Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:29])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C#N)cc1
Temperature: 70 °C

Procedure:
To a solution of 8-[2-(4-cyano-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.700 g; 1.840 mmol) in anhydrous MeCN (20 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.250 g; 1.840 mmol; 1 eq.) in anhydrous MeCN (5 ml). The resulting solution was then heated to 70° C., under nitrogen, for 4 h. Concentration to dryness afforded an oily residue which was dissolved in EA (80 ml), and this organic layer was washed with aq. sat. NaHCO3 (2×100 ml), was then dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=2/3) gave the expected 1-chloro-8-[2-(4-cyano-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.417 g; 55%). LC-MS: tR=1.00 min.; [M+H]+=414.94 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18](OS(C2C(C)=CC=CC=2)(=O)=O)=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH3:57][O:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH3:66])[C:60]=1B(O)O>O1CCOCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([C:60]2[C:59]([O:58][CH3:57])=[CH:64][CH:63]=[CH:62][C:61]=2[O:65][CH3:66])=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1ccc(OS(=O)(=O)c2ccccc2C)cc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: COC(=O)CC(NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cccc2OC)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, methyl N-(t-butyloxycarbonyl)-3-amino-3-(4-toluenesulfonyloxyphenyl)propionate (0.45 g, 1.0 mmol), cesium carbonate (0.65 g, 2.0 mmol), tricyclohexylphosphine (0.059 g, 0.2 mmol), bis(1,5-cyclooctadiene)nickel (0.028 g, 0.1 mmol) and 2,6-dimethoxyphenylboronic acid (0.36 g, 2.0 mmol) were mixed in dioxane (1 ml). The reaction mixture was heated to 50° C. and then stirred at the same temperature for 2 hrs. After the reaction was completed, the mixture was left to cool to room temperature and insoluble substances were filtered off. The filtrate was subjected to column chromatography purification to obtain methyl N-(t-butyloxycarbonyl)-3-amino-3-[4-(2,6-dimethoxyphenyl)phenyl]propionate (0.34 g, yield 83%) as colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([CH2:8][CH2:9][C:10]2[C:11]([CH3:33])=[N:12][O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:7])[CH2:3][CH2:2]1.I[CH3:35]>>[CH:1]1([CH2:4][N:5]([CH3:35])[C:6]([CH2:8][CH2:9][C:10]2[C:11]([CH3:33])=[N:12][O:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NCC1CC1
Reactant: CI
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)CC1CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-(4′-{4-[2-(cyclopropylmethyl-carbamoyl)-ethyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]=[C:17]=[S:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][NH2:21].[N-]=C=S>C(OCC)C>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([N:20]([CH3:19])[NH2:21])=[S:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S
Reactant: CNN
Agent: [N-]=C=S
Solvent: CCOCC
Product: CN(N)C(=S)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 91 %

Procedure:
A solution of 5.48 grams (0.02 mole) of 2-benzoyl-4-chlorophenylisothiocyanate in about 50 ml of ethyl ether was added dropwise to a solution containing 1.5 ml (0.028 mole) of methyl hydrazine (98%) in about 50 ml of ethyl ether cooled in an ice bath. Additional ethyl ether was added to facilitate stirring. Following addition of the isothiocyanate, the reaction mixture was stirred at room temperature for about 30 minutes. The solid was collected and washed with additional ethyl ether to yield 5.82 grams (91% yield) of N-(2-benzoyl-4-chlorophenyl)-methyl-hydrazinecarbothioamide as a white solid. The melting point was found to be 168.5°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18]CC4C=CC(OC)=CC=4OC)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>CO.ClCCl>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: COc1ccc(CNc2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)c(OC)c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.1 g, 2.7 mmol) was dissolved in 8 mL methanol and 30 mL dichloromethane. Then 10 mL of trifluoroacetic acid was added and the solution was stirred at ambient temperature. After 1 hour, reaction was concentrated, dissolved in 500 mL of ethyl acetate and washed with 200 mL saturated sodium bicarbonate. The organic layer was separated, dried with magnesium sulfate, filtered, and purified by flash column chromatography (0-10% methanol/dichloromethane gradient) and reverse phase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford title compound. LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[CH:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[CH2:15].Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([CH:14]=[CH2:15])[CH2:17][CH2:18]2)=[C:4]([F:13])[C:5]=1[F:12])[CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: C=CC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC1CCC(O)(c2ccc(OCC)c(F)c2F)CC1
Temperature: 53 °C
Reaction time: 0.5 h
Yield: 135.6 %

