Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=C)[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5].[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:1])[N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:8])[CH3:5]
Reactant: O=[O+][O-]
Reactant: C=CCC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Ozone was passed at −78° C. through a solution of 1.00 g of 169 (3.53 mmol) in a mixture of 12 ml of MeOH and 6 ml of CH2Cl2 until the solution turned blue. The reaction was subsequently terminated and excess ozone removed by purging with oxygen. Thereafter, 270 mg of NaBH4 (7.06 mmol, 2 eq.) was added and the mixture stirred overnight to allow warming to RT. After checking completion of the reaction by means of TLC (EE/CH 1:1), the batch was concentrated and the remaining residue taken up in 60 ml of CH2Cl2 and 40 ml of half-conc. NaCl solution. The aqueous phase was extracted with 3×20 ml of CH2Cl2, the combined organic phases were dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (EEICH 1:1) to obtain 691 mg (2.40 mmol, 68%) of alcohol 170 as a mixture of epimers (colorless oil).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)C.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH3:12][S:13]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:15])=[O:14]
Reactant: CC(=O)OCc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccn1

Procedure:
2-Methylpyridine of general structure III is prepared by α-methylation of substituted pyridine II using the method of Kray and Reinecke (J. Am. Chem. Soc., 1964, 86, 5355). Oxidation with m-chloroperbenzoic acid gives substituted 2-methylpyridine N-oxide IV. Treatment of the latter with phosphoryl chloride gives the 2-chloromethyl substituted pyridine VII. Alternatively, refluxing IV in acetic anhydride gives the 2-(acetoxymethyl) pyridine VII which is hydrolysed with aqueous base to the corresponding alcohol VII. When this hydroxymethyl derivative is treated with methanesulfonyl chloride in the presence of triethylamine, the 2-(methanesulfonyloxymethyl)pyridine is obtained, whereas treatment with brominetriphenylphosphine gives the 2-(bromomethyl)pyridine VII. When either the bromomethyl, chloromethyl, or the mesyloxymethyl pyridine derivative VII is refluxed in acetonitrile in the presence of triphenylphosphine, the corresponding phosphonium salt VIII is formed.
Reaction SMILES: [C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:41].[C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:24]=[CH:25][C:26]([C:29](=[NH:46])[NH2:30])=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C#N)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](N(OC)C)=[O:13])[CH2:8][CH2:7]1.CCOC(C)=O>C1COCC1>[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:13])[CH2:2][CH3:1])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1CCC(O)CC1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)C1CCC(O)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
EtMgBr (1 M, 3.0 eq, 20 mL) was added to a solution of 4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (1.0 g, 1.0 eq) in dry THF at 0° C. Once addition was complete, the mixture was stirred overnight. The reaction mixture was washed with saturated NH4Cl (aq), and extracted by EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (0.6 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 3.50-3.64 (m, 1H), 2.47 (q, J=7.2 Hz, 2H), 2.28-2.37 (m, 1H), 2.00-2.10 (m, 2H), 1.88-1.94 (m, 2H), 1.70-1.80 (m, 1H), 1.21-1.49 (m, 4H), 1.05 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([N:13]2[C:17]([CH2:18][F:19])=[N:16][N:15]=[C:14]2[SH:20])=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[Cl:42])=[O:30].O>CN(C=O)C>[Cl:42][C:33]1[CH:34]=[C:35]([S:38](=[O:41])(=[O:40])[NH2:39])[CH:36]=[CH:37][C:32]=1[NH:31][C:29](=[O:30])[CH2:28][S:20][C:14]1[N:13]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:17]([CH2:18][F:19])=[N:16][N:15]=1
Reactant: CCc1ccc(-n2c(S)nnc2CF)c2c1CCCC2
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(-n2c(CF)nnc2SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
In a solution of 4-(4-ethyl-5,6,7,8-tetrahydro-naphthalen-1-yl)-5-fluoromethyl-4H-[1,2,4]triazole-3-thiol (85 mg, 0.29 mmol), K2CO3 (44.4 mg, 0.32 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-chloro-4-sulfamoyl-phenyl)-acetamide (82.6 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered to give solid (73.0 mg, 47% yield).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:25]1([CH2:31][C:32]([N:1]=[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[SH:4](=[O:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:3]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
2.4 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are boiled for 1 hour with 1.32 g. triethylamine and 1.6 g. phenylacetyl chloride in 50 cc. chloroform. After working up in the usual manner, there is obtained 3-(phenylacetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide in the form of yellow crystals which, after recrystallisation from ethyl acetate, melt at 120°C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH:15]=[CH:14][O:13][C:12]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[H][H]>CO.[Pt](=O)=O>[N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH2:15][CH2:14][O:13][C:12]=23)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: c1cc2ccoc2c(N2CCNCC2)n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2c(c(N3CCNCC3)n1)OCC2
