Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH:44][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 624.3 [(M−H)−]; mp 231° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH:15]([CH3:16])[CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: CC(C)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.6 mmol), 4-(4-isopropyl-piperazin-1-yl)-benzoic acid hydrochloride (0.6 mmol), HOBT (0.6 mmol), WSCD (0.6 mmol) and triethylamine (0.6 mmol) are dissolved in DMF (2 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in ethyl acetate/diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 218-220° C., Rf=0.28 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31].[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:43][C:44]([NH:10][C@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[NH:15][C:14]1=[O:31])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)[C@@H](N)CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.08 g (16.1 mmol) of diisopropylethylamine in 25 ml of absolute DMF are added to a solution of 3.14 g (8.48 mmol) of (34.5) and 2.11 g (8.48 mmol) of N-benzyloxycarbonyloxysuccinimide in 80 ml of absolute DMF and the mixture is left to stir at room temperature for 3 h. The solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. (34.6) is obtained after concentrating the product fractions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][C:36]1[CH:37]=[N:38][C:39]2[CH2:40][CH2:41][N:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:43][C:44]=2[CH:45]=1>CN(C)C=O.ClCCl>[CH2:46]([N:42]1[CH2:41][CH2:40][C:39]2[N:38]=[CH:37][C:36]([NH:35][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=3)=[CH:45][C:44]=2[CH2:43]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: Nc1cnc2c(c1)CN(Cc1ccccc1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CN(Cc2ccccc2)CC3)cc1Br
Temperature: 2.5 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
3-Bromo-4-methoxybenzoic acid (270 mg; 1.17 mmol) was dissolved in N,N-dimethylformamide (5 ml), the solution was cooled to 0-5° C. and treated with 1-hydroxybenzotriazole(158 mg; 1.17 mmol) then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg; 1.17 mmol) and the mixture stirred at 0-5° C. for 0.5 h and treated with a solution of 3-amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine (255 mg; 1.06 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 72 h then diluted with dichloromethane (100 ml). The resulting mixture was washed with water (5×25 ml), saturated brine, dried (anhydrous magnesium sulfate) and evaporated to dryness in vacuo to yield a mobile, brown oil, which on trituration under 60-80° C. petroleum ether gave a biege powder, which was collected by filtration, washed with 60-80° C. petroleum ether and dried in air. Recrystallisation from ethyl acetate 60-80° C. petroleum ether gave the title compound as a beige powder (236 mg; 49%), m.p. 214-215° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH2:41][CH3:42])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:41]([O:40][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:3]=2)=[C:37]2[C:33]=1[CH2:34][N:35]([CH3:39])[C:36]2=[O:38])[CH3:42]
Reactant: CCOc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOc1ccc(Nc2nc(Nc3ccc(CP(=O)(OCC)OCC)cc3)ncc2C(F)(F)F)c2c1CN(C)C2=O

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-4-ethoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 206A). MS (ES+): m/z 594.25 (100) [MH+]; HPLC: tR=1.14 min (UPLC, purity).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Cl.CN.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([O-:10])=[O:9].Cl>CO.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH2:14][NH:2][CH3:1])[CH:16]=[CH:17][CH:18]=1)([O-:10])=[O:9]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a mixture of sodium cyanoborohydride (2.52 g), triethylamine (18.7 ml), methylamine hydrochloride (5.42 g) and methanol (660 ml), m-nitrobenzaldehyde (10.10 g) was added dropwise over 20 minutes at room temperature and the resulting mixture was stirred at room temperature for 20 h. The pH of the reaction mixture was adjusted to 2 by addition of 10% HCl and the methanol was distilled off under reduced pressure. The residue was washed with chloroform and a 10% aqueous potassium hydroxide solution was added to the aqueous layer for pH adjustment to 12, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=95:5) to give 3.0 g of the titled compound (yield, 27%).
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2)(C)(C)C.[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[NH2:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@](NC(=O)c3cnccn3)(CC1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@]12CCC[C@](NC(=O)c3cnccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {(1R,5S)-5-[(pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester (intermediate 15, 0.9 g, 2.6 mmol) in methylene chloride (5.0 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (6.5 mL). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to afford 0.7 g of pyrazine-2-carboxylic acid ((1S,5R)-5-amino-bicyclo[3.2.1]oct-1-yl)-amide HCl salt, which was used in the next step without further purification. ESI-MS m/z: 247 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](N2CCNCC2)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][CH:11]=[C:10]5[C:25](=[O:26])[N:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[N:8]=[C:9]5[C:18]=4[N:17]=3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=c1c2c[nH]c3ccc(N4CCN(c5ccc(F)cc5)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 1-(4-fluorophenyl)-piperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.22 (4H, brm), 3.83 (4H, brm), 7.07 (5H, m), 7.32 (1H, d, J=9.34 Hz), 7.43 (2H, dd, J=8.24, 7.69 Hz), 7.85 (1H, d, J=9.34 Hz), 8.19 (2H, dd, J=8.24, 0.82 Hz), 8.57 (1H, s). m/z 441.5 (MH+).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(SCC(C)C(O)=O)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27]([N:3]1[C@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1Cc2ccccc2CN1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Agent: CC(CSC(=O)c1ccccc1)C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1Cc2ccccc2CN1C(=O)C(C)CSC(=O)c1ccccc1
Yield: 80.5 %

