Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=O)=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:31]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:25]2[C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C=O)c2c1CCCC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c2c1CCCC2

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid ethyl ester (48 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:6]2[S:7][CH2:8][C:9]3[CH:13](O)[O:12][C:11](=[O:15])[C:10]=3[N:5]2[C:4]1=[O:16].[NH2:17][OH:18]>ClCCl>[NH2:2][CH:3]1[C:4](=[O:16])[N:5]2[C:10]([C:11]([OH:12])=[O:15])=[C:9]([CH:13]=[N:17][OH:18])[CH2:8][S:7][C@H:6]12
Reactant: NO
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Agent: Cl
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=O)O)=C(C=NO)CS[C@H]12
Reaction time: 2 h

Procedure:
A suspension of 0.79 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin in 10 ml of dichloromethane is treated under stirring at 4° with 2.67 g of N,O-bis-(trimethylsilyl)acetamide. A clear solution is obtained within 10 minutes. 0.21 g of the hydrochloride of hydroxylamine are added. The reaction mixture is stirred for ca. 2 hours under nitrogen at 4° and the solvent is evaporated off. The residue is treated with 10 ml of isopropylalkohol, precooled to 1°. 7-Amino-3-[(hydroxyimino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost colourless crystals which are filtered off, washed with 5 ml of acetone and dried.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(O)C>[F:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([CH3:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 5 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
To a solution of 9.0 g (27.0 mmol) of ethyl 2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)-3-ethoxyacrylate in 30 ml of absolute ethanol at 5° C. was added 1.68 g (29.4 mmol) of cyclopropylamine. The mixture was stirred at 5° C. for 1.5 hours and at room temperature for 2.5 hours. The solution was concentrated to an oil which was triturated with hexane to give a tan solid. The crude product was recrystallized from hexane to give 9.07 g of the title compound, mp 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-3-methyl-1-butanol (CAN 4276-09-9) as starting materials and isolated (51 mg, 54%) as colorless oil; MS (ESI, m/z): 313.1 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=[O:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N+:28]([CH:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:31])#[C-:29].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:26]3[O:27][CH:29]=[N:28][C:30]=3[CH3:31])=[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(CCC(=O)O)c(-c3ocnc3C)nc21
Yield: 31.2 %

Procedure:
A mixture of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (30 mg), 1-[(1-isocyanoethyl)sulfonyl]-4-methylbenzene (17.6 mg), potassium carbonate (17 mg) in MeOH (1 ml) was refluxed for 1.5 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH3-4 by adding 1N HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10). Crystallization from EtOAc-n-hexane gave 3-[1-ethyl-6-(4-methyl-1,3-oxazol-5-yl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoic acid (10 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.4 %

Procedure:
To a round bottomed flask was added tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (124 mg, 0.291 mmol) in DCM (30 mL). The resulting white suspension was heated with a heat gun while stirring until all the starting material was dissolved. The solution was cooled to 0° C., and while stirring, 1-bromopyrrolidine-2,5-dione (51.7 mg, 0.291 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred for 30 min. The solution was diluted with DCM (20 mL) and was washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL). The organic layer was collected and concentrated to an orange solid, which was treated with Et2O (5 mL). Solids began to precipitate after the solution was allowed to sit undisturbed for 5 min. The mixture was allowed to sit for 1 h and was then filtered through paper. The solids were washed with Et2O (5 mL) and collected to give the title compound as a tan solid (137.3 mg, 93%). [M+H] calc'd for C22H29BrN6O3, 505. found, 505.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5]2.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:11]=[CH:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCOc1ccc2cc(Br)ccc2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCCCCCCOc1ccc2cc(/C=C/C(=O)OC)ccc2c1

