Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>COCCOC.C([O-])(O)=O.[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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:21]1[C:22]([C:23]#[N:24])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
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: COCCOC
Product: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 43.4 %

Procedure:
A mixture of 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (37.62 g, 0.141 mol), 2-bromobenzonitrile (35.30 g, 0.194 mol) and tetrakis(triphenylphosphine)palladium(0) (5.85 g, 5.06 mmol) in ethylene glycol dimethyl ether (350 ml) and saturated aqueous NaHCO3 (150 ml) was degassed by bubbling nitrogen through the mixture for 30 min. The mixture was then stirred at 90° C. under nitrogen for 15 h. After allowing to cool, the mixture was partitioned between dichloromethane (500 ml) and water (400 ml). The organic layer was washed with brine, dried (MgSO4), then passed through a pad of Florisil®, washing the product through with more dichloromethane. The filtrates were evaporated in vacuo, and the residue was triturated with diethyl ether (100 ml) and isohexane (100 ml). The resulting solid was collected by filtration, washed with 50% Et2O/isohexane and dried under vacuum to give 14.82 g (43%) of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a white solid. The combined filtrates were concentrated in vacuo to approximately 100 ml and the resulting solid was collected by filtration, washed with 20% Et2O/isohexane and dried under vacuum to give another 0.94 g (3%) of the product. The filtrates were evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 10-15% EtOAc/isohexane) to afford another 3.07 g (9%) of the product: 1H NMR (360 MHz, CDCl3) δ 7.40 (1H, t, J 8.5 Hz), 7.53 (1H, d, J 7.8 Hz), 7.59 (1H, td, J 7.7, 1.1 Hz), 7.74 (1H, td, J 7.7, 1.3 Hz), 7.84 (1H, dd, J 7.7, 0.9 Hz), 8.34-8.39 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:24])[N:3]=1.[F:25][C:26]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:24][C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:25])[CH:33]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(Cl)ccc4[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cc(Cl)ccc5[nH]4)C3)nc(N)n2)cc1F
Yield: 56.8 %

Procedure:
To a suspension of 4-chloro-6-(2-(5-chloro-1H-benzo[d]imidazol-2-yl)morpholino)pyrimidin-2-amine (200 mg, 0.548 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (176 mg, 0.712 mmol) and Na2CO3 (145 mg, 1.369 mmol) in 1,4-dioxane (2.4 mL) and water (0.8 mL) under nitrogen was added Pd(PPh3)4 (63.3 mg, 0.055 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial high to 140° C. for 1 hour. The reaction mixture was partitioned between EtOAc/THF (25/25 mL) and water (50 mL). The organic phase was washed with water (50 m, dried (Na2SO4) and evaporated in vacuo. The residue was triturated with EtOAc (1×10 mL). The resulting solid was filtered through a coarse fritted glass funnel and collected to afford the title compound (140 mg). LC-MS (ES) m/z=450 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:25]=[C:24]([Cl:26])[C:6]([C:7]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[C:12]=3[CH:11]=[CH:10]2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH2:35]>C(#N)C>[Cl:26][C:24]1[CH:25]=[C:3]([CH2:2][NH:35][CH3:34])[CH:4]=[C:5]([Cl:27])[C:6]=1[C:7]([N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C:12]=2[CH:11]=[CH:10]1)=[O:8]
Reactant: CN
Reactant: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CBr)cc1Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNCc1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
A solution of N-{1-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (50 mg, 0.107 mmol) in acetonitrile was treated with cesium carbonate (69.74 mg, 0.2140 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of methyl amine (10.68 mg, 0.16 mmol). The reaction mixture was then stirred at room temperature for about 20 minutes and concentrated under vacuum, followed by addition of ice cold water to give N-(1-{2,6-dichloro-4-[(methylamino)methyl]benzoyl}-1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (27.5 mg) as white solid.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=O)C.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To tert-butyl (6R,7S)-6-(acetylamino)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was desalted by a solid phase extraction resin (column: PL StrastoSphere solid phase extraction resin (PL-HCO3 MP StratoSpheres™), 500 mg, StrastoSphere, mobile phase: methanol). To a solution of the residue obtained by concentration under reduced pressure in ethanol was added a solution of fumaric acid (33.7 mg) in ethanol. The mixture was concentrated under reduced pressure to give the title compound (130 mg).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([OH:24])[CH2:22][OH:23].CC(C)([O-])C.[K+]>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[O:23][CH2:22][CH2:21][OH:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1ccccc1
Yield: 99.9 %

