Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH2:33][NH:34][S:35]([C:38]2[S:39][C:40](Br)=[CH:41][CH:42]=2)(=[O:37])=[O:36])[CH:30]=[C:29]([CH3:44])[N:28]=1>>[CH3:26][C:27]1[CH:32]=[C:31]([CH2:33][NH:34][S:35]([C:38]2[S:39][C:40]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:41][CH:42]=2)(=[O:36])=[O:37])[CH:30]=[C:29]([CH3:44])[N:28]=1
Reactant: Cc1cc(CNS(=O)(=O)c2ccc(Br)s2)cc(C)n1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(CNS(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)cc(C)n1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2,6-dimethyl-pyridin-4-ylmethyl)-amide (example B.58) (181 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (120 mg, 38%). MS (ISN) 634.0 [(M−H)−]; mp 200° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Se](=O)=[O:14]>O1CCOCC1>[O:12]=[C:8]1[NH:9][C:10]2[N:11]=[C:2]([CH:1]=[O:14])[CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7]1
Reactant: Cc1ccc2c(n1)NC(=O)CC2
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2ccc(=O)[nH]c2n1
Reaction time: 240 h
Yield: 49.7 %

Procedure:
A solution of 0.90 g of 7-methyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one in 150 mL of dioxane was heated under reflux while dividedly adding 25.7 g of selenium dioxide, and the mixture was stirred for 10 days. The insoluble substance was filtered off with celite, and the solvent was distilled off under reduced pressure. To the resultant residue, 2-propanol was added, and the solid was filtered off. The solid thus obtained was purified by silica gel column chromatography using an eluent of chloroform:methanol=20:1, and ethyl acetate was added thereto, and the solid was filtered off to obtain 0.48 g of 7-oxo-7,8-dihydro-1,8-naphthyridine-2-carbaldehyde as a light orange solid.
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:28])[C:11]([CH2:13][NH:14][CH:15]([C:19]2[C:20]([C:25]([OH:27])=[O:26])=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]([CH3:18])[CH3:17])=[O:12])=[CH:6][CH:5]=1>S(=O)(=O)(O)O.O>[CH3:1][O:26][C:25]([C:20]1[C:19]([CH:15]([NH:14][CH2:13][C:11](=[O:12])[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH3:28])[CH:16]([CH3:18])[CH3:17])=[CH:24][N:23]=[CH:22][N:21]=1)=[O:27]
Reactant: CC(C(=O)CNC(c1cncnc1C(=O)O)C(C)C)c1ccc(Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ncncc1C(NCC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Yield: 28 %

Procedure:
A few drops of concentrated sulfuric acid were added to a methanol solution of 2.00 g (5.32 mmol) of 5-(1-{[2-(4-chlorophenyl)-propionyl]methylamino}-2-methylpropyl)-pyrimidine-4-carboxylic acid, followed by heating and refluxing for 5 hours. After completion of the reaction, water was added, followed by extraction with ethyl acetate, and the extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.59 g (yield: 28%) of 5-(1-{[2-(4-chlorophenyl)-propionyl]methylamino}-2-methylpropyl)-pyrimidine-4-carboxylic acid methyl ester (diastereomer A-isomer) as colorless oily product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH:10]=2)[CH:2]=1.N[C@H](C(O)=O)CCSC.Cl.C[O:36][C:37](=[O:59])[C@H:38]([CH2:55][CH2:56][S:57][CH3:58])[NH:39][C:40](=[O:54])C1C=CC(N)=CC=1C1C=CC=CC=1.N>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:40]([NH:39][C@H:38]([C:37]([OH:59])=[O:36])[CH2:55][CH2:56][S:57][CH3:58])=[O:54])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH:10]=2)[CH:2]=1
Reactant: Cc1ccccc1-c1cc(CSc2cccnc2)ccc1C(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: CSCC[C@H](N)C(=O)O
Agent: Cl
Agent: N
Product: CSCC[C@H](NC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1C)C(=O)O

