Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:38]5[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: OB(O)c1ccncc1
Product: c1cc(-c2ccncc2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 42 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.19 mmol) and pyridine-4-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (41 mg, 42%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.66 (d, 2H), 8.02 (d, 1H), 7.96 (s, 1H), 7.76–7.69 (m, 3H), 7.58–7.51 (m, 3H), 7.33 (t, 1H), 6.36 (d, 1H), 6.06–6.04 (m, 2H), 5.15 (m, 1H), 4.32 (m, 1H), 4.01 (m, 1H), 2.17–2.03 (m, 4H), 1.81–1.52 (m, 12H); MS m/z 516 (M+1).
Reaction SMILES: [P:1]([O-:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[CH3:22][C:23]([CH3:25])=[O:24]>>[O:2]([P:1]([C:23]([OH:24])([CH3:25])[CH3:22])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 50 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (234 g) diphenyl phosphite (DPP) and 500 ml THF were added. The mixture was heated to 50° C. and then stirred. The mixture was heated to a temperature of 90° C. and the stirring was continued until DPP was dissolved completely. To this solution was added slowly 1.0 mole (58 g) acetone within two hours, and the temperature thereof was increased to 70° C. and maintained at that temperature for four hours after the addition of acetone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenoxy phosphoryl) propan-2-ol [DPOP; (II)]. Yield, 96%; m.p. 70–72° C. Anal. Calcd. for C15H17PO4: C, 61.64; H, 5.82; O, 21.92; P, 10.62. Found: C, 61.52; H, 5.96; O, 21.78; P, 10.74. EIMS, m/z: 292 (92. M+).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13][CH2:14]O>>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[I:1])[CH3:14]
Reactant: CCO
Reactant: Cc1cccc(C(=O)O)c1I
Agent: Cl
Product: CCOC(=O)c1cccc(C)c1I
Temperature: 0 °C

Procedure:
A solution of the 2-iodo-3-methylbenzoic acid (6 g-0.023 mol) in EtOH (150 mL) is treated with concentrated HCl (20 mL) and refluxed for 48 h. After removal of the EtOH in vacuo, the residue is diluted with water (125 mL) and cooled to 0° C. in an ice bath. The pH is adjusted to 10 with solid NaOH pellets and extracted with EtOAc (3×75 mL). The organic extracts are washed with water (2×50 mL) and brine (2×50 mL) and dried over MgSO4. Concentrated in vacuo to give the product as a pale yellow oil. (6 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1.C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[NH:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][O:15][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1)[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc(Cl)c2c(C#CCCOC(=O)OCC)cn(Cc3ncc(C)c(OC)c3C)c2n1
Temperature: 0 °C

Procedure:
A suspension of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (0.73 g) in anhydrous pyridine (5 mL) and DCM (25 mL) was treated with ethyl chloroformate (1 mL) at rt for 30 min. The mixture was cooled to 0° C., treated with addition EtOCOCl (1 mL), and the temperature was allowed to slowly reach rt overnight. The reaction mixture was diluted with DCM (30 mL) and washed sequentially with H2O, NH4OH 1M, and brine. The DCM was evaporated, but not the residual pyridine, Addition of MeOH (20 mL) induced crystallization of the product, as white needles. HPLC Rt=6.28 min.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:44])[NH:35][O:36][Si](C(C)(C)C)(C)C)[CH:29]=1)(=[O:3])[CH3:2].[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:44])[NH:35][OH:36])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)NO[Si](C)(C)C(C)(C)C)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)NO)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-[(1-{4-[N-(t-butyldimethylsilyloxy)carbamoyl]butyl}-1H-1,2,3-triazol-4-yl)methylidene]-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (148 mg) in dichloromethane (3 ml) was added 4N solution of hydrogen chloride in dioxane (230 μl) at 0° C. The resulting mixture was stirred at room temperature for 15 minutes. The solvent and excess hydrogen chloride were removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of methanol and dichloromethane (3:97 to 15:85) as the eluent to afford (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[4-(N-hydroxycarbamoyl)butyl]-1H-1,2,3-triazol-4-yl}methylidene)piperidine hydrochloride (110 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:17]=O.CO.[C:21]([O:25][CH3:26])(=[O:24])[NH:22][NH2:23]>C(O)(=O)C>[CH3:26][O:25][C:21](=[O:24])[NH:22][N:23]=[CH:17][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1]
Reactant: COC(=O)NN
Reactant: Cc1[nH]c(-c2cccc(C(F)(F)F)c2)nc1C=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)NN=Cc1nc(-c2cccc(C(F)(F)F)c2)[nH]c1C
Yield: 90.1 %

