Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(I)(I)P(I)I.[CH2:7]([O:9][C:10]([C:12]1[C:16]([CH:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)O)=[C:15]([S:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)[N:14]([CH:34]([CH3:36])[CH3:35])[N:13]=1)=[O:11])[CH3:8].S(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:16]([CH2:17][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[C:15]([S:25][C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)[N:14]([CH:34]([CH3:35])[CH3:36])[N:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccncc1
Agent: IP(I)P(I)I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution containing 660 mg of diphosphorus tetraiodide in 5 ml of anhydrous toluene was heated at 80° C. for 20 min under nitrogen in the dark. The mixture was then treated dropwise with a solution of 674 mg of 5-(3,5-dichlorophenylthio)-4-[(4-pyridyl)hydroxymethyl]-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml of anhydrous toluene. The mixture was stirred at 80° C. for 1 h and then left to cool to room temperature. The mixture was treated with 10 ml of a 10% solution of sodium bisulphite and then stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:1 to 2:1) for the elution to give 483 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-carboxylic acid ethyl ester as a pale yellow gum. Mass spectrum (ESI) m/z 450 [M+H]+.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[CH2:8][O:7]1)([CH3:3])[CH3:2].[CH3:9][CH:10]([CH3:12])[O-:11].[K+].C(O)(=O)C>CCCCCC.C(O)(C)C>[CH:10]([O:11][CH2:8][CH:6]([OH:7])[CH2:5][O:4][CH:1]([CH3:3])[CH3:2])([CH3:12])[CH3:9]
Reactant: CC(C)OCC1CO1
Reactant: CC(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C)OCC(O)COC(C)C
Temperature: 80 °C

Procedure:
2-(Isopropoxymethyl)oxirane (23.23 g, 25.1 mL, 200 mmol) was dissolved in hexane (20 mL) and placed in reactor. Separately (1.2 g, 20 mmol) of KH was slowly added to (90.1 g, 115 mL, 1.5 Mol) of isopropanol at RT. After deprotonation was complete the solution of potassium isopropoxide in isopropanol was added to the reactor. All operations were performed in a glove box. The reactor was sealed and heated 80° C. for 24 hours. After cooling acetic acid (20 mmols) and ca. 5 g. of powdered talc were added to the reaction mixture followed by filtration through a plug of celite. The solvent was evaporated and the residue distilled under vacuum affording 20.09 g of 1,3-diisopropoxypropan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][S:11]([CH3:13])=[O:12])=[CH:4][N:3]=1.[N-:15]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][S:11]([CH3:13])(=[NH:15])=[O:12])=[CH:4][N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Cc1ccc(Cl)nc1)CS(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(Cl)nc1)CS(C)(=N)=O
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 2-chloro-5-[2-methyl-3-(methylsulfinyl)propyl]-pyridine (2.15 g, 9.3 mmol) and sodium azide (1.81 g, 28 mmol) in chloroform (30 mL) cooled in an ice-water bath was added concentrated H2SO4 (6 mL) and the resulting mixture stirred at this temperature for 10 min. The reaction was then heated at 55° C. in an oil-bath for 16 hrs. Upon cooling down, the mixture was diluted with ice-water (70 mL) and the organic layer removed. The aqueous phase was washed with CH2Cl2 (2×30 mL) and the organic phase was discarded. The aqueous phase was made basic by the careful addition of aqueous ammonia whereupon an oil separated, which was extracted with CH2Cl2 (2×30 mL). The combined organic phase was dried over MgSO4 and solvent evaporated to give 2.15 g of the product as a yellowish oil in 94% yield. [M+H]+=247, 249; δ 1.11 (overlapping d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([NH2:21])=[N:18][C:19]=2[NH2:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:29]([O:31][CH2:32][C:33](Cl)=[O:34])[CH3:30]>C(Cl)(Cl)Cl>[CH2:29]([O:31][CH2:32][C:33]([NH:21][C:17]1[N:18]=[C:19]([NH2:20])[C:14]([CH2:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][N:16]=1)=[O:34])[CH3:30]
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCC(=O)Nc1ncc(Cc2cc(OC)c(OC)c(OC)c2)c(N)n1
Temperature: 50 °C

