Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH3:24])=[C:22]([C:25]([OH:27])=O)[N:21]=[N:20]2)=[C:15]([CH:28]2[CH2:30][CH2:29]2)[CH:14]=1.[NH2:31][C:32]1[C:33](=[O:46])[N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[N:35]([CH3:38])[C:36]=1[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([CH3:24])=[C:22]([C:25]([NH:31][C:32]3[C:33](=[O:46])[N:34]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[F:45])[N:35]([CH3:38])[C:36]=3[CH3:37])=[O:27])[N:21]=[N:20]2)=[C:15]([CH:28]2[CH2:30][CH2:29]2)[CH:14]=1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(Cl)cc1C1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of oxalyl chloride (0.035 ml, 0.396 mmol) and DMF (0.056 ml, 0.720 mmol) in DCM (10 ml) was added 1-(4-chloro-2-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.360 mmol) and the mixture was stirred for 30 mins. Further oxalyl chloride (0.035 ml, 0.396 mmol) was added to the reaction mixture and it was stirred for 1 hr. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (88 mg, 0.396 mmol) was added followed by triethylamine (0.151 ml, 1.080 mmol) and the mixture was stirred at RT for 1 hr. The resulting mixture was diluted with DCM, washed with 0.1 M HCl(aq) and sat. NaHCO3(aq). The organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure to give an oil. The oil was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a yellow glassy solid which was recrystallised from EtOH. The solid was collected by filtration and dried on the vacuum line to give the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(I)c1
Product: O=C(Cl)c1cccc(I)c1

Procedure:
A stirred suspension of 3-iodobenzoic acid (8.84 g) in thionyl chloride (44 mL) is heated at reflux for 30 minutes. The dark brown solution is evaporated to give 3-iodobenzoyl chloride (9.8 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][Br:31])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=c1ccc(-c2ccc(CO)cc2)cn1Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1ccc(-c2ccc(CBr)cc2)cn1Cc1ccc(Cl)cc1
Yield: 67.1 %

Procedure:
According to Scheme 25 Step 3: To a solution of 1-(4-chlorobenzyl)-5-(4-(hydroxymethyl)phenyl)pyridin-2(1H)-one (1 eq, 3.07 mmol, 1.00 g, Example 35 Step 1) in THF (8 mL) were added NBS (1.22 eq, 3.74 mmol, 0.67 g) and PPh3 (1.20 eq, 3.68 mmol, 0.97 g) at −20° C. for 4 hours. After evaporation of the solvent, the crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 50 g SiO2) using CH2Cl2/MeOH 98/2 to afford 1-(4-chlorobenzyl)-5-(4-(bromomethyl)phenyl)pyridin-2(1H)-one (2.06 mmol, 0.80 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[N:8]([C:20]([N:17]3[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]3)=[O:21])[N:9]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Product: Cc1cc(Cl)nc2c1c(OC(=O)N1CCC(C)CC1)nn2C(=O)N1CCC(C)CC1

Procedure:
In analogy to example 1, 1.2 g (6.54 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 1.29 g (7.98 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 238 mg (8%), M+H+: 434.27.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:10]1[N:11]=[CH:12][C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23](C(O)=O)[CH2:22][CH2:21]3)[N:16]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:14]=2[N:15]=1)#[N:9]>CCOCC>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:16]1[C:14]2[N:15]=[C:10]([C:8]#[N:9])[N:11]=[CH:12][C:13]=2[CH:18]=[C:17]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)Cn1c(CN2CCN(C(=O)O)CC2)cc2cnc(C#N)nc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)Cn1c(CN2CCNCC2)cc2cnc(C#N)nc21
Yield: 58.1 %

Procedure:
4N HCl/dioxane is added to 4-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid .tert.-butyl ester at 0° C. and stirred at 25° C. for 90 min. Ether is added to the residue to afford a precipitate, which is collected by filtration. The crude product is dissolved in MeOH and purified by reverse phase HPLC. The fractions (fraction Nos. 23-25) are collected and evaporated. The residue is extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate and filtrated. The solvent is removed by evaporation and dried in vacuo to afford the title compound. yield 58.1%, Rf=0.30 (CH2Cl2:MeOH=8:2). 1H-NMR (400 MHz, CDCl3) δ 1.01(s, 9H), 2.43(br, 4H), 2.90(br, 4H), 3.76(s, 2H), 4.36(s, 2H), 6.57(s, 1H), 8.89(s, 1H),
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].[Li+].[OH-]>CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:27])[F:26])[CH:6]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1C(F)(F)F
Yield: 99.8 %