Procedure:
A mixture of 5-methyl-2-(α,α,α-trifluoro-m-tolyl)imidazole-4-carboxaldehyde (20.0 g, 0.0787 mole), methanol (500 ml), methyl carbazate (7.8 g) and glacial acetic acid (0.5 ml) is refluxed overnight. The solution is then concentrated to afford 23.14 g of title product. A sample is recrystallized from methanol-acetone, m.p. 251°-251.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.Cl.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH2:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH:43][C:18]([C:7]1[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:6]=1)=[O:20])[CH3:42]
Reactant: C[C@@H](N)c1ccc(F)cc1F
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2F)cn1CC(OC)OC
Reaction time: 1 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.315 g, 1.00 mmol), was suspended in acetonitrile (4 ml) and treated with N,N-diisopropylethylamine (DIPEA) (0.348 mL, 2.00 mmol), (R)-1-(2,4-difluorophenyl)ethanamine HCl salt (0.213 mg, 1.10 mmol) and HATU (0.418 g, 1.10 mmol). The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step. LCMS-ESI+ (m/z): [M+H]+ calculated for C21H25F2N2O7: 455.16; found: 455.1.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1([CH3:28])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH3:17])[O:8]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([O:18][C:12]1[C:13]([CH3:17])=[C:14]2[C:9](=[C:10]([CH3:27])[C:11]=1[CH3:26])[O:8][C:7]([CH2:6][CH2:5][OH:4])([CH3:28])[CH2:16][CH2:15]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OCCC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2

Procedure:
To a solution of 0.5 g. of (±)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman in 15 ml. of methanol was added a solution of 358 mg. of potassium carbonate in 1.5 ml. of water. The mixture was heated at reflux under N2 for 40 minutes, cooled, poured into water and extracted with methylene chloride. The methylene chloride solutions were washed with brine, dried over magnesium sulfate and stripped of solvent to give (±)-6-benzyloxy-2-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman as an oil.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:21]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:21])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Yield: 60 %

Procedure:
Following the procedure of Preparation I, Part b, but substituting 2.0 gm. (0.0069 mole) of the dimethyl ester of 4-cyano-4-phenylpimelic acid (prepared in Part a, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 45 ml. of the tetrahydrofuran, 1.57 gm. (0.014 mole) of the potassium tert-butoxide, and 10 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm., and the 175 ml., respectively, there is obtained a residue which upon recrystallization from technical hexane gives 1.07 gm. (60% yield) of the desired 2-carbomethoxy-4-cyano-4-phenylcyclohexanone having a melting point at 79.5° to 81.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=S)[CH2:18][C:19](=O)[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].S(O)(O)(=O)=O.[CH2:32]([NH:40][NH2:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:26][O:25][C:23]([C@@H:14]1[CH2:13][C@@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]1[C:17]1[N:40]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:41]=[C:19]([CH3:20])[CH:18]=1)=[O:24]
Reactant: NNCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 464 a) was reacted with 2-phenethyl-hydrazine sulfate (CAS Reg. No. 56-51-4) to give the title compound as yellow oil. MS (ESI): m/z=506.1 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:12][CH2:11][C@H:7]1[C:8](O)=[O:9])=[O:5].C(=O)=O.CC(C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C@H:13]2[N:6]3[C@@H:7]([C:8](=[O:9])[S:1][CH2:2][CH2:3][C:4]3=[O:5])[CH2:11][CH2:12]2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc([C@H]2CC[C@@H](C(=O)O)N2C(=O)CCS)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2CC[C@@H]3C(=O)SCCC(=O)N32)cc1OC
Reaction time: 0.08 h

Procedure:
The compound produced in Example 2 is dissolved in about 500 milliliters methylene chloride and the solution is chilled under nitrogen to 15° C. in a dry ice-acetone mixture. 4-Dimethylaminopyridine is added and the mixture is stirred for five minutes. A slight excess of dicyclohexylcarbodiimide dissolved in methylene chloride is added with stirring. The chilled source is removed after 15 minutes and the solution is stirred overnight at room temperature. The volume of the reaction mixture is reduced on a rotary evaporator under reduced pressure to about 100 milliliters. A precipitate is removed by filtration and the filter residue is washed several times with methylene chloride. The filtrate and combined washings are washed successively with 1N HCl, saturated aqueous NaHCO3, water and saline and the solution is dried over MgSO4. Evaporation of the methylene chloride with a rotary evaporator under reduced pressure yields the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[O:11][N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>CO.[Pd]>[F:28][C:26]1[CH:25]=[CH:24][C:23]2[N:17]3[CH:16]=[N:15][C:14]([C:12]4[O:11][N:10]=[C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[N:13]=4)=[C:18]3[C@@H:19]3[CH2:31][CH2:30][N:20]3[C:21](=[O:29])[C:22]=2[CH:27]=1
Reactant: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)n1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)n1
Yield: 56.8 %