Procedure:
5.8 g of trimethoprim are suspended in 80 ml of chloroform. After addition of 4 g of triethylamine 2.5 g of ethoxyacetyl chloride are dripped in at room temperature. The mixture is stirred for another hour at 50° C. and then cooled. The triethylammonium chloride is separated by filtration, the filtrate is concentrated and the residue is recrystallized from isopropanol. 4 g of 2-ethoxyacetamido-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 175° to 176° C. are obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O>ClCCl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(-c2ccccc2)oc1-c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of (2-phenyl-5-(pyridin-3-yl)oxazol-4-yl)methanol (210 mg, 832 μmol) and triethylamine (253 mg, 348 μL, 2.5 mmol) in dichloromethane (4 mL) was added at 0-5° C. methanesulfonyl chloride (191 mg, 130 μL, 1.66 mmol). The ice bath was removed after 10 min and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give the product as light brown solid (197 mg, 728 μmol, 87.4%) which was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:28][CH3:29])=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:30])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:33].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:33][C:18]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:11]2[C:10]3[CH:9]=[C:8]([O:28][CH3:29])[C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:30])=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n(CC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 6.18 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Intermediate 14) (220 mg, 0.539 mmol) was dissolved in POCl3 (2 ml, 21.46 mmol), PCl5 (0.2 g, 0.960 mmol) was added and the mixture was heated at 120° C. for 24 h. The reaction mixture was evaporated in vacuo to give a beige solid. This was dissolved in DCM (3 ml) and loaded onto a 25 g silica column, then eluted with 0-10% 2M methanolic ammonia/DCM (25 column volumes) and product containing fractions were evaporated in vacuo to give 2-chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (14.2 mg, 0.033 mmol, 6.18% yield) as beige solid. LCMS (formate) Rt 0.81 min, MH+ 427.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[C:9](S(N3C4=NC=CC=C4C=C3)(=O)=O)[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2B(O)O)[CH:36]=[CH:35]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]4[C:42]=3[NH:34][CH:35]=[CH:36]4)=[CH:9][N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(S(=O)(=O)n3ccc4cccnc43)c(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1cccc2cc[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc4cc[nH]c34)c3cc(Br)cnc32)cc1
Yield: 81.9 %

Procedure:
To a mixture of 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.1 mmol) and 1H-indole-7-boronic acid (338 mg, 2.1 mmol) in a 20 mL microwave reaction flask was added THF (6.5 mL), acetonitrile (6.5 mL) and sodium carbonate (6.5 mL, 1 N aqueous solution, 6.5 mmol). The mixture was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]-palladium(II) dichloromethane adduct (164 mg, 0.2 mol) was added and the purging continued for another minute. The flask was sealed and irradiated in a microwave reactor to 60° C. for 30 minutes. Saturated sodium chloride (15 mL) was added and the pH was adjusted to 7 using hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 5-bromo-3-(1H-indol-7-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine as a light brown solid (802 mg, 82% yield). MS: m/z 466 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:11][C:9]1[N:10]=[C:6]([CH:5]=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[O:7][C:8]=1[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(C=Cc2ccccc2Cl)nc1CO
Product: Cc1oc(C=Cc2ccccc2Cl)nc1CCl

