Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:18]=[O:19])[CH:5]=1.[CH3:21][Zn]C.[Li+].[OH-]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:18]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:21])[C:3]([OH:2])=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Reactant: C[Zn]C
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1C=O
Temperature: 25 °C

Procedure:
Under nitrogen, Pd(dppf) (72 mg, 89 μmol) was added to a solution of 3-formyl-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (2.80 g, 8.97 mmol) in dioxane (40 mL). The mixture was stirred at rt and dimethyl zinc (11.2 g, 13.5 mmol, 12.1 mL of a 1.2M solution in toluene) was added. The mixture was stirred at 75° C. for 1 h. The mixture was cooled to rt before a 2M aq. LiOH solution (40 mL) was added. The mixture was stirred at rt for 2 h before it was concentrated. The residue was dissolved in EA and extracted with 1M aq. NaOH and water. The aq. extracts were acidified by adding 2N aq. HCl (30 mL) and then extracted with EA. The org. extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by prep. HPLC to give the title compound as a pale yellow powder (903 mg). LC-MS*: tR=0.27 min, [M−H]−=162.90; 1H NMR (D6-DMSO): δ 2.69 (s, 3H), 7.49 (d, J=7.8 Hz, 1H), 8.08 (dd, J=7.8, 1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 10.29 (s, 1H), 13.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15]>O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14]2=[O:15]
Reactant: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Solvent: O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Temperature: 100 °C
Yield: 80.6 %

Procedure:
4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (37 g, 123 mmol), from Step 5, was added dropwise to 200 g of polyphosphoric acid heated to 100° C. The resultant mixture was stirred and heated at 100° C. for 0.25 h. A mixture of 100 g of ice and 200 mL of water was added to the reaction mixture. The precipitate which formed was filtered, washed with 3×75 mL of water and dissolved in 300 mL of methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give 28 g (81% yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1 -one, m.p; 127°-128° C.; 1H NMR (CDCl3) δ: 2.75-3.0 (m, 3H), 3.3-3.5 (m, 2H), 3.8 (s, 3H), 3.95 (s, 3H), 6.93 (d, 1H), 7.25-7.4 (m, 5H), 7.9 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C([O-])([O-])=O.[K+].[K+].O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:11]#[N:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(-c2cnc(N)c(C=O)c2)c1
Yield: 41.2 %

