Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].[N+:31]([C:34]1[CH:35]=[C:36]([CH:43]=[CH:44][CH:45]=1)[CH2:37][C@@H:38]([C:40]([OH:42])=O)[NH2:39])([O-:33])=[O:32].[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:46]([O:48][C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:40](=[O:42])[C@H:38]([CH2:37][C:36]2[CH:43]=[CH:44][CH:45]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=2)[NH2:39])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)N1CCNCC1
Reactant: N[C@@H](Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
TIPPS-3-nitro-(L)-phenylalanine (210 g; 0.44 mmol; 76% purity), ethyloxycarbonylpiperazine (69.7 g; 0.44 mmol) and 1-hydroxybenzotriazole (101 g; 660 mmol) were dissolved in 650 ml of DMF and cooled to 10° C. A solution of dicyclohexylcarbodiimide (100 g; 0.484 mmol) in 216 ml of DMF was added dropwise over a period of 2 h and the reaction solution was stirred at RT overnight. After evaporating the solvent, the residue was dissolved in 436 ml of MTBE, the precipitate was filtered off, and the organic solution was extracted in each case 2× with 5% KHSO4, 5% NaHCO3 and distilled water. The solvent was evaporated under vacuum, toluene was added and then evaporated in a rotary evaporator and the product was dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:22][C:23](=[O:25])[CH3:24])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC(=O)CCl
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1ccc2c(c1)C(=O)NC(C)(C)O2

Procedure:
70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one in 400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone are stirred under reflux for 30 hours. After the addition of a further 3.2 ml of chloroacetone, the reaction mixture is refluxed for a further 15-20 hours. The reaction mixture is filtered whilst still warm; the residue is thoroughly washed with acetone, and the combined filtrate is concentrated by evaporation. The crystalline residue is recrystallised from toluene and yields 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one, m.p. 125°-126°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[C:14]1([NH:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:23][C:22]2[C:21]([NH:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: O=Cc1cccnc1Nc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2ccccc2)cc1OC
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
To a solution of 3,4-dimethoxyacetophenone (182 mg, 1.01 mmol) in methanol (5 mL) was added 2N Ba(OH)2solution (2 mL) and stirred for 5 minutes. Then added 2-(phenylamino)nicotinaldehyde (200 mg, 1.01 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture was acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6b) (328.5 mg, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:4]2[O:5][C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([CH3:1])[N:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1nc(CCOc2ccc([N+](=O)[O-])cc2)oc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(CCOc2ccc(N)cc2)oc1-c1ccccc1
Yield: 97 %

Procedure:
A solution of 4-methyl-2-[2-(4-nitrophenoxy)ethyl]-5-phenyloxazole (12.5 g) in methanol (150 ml) was subjected to catalytic reduction in the presence of 5% Pd-C (wet, 3.0 g). The catalyst was then filtered off and the filtrate was concentrated to give 2-[2-(4-aminophenoxy)ethyl]-4-methyl-5-phenyloxazole (11.0 g, 97.3%). Recrsytallization from ethanol gave colorless needles. M.p. 106°-107° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([S:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[O:20][N:19]=1>>[CH3:30][S:29][C:24]1[C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CSc1ncccc1-c1nc(CCl)no1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: CSc1ncccc1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2-(methylthio)pyridine: MS (ES) m/z 416 (M+1).
Reaction SMILES: [Br:1]Br.[CH:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([O:15][C:16](=[O:17])[C:9]3=[CH:8][CH:7]=[CH:6]2)=[O:14])[CH:12]=1>[N+]([O-])(O)=O>[CH:3]1[CH:12]=[C:11]2[C:13]([O:15][C:16](=[O:17])[C:9]3=[C:10]2[C:5](=[CH:6][C:7]([Br:1])=[CH:8]3)[CH:4]=1)=[O:14]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: BrBr
Solvent: O=[N+]([O-])O
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 70 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
Bromine (8.2 g, 51.3 mmol) was added to a solution of 1,8-naphthalic anhydride (10.0 g, 50.5 mmol) in 70% nitric acid (200 mL) at 25° C. The mixture was stirred at 70° C. for 2 hours and cooled overnight. The solids that separated were filtered, washed with water, and dried to give 2.0 g of the title compound (Reference: J. C. S., 1938:1764-1767).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:39])[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.Cl.[NH:41]([C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=[O:46])[NH2:42]>C(N(CC)CC)C>[CH3:36][O:35][C:27]1[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:39])[N:41]([C:43]3[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=3[C:45]([OH:47])=[O:46])[N:42]=2)[CH:26]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc2c1OCOC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 2 ml of a DMF solution containing 130 mg of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (21h)), 46 mg of 2-hydrazinobenzoic acid hydrochloride and 0.200 ml of triethylamine were added. The resulting mixture was stirred at 80° C. for 8 hours under a nitrogen atmosphere, and then the reaction mixture was concentrated. The residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid, and 250 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature overnight. To this reaction mixture, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-{(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro[1,2,4]triazol-1-yl)benzoic acid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:10]
Reactant: O=[O+][O-]
Reactant: C=CCCCCCCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCCCCCCBr
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 26 mmol) in a mixture of 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -50° C. and treated with O3 until a blue color persisted (45 min) and then for an additional 10 min. The mixture, at -40° C., was purged with N2 for 10 min, allowed to warm to -20° C., under N2, and kept at -20° C. while 1.3 g (34 mmol) of sodium borohydride was added in portions over 30 min (evolution of H2 was evident at each addition). The mixture was stirred 30 min more at -20° C. and quenched with the dropwise addition of 20 mL of H2O. This mixture was stirred for 10 min, and extracted with hexane; the organic extracts were washed with water, then brine, dried (Na2SO4) and concentrated to give 3.65 g (72%) of 7-bromo-1-heptanol: NMR (CDCl3) δ1.44 (m, 9H), 1.85 (m, 2H), 3.41 (t, 2H), 3.65 (t, 2H).