Procedure:
A mixture of 5.2 g of 6-bromo-2-heptyloxynaphthalene, 25 ml of triethylamine, 4.3 ml of methyl acrylate, 0.072 g of palladium acetate and 0.392 g of tri-o-tolylphosphine is refluxed for 16 hours. The reaction mixture is then cooled and is partitioned between ethyl acetate and water and the organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated down. The residue is chromatographed over 250 g of silica gel using toluene/ethyl acetate (3:1) and then crystallized from toluene. This gives methyl (E)-3-(heptyloxynaphth-2-yl)acrylate.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:11][C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=1)[CH2:4][CH2:5][CH3:6].Cl[CH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>O1CCOCC1>[CH2:3]([C:7]1[N:11]([CH:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)[C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCC1=NC2(CCCC2)C(=O)N1C1CCc2cc(-c3ccccc3C#N)ccc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
Sodium hydride (53 mg, 2.3 mmol) was added to 2-butyl-1,3-diaza-spiro[4.4]non-1-en-4-one (458 mg, 2.36 mmol) in anhydrous 1,4-dioxane (3 mL). After 0.25 hour, a solution of 2-(1-chloro-indan-5-yl)-benzonitrile (300 mg, 1.18 mmol)in dioxane (1.0 mL) was added. The reaction mixture was heated at 110° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 50% ethyl acetate/hexanes to give 150 mg of a colorless oil. 1H NMR (250 MHz, CDCl3): d 7.80 (d, 1 H), 7.65 (q, 1 H), 7.48 (m, 4 H), 7.10 (d, 1 H), 5.75 (m, 1 H), 3.42 (m), 3.15 (m), 2.85 (m), 2.55 (m), 2.40-1.60 (m), 1.40 (m), 0.88 (t, 3 H).
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)CCC(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 56.7 %

Procedure:
2.0 g (4.7 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) and 0.6 g (6.2 mmol) of succinic anhydride were dissolved in 50 ml of toluene; some triturated molecular sieves were added and the reaction mixture was refluxed in a Dean Stark apparatus for 4 hours. The reaction mixture was evaporated in vacuo to dryness, dissolved in 100 ml of CH2Cl2 and washed with sat. sol. NaCl, 20% citric acid and sat. sol. NaCl. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness to yield 2.3 g of the crude product which was purified by flash column chromatography on 230-400 mesh silica gel, eluting initially with a mixture of CH2Cl2/MeOH 9:1 and then with a mixture of CH2Cl2/MeOH 8:2. The crude solid obtained was triturated with i-Pr2O/i-PrOH, washed and dried to yield 1.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[O:21]([C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)Oc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Oc4ccccc4)cc23)CC1
Yield: 91 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 7.2 mg (0.0458 mMol) phenyl chloroformate, 13.9 mg (91%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].CO.[C:15](=O)=[O:16]>O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=C=O
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc2[nH]ccc12
Temperature: 170 °C

Procedure:
To 4-chloro-1H-pyrrolo[2,3-b]pyridine [2.3 g, Reference Example 64] in a stainless steel pressure vessel was added sodium hydroxide (2 g), and methanol (40 mL). The pressure vessel was sealed and heated at 170° C. for 4 hours. After cooling, water (100 mL) was added and the mixture was neutralised by addition of excess solid carbon dioxide pellets (30 g). After concentration to a slurry and filtration, the residue was washed twice with water (5 mL) to afford 4-methoxy-1H-pyrrolo[2,3-b]pyridine as a solid. To a mixture of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (5.85 g) in toluene (150 mL) and water (150 mL) was added potassium hydroxide pellets (2.5 g), 4-methylbenzene sulfonyl chloride (7.53 g) and tetra-n-butyl ammonium hydrogen sulfate (0.02 g). This mixture was stirred at room temperature for 20 hours then extracted four times with ethyl acetate (100 mL). The combined organic extracts were concentrated and then subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and heptane (35:65, v/v) to afford the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([C:12]2[C:16](S(C3C=CC=CC=3)(=O)=O)=[N:15][O:14][N+:13]=2[O-:26])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27]([CH:34]([CH:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[OH:37])[OH:35])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[OH:37][C@H:36]([C@@H:34]([O:35][C:16]1[C:12]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])=[O:11])=[N+:13]([O-:26])[O:14][N:15]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39]
Reactant: CC(C)(C)OC(=O)C(O)C(O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)c1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](O)[C@@H](Oc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
50% NaOH solution (1.2 g-30 mmol) is added in the course of ½ hour to a solution of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (7 g-19 mmol) and di-tert-butyl tartrate (5 g-19 mmol) in 100 ml of anhydrous THF. After stirring for 5 hours, the solvent is evaporated off to dryness and the residue is taken up in water and ethyl acetate. The organic fraction is dried with Na2SO4 and evaporated to dryness and subsequently purified by flash chromatography, using a (98:2) dichloromethane/ethanol mixture as eluant, to yield the expected product in the form of a colourless oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[CH2:9](N)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN1CCCC1=O>[CH2:26]([N:8]1[C:6](=[O:7])[NH:5][NH:4][C:1]1=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: NC(=O)NNC(N)=O
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCn1c(=O)[nH][nH]c1=O