Procedure:
2-amino-5-bromonicotinaldehyde (0.1 g, 0.5 mmol), 3-cyanophenylboronic acid (0.146 g, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.02 mmol), and K2CO3 (0.14 g, 1.0 mmol) were combined in 3 mL of 4:1 CH3CN:H2O and heated to 150° C. for 5 minutes in the SmithSynthesizer™ microwave instrument. Upon cooling, the reaction mixture was chromatographed on silica gel eluting with hexanes/ethyl acetate (0% EtOAc to 100% EtOAc over 10 minutes) to afford 3-(6-amino-5-formylpyridin-3-yl)benzonitrile (46 mg) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:28][C:29]([CH3:33])([CH3:32])[C:30]#[CH:31]>CN(C=O)C.C(N(CC)CC)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
To a solution of compounds 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (500 mg, 1.09 mmol) and 3,3-Dimethyl-but-1-yne (385 mg, 4.69 mmol) in DMF (0.5 mL), triethylamine (1.06 mL) and tris(dibenzylideneacetone) dipalladium (0) (70 mg, 0.08 mmol) are added and the reaction mixture is stirred under reflux conditions for 16 h under a N2 atmosphere. DMF and triethylamine are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer is separated, dried (Na2SO4), concentrated and the residue is purified by column chromatography using ethyl acetate and hexane (1:2) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid, 330 mg (66%).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+]>C(O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
In 20 ml of ethyl alcohol is dissolved 4.7 g of BOC-(D)-Met-Gly-OEt. After cooling, 16 ml of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. The ethyl alcohol is distilled off, and the residue, after adding aqueous citric acid solution to neutralize, is extracted with 100 ml of ethyl acetate, followed by washing with water and drying over anhydrous sodium sulphate. The AcOEt isdistilled off and the residue is crystallized with petroleum ether. Recrystallization from AcOEt-petroleum ether results in a yield of 3.8 g of the desired product, m.p. 124°-125° C., Rf1 =0.41, [α]D21 +12.3° (c=0.59, DMF)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20](=[O:22])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1
Product: O=C(NCC(=O)N1CCCCC1)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from {4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and piperidine according to the method described in Example 1.1/f. MS (EI) 533.3 (MH+).
Reaction SMILES: [C:1]([CH:4](CC(O)=O)[CH2:5][S:6][C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:8]=1[N+:16]([O-])=O)([OH:3])=[O:2].C(Cl)(Cl)Cl.[CH3:27][OH:28]>O.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]([CH2:4][CH:5]1[S:6][C:7]2[S:11][C:10]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:9][C:8]=2[NH:16][C:27]1=[O:28])([OH:3])=[O:2]
Reactant: CO
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])c(SCC(CC(=O)O)C(=O)O)s1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1cc2c(s1)SC(CC(=O)O)C(=O)N2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Titanium trichloride (256 ml, 15 wt % in 20-30 wt % HCl) was added in a steady stream to a stirred suspension of 5-(2,3-dicarboxypropylthio)-4-nitrothiophene-2-sulfonamide (21.8 g, 61.0 mmol) in water (128 ml) and acetic acid (128 ml). This mixture was stirred at ambient temperature for 18 hours and the yellow solid that precipitated was collected by filtration, washed with water and dried to yield 17.6 g. Chromatography over silica gel using chloroform/methanol/conc. aqueous ammonia (60:30:10; v/v/v) followed by recrystallization from water gave 3-carboxymethyl-2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazine, mp 240° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:33]([O-:36])([O-:35])=[O:34].[Na+:37].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:33]([O-:36])(=[O:35])=[O:34])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: O=S([O-])[O-]
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1n(CCCCCCCS(=O)(=O)[O-])c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (2.0 g) in ethanol (10 ml) was refluxed with a solution of sodium sulphite (0.55 g) in water (5 ml) for 20 hours. More sodium sulphite (0.2 g) was added and refluxing continued for a further 20 hours. The mixture was evaporated to dryness, boiled in ethanol, filtered hot and evaporated to an oil. This was taken up in a small volume of ethanol, excess diethyl ether added and the precipitated solid filtered off and chromatographed on silica gel (dichloromethane/methanol 5:1). The resulting oil in methanol/water 1:1 was passed down an Amberlyst 15 ion exchange resin (Na form) and evaporated to a solid. This was taken up in ethanol and precipitated with diethyl ether giving sodium 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanesulphonate (0.49 g), 23%) as a white solid, m.p. 160° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:41][OH:42]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@H:18]([O:42][CH3:41])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[C:10]1([CH2:20][CH3:21])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCC1(CC)c2cc(O)ccc2CC2C1N2C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a slurry of 7,7-diethyl-5-hydroxy-1a,2,7,7a-tetrahydro-1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (170.0 g, 535.6 mmol) and methanol (1700 mL) was added pyridinium p-toluenesulfonate (13.4 g, 53.6 mmol) and the reaction mixture was stirred at 40° C. for 4 h. The volume was reduced by rotary evaporation to ˜300 mL resulting in a thick white slurry. The product was isolated by filtration; the filter cake was washed with cold methanol (50 mL) and dried in air for 3 h to yield the title compound (150 g). The filtrate was reduced to ˜50 mL and stirred at 0° C. for 2 h, filtered, and dried to yield additional product (25 g).
Reaction SMILES: [C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31](F)=[O:32])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH3:34]>>[C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31]([NH2:34])=[O:32])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: N
Reactant: O=C(F)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Product: NC(=O)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h
Yield: 85.5 %