Procedure:
A mixture of 2-benzenesulfonylmethyl-4-fluoro-1-nitrobenzene (10.2 g, 34.7 mmol), ethylene glycol (80 mL, 1.4 mol), and 1 M potassium tert-butoxide in THF (78 mL, 78 mmol) in THF (50 mL) was refluxed under nitrogen for 30 minutes. After cooling to about ambient temperature, the reaction mixture was solvent evaporated. Water was added to the residue, and it was poured into 2.0 N hydrochloric acid and ice. The mixture was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 74° C. for 20 minutes. 2-(3-Benzenesulfonylmethyl-4-nitro-phenoxy)-ethanol as a dark brown gum (11.7 g, 100% yield) was obtained; Mass spectrum (−EI, [M−H]−) m/z 336. 1HNMR (500 MHz, DMSO-d6): δ8.01 (d, 1H, J=9.15 Hz), 7.67-7.73 (m, 1H), 7.54-7.63 (m, 4H), 7.10 (dd, 1H, J=9.51 Hz and 2.93 Hz), 6.85 (d, 1H, J=2.81 Hz), 5.12 (s, 2H), 4.88-4.90 (m, 1H), 3.93-3.96 (m, 2H), 3.65 ppm (d, 2H, J=4.51 Hz). Elemental Analysis for C15H15NO6S: Calcd: C, 53.41; H, 4.48; N, 4.15; Found: C, 53.47; H, 4.69; N, 4.04;
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: [O-][n+]1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Oc2ccncc2)cc1
Yield: 100.5 %

Procedure:
After 4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide (130.0 g) was dissolved in ethanol (500 mL) and (50% wet) 5 w/w % palladium on carbon (6.5 g) was added. The resulting mixture was stirred under 3 atms of atmosphere of hydrogen at 27-49° C. for 6.5 hr. The reaction mixture was filtered to remove the catalyst followed by concentration in vacuo to give a quantitative yield (122.9 g) of pale yellow oily crude product. Purification by flash column chromatography (600 g of Silica Gel 60, spherical, ethyl acetate) afforded the pure target compound product as a colorless oil (86.74 g, 70.91% yield).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O)([O-:9])=[O:8]>C(Cl)Cl.CN(C=O)C>[Cl:4][C:2]1[CH:19]=[C:18]([CH:17]=[CH:16][C:1]=1[Cl:6])[CH2:10][NH:7][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Oxalyl chloride (4.8 ml) was added to a solution of 3-nitro-4-methylbenzoic acid (9.06 g) in methylene chloride (100 ml) and DMF (a few drops) and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was dissolved in methylene chloride (100 ml). 3,4-Dichlorobenzylamine (7.04 g), 4-dimethylaminopyridine (0.31 g) and triethylamine (13.9 ml) were added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography using a 250:8:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium chloride solution as eluent to give N-(3,4-dichlorobenzyl)4-methyl-3-nitrobenzamide as a solid (9.95 g); NMR Spectrum: (DMSOd6) 2.57 (s, 3H), 4.47 (d, 2H), 7.31 (m, 1H), 7.56 (m, 2H), 7.61 (d, 1H), 8.1 (m, 1H), 8.47 (d, 1H), 9.3 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[NH:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[NH:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)[S:8][C:7]=4[C:6]=3[CH:28]=2)[CH:31]=[N:30]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(F)c1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(-c4cn[nH]c4)ccc2OCC3)c(F)c1