Procedure:
2-(2-Chlorostyryl)-4-hydroxymethyl-5-methyloxazole (3.6 g) was added portionwise to thionyl chloride (18 ml) with ice-cooling and stirring. The mixture was stirred at room temperature for 20 minutes and the thionyl chloride was distilled off. To the residue was added aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 4-chloromethyl-2-(2-chlorostyryl)-5-methyloxazole as crystals; yield 3.65 g (99.5%). Recrystallization from ethyl ether gave colorless needles melting at 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=3[N:17]=[C:18]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: COc1ccc(Nc2ccc(Br)cn2)c(NC(=O)C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(Br)cn1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of N-[2-(5-Bromo-pyridin-2-ylamino)-5-methoxy-phenyl]-2,2,2-trifluoro-acetamide (70 mg, 0.18 mmol) in toluene (15 mL) was added (CF3CO)2O (6 mL). The resulting solution was allowed to stir overnight at reflux. The volatile components were then removed under reduced pressure and the residue was purified by SGC using 1:7 EtOAc/petroleum ether as eluents to provide 5 mg (6%) of 1-(5-Bromo-pyridin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (cc) as a white solid. 1HNMR (400 MHz, DMSO-D6) δ 3.84 (3H, s), 7.11-7.13 (1H, d), 7.37 (1H, d), 7.45 (1H, s), 7.81 (1H, d), 8.46 (1H, d), 8.88 (1H, s) ppm.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2=[O:18])=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.[I-].[Zn+2].[I-]>[OH:18][C:15]1([CH2:5][NH2:6])[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:17]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(O)(CN)CC2
Reaction time: 16 h

Procedure:
60 g of trimethylsilyl cyanide are added via syringe to a mixture of 75 g of 6-methoxy-1-indanon, 0.8 g of anhydrous zinc iodide and 150 milliliters of anhydrous toluene. The reaction mixture was heated to 60 degrees Centrigrade for 6 hours and then stirred for 16 hours without heating. To a cooled suspension of 44 g of lithium aluminium hydride in 1300 milliliters of anhydrous ether was added the solution of the unpurified cyanohydrin in ether at 0°-5° C. After the addition had been completed the reaction mixture was refluxed with stirring for 21/2 hours. After cooling destruction of the excess lithium aluminium hydride was completed by cautious dropwise addition of 45 milliliters of water followed by dropwise addition of 45 milliliters of 14% sodiumhydroxide solution and subsequent addition of 190 milliliters of water. Stirring was continued for 30 minutes. Filtration and extraction with dichloromethane gave a clear organic solution which was dried over anhydrous magnesium sulphate and evaporated, and the residue was crystallized from ether. Yield: 58 grams of product.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.[CH3:13]OC(OC)N(C)C>>[N:1]12[CH:13]3[N:9]([CH2:8][CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH2:12]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCCNCCCNC1
Product: C1CN2CCCN3CCCN(C1)C23
Yield: 73.1 %

Procedure:
In a manner similar to that of Example 1 (C), 5.00 g (29.2 mmol) of 1,5,9-triazacyclododecane and 3.48 g of dimethylformamide dimethyl acetal were reacted to give 3.87 g of 1,5,9-triazatricyclo[7.3.1.05,13 ]tridecane as a clear, colorless liquid, bp 93° (three fractions) (0.35 mm), which solidified on standing at room temperature. One fraction was analyzed.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=3)[N:8]=2)[CH:2]=1.[CH:38](B(O)O)=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([C:25]3[CH:26]=[C:27]([C:43]4[CH:44]=[CH:45][C:40]([CH:39]=[CH2:38])=[CH:41][CH:42]=4)[CH:28]=[CH:29][CH:30]=3)[N:8]=2)[CH:2]=1
Reactant: OB(O)C=Cc1ccccc1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)cc1
Temperature: 25 °C

Procedure:
50 g of 2,4-bisbiphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 13.8 g of styreneboronic acid [2156-04-9] are dissolved in 300 ml of toluene, and 100 ml of a 2M sodium carbonate solution are added. The reaction mixture is carefully degassed, and 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 hours. The solution is cooled to room temperature. The phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:12]
Reactant: OCc1cccc(I)c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: ClCc1cccc(I)c1

Procedure:
A solution of 3-iodobenzyl alcohol (600 mg, 2.56 mmol) in DCM (3 ml) was treated with thionyl chloride (3 ml, 41.3 mmol) and stirred at ambient temperature for 18 h, before addition of further thionyl chloride (1 ml, 13.7 mmol) and heating to reflux for 12 h. The cooled solution was basified with 50% NaOH, diluted with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to afford a clear syrup which crystallises on standing to give 3-iodobenzyl chloride as a white solid (650 mg, quant.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=O)[C:6]([NH2:9])=[N:7][CH:8]=1>FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>[OH:12][N:10]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=2)[N:9]=[C:3]1[C:2]([F:14])([F:13])[F:1]
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: On1c(C(F)(F)F)nc2ncc(C(F)(F)F)cc21