Yield: 95.1 %

Procedure:
A mixture of 7-(piperazin-1-yl)-furo[2,3-c]pyridine [CAS-No. 209160-83-8] (1 g, 4.92 mmol), platinum(IV) oxide (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9 ml) was stirred in a hydrogen atmosphere at room temperature for 24 h. After removal of the catalyst by filtration the mixture was evaporated, the residue was dissolved in dichloromethane (70 ml), washed with 2N sodium carbonate solution (40 ml), dried (MgSO4) and evaporated to yield 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine as a light brown oil (0.96 g, 95%), MS (ISP) m/z=206.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([NH:11][NH:12][CH:13]=O)=O.C(N(CC)CC)C.Cl[Si](C)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:13]=[N:12][N:11]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Brc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromoaniline (1.71 g, 9.94 mmol), N′-formylformohydrazide (2.64 g, 30.0 mmol), and triethylamine (9.74 mL, 69.9 mmol, 7.00 equiv) in pyridine (40 mL). Chlorotrimethylsilane (19.2 mL, 151 mmol) was added drop-wise and the resulting solution was stirred for 18 h at 100° C., then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was diluted with brine (50 mL) and extracted with ethyl acetate (6×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was washed with ether (30 mL) and the solids were collected by filtration to yield the title compound as a pink solid (1.6 g, 72%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:22])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)=[O:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2c(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)cccc21
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4c3ccn4C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 44.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(1-methyl-4-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.026 g, 44%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 80 mL of acetonitrile. To the stirred solvent was added 4-hydroxy benzaldehyde (4 g, 33 mmol) and K2CO3 (9 g, 65 mmol). Then it was stirred for 5 min. Benzyl bromide (6.7 g, 39 mmol) was added. Then RM heated 80° C. for 2 h. After completion of the reaction (reaction monitored by TLC), the RM was concentrated in vacuum to remove the acetonitrile. To the residue was then added 100 mL of water and extracted with ethyl acetate (150 mL×2). The organic layer was washed with saturated brine solution (50 mL), dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (4.5 g, 64.75%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25]O)[C:18]=2[O:17]1>>[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)[C:18]=2[O:17]1
Reactant: CC1(C)Cc2cccc(CO)c2O1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC1(C)Cc2cccc(COc3ccnn3-c3cc(C#N)ccn3)c2O1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,2-dimethyl-3H-1-benzofuran-7-yl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.48 (6H, s), 3.03 (2H, s), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.83 (1H, q, J=8.0 Hz), 7.13 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.0 Hz), 7.37 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.07 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O2, 347. Found, 347.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1.[H-].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:15]2)[N:3]=1
Reactant: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccc(F)cc1)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 100 mg (0.245 mmol) of methyl {4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate (preparation described in WO 2008/031513, example 9) were initially charged in tetrahydrofuran (10.0 ml) and the suspension was cooled to 0° C. Subsequently, 9.8 mg (0.245 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 30.5 μl (0.245 mmol) of 4-fluorobenzyl bromide were added dropwise and the reaction mixture was stirred at RT overnight. Subsequently, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed twice with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 91.8 mg (72% of theory) of the title compound in solid form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20][OH:21])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.CCCCCC.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(C=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (2.0005 g, 7.037 mmol, Prepared in Example 1) and manganese(IV) oxide (6.118 g, 70.37 mmol) in toluene (46.91 mL) was heated to reflux. After 3 h, the mixture was cooled to rt and filtered through a pad of Celite™. The pad was rinsed with DCM (200 mL). The filtrate was concd under reduced pressure to give an orange solid. The orange solid was suspended in hexane (50 mL), sonicated, and filtered to give 3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (1 H, s), 7.78 (1 H, dd, J=8.6, 7.0 Hz), 7.18-7.68 (5 H, m), 7.06 (1 H, d, J=6.7 Hz), 2.92 (3 H, s); Mass Spectrum (ESI) m/e=283.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([C:16]#N)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C(O)=[O:21]>[Al].[Ni]>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[O:21])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: N#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2