Procedure:
5-(9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole was treated with 4-pyrazoleboronic acid pinacol ester using standard Suzuki condition to yield 400. NMR: (CDCl3): 3.15 (2H, t), 4.31 (2H, t), 6.82 (1H, s), 7.01 (1H, d), 7.08-7.18 (2H, m), 7.31 (1H, d), 7.51-7.55 (1H, m), 7.72 (1H, s), 7.90 (2H, s, br.), 8.18 (1H, s). MS. ESI+ 489 (MH++MeCN)
Reaction SMILES: [CH:1](OC)(OC)[O:2][CH3:3].[NH2:8]/[C:9](/[C:14]#[N:15])=[C:10](\[NH2:13])/[C:11]#[N:12].CO>O1CCOCC1>[NH2:13]/[C:10](=[C:9](\[N:8]=[CH:1][O:2][CH3:3])/[C:14]#[N:15])/[C:11]#[N:12]
Reactant: COC(OC)OC
Reactant: N#C/C(N)=C(/N)C#N
Solvent: C1COCCO1
Solvent: CO
Product: COC=N/C(C#N)=C(\N)C#N
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Trimethyl orthoformate (31-8 g; 0.3 mol) was added dropwise to a slowly distilling solution of diaminomaleonitrile (32.4 g; 0.3 tool) in 1,4-dioxane (250 mL). The methanol that formed during the reaction was removed by distillation. The reaction mixture was concentrated in vacuo and cooled to room temperature. The precipitate was collected and crystallized from THF-pentane to yield 33.6 g (62%) of 2-amino-3-(methoxymethylenamino) maleonitrile having a melting point of 138°-139° C.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16](Cl)=[CH:17][C:12]=3[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22][NH2:23]>>[C:1]1([O:7][C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16]([NH:22][NH2:23])=[CH:17][C:12]=3[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)Oc1ccccc1)C2

Procedure:
A solution of 20.3 g of crude oily 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid phenyl ester in 100 cc of hydrazine hydrate is stirred in an oil bath of 100° for 11/2 hours. The reaction solution is concentrated in a vacuum and the residue is divided between 225 cc of chloroform and 25 cc of water. The crude title compound is obtained as semicrystalline residue upon concentrating the organic phase in a vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 2-hydroxy-4-methoxy-1-nitrobenzene (520 mg, 3.08 mmol), benzyl bromide (522 mg, 3.08 mmol) and potassium carbonate (637 mg, 4.61 mmol) in DMF (3 mL) is stirred at 65° C. for 18 h. The mixture is poured into water and the mixture extracted with EtOAc. The organic phase is washed with water (3×) and brine (1×) and is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:40]([Cl:42])=[O:41])[C:10]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 94 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole (1.25 g, 2.88 mmol, example 25) was dissolved in methylene chloride and diisopropylethylamine (2.41 mL, 13.8 mmol) was added. The mixture was cooled in an ice bath and phosgene (6.09 mL, 11.52 mmol, 20% in toluene) was added. The reaction mixture was stirred for 30 mm at ice temperature and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (1.35 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@@H:19]([CH3:21])[C@@H:18]([CH2:22]S([O-])(=O)=O)[C@@H:17]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#[N:43].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:43])[C@H:17]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:16]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CS(=O)(=O)[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 80 °C
Reaction time: 6 h
Yield: 5 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-(tert-butoxycarbonylamino)-5-methylpiperidin-4-ylmethanesulfonate (1.0 equiv.) in DMF (0.10 M) was added NaCN (5.0 equiv.). The mixture was stirred at 80° C. for 6 hrs and partitioned between EtOAc and H2O. The organic layer was washed NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate in 5% yield. LC/MS (m/z)=432.2 (MH+), Rt=0.73 min.
Reaction SMILES: C(O)(=O)C.Cl.C(OC(=O)[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH:30]C(=O)C2C=CC=CC=2)=[N:25][CH:24]=[CH:23]3)[CH2:15][CH2:14]1)(C)(C)C>CO>[NH2:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([S:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([NH2:30])=[N:25][CH:24]=[CH:23]3)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Sc2ccc3c(NC(=O)c4ccccc4)nccc3c2)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nccc2cc(S[C@H]3CC[C@H](N)CC3)ccc12

