Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN(C)C1CCNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(N(C)C)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and N,N-dimethylpyrrolidin-3-amine. LCMS (M+H)+=544.2/546.3.
Reaction SMILES: C([O-])(=[O:3])C.[K+].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1([C:17]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([CH3:19])[CH3:18])[CH2:16][O:15]1.C1OCCOCCOCCOCCOCCOC1>O.CC(N(C)C)=O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]([OH:3])([C:17]([S:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)([CH3:19])[CH3:18])[CH2:16][OH:15]
Reactant: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
A solution of 1.12 g (11.4 mmol) of potassium acetate in 2 ml of water was added to a solution of 2.0 g (5.7 mmol) of (±)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane and 0.15 g (0.57 mmol) of 18-crown-6 in 12 ml of DMA, and the mixture was stirred at 110° C. for 30 hours. After being allowed to cool, 50 ml of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried, and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) as an eluent. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and diethyl ether to obtain 1.58 g (75%) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)- 3-methylbutane-1,2-diol as a colorless crystal.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 81.5 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.20 g, 0.92 mmol), phenylacetyl chloride (0.14 mL, 1.0 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-phenylacetamide (0.25 g). MS (ESI) m/z 334.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[C:20]([NH2:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[NH2:21][C:20]1[C:9]([C:4]2[C:3]([Cl:22])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([S:17][CH3:18])=[N:13][C:12]=2[N:19]=1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-(3-amino-2,6-dichloro-phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (600 mg, 1.7 mmol) in dichloromethane (60 ml) is added 3-trifluoromethyl-benzoyl chloride (1.76 g, 8.5 mmol) slowly at 0° C. on an ice bath. The reaction is then raised to room temperature and stirred at room temperature for 18 hours. The reaction mixture is washed with 10% NaHCO3 and brine. The organic phase is dried over MgSO4. The crude product is purified by flash silica gel column eluting with CH2Cl2/MeOH (7N NH3) (v/v: 98/2) to give the title compound as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:26][C:27]1[CH:28]=[C:29]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1ncc(Cl)cc1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Product: COc1ncc(Cl)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in hexanes) to yield the product (55 mg, 39%). ESI-MS m/z calc. 473.1. found 474.0 (M+1)+. Retention time 2.33 minutes.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH2:14]([NH:19][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)CN
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CC(C)(C)CN[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and neopentylamine. Colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:18]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:17][N:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:15][CH:14]2[OH:40])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].Cl[CH2:42][C:43]1[CH:44]=[CH:45][C:46]2[O:51][CH2:50][C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:47]=2[CH:58]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:18]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH2:17][N:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:15][CH:14]2[O:40][CH2:42][C:43]2[CH:44]=[CH:45][C:46]3[O:51][CH2:50][C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:47]=3[CH:58]=2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(C2C(O)CN(C(=O)OCc3ccccc3)CC2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C2C(OCc3ccc4c(c3)N(CCCOC)C(=O)CO4)CN(C(=O)OCc3ccccc3)CC2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 18 h

Procedure:
1.61 g of sodium hydride dispersion (60%) are added to a solution of 19.76 g of benzyl 4-(4-allyloxyphenyl)-3-hydroxy-5 -triisopropylsilanyloxypiperidine-1-carboxylate and 9.95 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benz[1,4]-oxazin-3-one in 285 ml of N,N-dimethylformamide while the reaction mixture is stirred at 10° C. for 1 hour and at room temperature for 18 hours. The mixture is poured into 1M aqueous sodium bicarbonate solution (700 ml) and extracted with tert-butyl methyl ether 2×800 ml). The organic phases are washed successively with water (2×500 ml) and brine (1×500 ml), dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO260 F). Rf (EtOAc/heptane 2:3)=0.30, Rt=7.15.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9])=O.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]1[N:10]([CH:11]2[CH2:13][CH2:12]2)[C:8](=[O:9])[NH:7][N:6]=1
Reactant: O=C(NNC(=O)c1ccccc1Cl)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]nc(-c2ccccc2Cl)n1C1CC1

Procedure:
7.00 g (27.6 mmol) of 2-(2-chlorobenzoyl)-N-cyclopropylhydrazinecarboxamide from Example 10A are heated under reflux for about 60 hrs in 30 ml 3 N aqueous sodium hydroxide (conversion testing by LC/MS analysis). After cooling, it is acidified with 1 N hydrochloric acid and the mixture extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and concentrated. 3.32 g (48% of theory) of the target compound are thus obtained.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH3:10])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH2:8][O:9][CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COCc1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-diiodo-2-methoxymethyl-1H-imidazole (3.000 g; 8.244 mmol) in anhydrous DMF (35 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (395 mg; 9.895 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (2.032 g; 9.068 mmol) in anhydrous DMF (30 ml) was added dropwise, over 15 min., with an addition funnel. After completion of the addition, the resulting dark-orange homogeneous mixture was further heated at 100° C. for 1 h45. The reaction mixture was cooled to rt, and water (175 ml) was added slowly. This mixture was extracted with ether (4×120 ml). The combined organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=50/1) to give the pure product [2-(4,5-diiodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butylester as a pale yellow solid which was further dried under HV (3.050 g; 73%). LC-MS: tR=0.87 min.; [M+H]+=508.16 g/mol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([C:33]3[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=3)=[O:32])[CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:36]1[CH:37]=[CH:38][C:33]([C:31]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[C:18]([CH3:17])=[CH:23][C:22]([CH3:24])=[CH:21][N:20]=3)[CH2:26][CH2:27]2)=[O:32])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 77.2 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (287 mg) described in Preparation Example 1 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (500 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, (S)-[4-(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethyl-pyridin-2-yl)piperazin-1-yl]methanone (490 mg) was obtained. The obtained (S)-[4-(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethyl-pyridin-2-yl)piperazin-1-yl]methanone (490 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (410 mg).
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[CH:6]/[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH:8]1([CH2:7]/[CH:6]=[C:5](\[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)/[CH2:4][OH:3])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)/C(=C/CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCCC2)CO)cc1
Yield: 79.1 %

