Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:45])[C@@H:24]([NH:25][C:26](=[O:44])/[C:27](/[C:31]4[N:32]=[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:34][CH:35]=4)=[CH:28]\[CH2:29][CH3:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:46][O:47][C:48](=[O:50])[NH2:49])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:40]([O:39][C:37]([NH:36][C:33]1[S:34][CH:35]=[C:31](/[C:27](=[CH:28]/[CH2:29][CH3:30])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:45])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH2:46][O:47][C:48](=[O:50])[NH2:49])[CH2:19][S:20][C@H:21]23)=[O:44])[N:32]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To an ice cold solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (855 mg), anisole (3.3 ml), and dichloromethane (8.3 ml) is added trifluoroacetic acid (1.93 ml) with stirring. After reacting at the same temperature for 30 minutes, the mixture is concentrated in vacuum. The residue is washed with petroleum ether and ether to give pale brown 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (640 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:10]1[CH:9]([CH2:8][C:3]2[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]21[C:29]1[C:20](=[CH:21][C:22]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:28]=1)[O:19][CH2:18]2
Reactant: [C-]#N
Reactant: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1CC1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3′-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[1(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[F:15])=[O:5].[O:21]1CCOC[CH2:22]1>>[Br:20][C:18]1[CH:19]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:22](=[O:21])[NH:1]2)=[CH:16][CH:17]=1
Reactant: C1COCCO1
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccc(I)cc1F
Product: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(I)cc1F

