Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[O:10][C:9]([C:11]3[NH:19][N:18]=[N:17][N:12]=3)=[CH:8][C:7](=[O:13])[C:6]=2[C:14]=1[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2oc(C#N)cc(=O)c2c(C)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2oc(-c3nnn[nH]3)cc(=O)c2c(C)c1Cl

Procedure:
A mixture of 23.4 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, 7.8 parts of sodium azide, 6.4 parts of ammonium chloride and 200 parts of N,N-dimethylformamide was stirred and heated on the steam bath for 18 hours. Most of the solvent was then removed by distillation under reduced pressure. A solution of the residue in 400 parts of water was acidified with 20% hydrochloric acid. The precipitated solid was filtered off, washed with water and crystallised from dioxan to give 15.5 parts of 5-(6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-yl) tetrazole as a colourless solid, melting point 246°-247°C (decomposition).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Yield: 90.8 %

Procedure:
A mixture of 0.975 g of 6,11-dihydro-5H-dibenz[b,e]azepine and 0.20 g of NaH (60% in oil) in 20 ml of tetrahydrofuran is stirred at room temperature for 0.5 hr. Then 1.1 g of mono-methyl terephthalyl chloride (prepared from mono-methyl terephthalate and thionyl chloride) is added and the mixture refluxed 18 hours. The mixture is cooled, poured into ice water and filtered. The solid is triturated with dichloromethane-hexane to give 1.0 g of crystals, m.p. 182°-185° C. The preceding compound, methyl 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoate (2.11 g), 20 ml of 2N NaOH and 20 ml of methanol is stirred overnight and then heated on a steam bath for 1 hr. The solvent is removed to give a solid. The solid is extracted with ether (discarded). The solid is dissolved in water and the solution acidified with citric acid to give a solid. The solid is filtered and washed with water to give 1.84 g of crystals, m.p. 220°-225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]=[CH2:35]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:35][CH:34]=[CH2:33])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (300 mg, 0.88 mmol), anhydrous Cs2CO3 (573 mg, 1.76 mmol), and KI (30 mg, 0.18 mmol) in DMF (8 mL) is added 3-bromo-propene (90 μL, 1.06 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-30% EtOAc in heptane) to give a pure product (4) as white solid (303 mg, 91%).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)=[O:7].Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>O.COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]=[O:7])=[CH:9][CH:10]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 34.7 %

Procedure:
A mixture of NaHCO3 (3.83 g, 45.6 mmol) and 4-formylphenylboronic acid (2.69 g, 18.0 mmol) in water (60 mL) was added to a solution of 2-bromothiazole (2.50 g, 15.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.43 mmol) in DME (60 mL). The reaction mixture was heated to reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Two consecutive recrystallizations from hexanes/ethyl acetate yielded 998 mg (35%) of the title compound. MS 190 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:57][C:58]1[CH:63]=[CH:62][C:61]([NH2:64])=[C:60]([NH2:65])[CH:59]=1>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:64][C:61]3[CH:62]=[CH:63][C:58]([F:57])=[CH:59][C:60]=3[NH2:65])=[O:26])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)ccc1NC(=O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid (363 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxyl-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (330 mg, 70% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.33 (m, 6H, 3×CH2), 1.52 (m, 2H, CH2), 1.58 (m, 2H, CH2), 2.29 (t, J=8.0 Hz, 2H, CH2CO), 3.24 (m, 2H, NCH2), 5.12 (s, 2H, benzene-NH2), 6.28 (t, J=8.0 Hz, 1H, Ar—H), 6.46 (d, J=8.0 Hz, 1H, Ar—H), 7.08 (s, 1H, ═CH—CO and Ar—H), 7.33 (m, 2H, Ar—H), 7.41 (m, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.52 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H), 9.02 (s, 1H, benzene-NH). LC-MS (m/z) 472 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][NH:7][C:6]=2[N:16]=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])=[CH:20][C:19]=1[O:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][NH:7][C:6]2[N:16]=[C:2]([NH:17][C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:23])=[CH:20][C:19]=3[O:34][CH3:35])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CNc2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)NCC(F)(F)C(=O)N2C
Yield: 33.5 %