Procedure:
Following the method of example 54e, using (E)-4-cyclohexyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid ethyl ester (956 mg, 2.73 mmol) and 3 h at ambient temperature after the addition of DIBAL in toluene (4.95 mL, 6.0 mmol) gives the title compound as an amorphous solid (666 mg). MS (m/e): 291 ([M−H2O]+H).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=2[NH:27][C:28](=[O:37])[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36].[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>ClCCl>[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][C:24](=[O:25])[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[NH:27][C:28](=[O:37])[C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36]
Reactant: O=C(O)Cc1c(Br)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: NCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1c(Br)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)NCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a mixture of dimethylformamide (17.4 mg) and dichloromethane was added oxalyl chloride (27.7 mg), and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added 3-bromo-4-carboxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (90 mg) at 0° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2-aminomethylpyridine (107 mg) at 0° C., and the mixture was stirred for 30 minutes at ambient temperature. The mixture was partitioned between dichloromethane and saturated ammonium chloride solution. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and recrystallized from ethanol to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-[(pyridin-2-ylmethyl)carbamoylmethyl]quinoline (58.0 mg).
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([OH:11])=[N:4][N:3]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[S:22][CH2:23][C:24]([NH:26][CH:27]1[C:42](=[O:43])[N:29]2[C:30]([C:39]([OH:41])=[O:40])=[C:31]([CH2:34]OC(=O)C)[CH2:32][S:33][C@H:28]12)=[O:25].[Na]>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[S:22][CH2:23][C:24]([NH:26][CH:27]1[C:42](=[O:43])[N:29]2[C:30]([C:39]([OH:41])=[O:40])=[C:31]([CH2:34][S:1][C:2]3[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([OH:11])=[N:4][N:3]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3cc(Cl)ccc3Cl)[C@H]2SC1
Reactant: CCn1c(S)nnc(O)c1=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCn1c(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)nnc(O)c1=O

Procedure:
To 12 ml. of water were added with stirring 571 mg. of 3-mercapto-4-ethyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine. The pH of the resulting mixture was 2.3 and was adjusted to 6.6 by addition of 2.9 ml. of 1 N sodium hydroxide. 7-(2,5-Dichlorophenylthio)acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, sodium salt (1.54 g., 3 mmol.) was added, and the resulting mixture was treated in accordance with the procedure described in Example 8 to obtain 7-(2,5-dichlorophenylthio)acetamido-3-(4-ethyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-ylthio)methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:20]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 52 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]-benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 52% of theory.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[N:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ncc(I)cn1
Product: Nc1ncc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyrimidine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (270 mg, 67%). MS (ISP) 380.3 [(M+H)+]; mp 244–246° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[C:5]([CH3:7])[N:6]=1.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][CH:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(Cc2ccc(N)cc2)s1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: Cc1nc(C)c(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
3 g of 2,4-dimethyl-5-(4-aminobenzyl)thiazole are dissolved in 75 ml of acetonitrile, and 2 g of phthalic anhydride are added in portions. The medium is stirred for 6 hours at room temperature and the precipitate is then filtered off and washed with ethyl acetate to give 3.3 g of 2-[4-((2,4-dimethylthiazol-5-yl)methyl)phenylaminocarbonyl]benzoic acid in the form of crystals melting at 182° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[C:5]([C:18]([O-])=O)[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[C:12]1([CH:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:21])=[C:5]2[CH3:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)[O-])C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C)C1c1ccccc1
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 35.9 %

Procedure:
24.1 g (80 millimols) of methyl 1,4-dihydro-2,6-dimethyl-4-phenyl-pyridine-3,5-dicarboxylate were introduced in portions, at 60° C. and while stirring, into a solution of 12.2 g (320 millimols) of LiAlH4 in 400 ml of absolute tetrahydrofuran (N2 atmosphere), and the mixture was stirred for a further 6 to 7 hours at 60° C. After the mixture had cooled, 19.7 ml of ethyl acetate, 15.9 ml of water, 19.6 ml of 10N NaOH and 15.9 ml of water were successively added dropwise. The mixture was then filtered under suction, the residue was rinsed thoroughly with ether, and the filtrate was evaporated down in vacuo. The syrupy residue was dissolved in 50 ml of ether, and the solution was left in a cold place to crystallize giving 7.4 g of the above compound (36% of theory). After recrystallization from acetonitrile, colorless prisms; melting point 120° C., were obtained.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[CH3:12][NH:14][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCCCCC1
Temperature: 25 °C

Procedure:
In 1,2-dichloroethane (50 ml) were suspended cycloheptanone (2 g), methylamine hydrochloride (3 g) and triethylamine (6.2 ml), and to the suspension was added sodium triacetoxy boron hydride (5.3 g) under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature over night. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N-methylcycloheptylamine (1.8 g) as colorless oil.