Procedure:
3-Trifluoracetyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (20.3 g) and nickel-aluminium alloy (35.5 g) in 75% aq. formic acid (400 ml) were heated at 80° C. for 3 h. The reaction was allowed to cool, filtered and the filtrate extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, dried and evaporated to give 3-trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde (20.0 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13](O)=[O:14])[CH:5]=[CH:6][CH:7]=1.C[N:36](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:36])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: O=C(O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 0.050 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.41 g), 1 mL of dimethylformamide and 0.0418 g (0.11 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) was added 0.016 g (0.3 mmole) of ammonium chloride and 0.052 mL (0.3 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour. The solid was removed by filtration and the filtrate was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.032 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.41) as a white powder. MH+/Z=496
Reaction SMILES: C(ON=O)CC(C)C.[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=1.[I:24]CI.O>C(#N)C>[F:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([I:24])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Oc2ccccc2F)cc1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: Fc1ccccc1Oc1ccc(I)cc1
Temperature: 55 °C
Yield: 91.7 %

Procedure:
Add isoamylnitrite (2.45 g, 2.5 Eq.) to 4-(2-fluoro-phenoxy)-phenylamine (1.70 g, 8.37 mmol) and diiodomethane (7.84 g, 3.5 Eq.) in acetonitrile (10 mL) while stirring at 55° C. under a nitrogen atmosphere. Slowly heat mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the desired material into ethyl acetate. Wash this organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 2.41 g of an oil. Purify the material by silica gel chromatography (Prep. 2000) eluting with hexane/methylene chloride 9:1 to provide 1.60 g of the title compound as a thin oil. Mass spectrum (m/e): 314.0 (M*): (Bruker 300) 1H NMR (CDCl3) δ 7.55-7.60 (2H, d), 7.02-7.20 (4H, m), 6.69-6.72 (2H, d).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36]([OH:38])=O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.[NH2:48][C:49]1[N:50]=[CH:51][C:52](/[C:64](=[N:66]/[NH2:67])/[NH2:65])=[N:53][C:54]=1[C:55]1[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=1>CC(N(C)C)=O>[NH2:65]/[C:64](/[C:52]1[CH:51]=[N:50][C:49]([NH2:48])=[C:54]([C:55]2[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=2)[N:53]=1)=[N:66]\[NH:67][C:36]([CH:35]1[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:40][CH2:39]1)=[O:38]
Reactant: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (74.3 g, 195.44 mmol) was added to a solution of N-Boc-isonipecotic acid (41.1 g, 179.15 mmol) and 4-methylmorpholine (35.9 mL, 325.74 mmol) in DMA (800 mL). The mixture was stirred for 10 minutes then (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (45 g, 162.87 mmol) was added to the solution in one portion (exotherm observed from 22° C. to 27° C.). After a few minutes the product crystallised from the reaction mixture. The reaction mixture was removed from the vessel and filtered through a sinter. Additional DMA was added to wash product from the sides of the vessel (150 mL) and this was poured onto the filter cake. Isopropanol (600 mL) was added to the vessel and the remainder of the product in the vessel was suspended in this solvent using vigorous agitation. The isopropanol suspension was used to wash the filter cake once the DMA had been removed by suction. The filter cake was sucked dry then washed with MTBE and sucked dry once again. The filter cake was dried in vacuo to afford (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate (76 g, 95%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.40 (9H, s), 1.46 (9H, s), 1.63-1.9 (2H, m), 2.33-2.6 (2H, m, obscured by DMSO signal), 2.63-3.03 (2H, m), 3.18-3.48 (4H, m, obscured by water signal), 3.88-4.11 (2H, m), 6.43 (2H, s), 7.76 (2H, br), 8.84 (0.5H, s), 8.87 (0.5H, s), 9.85 (1H, s); Mass Spectrum [M+H]+=488
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](O)(=O)[CH2:24]CCCCCCCCCCCCCCCC.[OH-].[Na+:44].[N+]([O-])(O)=O>C(O)(=O)CCCCCCCCCCCCCCCCCCCCC.O>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH3:24].[Na+:44]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In an amount of 32.4 g of behenic acid, 9.9 g of arachidic acid and 5.6 g of stearic acid were dissolved in 945 mL of pure water at 90° C. Then, the solution was added with 98 mL of 1.5 mol/L sodium hydroxide aqueous solution with stirring at high speed. Subsequently, the solution was added with 0.93 mL of concentrated nitric acid, cooled to 55° C. and stirred for 30 minutes to obtain a sodium behenate solution.