Procedure:
The desired compound was prepared by coupling of 4-(3-pyridylthiomethyl)-2-(2-methylphenyl)benzoic acid with methionine phenylsulfonimide hydrochloride using the procedure used in step C of the preparation of compound 8. 1H NMR (300 MHz, CDCl3) δ 8.50 (m, 2H), 8.02 (m, 2H), 7.93 (t, 1H), 7.62 (m, 2H), 7.51 (m, 2H), 7.17-7.42 (m, 5H), 7.09 (m, 2H), 5.71 (d, 1H), 4.40 (m, 1H), 4.13 (s, 2H), 1.86-2.13 (m, 8H), 1.71 (m, 1H), 1.25 (m, 1H). MS (CI, NH3) m/e 606, 225. Anal calcd for C31H31N3O4S3 1.53 TFA: C, 52.43; H, 4.20; N, 5.39. Found: C, 52.42; H, 4.14; N, 5.43.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4](OC)=[O:5].C[Si](C)(C)[O-].[K+].C(N(CC)C(C)C)(C)C.Cl.Cl.[O:27]1[C:32]2=[CH:33][CH:34]=[CH:35][C:31]2=[CH:30][C:29]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][N:37]2[CH2:42][CH2:43][C@H:44]2[CH2:49][CH2:48][C@H:47]([NH2:50])[CH2:46][CH2:45]2)=[CH:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>O1CCOCC1>[O:27]1[C:32]2=[CH:33][CH:34]=[CH:35][C:31]2=[CH:30][C:29]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][N:37]2[CH2:42][CH2:43][C@H:44]2[CH2:45][CH2:46][C@H:47]([NH:50][C:4](=[O:5])[CH2:3][C@H:2]([OH:1])[CH2:8][CH3:9])[CH2:48][CH2:49]2)=[CH:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC[C@@H](O)CC(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC[C@@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.6 mg, 48.2 μl) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (64.2 mg, 0 5 mmol) and the mixture was allowed to stir for additional 18 h. Afterwards N,N-diisopropylethylamine (178 mg, 1.38 mmol), trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and TBTU (121 mg, 0.376 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (130 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) to yield the title compound as white solid (95 mg, 89%), MS (ISP) m/z=427.3 [(M+H)+], mp 142° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C(=O)C>[OH:19][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(CC(O)(c1ccccc1)c1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
To a stirred solution of 4-acetylpyridine (1.25 g) in N,N-dimethylacetamide (10 ml) was added NaH (0.413 g, as a 55% suspension in mineral oil) at 0° C. After stirring for 30 min, benzophenone (1.882 g) was added. After 30 min, the cooling bath was removed. The mixture was stirred overnight at room temperature. The mixture was cooled to 0° C. NaH (0.413 g, as a 55% suspension in mineral oil) was added and the mixture was stirred for 3 h. Water and ethyl acetate were added. The pH was adjusted to 8 using 1 M aqueous HCl. The mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (119 mg) as a colorless solid, MS (ESI+): m/z=304.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>ClCCl>[CH3:28][N:29]([CH:31]=[N:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1)[CH3:30]
Reactant: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.25 g) from Example 45 and dimethylformamide dimethylacetal (20 ml) was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1,40 g), m.p. 232-234° C.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[C:21]([F:30])[CH:20]=1.[NH4+].[Cl-]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:12]([O:11][C:1](=[O:10])[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[C:21]([F:30])[CH:20]=1)[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: Fc1cc(Br)ccc1C1OCCO1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(C2OCCO2)c(F)c1
Reaction time: 0.17 h

Procedure:
Di-tert-butyl malonate (1.95 g, 9.02 mmol) was dissolved in THF (8 mL) and sodium hydride (60% dispersion in mineral oil, 0.36 g, 9.00 mmol) was added. The mixture was stirred for 10 minutes before adding Pd(PtBu3)2 (0.17 g, 0.333 mmol) and a solution of 2-(4-bromo-2-fluorophenyl)-1,3-dioxolane (2.03 g, 8.22 mmol) in THF (16 mL). The resulting mixture was heated to reflux under N2 for 18 hours. Room temperature was attained, saturated NH4Cl (150 mL) was added and the products extracted into EtOAc (125 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave the desired product (pale yellow oil). 1H NMR (CDCl3) δ 7.50 (t, J=8.1 Hz, 1H), 7.16 (m, 2H), 6.07 (s, 1H), 4.40 (s, 1H), 4.13 (m, 2H), 4.03 (m, 2H), 1.45 (s, 18H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
100 mg (0.25 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 46.9 mg (0.28 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 69.5 mg (52% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CI.[C:29](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH3:29])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.03 g), methyl iodide (0.24 mL), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (1.06 g, yield 99%) as colorless crystals. melting point 143-145° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([CH2:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([OH:42])=[O:41]>>[C:40]([CH2:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:49])=[CH:46][CH:45]=1)([OH:42])=[O:41]
Reactant: O=C(O)Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(CC(=O)O)cc3)CN2C1=O
Yield: 7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-caboxymethylbenzoyl chloride (70 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 9.0 mg (7.0%) of 18-(4-carboxymethylbenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 729 (M−H)−, HRMS: calcd. 731.2962 and found 731.2957 (M+H)+, mp 154-156° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH2:15])[C:13](=[O:16])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11].C(Cl)Cl.[C:20]([NH:39][C:40]1[S:41][CH:42]=[C:43]([C:45](=[N:49][O:50][CH3:51])[C:46](O)=[O:47])[N:44]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.C(N(CC)CC)C.CC(C)=O>[CH3:1][S:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:46](=[O:47])[C:45]([C:43]3[N:44]=[C:40]([NH:39][C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:41][CH:42]=3)=[N:49][O:50][CH3:51])[C:13](=[O:16])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C