Procedure:
360 g of hydrazodicarbonamide, 807 g of stearyl amine and 1 ml of tin(II)dioctoate are stirred in 1 liter of N-methyl pyrrolidone for 4 hours at 175° C. and for 6 hours at 200° C. A deposit precipitates on cooling and is isolated by filtration under suction and washed with water, giving 955 g (90% of the theoretical) of 4-stearyl-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 118° to 120° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.17 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.16 g, 47% yield), mp=87–89° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=−23.1° (c=1, EtOH).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16](Cl)(=O)[CH3:17]>C1COCC1>[CH:10]1([C:4]2[S:3][C:2]3[N:1]=[C:16]([CH3:17])[NH:9][C:7](=[O:8])[C:6]=3[CH:5]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: NC(=O)c1cc(C2CCCCC2)sc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: Cc1nc2sc(C3CCCCC3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-amino-5-cyclohexylthiophene-3-carboxamide (53.5 g) and THF (500 mL) were added dropwise acetyl chloride (18 mL) and TEA (36 mL) under ice-cooling, followed by stirring at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added EtOH (500 mL) and a 1 M aqueous NaOH solution (500 mL), followed by stirring at 80° C. for 24 hours. The reaction mixture was left to be cooled to room temperature, and 1 M hydrochloric acid (500 mL) was added thereto, followed by stirring. The precipitate was collected by filtration, washed with water, and dried by blowing air to obtain 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (57.0 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[NH:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1>>[OH:26][CH:23]1[CH2:24][CH2:25][N:21]([C:10]([C:9]2[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:22]1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: OC1CCNC1
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1)C(F)(F)F

Procedure:
Prepared in analogy to Example C1 from 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (CAS: 845616-82-2) and rac-3-pyrrolidinol. The crude material was crystallized with dichoromethane to provide the title compound as white solid. MS (m/e): 382.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:53])[C:22]([C:28]4[N:29]=[C:30]([NH:33]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:31][CH:32]=4)=[N:23][O:24][CH2:25][CH2:26][NH2:27])[C:18](=[O:54])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C(O)=O.O>Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:53])[C:22]([C:28]4[N:29]=[C:30]([NH2:33])[S:31][CH:32]=4)=[N:23][O:24][CH2:25][CH2:26][NH2:27])[C:18](=[O:54])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1

Procedure:
A mixture of 2 g of the product of Step B and 5 ml of formic acid was heated with stirring to 40°-45° C. and after the addition of 5 ml of water, the mixture was stirred at 40°-45° C. for 15 minutes and was then cooled. The mixture was vacuum filtered to remove triphenylcarbinol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ethanol with efflorescence and the mixture was vacuum filtered. The recovered product was rinsed with ethanol and then with ether to obtain 1.36 g of raw product which was taken up in 15 ml of 2 N hydrochloric acid. The mixture was vacuum filtered and the filtrate was adjusted to a pH of 4 with 3 ml of an aqueous molar solution of lithium acetate and then with aqueous lithium hydroxide. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 30 ml of ethanol with efflorescence and the mixture was vacuum filtered to obtain 515 mg of syn isomer of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(2-aminoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid. The mother liquors were evaporated to dryness to obtain another 133 mg of the said product and the combined products were treated again in the same manner to obtain a final yield of 430 mg of the product in the form of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][N:13]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Benzyloxybenzyl azide, as described above in Step H, (5.0 g, 20.9 mmol) was dissolved in dry THF (100 mL) and the solution was cooled to −70° C. Lithium aluminum hydride (31.4 mL of a 1.0 M solution in THF, 31.4 mmol) was added dropwise, then the reaction mixture was warmed to 0° C. and stirred for 30 min. The reaction was quenched with EtOAc (1.2 mL), then water (1.2 mL), then 15% NaOH (1.2 mL), and finally water (3.6 mL). The resulting mixture was filtered, concentrated under reduced pressure and purified by flash column chromatography on silica, eluting with CH2Cl2—3% MeOH—0.3% NH4OH, to yield the titled product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1.ClCCl>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5 g (27.64 mmol) of 4-fluoro-2-(trifluoromethyl)-aniline is dissolved in 25 ml of dry pyridine and the solution is cooled to 0° C. A solution of 4.82 g (27.4 mmol) of chlorosulfonyl acetic acid methyl ester in 20 ml of dichloromethane is instilled in the cooled solution in the course of about 10 minutes with the temperature being maintained. Then it is stirred for 6 hours at room temperature. The reaction solution is then diluted with 100 ml of dichloromethane, the pyridine is shaken out with 2N hydrochloric acid, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether/hexane yield is obtained as a crystallizate. Melting point 84°-86° C.