Procedure:
5.69 g of methyl (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride are suspended in 50 ml of chloroform, and 5.6 g of triethylamine are added thereto under ice-cooling and stirring. 3-benzoylthio-2-methylpropionyl chloride (which is prepared by heating a mixture of 5.6 g of 3-benzoylthio-2-methyl-propionic acid and 6 ml of thionyl chloride at 60° C. for 2 hours, followed by distillation thereof to remove the excess of thionyl chloride) is dissolved in 10 ml of tetrahydrofuran, and said tetrahydrofuran solution is added dropwise to the suspension obtained above. After the mixture is stirred at room temperature overnight, the chloroform layer is collected therefrom and washed with water, an aqueous sodium bicarbonate solution, diluted hydrochloric acid and water, successively. The chloroform solution is dried and then distilled to remove solvent. The residue thus obtained is purified by silica gel column chromatography (Solvent, toluene-ethyl acetate (4:1)). 8.0 g of methyl (3S)-2-(3-benzoylthio-2-methylpropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate are obtained as colorless oil. Yield: 80.5 %
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)cc2)CC1
Yield: 48.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-chlorophenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 1.0 g of 4-amino-5-chloro-N-((1-(6-(4-chlorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[S:3][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CO[C@@H]1CN(C(N)=S)CC[C@@H]1NC(=O)OCc1ccccc1
Product: CCOC(=O)Cc1csc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)n1
Yield: 96.4 %

Procedure:
The same operation as in Example (22b) was performed using benzyl cis(±)-(1-carbamothioyl-3-methoxypiperidin-4-yl)-carbamate obtained in Example (64b) (97 mg, 0.30 mmol) and ethyl 4-chloro-acetoacetate (60 μL, 0.44 mmol), to obtain 125.4 mg of the title compound as a colorless oily substance (96%).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].C[O:9][C:10](=O)[C:11](Cl)=[CH2:12].Cl>CO>[OH:9][C:10]1[CH:11]=[CH:12][S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: C=C(Cl)C(=O)OC
Reactant: COC(=O)CS
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To dry methanol (81 mL), under nitrogen, was added sodium metal (3.68 g, 304 mmol). After H2 evolution ceased, the solution was cooled to 0° C. and methyl thioglycolate (10 g, 179 mmol) was added dropwise. A solution of methyl-2-chloroacrylate (10.88 g, 179 mmol) in methanol (21 mL) was then added slowly, resulting in the formation of yellow precipitate. The solution was allowed to warm to ambient temperature and stirred for 2 h. The solvent was removed in vacuo to give a dark yellow solid that was acidified to pH 2 with 4 N HCl. The resulting aqueous solution was extracted with dichloromethane (3×150 mL) and the combined organic solutions were washed with water (3×150 mL), dried over MgSO4, filtered, and concentrated to give a dark oil. The oil was subjected to column chromatography on silica gel (20:1 hexanes/ethyl acetate) to give (12) (18.4 g) as a crystalline solid in 64% yield. TLC (20:1 hexanes/ethyl acetate) Rf 0.47; 1H NMR (CDCl3) δ 9.58 (s, 1H), 7.59 (d, J=5.7 Hz, 1H), 6.75 (d, J=4.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.7, 131.7, 119.4, 52.2; EI-MS m/e 158.0039 (M+ calculated 158.0038 for C6H6O3S).
Reaction SMILES: C[C:2](C)([C:6]([O-:8])=O)[C:3]([O-])=[O:4].Cl.[CH:11]1([C:14]([NH2:16])=[NH:15])[CH2:13][CH2:12]1.C[O-].[Na+]>>[CH:11]1([C:14]2[N:16]=[C:6]([OH:8])[CH:2]=[C:3]([OH:4])[N:15]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: N=C(N)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1cc(O)nc(C2CC2)n1

Procedure:
Under a nitrogen atmosphere 1.50 mL (13.06 mmol) dimethylmalonat, 1.60 g (13.27 mmol) cyclopropanecarboxamidine hydrochloride and 15.0 mL (80.80 mmol) sodium methoxide solution (30%) were refluxed for 1.25 h with stirring. The reaction mixture was slightly acidified and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[CH3:8][C:9]1([CH3:18])[NH:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:11](=[O:12])[CH2:10]1>C(O)C>[CH3:16][C:14]1([CH3:17])[CH2:13][C:11](=[O:12])[CH2:10][C:9]([CH3:18])([CH3:8])[N:15]1[CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=CN1C(C)(C)CC(=O)CC1(C)C
Reaction time: 4 h
Yield: 63 %