Procedure:
Potassium carbonate (160 mg) and methanesulfonic acid cis-4-tert-butoxycarbonylaminocyclohexyl ester (140 mg, 0.47 mmol) were added to a solution of N-(6-mercaptoisoquinolin-1-yl)benzamide residue in DMA (4 ml). The mixture was irradiated in a microwave at 120° C. for 600 s then concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester. Glacial acetic acid (1 ml) and 6M hydrochloric acid (2 ml) were added to the trans-[4-(1-benzoylaminoisoquinolin-6-ylsulfanyl)cyclohexyl]carbamic acid tert-butyl ester and the mixture was refluxed for 24 h. The mixture was then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and then eluted with 2M ammonia in methanol to give cude trans-6-(4-aminocyclohexylsulfanyl)isoquinolin-1-ylamine, which was further purified using prep-HPLC (9 mg), EIMS: m/z=274.5 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(C(=NO)N)[CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:26]4[CH2:28][CH2:27]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)C1CC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCN12
Reaction time: 2 h

Procedure:
15.0 g (42 mmol) of 1-[[(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 60 ml of N,N-dimethylformamide, whereupon the solution is treated with 4.60 g (46 mmol) of cyclopropanecarboxamidoxime and the mixture is heated to 100° for 2 hours. The mixture is evaporated to dryness, the residue is treated with 50 ml of acetic acid and the mixture is stirred at 115° for 2 hours. After evaporation of the solvent the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there is obtained (S)-8-chloro-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 140°-142°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)C1CCN(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-4-piperidinecarboxylic acid (0.1 g, 0.45 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.165 mL, 2.25 mmol) was added drop-wise. After stirring for 1 h the solvent was removed by evaporation, DCM was added to the residue which was then re-concentrated to give 1-(4-fluorophenyl)-4-piperidinecarbonyl chloride which was used directly in step 2. Step 2: The acid chloride from step 1 was taken up in DCM (2.5 mL) and added drop-wise to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.121 g, 0.38 mmol) in DCM (2.5 mL), followed by triethylamine (0.080 mL, 0.57 mmol). The reaction mixture was stirred for 3 h under argon, then the solvent was removed by evaporation. The residue was partitioned between DCM (30 mL) and water (30 mL). The aqueous was re-extracted with DCM (30 mL) and the combined organic layers were dried and concentrated to yield the title compound as a yellow oil. δH (CDCl3, 400 MHz) 7.40 (2H, d), 7.15 (2H, d), 6.89 (2H, m), 6.80 (2H, m), 4.20 (1H, br.s), 3.82 (1H, d), 3.50 (4H, m), 3.27 (3H, s), 3.10 (1H, m), 2.76 (1H, d), 2.58 (1H, d), 2.35 (3H, m), 2.17 (1H, m), 2.00 (3H, m), 1.70 (2H, d), 1.46 (9H, s), 1.22 (3H, d). MS (ES): MH+ 525.4. Description 60
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (11.1 g, 80.5 mmol) was added to a solution of the (4-benzyloxy-phenylethynyl)trimethylsilane 101 (13, from above) in methanol (70 mL). The mixture stirred at room temperature for 16 h and was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a dark brown solid. This material was purified via column chromatography (eluting with 0-5% ethyl acetate-hexane) to afford 1-benzyloxy-4-ethynyl-benzene 102a as an off-white solid.