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.[F:37][C:38]([F:49])([F:48])[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][N:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C@H:2]1[C@@H:7]([N:8]2[CH2:11][C:10]([CH2:34][C:35]#[N:36])([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][NH:23][C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9]2)[CH2:6][CH2:5][N:4]([C:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:38]([F:49])([F:37])[F:48])[N:44]=2)=[O:46])[CH2:3]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN([C@H]2CCN(C(=O)c3ccnc(C(F)(F)F)n3)C[C@H]2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a solution of {1-[cis-3-fluoropiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (200 mg, 0.4 mmol) and 2-(trifluoromethyl)pyrimidine-4-carboxylic acid (83 mg, 0.43 mmol) in DMF (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.20E2 mg, 1.17 mmol) and triethylamine (0.14 mL, 0.98 mmol). The mixture was stirred at room temperature overnight and purified with prep-LCMS to give 100 mg (36% yield) of the desired compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([NH:9][C:5]2[C:4]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccnc1O
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=C(Nc2ccccc2)C(Nc2ccccc2)=NC1=O
Reaction time: 2 h
Yield: 25 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), aniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. Product was then filtered and recrystallized with petroleum ether. 5,6-diphenylamino-2,3-pyridindione can then be obtained in a brown yellow powder. The yield was 25%-45%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](OC)=O)[CH:2]=1.C[OH:13].[BH4-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:13])[CH3:8])[CH:2]=1
Reactant: COC(=O)Cc1cccnc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(O)c1cccnc1
Temperature: 25 °C

Procedure:
Into a 500-mL flask to which a nitrogen gas introduction tube, thermometer, and Dimroth condenser had been attached were introduced 21.29 g (0.141 mol) of the methyl 3-pyridylacetate obtained above and 250 mL of anhydrous methanol. The contents were stirred at room temperature. The atmosphere in the flask was replaced with nitrogen, and 15.62 g (0.372 mol) of sodium borohydride was added to the contents little by little. The resultant mixture was heated and reacted for further 3.5 hours with refluxing. Thereafter, the liquid reaction mixture was cooled to room temperature, and 100 mL of water was added thereto to hydrolyze the excess sodium borohydride remaining unreacted. The methanol was distilled away under vacuum. Thereafter, an extraction operation using 100 mL of chloroform was conducted twice, and the resultant organic phase was washed with 100 mL of saturated aqueous sodium chloride solution and dried by adding anhydrous sodium sulfate thereto. The anhydrous sodium sulfate was removed by decantation. Thereafter, vacuum distillation was conducted to obtain 12.59 g (0.102 mol) of 3-pyridylethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)Nc3ccccc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) was added to the solution and stirred for 10 min. at RT. 2-Chloro-N-phenylacetamide (87 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobil e Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+]>CO>[F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:36])=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a dry flask was added a solution of 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanone (CB55) (0.98 g, 2.4 mmol) in dry methanol (30 mL). The flask was evacuated/backfilled with nitrogen and ammonium acetate (2.6 g, 34 mmol) was added, followed by sodium cyanoborohydride (0.18 g, 2.9 mmol). The reaction was stirred at room temperature overnight. The solution was quenched with water and extracted with ethyl acetate. The organics were dried, filtered, and concentrated to provide the title compound as a white solid (0.42 g, 34%): 1H NMR indicated the presence of 2 isomers, which were not separated. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (two s, 1H), 8.14-8.03 (m, 4H), 7.66-7.60 (m, 2H), 7.53-7.40 (m, 2H), 3.47-3.16 (br s, 2H), 3.29 (td, J=11.0, 3.8 Hz, 1H), 2.59 (td, J=11.6, 11.1, 3.7 Hz, 1H), 2.17-2.04 (m, 1H), 1.86-1.68 (m, 3H), 1.68-1.30 (m, 4H); ESIMS m/z 402 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(O)(=O)C.C(O)(=O)C.[I:20]C1C=CC=CC=1.II>CN(C)C=O.COC(C)(C)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([I:20])[CH:10]=1
Reactant: Ic1ccccc1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1cc(Cl)cc(I)c1C(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
