Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][S:6][C:7]1[N:12]=[C:11](SC)[C:10]2=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:9]2[N:8]=1>C1COCC1>[CH:1]1([NH:4][C:11]2[C:10]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:9]3[N:8]=[C:7]([S:6][CH3:5])[N:12]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CSc1nc(NC2CC2)c2ncc(C#N)n2n1
Temperature: 50 °C
Yield: 97.5 %

Procedure:
(I2B): Cyclopropanamine (2.69 mL, 42.4 mmol) was added to a suspension of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.35 g, 14.12 mmol) in THF (30 mL) and the resulting mixture was heated at 50° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (120 g column, eluting with 5-30% ethyl acetate/hexanes). 4-(cyclopropylamino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.39 g) was obtained as light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)C.CCCCCC.C(OCC)(=O)C.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
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: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: N#Cc1cc(-c2cccc(F)c2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 37.6 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-fluorophenylboronic acid (60 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a mixture of hexane:ethyl acetate:dichloromethane (3.5:0.5:4), followed by trituration with diethyl ether afforded 27 mg (36%) of 3-(2-pyridyl)-5-(3-cyano-5-(3-fluorophenyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3):δ-8.86 (d, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.91 (t, 1H), 7.49 (m, 3H), 7.40 (m, 1H), 7.19 (m, 1H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C([O-])([O-])=O.[K+].[K+].[Br-].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>CC(C)=O>[CH2:16]([N:4]1[C:5](=[O:6])[CH2:7][S:1][C:2]1=[S:3])[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(=O)c1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1C(=O)CSC1=S)c1ccccc1

Procedure:
Reagents: Rhodanine (133 mg, 1 mmol), K2CO3 (excess) and acetophenone bromide (199 mg, 1 mmol) in 25 ml of acetone.
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:14]2[S:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:18][C:16]1([CH3:19])[S:15][C:14]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:17]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1SC(C)(C)C2
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cccc(S(N)(=O)=O)c2S1
Temperature: 20 °C
Yield: 60.1 %

Procedure:
A solution of 17.2 g of N-t-butyl-2,3-dihydro-2,2-dimethyl-7-benzo[b]thiophenesulfonamide (Example 13) in 100 ml of trifluoroacetic acid was stirred at 20° C. for 16 hours. The solution was concentrated in vacuo, 100 ml of fresh trifluoroacetic acid was added and the mixture stirred at 20° C. for four more hours. After concentrating the solution in vacuo, the residue was dissolved in methylene chloride and the solution was washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate and concentrated in vacuo. The solid residue was slurried in 50% ether in hexane for several minutes then filtered to yield 8.4 g of the title compound; m.p. 102°-104° C.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Reactant: COc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)ccn1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.2017 g, 0.566 mmol), 2-methoxypyridin-4-ylboronic acid, trans-dichlorobis(triphenylphosphine) palladium (II) (0.032 g, 0.045 mmol), and sodium carbonate (0.300 g, 2.83 mmol) in DME (0.906 mL) and water (0.226 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 30 min. The crude product was purified by chromatography to give the title compound. MS (ESI, pos. ion) m/z: 356 (M+1). IC50 (uM) 0.003548.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[C:1]([O:4][CH2:8][CH:7]([OH:9])[CH2:5][Cl:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: ClCC1CO1
Product: CC(=O)OCC(O)CCl
Temperature: 28 °C

Procedure:
To a stirred solution of 1.5 g of anhydrous ferric chloride in 612 g (10.02 moles) of glacial acetic acid was added 925 g (10.0 moles) of epichlorohydrin at 20° C. over a period of 10 minutes. The reaction temperature increased to 28° C. The mixture was then heated at 65°-70° C. for 24 hours. The 1H NMR spectrum of the product was identical with that of Example 1. The material was used in the next step.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:33])[CH:19]=1>C1(C)C=CC=CC=1>[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[C:20]([CH3:33])[CH:19]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol) and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (200 mg, 0.67 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. (113.20 mg, 50%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].S([O-])(O)(=O)=O.[K+]>CN(C)C=O.O.C(OCC)(=O)C>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])#[N:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#CCCCCCCBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCCCC#N)C(=O)OCC
Reaction time: 0.5 h