Procedure:
The acid fluoride, C3F7OCF(CF3)CF2OC(CF3)2COF, (4.51 g, 8.20 mmol) was reacted with ammonia (18.88 mmol) in vacuo at -78° C. for 10 minutes, then at -23° C. for 3 hours. The volatiles were removed at room temperature by pumping and the involatile residue was treated with dry Freon 113 (20 ml) and filtered in an inert atmosphere enclosure. The filtrate, after Freon 113 removal, gave 3.82 g (86% yeild) of C3F7OCF(CF3)CF2OC(CF3)2CONH2 which was characterized by mass spectrometry. MS(70 eV) m/e (intensity, ion): 526 (2.1%, M-F), 360 (29.4%, M-C3F7O), 260 (7.0%, CF2OC(CF3)2CONH2), 194 (17.2%, C(CF3), 169 (25.7%, C3F7), 69 (48.4%, CF3), 44 (100%, CONH2), 169 (25.7%, C3F7), 69 (48.4%, CF3), 44 (100%, CONH2).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:17])[CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:17][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:16][CH2:15]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC1(N)CC1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CC1
Yield: 62.7 %

Procedure:
A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid 6-yl)oxirane and 950 mg of (1-methylcyclopropyl)amine in 1 ml of absolute ethanol was heated at 70° C. for 4 hours in a sealed reaction tube. The reaction mixture was concentrated under reduced pressure and the residue chromatographed on silica gel plates (95:5:1 methylene chloride: methanol:conc. ammonium hydroxide) to give 338 mg of product, m.p. 72°-73° C.
Reaction SMILES: [P:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=[O:22]>CO.C(Cl)Cl>[P:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[N:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=2)=[CH:13][CH:14]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Reactant: NNC(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCSP(=O)(OC)Oc1ccc(C=NNC(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-methyl S-ethyl O-(4-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 3-chlorobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O-methyl S-ethyl O-[4-(3-chlorobenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: C[C:2]1[C:32](C)=[CH:31][C:5]2[N:6](C(=O)CN3CCN(CCO)CC3)[C:7]3N=CC=C[C:8]=3[C:9]3[N:10](C(=O)NN=3)[C:4]=2[CH:3]=1.[H-].[Na+].CN(C)CCCCl.CN(C)C=[O:46]>C1(C)C(C)=CC=CC=1>[N:10]1[C:4]2[CH:3]=[CH:2][CH:32]=[CH:31][C:5]=2[N:6]=[CH:7][C:8](=[O:46])[CH:9]=1
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(CCO)CC1
Reactant: CN(C)C=O
Agent: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=c1cnc2ccccc2nc1
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-9-[[4-(2-hydroxyethyl)piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling [3-(dimethylamino)propyl]-chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[[4-(2-hydroxyethyl)-piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo]4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[OH:28])=[CH:11][C:10]=1[F:29])C1C=CC=CC=1>CO.[Pd]>[F:29][C:10]1[CH:11]=[C:12]([C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][C@H:16]2[OH:28])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)c(F)c2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](O)C1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To (3S,4S)-tert-butyl 4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate (4.0 g, 9.96 mmol, E-2 from step C) in degassed MeOH (100 mL) was added 10% Pd/C (0.191 g, 1.79 mmol) and the reaction was repeated evacuated and flushed with hydrogen gas. Then placed under 1 atm of hydrogen for 4 h. The reaction solution was purged with nitrogen and filtered through celite. The filtrated was concentrated to afford (3S,4S)-tert-butyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate (2.99 g, 96% yield) as a grey oil. LC-MS [M+H]+−tBu=256.05; 1H NMR (500 MHz, DMSO-d6) δ 7.03-6.95 (m, 1H), 6.89-6.78 (m, 2H), 4.78 (d, J=4.6 Hz, 1H), 4.09 (br. s., 2H), 3.94 (br. s., 1H), 3.36 (dd, J=9.5, 4.7 Hz, 1H), 3.17 (s, 1H), 2.80-2.58 (m, 1H), 2.42-2.27 (m, 1H), 1.65 (dd, J=13.4, 3.4 Hz, 1H), 1.56-1.33 (m, 10H).
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:8][OH:9].[ClH:10]>CCOCC>[ClH:10].[C:1](=[NH:7])([O:9][CH3:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC#N
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: C=CCCCC(=N)OC