Procedure:
Seventh Step: 1.76 g of well dried magnesium and 10 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 53° C. 17.2 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 56° C., followed by stirring for 30 minutes. Thereafter, 6.0 g of the compound (16) dissolved in 10 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was then separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 18.5 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-vinylcyclohexanol (17) as a yellow liquid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[NH:15][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (0.90 mmol,0.38 g) in THF (10 mL) was added lithium aluminum hydride (2.7 mmol,2.7 mL of a 1M solution in tetrahydrofuran). The reaction was heated to reflux overnight. The reaction was diluted with ethyl acetate (20 mL) and quenched with water (2.0 mL). The suspension was filtered and the filtrates dried over anhydrous sodium sulfate. The filtrates were then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether, filtered and recrystallized from ethanol:diethyl ether to give 160 mg. of the title compound as a white powder. mp=259°-261° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.O.[Cu]I>[N:12]1[N:13]([C:2]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]nn1
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in water with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid A-5, followed by the undesired regioisomer isomer, 1-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for A-5: 1HNMR (500 MHz, DMSO-d6) d 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15].[BrH:16]>C(O)(=O)C>[Br:16][CH2:2][CH2:3][C:4]1[C:13](=[O:14])[N:12]2[C:7]([S:8][CH2:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[CH3:15]
Reactant: Br
Reactant: Cc1nc2n(c(=O)c1CCO)CCCS2
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, 50 parts of acetic acid and 180 parts of a hydrobromic acid solution 67% in acetic acid was stirred and heated to reflux. Stirring was continued overnight at reflux temperature. The reaction mixture was evaporated and the solid residue was triturated in 2-propanone. The product was filtered off and dried, yielding 24 parts (100%) of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; monohydrobromide; mp. 215° C. (intermediate 8).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1.[N:27]1([CH2:33][CH2:34][C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=4[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=3[CH:26]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1[C@@H](NC(C)=O)CC2
Reactant: O=C(O)CCN1CCCCC1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)CCN3CCCCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 61 %

Procedure:
Using an analogous procedure to that described for Example 21, N-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with 1-piperidinepropionic acid to give N-[(5S)-3-(3-piperidinopropanoylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cc(-c2ccccc2C(F)(F)F)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2C(F)(F)F)on1
Yield: 73.9 %

Procedure:
3-Hydroxy-5-(2-trifluoromethylphenyl)isoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.36 g, 74%) as a colorless oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]([NH:20][NH2:21])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[O:19][C:1](=[O:2])[NH:21][N:20]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Yield: 91.6 %

Procedure:
6.5 g of phosgene are dissolved in 60 ml of chloroform. 1.45 g of the hydrazide prepared in step A in 40 ml of chloroform are added dropwise and the mixture is refluxed for 4 hours. It is evaporated and the residue is taken up with DCM, washed with water, dried over sodium sulfate, filtered and evaporated to give 1.48 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15](OCC)=[O:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C=Cc1ccc(CCc2nc(-c3ccccc3)c(C)s2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1sc(CCc2ccc(/C=C/CO)cc2)nc1-c1ccccc1

Procedure:
Ethyl 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]cinnamate was reduced with diisobutylaluminum hydride in the same manner as in Reference Example 22 to yield (E)-3-[4-[2-(5-methyl-4-phenyl-2thiazolyl)ethyl]phenyl]-2-propenol, which was then recrystallized from hexane to yield colorless plates having a melting point of 93°-94° C.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11].[N+:19]([CH2:22][CH3:23])([O-])=[O:20].C(N(CC)CC)C>C1C=CC=CC=1.O>[CH3:23][C:22]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:20][N:19]=1
Reactant: CC[N+](=O)[O-]
Reactant: C#Cc1ccc(F)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(F)cc2)on1

Procedure:
2.41 ml (22.19 mmol) of phenyl isocyanate are added dropwise at room temperature to a solution of 2 g (16.64 mmol) of 1-ethynyl-4-fluorobenzene, 0.4 ml (5.55 mmol) of nitroethane and 0.15 ml (1.11 mmol) of triethylamine in 40 ml of benzene. The reaction mixture is then stirred under reflux for 12 h. After cooling, the suspension is mixed with water (20 ml) and stirred at room temperature for a further 4 h. The precipitate is filtered off with suction and washed with benzene (10 ml). The organic phase of the filtrate is separated off, dried with magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 0.62 g (63% of theory) of the title compound is obtained as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[C:21]([NH2:23])=[O:22])=O)[CH2:5][CH2:4]1)#[N:2].C([O-])([O-])=O.[Na+].[Na+]>CO>[O:22]=[C:21]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=[C:6]([C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)[NH:23]1
Reactant: N#CC1(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2nc3cccc(-c4ccccc4)c3c(=O)[nH]2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
To a solution 3-(1-cyanocyclopropanecarboxamido)biphenyl-2-carboxamide (0.7 g, 2 mmol) in methanol was added saturated aqueous Na2CO3 (23 mmol) and the reaction mixture stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate then washed with water. The organic extracts were dried, concentrated and purified by silica gel chromatography (4% MeOH in DCM) to yield 1-(4-oxo-5-phenyl-3,4-dihydroquinazolin-2-yl)cyclopropanecarbonitrile (0.65 g, 99% yield) as a white solid. LCMS Method T: retention time 1.810 min; [M+1]=288.2.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1CSc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)CSc2ccccc21
Yield: 70.4 %