4-Chloro-2-methylbenzoic acid (1.7 g, 10 mmol), palladium(II) acetate (112 mg, 0.5 mmol), iodobenzene diacetate (6.44 g, 20 mmol) and elemental iodine (5.08 g, 20 mmol) were dissolved in N,N-dimethylformamide (50 mL) and stirred overnight at 100° C. The reaction mixture was cooled to room temperature, diluted with methyl-tert-butylether and 2M hydrochloric acid and washed with 10% aqueous solution of sodium metabisulphite. Organic phase was extracted with 2M sodium hydroxide and the resulting basic aqueous phase was acidified with concentrated aqueoushydrochloric acid and re-extracted with methyl-tert-butylether. The solvent was removed under reduced pressure affording 4-chloro-2-iodo-6-methylbenzoic acid (2.8 g, 94% yield) without further purification. So obtained iodinated benzoic acid (2.8 g, 9.4 mmol) was dissolved in N,N-dimethylformamide (25 mL) and methyliodide (1.25 mL, 20 mmol) and potassium carbonate (2.8 g, 20 mmol) were added. The reaction mixture was stirred overnight at room temperature, diluted with methyl-tert-butylether and washed with water, 1M sodium hydroxide, water and brine. Solvent was removed under reduced pressure and the crude was purified by flash chromatography (n-hexane/diethyl ether 100:2) to give title compound (2.2 g, 75% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][N:13]=[C:18]=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccccc1OCc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
38.5 g of 2-benzyloxybenzylamine hydrochloride are suspended in 400 ml of distilled toluene and heated at a bath temperature of 140°. Whilst stirring, phosgene is introduced and after about 50 minutes the solution becomes clear. After a further 10 minutes, the addition of phosgene is interrupted and boiling is continued for a further hour. The solution is then left to cool a little and the toluene is distilled off in vacuo. A sample of the oil remaining was distilled in a bulb tube: Boiling point, bath temperature 120°/0.06 torr.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([OH:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([OH:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-hydroxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>CO>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]1=[O:2]
Reactant: Oc1ncccn1
Reactant: ClCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Product: O=c1ncccn1Cc1ccc2ccccc2c1
Yield: 92 %

Procedure:
A 14.6 g (0.11 mole) portion of 2-hydroxypyrimidine hydrochloride in 700 ml of methanol was treated with 23.3 g (0.22 mole) of Na2CO3, 7.5 g (0.05 mole) of NaI and 20.0 g (0.11 mole) of 2-(chloromethyl) naphthalene. The reaction mixture was refluxed for 18 hrs and concentrated to dryness under reduced pressure. The solid was taken up in 200 ml of H2O and extracted with 300 ml of CHCl3. The chloroform extract was washed with 100 ml of H2O, dried over MgSO4 for 2 hrs and filtered. The filtrate was concentrated under reduced pressure to give 24 g (92%) of a cream solid, m.p. 136°-145°.
Reaction SMILES: [I-].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[CH:4]1.[BH4-].[Na+].[ClH:26]>C(O)C.O>[ClH:26].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:13][C:14]([C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH:18]=3)=[N:15][N:16]=2)=[CH:4]1
Reactant: Cn1cc(-c2nnc(-c3cc[n+](C)cc3)o2)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: CCO
Solvent: O
Product: CN1CC=C(c2nnc(-c3cn(C)c4ccccc34)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-(1-methylindol-3-yl)-1,3,4-oxadiazol-5-yl]-1-methylpyridinium iodide (1.0 g) was suspended in a mixture of ethanol (50 ml) and water (5 ml) with vigorous stirring. NaBH4 (200 mg) was added portionwise until the solution was clear and colourless. The solution was stirred for one hour at room temperature. 2N Hydrochloric acid (10 ml) was added to quench the excess NH4OH, followed by 0.88 NH3 to pH 12, the solution was then extracted with dichloromethane (4×100 ml), dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography on silica eluting with methanol/dichloromethane (2:98). The isolated product was treated with an excess of ethereal HCl, recrystallisation from absolute methanol afforded the title compound as a white solid m.p. 245°-250° C. Found: C, 61.35; H, 5.85; N, 16.74; C17H18N4OCl requires C 61.72; H, 5.78; N, 16.93%; δH (360 MHz, D2O 2.67 (2H, bm, CH2 --N--CH3), 3.07 (3H, s, N--CH3), 3.4 (2H, brm, CH2N--CH3), 3.55 (3H, s, N--CH3), 3.48 (2H, brm, CH2CH2N), 6.27 (1H, brm, C=CH--CH2), 7.09 (2H, brm, H-5,6), 7.11 (1H, d, J=5 Hz, H-4), 7.22 (1H, s, H-2), 7.35 (1H, d, J=5 Hz, H-7); m/z 294 (M+ free base, 100%), 158 (40), 110 (30), 94 (30), 77 (10).