Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[NH:6][CH2:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[CH3:16][N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]=2[N:6]([C:18](=[O:19])[NH:17][CH3:16])[CH2:5][C:4]2=[CH:13][CH:14]=[CH:15][N:3]12
Reactant: CN=C=O
Reactant: CN1c2ccncc2NCc2cccn21
Solvent: c1ccccc1
Product: CNC(=O)N1Cc2cccn2N(C)c2ccncc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 3.7 g of 10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 100 ml of benzene was treated with 1.6 ml of methyl isocyanate and then stirred at 70° C. for five hours. After cooling, the mixture was evaporated under reduced pressure and the residue was dissolved in water. The aqueous layer extracted with ethyl acetate. The combined organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue was achieved by means of high pressure liquid chromatography (silica gel; elution with 2.5% methanol/dichloromethane) to afford 2.3 g of 10,11-dihydro-5-methyl-11-methylcarbamyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine m.p. 197°-200° C. (dec.). The solid was dissolved in ethanol and acidified with an ethanol solution of maleic acid to precipitate the corresponding maleate salt. Recrystallization of the salt from ethanol yielded 1.8 g of 10,11-dihydro-5-methyl-11 -methylcarbamyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine maleate, m.p. 160°-161° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: Cc1nn(C)cc1C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1cn(C)nc1C
Yield: 58.1 %

Procedure:
In the same manner as in Example 55 and using 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (67.0 mg, 0.478 mmol), tetrahydrofuran (5 mL), thionyl chloride (83.0 μL, 0.957 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (140 mg, 0.433 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (112 mg, 58%) was obtained as a pale-brown solid.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:41]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:26]=3)[N:20]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Yield: 51.9 %

Procedure:
According to the preparation of 42, 27 (1.0 g, 4.6 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.6 mmol) were used to afford 57 (0.8 g, 55.0%) as pale yellow prism crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:26][C@@H:25]([OH:27])[CH2:24]2)[C:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.F[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(#N)C.FC(F)(F)C(O)=O>O>[CH3:29][C:2]([CH3:28])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:24][C@@H:25]([O:27][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:26]2)[CH:6]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2C[C@@H](O)C2)CC1
Reactant: Fc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2C[C@@H](Oc3cccnc3)C2)c(C(=O)O)s1

Procedure:
The title compound was synthesized in a manner analogous to Example 1, using 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid in place of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid and 3-fluoro-pyridine in place of 2-fluoro-pyridine: MS (m/z): 492.8 [M−H]−; HPLC retention time: 3.44 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:30]=[CH:29][C:28]#[N:31])=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: C=CC#N
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4c3OCO4)c2cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(C=CC#N)c4c3OCO4)c2cc1OC
Temperature: 115 °C

Procedure:
A mixture of 3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2 g), acrylonitrile (0.2 ml), triethylamine (0.2 ml), palladium(II) acetate (0.01 g) and DMF (2 ml) was stirred and heated to 115° C. for 3 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound, in the form of a 4:1 mixture of trans and cis isomers and as a yellow solid (0.095 g); NMR Spectrum: (DMSOd6, data relating to the major trans isomer) 3.91 (s, 3H), 3.93 (s, 3H), 6.12 (s, 2H), 6.26 (d, 1H), 6.88 (d, 1H), 7.14 (d, 1H), 7.35 (s, 1H), 7.56 (d, 1H), 7.7 (s, 1H), 8.51 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 675.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:22][CH3:23])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCI
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(-c2ccc(OC)c(OC)c2)cc(=O)n1C
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.17 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to ambient temperature. To the mixture was added ethyl iodide (5 ml) with stirring, which was continued at ambient temperature for 3.5 hours. To the reaction mixture was added water, and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether and the resulting precipitates were collected by filtration to give 6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4(3H)-pyrimidinone (0.18 g) as by-product.
Reaction SMILES: C1(COC([N:11]2[CH2:19][C@@H:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=O)C=CC=CC=1.[H][H]>CO.[Pd].O>[N:20]1([C@@H:18]2[CH2:19][NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1

