (1.9 g) under cooling at -15° C. To a solution was dropwise added a solution of (2-thienyl)acetyl chloride (2.0 g) in dried dichloromethane (10 ml) under stirring and cooling at the same temperature, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, the residue was dissolved in ether, allowed to stand, after which the precipitated crystals were collected by filtration and dried to give crystals of 2,2,2-trichloroethyl 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate (3.2 g), mp 161° to 162° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-:3])=[O:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])([O-:3])=[O:2]
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CCN(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
To a solution of N-(2-nitrophenyl-N',N'-dimethylethylenediamine (1.20 g) in chloroform (25 ml) was added ethyl chloroformate (0.64 g) dropwise. The reaction mixture was stirred at room temperature for 5 hours, washed with 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution in turn and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=10:1) to give 1.10 g of N-(2-nitrophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: CS(O[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[C:9]([OH:11])(=[O:10])[CH:8]([C:7]1[CH:6]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccccc1OS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 24.5 g. of 2-methane-sulphonyloxyhydratropic acid in 200 ml. of methanol 28 ml. of triethylamine and 2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and acidified with a 20% aqueous hydrochloric acid solution. The separated hydratropic acid is extracted with chloroform. The chloroform solution is dried over sodium sulphate, evaporated and the residue is distilled off. 13.5 g. (90%) of hydratropic acid are obtained, boiling at 145° C. (13 mmHg.); nD25 =1.5219.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Yield: 94.4 %

Procedure:
To (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (1440 g, 4.26 mol) and triethylsilane (1.37 L, 8.6 mol) in trifluoroacetic acid (820 mL) was slowly added trifluoromethanesulfonic acid (1.9 mL). After refluxing for 6 hours, additional triethylsilane (400 mL, 2.47 mol) was added. After refluxing for another 8 hours, the mixture was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 L), washed with water (10 L), aqueous sodium carbonate (10 L), and brine (10 L), and concentrated to give crude product. The crude product was distilled to remove (Et3Si)2O under vacuum. The residue was recrystallized from absolute ethanol (5 L) and dried under vacuum to give compound 3 (1310 g, 94% yield, HPLC purity>99%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Cl.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]
Reactant: [O-][n+]1ccccc1S
Reactant: ClCc1c(Cl)ccc(Cl)c1Cl
Agent: [Na]
Product: [O-][n+]1ccccc1SCc1c(Cl)ccc(Cl)c1Cl

Procedure:
The compound 2-(2,3,6-trichlorophenylmethylthio)pyridine N-oxide is prepared from 2,3,6-trichlorobenzylchloride and 2-mercaptopyridine N-oxide sodium salt by the procedure employed in Example 1. Melting point 232° - 234° C. Yield quantitative. Structure confirmed by IR and NMR.
Reaction SMILES: [CH3:1][CH:2](OC(=O)C)[C:3]#[CH:4].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1.C(OCC)C.[Cu]Cl>[N:9]1([CH:2]([C:3]#[CH:4])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: C#CC(C)OC(C)=O
Agent: Cl[Cu]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(C)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution acetic acid 1-methyl-prop-2-ynyl ester (prepared by the method of Clarke and Pinder, J. Chem. Soc. 1958, 1967).(7 g) and pyrrolidine (10.4 ml) in anhydrous tetrahydrofuran (125 ml) was treated with copper (I) chloride (0.3 g) and the mixture was heated to reflux temperatures for 1.5 hours. After then allowing the mixture to stir at room temperature for approximately 15 hours, the mixture was diluted with diethyl ether, and extracted thrice with 2N aqueous hydrochloric acid. These pooled acidic extracts were basified by addition of solid sodium hydroxide, and the solution was then extracted three times with ethyl acetate. These pooled organic extracts were then washed with water, brine, and dried over anhydrous magnesium sulfate. After removing the solvent in vacuo the resulting residue was distilled to obtain the desired product as a colorless oil. b.p. 35° C. (1.1 mm Hg). MS(+ES), m/z: 124 (M+H)+.