Procedure:
2.3 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were gradually added with ice cooling to a solution of 8.0 ml of diethyl malonate dissolved in 80 ml of dimethylformamide. The mixture was stirred for 30 minutes, and then 10 g of 7-bromoheptanenitrile were added dropwise to it over a period of 30 minutes. The mixture was then stirred at room temperature for 20 hours in an atmosphere of nitrogen. At the end of this time, ethyl acetate and water were added to the mixture, which was then acidified by adding an aqueous solution of potassium hydrogen sulfate, after which the organic layer was separated. This layer was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 3:1 by volume mixture of cyclohexane and ethyl acetate) to afford 8.9 g of the title compound as a liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]1([CH:24]=[CH:23][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)C=Cc3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cinnamoyl chloride (1.7 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours and then poured into ice water and excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl 3-phenyl-2-propenoate.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C@H:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:13][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: C[C@@H](NCCBr)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: C[C@H]1NCCc2ccccc21
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
73.45 g (240 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 260 ml of decalin and the resulting suspension was heated to 150° C. 95.10 g (710 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at same temperature and then cooled to room temperature. The supernatant was removed and the lower layer was poured onto 1600 g of ice-water with stirring. 70 ml of con. hydrochloric acid was added thereto and the resulting mixture was stirred for 10 minutes. This solution was washed three times, each time with 700 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and extracted three times, each time with 900 ml of ethyl acetate. The extracts were combined, washed with 200 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 28.2 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH:13]=O)=[CH:3]1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1.N1CCCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:3]1
Reactant: Cn1cc(C=O)c(=O)c2ccccc21
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(/C=C/C(=O)O)c(=O)c2ccccc21

Procedure:
A mixture of 1-methyl-3-formyl-4(1H)-quinolone (5.61 g) and malonic acid (4.5 g) in pyridine (45 ml) with 3 drops piperidine was heated on a steam-bath for two hours. The pyridine was removed in vacuo and the solid residue washed with water and dried. Recrystallisation from DMF/H2O gave the title compound. NMR confirmed the structure as pure trans-isomer, m.p. 248°-250° (with decomposition).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.O.[NH2:22][NH2:23].CCOC(C)=O.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:23][N:22]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: O=C(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
(2-Fluoro-3-trifluoromethyl-phenyl)-(4-fluoro-phenyl)-methanone (6.58 g, 23 mmol) was dissolved in 20 ml of pyridine. Hydrazine hydrate (7.36 mL, 230 mmol) and 4-(dimethylamino)-pyridine (2.8 g, 23 mmol) were added. The reaction mixture was stirred overnight at 110° C. After cooling to room temperature, EtOAc and 2N HCl were added. The organic phase was washed three times with brine, dried over NaSO4 and concentrated under vacuum. Purification of the crude product by plug filtration (silica gel, CH2Cl2) provided 5.18 g product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH:9]2[CH2:19][CH:6]1[CH2:7][CH2:8]2)[CH3:3].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:13]=[C:14]([O:18][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH:9]2[CH2:19][CH:6]1[CH2:7][CH2:8]2)[CH3:1]
Reactant: CN(C)CC1C2CCC(C2)CC1c1cccc(O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC1C2CCC(C2)CC1c1cccc(OC(=O)C(C)(C)C)c1
Yield: 81.8 %