Procedure:
A solution of 10.0 g of [4S]-1-[(phenylmethoxy)carbonyl]-4-(1-piperidinyl)-L-proline, methyl ester in 100 ml of methanol is treated with a suspension of 2 g of 5% palladium on charcoal in 10 ml of water and placed under 3 atmospheres of hydrogen. After an equivalent quantity of hydrogen is consumed, the suspension is filtered and the solvent evaporated to give the title compound.
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19]C=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Agent: NC1CCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1ccccc1-c1csc2c(=O)n(C3CCCCCC3)cnc12
Yield: 32.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), cycloheptylamine (0.098 ml, 0.77 mmol), and acetic acid (0.1 ml) were used to give 44 mg (0.13 mmol, 32.5% yield) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([SH:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Cl:13][CH2:14][CH2:15]Cl>>[Cl:13][CH2:14][CH2:15][S:10][C:8]1[NH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=1
Reactant: CC(C)(C)c1n[nH]c(S)n1
Reactant: ClCCCl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1n[nH]c(SCCCl)n1

Procedure:
31.4 g. 3-t-Butyl-1,2,4-triazole-5-thiol was dissolved in 180 ml. industrial methylated spirits containing 12.4 g. potassium hydroxide. 99 g. 1,2-Dichloroethane was added and after four days the insoluble matter removed. 5-(2-Chloroethylthio)-3-t-butyl-1,2,4-triazole was obtained from the solution by evaporation.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34]\[CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35]/[CH:34]=[C:33](\[C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: OC/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 650 mg (74%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([C:27](=[O:28])/[C:9](/[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:8]\[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)=[CH:25][CH:24]=1
Reactant: O=C(CS(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=C(/C(=C\c1ccc(I)cc1)S(=O)(=O)Cc1ccc(I)cc1)c1ccc(Br)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-iodophenyl)-2-(4-iodobenzylsulfonyl)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:20]3[C:19](=[O:21])[O:18][CH2:17][NH:16][C:15]=3[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:27]#[N:28].[Na+].C(O)(=O)C>CS(C)=O.O>[C:1]1([S:7]([CH2:10][C:11]2[C:20]([C:19]([OH:18])=[O:21])=[C:15]([NH:16][CH2:17][C:27]#[N:28])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCNc2c(-c3ccoc3)ccc(CS(=O)(=O)c3ccccc3)c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: N#CCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 60 °C
Yield: 85.9 %

Procedure:
A solution of 5-(benzenesulphonylmethyl)-8-(furan-3-yl)-1,2-dihydro-benzo[d][1,3]oxazin-4-one (Intermediate 210, 0.115 g) and sodium cyanide (0.03 g) in DMSO (4 ml) was stirred and heated at 60° C. for 2 hours. After cooling, the mixture was diluted with water, acidified with acetic acid and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM:methanol:water:acetic acid (350:20:3:2). The product was crystallized from DCM and cyclohexane to give 6-(benzenesulphonylmethyl)-2-(cyanomethylamino)-3-(furan-3-yl)benzoic acid (0.106 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C@H:11](O[Si](C(C)(C)C)(C)C)[CH2:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si](C)(C)O)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH:11]=[CH:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC(C)(C)[Si](C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C[C@@H]2CN(Cc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.8 %