Procedure:
A mixture of 2-amino-4-bromo-N-(2-fluoro-4-iodobenzyl)benzamide (3.80 g), N,N'-carbonyldiimidazole (5.5 g) and 1,4-dioxane (30 ml) was refluxed for 2 hours. The resulting crystals were collected by filtration, washed with 1,4-dioxane and dried over phosphorus pentoxide to give 7-bromo-3-(2-fluoro-4-iodobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.85 g).
Reaction SMILES: CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH2:32][C:33]1[CH:63]=[CH:62][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][NH:45][C:46](=[O:61])[CH2:47][NH:48][C:49](=[O:60])[C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH2:40][CH2:39]2)=[CH:35][CH:34]=1>ClCCl.C(N(CC)CC)C>[C:23]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][NH:45][C:46](=[O:61])[CH2:47][NH:48][C:49](=[O:60])[C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=3)[CH2:40][CH2:39]2)=[CH:62][CH:63]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
EDCI (4.7 mg), 1-hydroxybenzotriazole hydrate (3.3 mg), triethylamine (2.5 mg) and benzoic acid (3.0 mg) were added to a dichloromethane (2.5 mL) solution of 1-(4-aminobenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (10.1 mg, 0.023 mmol), and the resulting mixture was shaken at 25° C. for 16 hours. The reaction mixture was washed with a 2 M aqueous solution of NaOH (2 mL×2) and brine (1 mL) and then filtered through a PTFE membrane filter. The solvent was evaporated under reduced pressure to thereby provide yellow oil. The obtained yellow oil was purified by preparative TLC (SiO2, 10% methanol/dichloromethane) to afford 1-[4-(benzoylamino)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 519) as a colorless oil (4.6 mg, 36%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 553.2 (M++H, C30H31F3N4O3).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S-:13].[K+].[CH3:15]I.O>CN(C)C=O>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][CH3:15]
Reactant: Nn1c([S-])nc2ccccc2c1=O
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccccc2c(=O)n1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution 209 mg of potassium 3-amino-3H-quinazolin-4-one-2-thiolate in 5 ml of dimethylformamide, 141 mg of methyl iodide was added, and stirred for 20 minutes at room temperature. Water was added to the solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 161 mg (86%) of 3-amino-2-methylthio-3H-quinazolin-4-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:34][CH2:35]1)=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol) and THF (10 mL) was added methanesulfonyl chloride (98.3 μL, 1.27 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (141 mg, 61%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:34]([O-])=O)[C:6]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)[CH2:18][CH2:17]2)=[O:13])=[N:7][C:8]=1[O:9][CH2:10][CH3:11])#[N:2].[Cl-:37].[NH4+]>O1CCCC1.C(OCC)(=O)C.O.[Zn]>[ClH:37].[NH2:34][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][C:23]3[O:27][N:26]=[C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:24]=3)[CH2:20][CH2:21]2)=[O:13])=[N:7][C:8]([O:9][CH2:10][CH3:11])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)c([N+](=O)[O-])cc1C#N
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)c(N)cc1C#N
Product: Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of the compound prepared in Example 450 (120 mg) in tetrahydrofuran (2 mL) at ambient temperature was added zinc dust (160 mg), followed by saturated ammonium chloride (1 mL). The resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and water, and then filtered through a glass filter. The filter was washed with ethyl acetate. The combined two-phase filtrate and wash were transferred to a separatory funnel and the organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in methanol, and to convert to the hydrochloride salt, a 4 mol/L solution of hydrogen chloride in dioxane (0.1 mL) was added. The solvent was concentrated to provide the title compound (102 mg) with the following physical data.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[C:14]#[N:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1>N.C(O)C.[Co]>[CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: N#C/C=C1\CCc2ncc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: NC/C=C1\CCc2ncc3c(c21)CCO3
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
A suspension of (2E)-1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylideneacetonitrile (10.0 mg, 0.054 mmol) and Raney cobalt (100 mg) in 2M ammonia/ethanol (1 mL) was stirred at 50° C. for 3 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (10.0 mg, yield 99%).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([NH:14][C@@H:15]([CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:16](O)=[O:17])=[O:13])[CH2:2]1.ON1[C:29]2[N:30]=C[CH:32]=[CH:33][C:28]=2[N:27]=N1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>C1COCC1.CN(C=O)C>[C:29]([C:28]1([NH:27][C:16]([C@@H:15]([NH:14][C:12]([N:3]2[CH2:2][CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][CH2:4]2)=[O:13])[CH2:19][C:20]([F:22])([F:23])[CH3:21])=[O:17])[CH2:32][CH2:33]1)#[N:30]
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)O
Reactant: On1nnc2cccnc21
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(F)(F)C[C@H](NC(=O)N1CCC2(CCCCC2)CC1)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The crude product from example 8, (S)-2-[(3-azaspiro[5.5]undecane-3-carbonyl)amino]-4,4-difluoropentanoic acid, was dissolved in 6 ml of 2:1 THF/DMF and admixed with 161.8 mg (1.365 mmol, 1.05 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 176.9 mg (1.3 mmol, 1 eq.) of 1-hydroxy-7-azabenzotriazole, cooled to 0° C. and admixed with 250 mg (1.3 mmol, 1 eq.) of EDCl and with 0.496 ml (3.9 mmol, 3 eq.) of N-ethylmorpholine. Subsequently, the mixture was stirred at 0° C. to RT for 2 h, THF was distilled off under reduced pressure, ethyl acetate was added and the mixture was extracted by shaking with highly dilute HCl, sat. NaHCO3 solution and sat. NaCl solution. After concentration of the organic phase, a preparative HPLC separation (Merck Hibar Purospher RP18, 250×25, Standard-Gradient of acetonitrile-water-TFA) was performed directly. Product fractions were combined and freeze-dried.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])(F)F.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:19]1CCCC1>C(OCC)C>[F:10]/[C:4](=[CH:3]\[CH2:2][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:5]([O:8][CH3:9])=[O:19]
Reactant: Br[Mg]c1ccccc1
Reactant: COC(F)(F)C(F)=CCBr
Reactant: C1CCOC1
Solvent: CCOCC
Product: COC(=O)/C(F)=C/Cc1ccccc1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 1.0 g (4.5 mmol) 4-bromo-1-methoxy-1,1,2-trifluoro-2-butene in 15.0 mL tetrahydrofuran at -60° C. was added a solution of phenylmagnesium bromide (3M, 1.6 mL, 4.8 mmol) in diethyl ether and the mixture was stirred for 1 hr. at -60° C. then stirred for 12 hours at 20° C. The workup and acidic hydrolysis was done as mentioned in Example 3 to give 0.34 g (42%) of methyl (Z)-2-fluoro-4-phenyl-2-butenoate. 1H-NMR (300 MHz, CDCl3): δ 3.58(2H, dd, J=2, 9Hz), 3.81(3H, s), 6.29(1H, dt, J=9, 31 Hz), 7.18-7.34(5H, m). Mass spectrum: m/e=194 (M+). 19F-NMR (CDCl3): φ 131.3(d, J=31.1 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([SH:12])=[N:5][N:4]=1.I[CH2:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([S:12][C:6]1[N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][N:5]=1)[CH3:15]
Reactant: CC(C)Cn1c(S)nnc1CO
Reactant: CCI
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCSc1nnc(CO)n1CC(C)C
Yield: 87 %

Procedure:
A solution of 3-hydroxymethyl-4-isobutyl-5-mercapto-4H-1,2,4-triazole (1.0 g), iodoethane (1.0 g) and triethylamine (1.1 ml) in ethanol (10 ml) was stirred for 2 days at 70° C. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) as pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][NH:7][CH2:6][C:5]2[CH:9]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[S:11][C:4]=2[S:3]1(=[O:17])=[O:16].[CH2:18](Br)[CH:19]([CH3:21])[CH3:20].C(N(CC)CC)C.O>CN(C)C=O>[CH3:1][CH:2]1[CH2:8][N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]2[CH:9]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[S:11][C:4]=2[S:3]1(=[O:17])=[O:16]
Reactant: CC(C)CBr
Reactant: CC1CNCc2cc(S(N)(=O)=O)sc2S1(=O)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN1Cc2cc(S(N)(=O)=O)sc2S(=O)(=O)C(C)C1
Temperature: 80 °C
Yield: 63.8 %