Procedure:
Stir a mixture of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (200 mg, 0.772 mmol), 2,2-dimethyl-propionyl chloride (111.6 mg, 0.927 mmol) and triethyl amine (234 mg, 2.316 mmol) in CH2Cl2 (40 mL) at ambient temperature for 12 hours. Concentrate the mixture under reduced pressure, and purify the residue by preparative TLC to afford 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester as white solid (217 mg, Yield: 81.9%). MS (m/z): 344 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.40 (t, J=13.6, 1H), 7.19-7.21 (d, J=7.2, 1H), 7.03 (s, 1H), 6.92-6.94 (d, J=8.0, 1H), 2.97-3.03 (t, J=23.6, 1H), 2.49-2.68 (m, 6H), 2.40-2.44 (d, J=13.2, 1H), 2.35 (s, 2H), 2.17-2.21 (m, 2H), 1.60-1.84 (m, 8H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]5[CH2:38][CH2:39]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(OCC2CC2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCC5CC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclopropylmethoxy-pyridine.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:20])([F:18])[F:19])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])=[N:29][N:28]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1ccc(F)cc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2ccc(F)cc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 4-fluorobenzohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.7 and 5.4 Hz, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.41 (t, J=8.7 Hz, 2H), 6.65 (s, 1H), 5.97 (s, 2H), 2.57 (s, 3H); MS (ES) m/z 401 (M+1).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:35](=[O:37])[NH2:36])([CH3:34])[CH3:33])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:63][C@@H:64]1[C:82](=[O:83])[N:66]2[C:67]([C:79]([OH:81])=[O:80])=[C:68]([CH2:71][S:72][C:73]3[N:77]([NH2:78])[N:76]=[N:75][N:74]=3)[CH2:69][S:70][C@H:65]12.C(N(CC)CC)C.NC1SC=C(/C(=N/OCCCC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(N)N=NN=4)CS[C@H]23)=O)N=1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:35](=[O:37])[NH2:36])([CH3:34])[CH3:33])/[C:27]([NH:63][C@@H:64]2[C:82](=[O:83])[N:66]3[C:67]([C:79]([OH:81])=[O:80])=[C:68]([CH2:71][S:72][C:73]4[N:77]([NH2:78])[N:76]=[N:75][N:74]=4)[CH2:69][S:70][C@H:65]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(N)=O
Yield: 70.5 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-carbamoyl-2-propyloxyimino)acetic acid (2.00 g, 3.9 mmol), 1-hydroxybenzotriazole (0.560 g, 4.29 mmol) and N,N'-dicyclohexylcarbodiimide (0.840 g, 4.10 mmol) in dimethylacetamide (24 ml) was stirred at room temperature for 4 hours. To this solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.41 g, 4.29 mmol) and triethylamine (0.790 g, 8.58 mmol) in dimethylacetamide (10 ml) and water (1.4 ml) and the mixture was allowed to react at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale yellow powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-carbamoyl-2-propyloxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.27 g, 70.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH:44]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)([CH2:46][CH3:47])[CH3:45]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([CH:44]([CH2:46][CH3:47])[CH3:45])=[CH:49][CH:50]=1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Reactant: CCC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-amino-5-methanesulfonyl-benzoic acid (0.750 g, 3.48 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.730 g, 3.83 mmol), 1-hydroxybenzotriazole (0.510 g, 3.83 mmol), and 4-methylmorpholine (0.380 g, 3.83 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then 4-sec-butyl-aniline (0.780 g, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, water was added, and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was washed with ether to obtain 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide as white solid. Yield: 0.75 g (62%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[NH:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:7]=2)[CH2:3]1.[CH3:17][C:18]1[N:40]=[C:21]2[N:22]=[C:23]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:25][N:20]2[N:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(N(CC)CC)C.CN(C=O)C>[CH3:17][C:18]1[N:40]=[C:21]2[N:22]=[C:23]([C:32]3[CH:33]=[CH:34][C:35]([CH2:36][N:2]4[CH2:5][CH:4]([C:6]5[N:7]=[C:8]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=6)[NH:9][N:10]=5)[CH2:3]4)=[CH:38][CH:39]=3)[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:25][N:20]2[N:19]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn2n1
Yield: 27.1 %

Procedure:
77 mg (0.38 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt was dissolved in 6 mL methanol and 0.1 mL triethylamine. After addition of 100 mg (0.31 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde dissolved in 6 mL DMF, 0.06 mL acetic acid and 131 mg (0.76 mmol) NaBH(OAc)3 the reaction mixture was stirred at room temperature. Three additional portions of 2 equivalents NaBH(OAc)3 each were added after 2, 4 and 6 hours. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel (dichloromethane/methanol) to yield 42 mg of the desired product.