Procedure:
Trifluoroacetic acid (154 μl) was added to a solution of (4R)-4-t-butyldimethylsilyloxy-2-cyclopenten-1-one (5.79 g, 27.3 mmol) and benzylbutoxymethyltrimethylsilylmethylamine (15.4 g, 55.0 mmol) in dichloromethane (100 ml) at room temperature, followed by stirring for 20 minutes. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After removing the solvent by evaporation, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4.21 g (19.7 mmol, 72%) of the title compound as a colorless oily substance. (1R,4R,5S)-7-Benzyl-4-t-butyldimethylsilyloxy-2-oxo-7-azabicyclo[3.3.0]octane was also obtained as a mixture with t-butyldimethylsilanol (3.10 g). The resulting mixture (3.10 g) of (1R,4R,5S)-7-benzyl-4-t-butyldimethylsilyloxy-2-oxo-7-azabicyclo[3.3.0]octane and t-butyldimethylsilanol was dissolved in tetrahydrofuran (30 ml), and a 1 M tetrahydrofuran solution (15 ml) of tetrabutylammonium fluoride was added thereto under cooling with ice, followed by stirring at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 1.57 g (7.34 mmol) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH2:26][CH2:25][C:24]1=[O:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:23]([CH3:22])[C:24](=[O:42])[CH2:25][CH2:26]3)[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Product: CN1C(=O)CCc2cc(-c3cncc(OC[C@H]4CCCN4C(=O)OC(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, reaction of (R)-2-((5-bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate A-55) and 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as a colorless solid. MS: 438.6 (M+H+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:25])=[CH:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O.[C:26]1([S:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([S:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH:18]=[C:17]([F:16])[F:25])=[CH:35][CH:34]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(Sc2ccccc2)cc1
Reactant: O=C(O)CCCC=C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCC=C(F)F)Nc1ccc(Sc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
At from 0° to 10°, 20.6 g of N,N'-dicyclohexylcarbodiimide are added, while stirring, in portions to 15 g of 6,6-difluorohex-5-enoic acid in 150 ml of dichloromethane. The mixture is stirred for a further 15 minutes under cooling and then 20.1 g of 4-phenylthioaniline are added in portions. The reaction mixture is stirred for 3 hours at room temperature and then filtered. The organic phase is washed with saturated sodium hydrogen carbonate solution and then dried over sodium sulfate. After concentration by evaporation, the residue is recrystallised from toluene/hexane, yielding the title compound having a melting point of from 80° to 81° (compound no. 2-1).
Reaction SMILES: [C:1]([O:5][C:6](/[N:8]=[C:9](\[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([O:19]CC)=[O:18])=[CH:14][C@@H:13]([O:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C@@H:12]1[NH:28][C:29](=[O:33])[CH:30]([F:32])[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)(=O)C>O1CCOCC1>[C:1]([O:5][C:6](/[N:8]=[C:9](\[NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])/[NH:10][C@H:11]1[CH2:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C@@H:13]([O:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C@@H:12]1[NH:28][C:29](=[O:33])[CH:30]([F:32])[F:31])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(=O)C(F)F)[C@@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a solution of (3R,4R,5S)-ethyl 5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate 6b (250 mg) in dioxane (5 ml) 5% solution of lithium hydroxide (2.5 ml) was added and the reaction mixture was stirred at room temperature for 45 min. Then lithium hydroxide was passivated by adding acetic acid (300 mcl), the solvents were evaporated in vacuo. The solid was extracted with isopropyl alcohol, the extract was dried over Na2SO4 and evaporated in vacuo. It gives (3R,4R,5S)-5-((Z)-2,3-bis(tert-butoxycarbonyl)guanidino)-4-(2,2-difluoroacetamido)-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 8b (200 mg, 84%). LCMS (M+H): found 563; calculated 562.62. The obtained acid 8b (200 mg) was dissolved in 10% solution of trifluoroacetic acid in methylene chloride (2 ml) and stirred at room temperature for 12 h. Then the solvents were evaporated in vacuo. (3R,4R,5S)-4-(2,2-Difluoroacetamido)-5-guanidino-3-(pentan-3-yloxy)cyclohex-1-enecarboxylic acid 1.4 was separated by HPLC method. LCMS (M+H): found 363; calculated 362.28. 1H NMR (DMSO-d6), 400 MHz: 8.68 (d, J=8.4 Hz, 1H), 7.6 (d, J=10 Hz, 1H), 7.26 (br, 2H), 6.91 (br, 2H), 6.63 (s, 1H), 6.27 (t, J=53.6 Hz, 1H), 4.18 (d, J=8 Hz, 2H), 4.09 (m, 1H), 3.54 (q, J=10 Hz, 1H), 3.39 (m, 2H), 2.57 (dd, J1=18 Hz, J2=6 Hz, 1H), 2.31 (m, 1H), 1.44 (m, 4H), 0.85 (t, J=8 Hz, 3H), 0.795(t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])=[N:9]2)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ncn(-c3ccc(Br)cc3)n2)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: O=C(O)c1cccc(-c2ncn(-c3ccc(-c4ccccc4)cc3)n2)c1
Yield: 79.2 %

Procedure:
A 10 mL glass tube with a stirbar is charged with methyl 3-[1-(4-bromo-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoate (265 mg, 0.74 mmol), benzeneboronic acid (90.2 mg, 0.74 mmol), sodium carbonate (235 mg), tetrabutylammonium iodide (273 mg), palladium acetate (0.8 mg) and 6 mL water. The vessel is sealed and placed into the reaction cavity of a microwave reactor. The reaction is performed with 60 W power at 150° C., with monitoring by LC/MS. After the reaction is determined to be complete, the mixture is filtered through celite and acidified using 1N HCl until the pH of the medium is less than 7. The resulting solid is collected by filtration and recrystallized to purity from THF-hexane to afford the title product (200 mg, 79%) as a white powder, m.p. 263-265° C. 1H NMR (300 MHz, DMSO-d6): δ 9.47 (1H, s), 8.69 (1H, s), 8.34 (1H, d, J=7.5 Hz), 8.05-7.39 (1H, m). MS (ES+): m/e 343 (30), 342 (100).