Procedure:
A mixture of 2.6 g of 3-methylthiomethyl-7-amino-ceph-3-eme-4-carboxylic acid, 26 ml of methylene chloride and 3 ml of triethylamine was stirred at 20° C. under an inert atmosphere and after cooling the mixture to -20° C., an acetone suspension of the mixed anhydride of Example 3 prepared from 6 g of the triethylamine salt of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid was added thereto. The mixture was stirred for 2 hours at 0° C. and was then acidified with 1 ml of acetic acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in 50 ml of methylene chloride. The organic solution was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken up in 50 ml of ether and the mixture was vacuum filtered to obtain 8.06 g of syn isomer of 3-methylthiomethyl-7-[2-(2-tritylamino- 4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:44](OC(=O)C)([F:46])[F:45]>[Cl-].[NH4+]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:10]([O:17][CH:44]([F:46])[F:45])=[N:11]2
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c3c(OCC(=O)OC)ccc(F)c3[nH]c2=O)cc1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cc2c(OC(F)F)nc3c(F)ccc(OCC(=O)OC)c3c2C)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of [3-(4-ethanesulfonylbenzyl)-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.33 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.16 g) and acetic acid chlorodifluoromethyl ester (1.2 mL) was stirred at 70° C. for 3 days. The mixture was diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave title as a white solid, 0.10 g.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][N:22]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:23]=[N:22][C:21]([O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)=[CH:26][CH:25]=2)[C:11]=1[CH3:12]
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(OCC3CC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.0 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.666 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.84 g, 6.1 mmol) in toluene (4.0 mL) at 100° C. for 18.3 h to give 4-chloro-2-(6-(cyclopropylmethoxy)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a light yellow solid. Mass Spectrum (ESI) m/e=361.1 (M+1).
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:20]([OH:22])=O)[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[C@@H:41]([CH3:43])[NH2:42])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl.O>[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:20]([NH:42][C@@H:41]([C:40]([NH:39][C:36]1[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=1)=[O:44])[CH3:43])=[O:22])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])([CH3:9])[CH3:10]
Reactant: C[C@@H](N)C(=O)Nc1ccc(C#N)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)C)C(=O)N[C@H](C)C(=O)Nc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
0.26 g of N-methylpiperidine was added to a solution containing 0.57 g of N-isopropoxycarbonyl-L-isoleucine dissolved in 60 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.36 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.5 g of N1 -(4-cyanophenyl)-D-alaninamide was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of white powder (yield: 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:34])=[C:23]([CH:25]=[N:26][C:27]([O:29][Si](C)(C)C)=[CH2:28])[CH:24]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:28][C:27](=[O:29])[NH:26][CH:25]3[C:23]3[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(CC(C)(C)C)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-Chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.2 g, 0.80 mmol) prepared in example 1a was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a to give racemic (2′R,3R,4′S)-6-chloro-4′-(2,2-dimethylpropyl)-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an white solid (7 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][C@@H:9]2[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[SH:22]>>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[S:22][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C@H:9]([OH:13])[C:10]([NH2:12])=[O:11]
Reactant: Cc1ccc(N)c(S)c1
Reactant: Cc1ccc([C@H]2O[C@@H]2C(N)=O)cc1
Product: Cc1ccc([C@@H](Sc2cc(C)ccc2N)[C@H](O)C(N)=O)cc1

Procedure:
(2S,3R)-3-(4-Methylphenyl)-2,3-epoxypropionamide and 2-amino-5-methylthiophenol are treated in the same manner as in Reference Example 1-(2) to give (2R,3R)-3-(2-amino-5-methylphenylthio)-2-hydroxy-3-(4-methylphenyl)propionamide.
Reaction SMILES: [CH:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:20](=[O:21])[C@@H:9]2[N:8]([C@@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](C2CCCCC2)N1
Product: O=C1[C@H]2Cc3c([nH]c4ccccc34)[C@H](C3CCCCC3)N2C(=O)N1Cc1ccccc1

Procedure:
The same method as employed in the preparation of Example 1 but starting from cis methyl 1,2,3,4-tetrahydro-1-cyclohexyl-9H-pyrido[3,4-b]indole-3-carboxylate (see J. Cook et al., Heterocycles, 4(7), 1249-1255 (1976)) and benzyl isocyanate gave after recrystallization from methanol, the title compound as white crystals m.p.: 170-173° C.