Procedure:
4H-Benzo[1,4]thiazin-3-one (2.75 g, 16.7 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.04 g, 15.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM25-22) (3.74 g, 70%). 1H NMR (CDCl3) δ 7.35 (d, J=7.6 Hz, 1H), 7.28-7.18 (m, 2H), 6.99 (t, J=7.6 Hz, 1H), 4.13 (dd, J=8.9 Hz, J=13.3 Hz, 1H), 3.95 (dd, J=5.9 Hz, J=13.3 Hz, 1H), 3.52-3.40 (m, 2H), 3.37 (s, CH2), 1.96-2.07 (m, 1H), 0.92-0.83 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:37]=[O:38])(C)(C)C.C1C=CC=CC=1.[Pb](=O)=O>ClCCCl.O>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:38][CH3:37])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:19][CH2:20][C:21](=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=[Pb]=O
Solvent: c1ccccc1
Solvent: ClCCCl
Solvent: O
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(N)=O)Sc3nnn[nH]3)CS[C@@H]21
Reaction time: 0.5 h

Procedure:
A solution of 1.76 g. (4 mmol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.94 g. (4 mmol.) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 150 ml. of dry benzene is refluxed for ca. 4 hours under a Dean-Stark trap until no more water separates. The solution is evaporated uner reduced pressure to give a residue which is dissolved in 150 ml. of 1,2-dichloroethane and cooled to 0°-5° in an ice bath. Freshly prepared lead dioxide (5 g.) is added in 1 g. portions over 30 minutes and the reaction is stirred in the cold until complete consumption of starting material is shown by thin layer chromatography. The mixture is then filtered through Celite and the filter cake is washed with two 30 ml. portions of cold 1,2-dichloroethane. The filtrate is treated with 30 ml. of dry methanol (distilled from magnesium) and the reaction mixture is stirred at ambient temperature until complete consumption of the intermediate and formation of a new product are shown by thin layer chromatography. The reaction mixture is evaporated to dryness and the residue is taken up in 50 m. of methanol and treated with 4.0 g. of Girard reagent T. This solution is stirred at ambient temperature for 3 hours, evaporated under vacuum to a solid residue and partitioned between 150 ml. of ethyl acetate and 100 ml. of 20% aqueous sodium chloride solution. The organic phase is washed with three 100 ml. portions of 10% aqueous sodium chloride, two 100 ml. portions of water and 100 ml. of a saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.CO[CH:11]=[CH:12][C:13](=O)[CH3:14]>>[CH3:14][C:13]1[CH:12]=[CH:11][C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[N:1]=1
Reactant: NC1=CC(=O)CCC1
Reactant: COC=CC(C)=O
Product: Cc1ccc2c(n1)CCCC2=O
Temperature: 120 °C
Yield: 69.8 %

Procedure:
A mixture of 3-aminocyclohex-2-enone (22 g., 0.2 mol.) and 4-methoxybut-3-en-2-one (20.0 g., 0.2 mol), in an apparatus equipped for downward distillation, was heated in an oil bath at 120° C until the theoretical amount of distillate had been collected (13 ml.). The cooled residue was dissolved in 2N HCl (50 ml.) and extracted with ethyl acetate (3 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with sodium carbonate and extracted with chloroform (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled to give the title compound (22.5 g., 72%) b.p. 72°-6°/0.1 mm Hg. The free base was dissolved in ether and treated with an excess of ethereal hydrogen chloride. The resultant solid was isolated and recrystallised from isopropanol to give the hydrochloride of the title compound as colourless needles m.p. 225° C. (Found: C, 60.9; H, 6.3; N, 6.99. C10H11NO.HCl requires: C, 60.7; H, 6.1; N, 7.1%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:10]=1)=O)(C)(C)C.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 5 h
Yield: 152.5 %

Procedure:
2-(4-tert-Butoxycarbonylamino-2-pyridyl)-4H-1,3-benzo thiazine-4-one (100 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (2.5 ml) under ice cooling condition, and the mixture was stirred for 5 hrs. The reaction mixture was combined with diisopropyl ether to precipitate crystals, which were collected by filtration, washed with diethyl ether and dried to give the titled compound (109 mg, 60%).