Procedure:
54 g (0.55 mol) of ethyl propiolate were added dropwise to 78 g (0.50 mol) of triacetoneamine in 200 ml of ethanol at reflux, and the mixture was then stirred at this temperature for a further 4 hours. After cooling, the precipitated product was filtered off, thoroughly washed with petroleum ether and subsequently dried at 60° C. and under 0.1 mbar. 80 g (corresponding to a yield of 63%) of ethyl β-(2,2,6,6-tetramethyl-4-oxo-1-piperidinyl)acrylate were obtained in the form of a colorless solid of melting point 145° C.
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=1)(C)C>>[CH3:29][CH:28]([CH3:30])[CH2:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]#[CH:17])=[CH:24][CH:23]=1
Reactant: CC(C)CCCc1ccc(C#C[Si](C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Product: C#Cc1ccc(CCCC(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 19 ), but using instead trimethylsilyl [4-(4-methylpentyl)]phenylethyne (Compound 31), the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.94 (6H, d, J~6.6 Hz), 1.20-1.32 (2H, m), 1.56-1.62 (3H, m), 2.64 (2H, t, J~7.8 Hz), 3.08 (1H, s), 7.18 (2H, d, J~8.1 Hz), 7.47 (2H, d, J~8.1 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:12][C:13]([C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14])C>C1COCC1>[O:23]1[C:24]2[C:16]([C:13]([CH3:15])([CH3:14])[CH2:12][C:11]([C:25]([F:26])([F:27])[F:28])([OH:29])[CH2:10][OH:9])=[CH:17][CH:18]=[CH:19][C:20]=2[CH2:21][CH2:22]1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A suspension of LiAlH4 (4.52 g, 119 mmol) in 230 mL of THF was treated with a solution of 4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester (27.5 g, 79.4 mmol) in 40 mL of THF at 0° C. over 30 minutes. After stirring overnight, the reaction was cooled to 0° C., quenched with 3 mL of water, and treated with 3 mL of 4 M NaOH solution. After 10 minutes, the mixture was treated with additional 18 mL portion of water and the resulting mixture was warmed to room temperature for 4 hours. The mixture was filtered and the filter cake was washed with five 100 mL portions of diethyl ether. The filtrate was concentrated in vacuo to give 24.0 g of 4-(2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol as an oil (99%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:29])[C:13]([C:26]([OH:28])=[O:27])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:10][C:9]=1[F:30].C[C:32](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:33].C(O)=O>CN(C=O)C>[CH:32]([N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:29])[C:13]([C:26]([OH:28])=[O:27])=[CH:14][N:15]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:10][C:9]=1[F:30])=[O:33]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4)c(F)cc2c1=O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=CN1CC2CC1CN2c1cc2c(cc1F)c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
0.5 g (1.2 m Mol) 7-(2,5-diazabicyclo(2.2.1)hept-2-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was suspended in 20 ml DMF and treated with 3 ml of the mixed anhydride of acetic and formic acid. After 90 mins. stirring at room temperature the volatiles were removed under reduced pressure. The oily residue was triturated with ether, the residue filtered and recrystallized from a mixture of 20 ml DMF and 5 ml ligroin to give 0.24 g (45.3%) of product, mp 252° C.-258° C. dec.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][OH:36])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:38][C:39]([NH2:41])=[S:40].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CN(C)C(=O)C>[NH2:41][C:39]1[S:40][CH:2]=[C:3]([C:4](=[N:35][OH:36])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:38]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-2-hydroxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (48 g) in N,N-dimethylacetamide (200 ml) was added thiourea (7.0 g) at 5° C., and the mixture was stirred at ambient temperature for an hour. After the reaction mixture was poured into 3% aqueous sodium bicarbonate (2 liter), sodium chloride (150 g) was added thereto. The precipitates were collected by filtration and then dissolved in a mixture of acetone (200 ml) and ethyl acetate (500 ml). The separated organic layer was washed with an aqueous sodium chloride, followed by evaporation. The resultant precipitates were collected by filtration, washed with ethyl acetate and diethyl ether and dried in vacuo to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (16.9 g), mp 133°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
6-Chloro-2-(4-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione (2.72 g, 7.40 mM was stirred in methanol (200 mL), and methanesulfonic acid (50 mL) was added. The tan suspension was heated to reflux for 16 hours during which it turned yellow. This yellow suspension was cooled to room temperature and filtered (the filtrate was saved for use in Example 8). The collected solids were washed with methanol to give the title compound as a yellow powder (1.19 g, 44%), mp 371°-373° C.; MS(CI): 370 (M+H). Analysis for C18 H2ClN3O4 : Calculated: C, 58.50; H, 3.27; N, 11.36; Found: C, 58.30; H, 3.41; N, 10.92; NMR: 13.33 (br s, 1H, exchangeable), 12.47 (s, 1H, exchangeable), 8.30 (d, J=8.73 Hz, 1H), 8.23 (br s, 1H), 7.61 (m, 3H), 7.08 (d, J=8.90 Hz, 2H), 3.83 (s, 3H).