Procedure:
1 g (2.2 mmol) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 5 ml of methanol were hydrogenated at room temperature and normal pressure in the presence of 22 mg of 5% palladium-on-charcoal. After separating the catalyst the residue was purified by chromatography on silica gel while eluting with ethyl acetate/hexane/triethylamine 17/2/1. There was obtained 0.53 g (56%) of (S)-7-fluoro-12,12a-dihydro-1-(3-di-n-propylaminomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one (oil: Rf. 0.36; Kieselgel 60 F254. Eluent: ethyl acetate/hexane/triethylamine 17/2/1), which was converted into the hydrochloride.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[CH:14]([C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:19]=[CH:18][C:17]=1B(O)O)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[N:19][N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=3[CH:14]=[O:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: C[Si](C)(C)CCOCn1ncc(B(O)O)c1C=O
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3cnn(COCC[Si](C)(C)C)c3C=O)cc2N1
Yield: 54.1 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.444 g, 1.70 mmol), (5-formyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)boronic acid (0.554 g, 2.05 mmol), cesium carbonate (2.77 g, 8.50 mmol), 1,2-dimethoxyethane (15 mL) and water (4 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.139 g, 0.17 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 2 h. Then, the mixture was poured into water (100 mL) and EtOAc (100 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford the title compound (374 mg, 54%) as a yellow solid:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccn1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccn1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and pyridin-2-yl-hydrazine according to example 43 gave the desired product. MS: M=472.0 (M+H)+
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1.Cl>ClCCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:18]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)/C=C/C(=O)c1cc(F)ccc1O
Temperature: 50 °C

Procedure:
Into 100 ml of 1,2-dichloroethane, maleic anhydride (11.3 g, 114 mmol) and anhydrous aluminum chloride (31.0 g, 228 mmol) were dissolved by heating at 50° C. for 15 minutes, and then p-fluoroanisole (12.6 g, 100 mmol) was added dropwise. The mixture was refluxed for an hour and then poured into 60 ml of concentrated hydrochloric acid with 400 g of cracked ice. Resulting crystals deposited out therein were obtained through a filtration, washed with water and dried in vacuo to give 16.0 g (80.0%) of the subject desired compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C(N[C:27]1[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=1[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=O)C>>[C:8]([NH:12][C:39]1[CH:40]=[CH:27][C:28]([O:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[C:5]([C:8]5[O:9][C:10]([CH3:13])=[N:11][N:12]=5)[CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])=[CH:35][CH:36]=2)=[CH:37][CH:38]=1)(=[O:9])[CH3:5]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(=O)Nc1ccccc1Oc1ccc(N)cc1
Product: CC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(-c4cc(-c5nnc(C)o5)ccc4C)cc3)cc2)cc1

Procedure:
N-[4-(4-Acetylaminophenoxy)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(acetylaminophenoxy)aniline using method I. LCMS; retention time 3.42 min, MH+ 519.
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(Cl)Cl>[ClH:28].[ClH:8].[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:33]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: C=CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 49.6 %

Procedure:
A solution of triethylamine (2.0 g; 20 mmole) in methylene chloride was added dropwise to a mixture of 1-(3-amino-propyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (7.54 g; 20 mmole) and allyl isocyanate (1.66 g; 20 mmole) in methylene chloride. After the addition was completed the mixture was washed with water and the solvent removed. The resulting orange oil was purified on a silica gel column (methylene chloride/methanol; 9:1), precipitated with ethereal hydrochloric acid, and recrystallized from ethanol/water to provide the title compound (2.1 g; 25% yield) as colorless crystals, m.p. 232°-234° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([N:25]2[CH2:29][CH2:28]SC2=S)=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40]CCN.CO>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([NH:25][CH2:29][CH2:28][O:40][CH3:39])=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=C(c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1)N1CCSC1=S
Solvent: CO
Solvent: ClCCl
Product: COCCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1

Procedure:
To a slurry of the trithiazolide 17 (31.0 g, 0.05 mol) in dichloromethane (600 mL), a solution of 2-methoxyethylamine (0.38 g, 5 mmol) in dichloromethane (30 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in methylene chloride). The desired product was obtained as yellow, thick oil; yield 2.1 g (73% based on the methoxyethylamine). 25.8 g of unreacted starting trithiazolide was also recovered during the separation.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].CC(O)=O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4.8 g of 2-butyl-4-chloro-5-formyl-1-[(2'-methoxycarbonyl-1,1'-biphenyl-4-yl)methyl]-1H-imidazole in 100 ml of absolute ethanol is added with a solution of 0.44 g of NaBH4 in 10 ml of ethanol. The mixture is stirred at room temperature for 1 hour then is acidified with glacial CH3COOH to pH 4. The resulting solution is evaporated to dryness under reduced pressure and the residue is taken up into ether. The in soluble part is filtered, the ether solution is evaporated to dryness and the residue is stripped more times with toluene.