Procedure:
5-(Trifluoromethyl)-3-nitro-2-aminopyridine (10.0 grams) in trifluoroacetic anhydride (10 ml.) and pyridine (20 ml.) were heated in a steam bath for two hours. Solvents were then evaporated on a rotary evaporator at 100°C. for one hour, and the residue was taken up in ethyl acetate and hydrogenated over 2.0 g. of 5 percent palladium on carbon. The reaction mixture was then filtered, evaporated, and taken up in ethanol; subsequently, the mixture was washed with 10 percent hydrochloric acid, dried over magnesium sulfate, and evaporated. The resulting 1-hydroxy-2,6-bis(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from acetone, m.p., 239°-40°C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH:15]1[C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1)=[O:24]
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
3-Amino-5-(4-methylphenyl)pyrazole (35 mg) and indan-2-carboxylic acid (33 mg) were dissolved in pyridine (2 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (30 ml), saturated aqueous sodium bicarbonate (30 ml) and saturated brine (30 ml) and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away. The resulting crystalline residue was washed with ethyl ether to obtain the title compound (34 mg) as white crystals (melting point: 220-225° C.).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:5]=1[CH2:6]P(=O)(OCC)OCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].COCCOC>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[CH:6][C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[Br:3])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOP(=O)(Cc1cc(OC)ccc1Br)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Br)c(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Sodium hydride (60% in paraffin, 14.4 g, 0.360 mol) was added in small portions to a mixture of the crude product (147 g) of diethyl 2-bromo-5-methoxybenzylphosphonate, N-tert-butoxycarbonyl-4-piperidone (65.1 g, 0.327 mol) and 1,2-dimethoxyethane (200 mL) at room temperature, and the resulting mixture was stirred as it was for 1.5 hours. Water (1200 mL) was added to the reaction mixture, followed by extraction with ether (500 mL×3). The combined organic layer was washed with water (200 mL) and a saturated aqueous sodium chloride solution (200 mL). The combined organic layer washed was dried over anhydrous magnesium sulfate and then concentrated to dryness, and the residue was washed with hexane to obtain 98.2 g (0.257 mol, 79%) of N-tert-butoxycarbonyl-4-(2-bromo-5-methoxybenzal)piperidine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:20][CH:21]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C=O.[C:32]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CC#N.C(O)(=O)C.CCOC(C)=O.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:20][CH:21]=2)[CH3:32])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(NCCNCc2cccc(C(=O)N3CCCCC3)c2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(NCCN(C)Cc2cccc(C(=O)N3CCCCC3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.4 %

Procedure:
To a solution of (3-{[2-(3-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 10; 0.048 g, 0.12 mmol) in CH3CN (10 mL) was added a solution of formaldehyde (0.0029 g, 0.097 mmol) in CH3CN (5 mL), followed by sodium cyanoborohydride (0.006 g, 0.1 mmol) and acetic acid (2 drops), and the resulting solution was stirred at 25° C. for 15 h. The solution was treated with aqueous satd NaHCO3 (20 mL), H2O (20 mL) and EtOAc (30 mL). The aqueous layer was back-extracted with EtOAc (3×40 mL), and the combined organic layers were washed with brine (40 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by preparative TLC (5% CH3OH/CH2Cl2) to provide a tan oil (0.0063 g, 13%). MS (ESI): mass calculated for C25H35N3O2, 409.27; m/z found, 410.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39-7.26 (m, 4H), 7.04 (t, J=8.0 Hz, 1H), 6.26-6.16 (m, 3H), 4.15 (hept, J=6.0 Hz, 1H), 3.71-3.61 (m, 4H), 3.31-3.20 (m, 4H), 2.72 (br s, 2H), 2.26 (br s, 2H), 1.66-1.50 (m, 8H), 1.32 (d, J=6.0 Hz, 6H).