Procedure:
A mixture of 0.08 g (0.32 mmole) of 2-chloro-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292), 0.093 g (0.35 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.092 g (0.48 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in pressure tube at 120 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 10:90-100:0) to gave 0.051 g of give 4-(7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-303) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:19][CH:18]=[CH2:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
N-tert-butoxycarbonyl L-serine (27.04 g, 0.1318 mol) was dissolved in DMF (220 mL). The solution was cooled to 0° C. (icebath) before sodium hydride (60% dispersion in mineral oil, 11.59 g, 0.2898 mol) was added slowly under stirring. After gas evolution had ceased allyl bromide (17.54 g, 0.1450 mol) was added dropwise and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated and the residue dissolved in H2O (500 mL). The solution was washed with Et2O (2×250 mL), cooled to 0° C. (icebath) and acidified to pH 2.5 by addition of 2M aqueous H2SO4. The resulting solution/suspension was extracted with EtOAc (5×250 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated overnight affording the title compound as a slightly yellow-orange viscous liquid (26.86 g, 83%) with spectral characteristics in accordance with published data;3,4 δH (200 MHz; d6-DMSO) 12.52 (1H, br s, COOH), 6.84 (1H, d, J 8, NH), 5.81 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.20 (1H, ddd, J 1, 3 and 17, CH═CHH), 5.09 (1H, ddd, J 1, 3 and 10, CH═CHH), 4.10 (1H, dt, J 5 and 8, CαH), 3.96-3.92 (2H, dt, J 1 and 5, CH2CH═CH2), 3.56 (2H, d, J 5, CH2), 1.34 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 171.9, 155.3, 134.8, 116.5, 78.1, 71.0, 69.1, 53.7, 28.1; m/z (ESI) 268.0 ([M+Na]+)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(c1ccc(Br)nc1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Nc2cc(Cl)ncn2)nc1)N1CCOCC1
Temperature: 150 °C
Reaction time: 13 h
Yield: 39.4 %

Procedure:
To a stirred solution of (6-bromopyridin-3-yl)(morpholino)methanone (0.75 g, 2.78 mmol) in toluene (5 mL) was added 6-chloropyrimidin-4-amine (0.43 g, 3.33 mmol), Pd2(dba)3 (100 mg, 0.3 mmol), Davephos (157 mg, 0.4 mmol) and NaOt-Bu (848 mg, 8 mmol). The mixture was stirred at 150° C. for 13 hrs under N2. The mixture was evaporated and the residue was taken up in ethyl acetate (50 mL) and H2O (20 mL). The organic phase was washed with H2O (2×20 mL) and then brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the final product (350 mg, 40%) was obtained as yellow solid. LC-MS: 320.1 [M+H]+, tR=1.306 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]3[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=3[CH3:20])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>O1CCCC1.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]3[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=3[CH3:20])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=S)c1cc(-c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c(C)s1
Agent: [Ti+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Yield: 72.2 %