Procedure:
A solution of 2(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepin-1,1-dioxide (1.18 g, 4.0 mmol) in dry dimethylformamide (6 mL) containing isobutylbromide (1.3 mL, 12 mmol) and triethylamine (2.3 mL, 16 mmol) was warmed at 80° C. for 20 hours in a sealed tube. The reaction mixture was poured into water and the product extracted into ethyl acetate. This extract was dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel and eluted with a 0-1% methanol/chloroform gradient to give 900 mg (64%) of title compound which slowly crystallized. Recrystallization from methylene chloride/butyl chloride gave analytically pure material, mp 158°-159.5° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[N+:18]([C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=2)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1-c1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 18.8 g (154.5 mmol) of phenylboronic acid, 30 g (74.6 mmol) of 2,5-dibromonitrobenzene and 53 g (212.7 mmol) of potassium carbonate in a mixture of 300 ml of water and 300 ml of THF, and the mixture is heated under reflux for 20 hours. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 23 g, 80% of theory; purity: 99.2% according to HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[N:10]1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[N:10]1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nccc2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of methyl 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoate (2.70 g) in a mixed solvent of methanol (20 mL) THF (20 mL) and water (10 mL) was added 8N aqueous sodium hydroxide solution (4.27 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.59 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22][OH:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22][OH:23])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1cccc(N)c1CO
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1CO
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a solution of t-butoxycarbonylaminoacetic acid (3.5 g) in methylene chloride (50 ml) was added triethylamine (2.0 g) and then ethyl chloroformate (1.9 ml) with ice-cooling. After being stirred for 1 hour, 2-amino-6-methylbenzyl alcohol (2.74 g) was added thereto and the mixture was stirred for 7 days at an ambient temperature. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with diethyl ether to give 2-(t-butoxycarbonylaminoacetamido)-6-methylbenzyl alcohol (1.04 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH:22]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50][C:32]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:32]([NH:28][NH:27][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])=[O:50])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: COC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NNC(=O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(c1C(=O)NNC(=O)C1CC1)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 80 °C
Yield: 519.8 %

Procedure:
Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (100 mg, 0.2178 mmol) and cyclopropanecarbohydrazide (1.5 equiv., 34.43 mg, 0.3267 mmol) were dissolved in dry N,N-dimethylformamide (0.87 mL) and triethylamine (0.13 mL). The solution was sparged with nitrogen. Palladium(II) acetate (0.05 equiv., 2.5 mg, 0.01089 mmol) and xantphos (0.05000, 6.430 mg, 0.01089 mmol) were added and the solution was purged and fixed with a CO balloon. The reaction was heated to 80° C. for 2 h. The reaction was monitored by LC/MS for consumption of starting material. The reaction was cooled to room temperature and diluted with methylene chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated. Purified by flash chromatography (10-100% EtOAc in heptanes) to afford 26 mg (26% yield) of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 Milliliters of acetonitrile was added to 500 mg of 4-[(4-cyanophenyl)amino]-4H-1,2,4-triazole, 0.42 ml of 4-fluorobenzyl bromide and 746 mg of potassium carbonate and the mixture was stirred for 2 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the resulting residue, which was then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The residue was subjected to silica gel column chromatography to give crude crystals from the chloroform/methanol (100/2) eluate. The crude crystals were recrystallized from ethyl acetate to give 314 mg of 4-[N-(4-cyanophenyl)-N-(4-fluorobenzyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([CH2:6][S:7][CH2:8][CH2:9][SH:10])=[N:2]1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[S:1]1[N:5]=[CH:4][C:3]([CH2:6][S:7][CH2:8][CH2:9][S:10][C:14](=[N:17][CH3:18])[NH:13][C:11]#[N:12])=[N:2]1
Reactant: CN=C(NC#N)SC
Reactant: SCCSCc1cnsn1
Product: CN=C(NC#N)SCCSCc1cnsn1

Procedure:
Conversion of 3-bromomethyl-1,2,5-thiadiazone into 2-((1,2,5-thiadiazol-3-yl)methylthio)ethane thiol by the precedure of Example 1 and treatment of this product with N-cyano-N',S-dimethylisothiourea according to the procedure of Example 2 leads to the production of the title compound.