Procedure:
Through a stirred solution of 5-hexenenitrile (3 g, 31Mmol) and MeOH (35 mmol) in Et2O (30 ml), at 0° C., HCl gas was bubbled for 10 minutes. Solvent was evaporated in vacuo and the residue treated with Et2O to give 5.1 g of the title compound as white solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[C:5]([NH2:31])=[CH:4][CH:3]=1.[CH3:32]OC(OC)OC.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:31]=[CH:32][N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH3:24])[N:15]4[CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:11]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[N:10]=3)[C:6]=2[CH:7]=1
Reactant: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3N)nc2n1C1CCOCC1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1nc2c(-c3ccncc3)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a vial containing crude 5-chloro-N1-(8-methyl-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.035 mmol) was added anhydrous methanol (2.5 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and methane sulfonic acid (catalytic amount) and the reaction mixture was stirred under Ar at room temperature for 4 h (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (3.5 mg, 22% yield on two steps), as a yellow oil. TFA salt. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.32 (s, 1H), 8.91 (br m, 4H), 8.79 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 4.76-4.72 (m, 1H), 4.32-4.29 (m, 2H), 3.72 (app t, J=11.7 Hz, 2H), 3.08-3.05 (m, 2H), 2.87 (s, 3H), 2.02 (br d, J=10.9 Hz, 2H); MS (EI) m/z 446.3 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][C:7]=1[CH3:8].C(O)CCC.[CH:21]([NH:23][NH2:24])=O.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([CH:21]=[N:23][N:24]=3)[N:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)nnc1Cl
Reactant: NNC=O
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1cc(-c2cccc(Cl)c2)nn2cnnc12

Procedure:
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 50 ml. of n-butanol and 1.08 g. of formylhydrazine is refluxed for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is added gradually until crystals separated. Cooling and filtering gives 1.20 g. of crystals, m.p. 173°-176° C. The crystals in methylene chloride are passed through a short column of hydrous magnesium silicate and the eluent concentrated with the addition of hexane to give 0.83 g. of crystals, m.p. 181°-182° C.
Reaction SMILES: [F-].[K+].I[C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10].[S:16]1[C:20](B(O)O)=[CH:19][C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]1=2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[S:16]1[C:20]([C:4]2[C:5]([O:14][CH3:15])=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=2)[CH:9]=[O:10])=[CH:19][C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]1=2
Reactant: COc1cc(OC)c(C=O)cc1I
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 60 °C

Procedure:
Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 1.0 g, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), and tri-tert-butylphosphine (100 mg, 0.05 mmol) were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter. The reaction mixture was heated at 60° C. for one hour under nitrogen. HPLC analysis indicated of 100% conversion of 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123) to the title compound prepared through another route (Ex-3A).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S-:15][C:16]#[N:17].[NH4+].BrBr>CO>[C:1]([C:5]1[C:6]([S:15][C:16]#[N:17])=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])c(N)c1
Agent: BrBr
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(N)c([N+](=O)[O-])cc1SC#N

Procedure:
The title compound was prepared according to the General Method 13 using 5-tert-butyl-2-nitro-phenylamine (prepared in Example PP-2; 170 g, 876 mmol), ammonium thiocyanate (400 g, 5260 mmol), bromine (140 g, 876 mmol), and MeOH (500 mL). The crude reaction mixture was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 252 (M+H).