Procedure:
Methyl 4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (800 mg, 2 mmol) was dissolved in 150 mL tetrahydrofuran and treated with 20% titanium chloride solution (Fisher Scientific, Pittsburgh, Pa., USA) for 1 h. The mixture was poured into 2 M sodium hydroxide solution (100 mL), extracted with dichloromethane (4×50 mL). The combined organic layers were washed with saturated brine solution and dried over anhydrous sodium sulfate. The solid was filtered off, and the solvent removed in vacuo. This material was purified by column chromatography on silica gel (30 g) eluting with dichloromethane:methanol 98/2 (v:v) to give methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (500 mg, 69%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.17 (s, 1H), 7.77 (s, 1H), 7.74 and 6.62 (AB quartet, 2H, J=8.6 Hz), 5.35 (s, 2H), 3.86 (s, 3H), 2.74 (s, 3H). ). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C16H14N2O2S3 363.0 (M+H), found 362.4.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 100.9 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene (58.2 mg, 0.0730 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a colorless oil (33.5 mg, 100%).
Reaction SMILES: C(=O)(O)[O-].[K+].[C:6]([S:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:38])[C:24]([C:28]3[N:29]=[C:30]([NH:33]C(=O)CCl)[S:31][CH:32]=3)=[N:25][O:26][CH3:27])[C:20](=[O:39])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[CH3:7].NC(N)=S.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O.C(O)C.C(O)=O>[C:6]([S:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:38])[C:24]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:25][O:26][CH3:27])[C:20](=[O:39])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[CH3:7]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: O=CO
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
1 g of potassium bicarbonate was added at 20° C. to a suspension of 5.48 g of the product of Step C in 10.6 ml of water and 912 mg of thiourea and after dissolution, the solution was stirred at 20° C. under nitrogen for 6 hours. The gummy precipitate started forming after 11/2 hours and then 30 ml of water and 3 ml of formic acid were added thereto. After cooling to 5° C., the mixture was vacuum filtered and the filter was washed with water containing 10% of formic acid. The residue was dissolved towards 5° C. in 30 ml of water containing triethylamine and then 3 ml of formic acid were added at 5° C. The mixture was vacuum filtered and the solid was empasted with water containing formic acid. The brown gum formed was removed and the combined aqueous phases were passed through carbon black to form a clear yellow solution. The solution was saturated with ammonium sulfate and was vacuum filtered. The precipitate was empasted with water and was vacuum filtered and washed with water to obtain precipitate A. The mother liquors were saturated with ammonium sulfate and the mixture was vacuum filtered. The solid was washed 3 times with water to obtain precipitate B. Precipitates A and B were combined and taken up in ethanol. The mixture was stirred for an hour at 20° C. and then stood at 0° C. for 16 hours. The mixture was vacuum filtered and the solid was washed with ethanol, with ether and dried under reduced pressure to obtained the syn isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl{amino]-ceph-3-eme-4-carboxylic acid identical to the products of Examples 6 and 18.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>CCO>[Cl:15][C:16]1[N:21]=[C:20]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 5-methyl-1H-pyrazol-3-amine (2.78 g, 27.3 mmol) in absolute EtOH (30 ml) was added triethylamine (5 ml) and 2,4,5-trichloropyrimidine (5.0 g, 27.3 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound (4.1 g). m/z: 245.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 20 mg (0.17 mmol, 1.1 eq.) of benzoic acid were reacted according to General Method 1. Yield: 35 mg (56% of theory)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:8][C:9](=O)[CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:13]=2[N:12]=1)C>C(OCC)(=O)C>[O:8]=[C:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:35])([F:36])[F:34])=[O:26])[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:13]=2[N:12]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)Cc1nc2c(C(=O)OC)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(CC(=O)N3CCCC3)nc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (1 mL) was added to methyl 2-(2-ethoxy-2-oxoethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate (80 mg), and the solution was stirred at 70° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, and washed with brine. The ethyl acetate layer was concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (74 mg) as white powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Yield: 32.7 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 326 mg; 1.0 mmol) and 2-aminothiazole (231 mg; 2.23 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40M column, eluent: 5% to 30% gradient of ethyl acetate/hexanes) 132 mg of (S)-3-Cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22ClN3O2S (M++Na+) 426.1013, found 426.1016; and 91 mg of regioisomeric (S)-3-Cyclohexyl-2-(7-Chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22ClN3O2SNa (M++Na+) 426.1013, found 426.1017.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O>[C:13]1([CH:12]=[N:11][N:7]2[CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:9][C:8]2=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OC(CCCCl)CN1N=Cc1ccccc1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1OC(CCCN2CCCCC2)CN1N=Cc1ccccc1
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A stirred solution of 5-(3-chloropropyl)-3-phenylmethyleneamino-2-oxazolidinone (2.7 g, 0.0101 mole), dimethylformamide (75 ml) and piperidine (2.15 g, 0.0253 mole, 2.5 eq.) is heated to reflux. Reflux is maintained for 2 hours. After cooling, the solution is concentrated under reduced pressure to a solid-oily residue. This residue is suspended in H2O (200 ml) then extracted with ethyl acetate (3×100 ml). The ethyl acetate is dried over MgSO4, filtered, then concentrated under reduced pressure to an oily-solid residue. This residue is triturated in hexane by stirring 1 hours. The solid is collected and air-dried giving 1.67 g (0.0053 mole) of 3-phenylmethyleneamino-5-[3-(1-piperidinyl)propyl]-2-oxazolidinone.