Procedure:
The product of Example 304D (241 mg, 0.62 mmol) was dissolved in methanol (5 mL) and saturated aqueous LiOH (1 mL) was added. The reaction was heated at reflux for 1 hour. The reaction mixture was then evaporated and fomlic acid (1 mL) was added to acidify the crude product to pH3. The reaction was evaporated again to remove formic acid and ethyl acetate (5 mL) and H2O (1 mL) were added to completely solubilize the reaction mixture. The aqueous layer was extracted with ethyl acetate (3×) and the ethyl acetate layers were combined and dried over Na2SO4, filtered and evaporated to give the acid (231 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: Oc1ccccc1
Product: COc1ccc(Br)c(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 1, Step 1, using 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene and phenol as the starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][C:34]([F:37])([F:36])[F:35])[CH:27]=1)([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)ncc1Cl
Temperature: 90 °C
Yield: 8.6 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.035 g, 0.12 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (5.8 mg, 9% yield). MS/ES+: m/z=563.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@@H:15]([O:17][S:18]([O:21][CH2:22][CH3:23])(=[O:20])=[O:19])[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2].CC(C)=O.[Br:33]Br.C(N(CC)CC)C>ClCCl.C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][CH:5]=[C:6]([Br:33])[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@@H:15]([O:17][S:18]([O:21][CH2:22][CH3:23])(=[O:19])=[O:20])[CH3:16])[C:9]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)O[C@@H](C)[C@@H]1C(=O)N2C(C(=O)OC)=C(S/C=C/NC(C)=O)C[C@H]12
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOS(=O)(=O)O[C@@H](C)[C@@H]1C(=O)N2C(C(=O)OC)=C(SC(Br)=CNC(C)=O)C[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(1S)-1-ethoxysulphonyloxy-ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (110 mg) in dry dichloromethane (4 ml) was cooled to -70° (acetone/solid CO2 bath) and bromine (0.25 ml of a 1 M solution in CCl4) was added to the stirred solution. After 20 mins, triethylamine (50 mg) in dichloromethane (0.5 ml) was added and stirring was continued at -70° for 15 min. The mixture was allowed to warm to room temperature over 30 min. The solution was then washed with water (2×), dried (MgSO4) and evaporated in vacuo to give a brown oil (130 mg). This was chromatographed on silica gel (10 g; 230-430 mesh ASTM) eluting with ethyl acetate/cyclohexane (8:2) to give, after combination and evaporation of the appropriate fractions, methyl (5R,6R)-3-(2-acetamido-1-bromoethylthio)- 6-[(1S)-1-ethoxysulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0.]hept-2-ene-2-carboxylate (39 mg), λmax (EtOH), 310 and 245 nm, νmax (CH2Cl2) 1790, 1720, 1625 cm-1, δ(CDCl3) 1.40 (3H, t, J 7 Hz, CH3CH), 2.12 (3H, s, CH3CO), 3.07 (1H,dd, J1 19 Hz, J2 10 Hz 4-CHAHBCH), 3.39 (1H,dd, J1 19 Hz, J2 9.5 Hz, 4-CHAHBCH), 3.7-3.9 (4H, s, at δ 3.80 superposed on m, OCH3 6-CH), 4.1.-4.5 (3H, q, J 7 Hz at 4.30, superposed on m, OCH2CH3, 5-CH) 4.7-5.2 (1H,m, CH.CH.CH3), 7.42 (1H, broad d, J 11.5 Hz, CONHCH), 7.70 (1H, d, J 11.5 Hz,=CHNHCO).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]([N:30]([CH3:41])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36](=[O:39])(=[O:38])[NH2:37])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C3C(=CC(C([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=O)=CC=3)N(C)C=2C2C=CC=CC=2OCC(N(C)CCOCCN(C)S(=O)(=O)N)=O)CCCCC1>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]([N:30]([CH3:41])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36](=[O:39])(=[O:38])[NH2:37])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Reactant: CN(CCCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Product: CN(CCCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Yield: 92 %

Procedure:
2-{2-[3-cyclohexyl-6-(1H-imidazol-1-ylcarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}-N-methyl-N-{4-[methyl(sulfamoyl)amino]butyl}acetamide 14 was synthesized in 92% yield from intermediate 13 following the procedure reported for the synthesis of intermediate 9: m/z=635 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:14]([C:11]2[CH:10]=[N:9][C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][N:12]=2)=[O:16])[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cnc(CN2CCCCC2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N1CCN(C(=O)c2cnc(CN3CCCCC3)cn2)CC1
Reaction time: 1 h
Yield: 28.5 %

Procedure:
A mixture of 5-piperidin-1-ylmethyl-pyrazine-2-carboxylic acid (0.125 g, 0.53 mmol),1-isopropyl-piperazine dihydrochloride (0.117 g, 0.58 mmol), HOBt (0.086 g, 0.64 mmol) and N-methylmorpholine (0.323 g, 3.19 mmol) in DCM (7 mL) was stirred for 1 h. The mixture was then treated with EDC (0.122 g, 0.64 mmol) and stirring was continued for 18 h. The reaction was quenched by the addition of 1 N NaOH (10 mL), and was stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield the crude product (0.145 g). The crude was purified on SiO2 using 0-5% 2 M NH3 in MeOH/DCM to provide the title compound (0.05 g, 26%). MS (ESI): exact mass calcd. for C18H29N5O, 331.46; m/z found 332.5 [M+H]+. 1HNMR (500 MHz, CDCl3): 8.85 (d, J=1.4,1H), 8.64 (d, J=1.4, 1H), 3.82 (t, J=4.9, 2H), 3.68 (s, 2H), 3.63 (t, J=4.9, 2H), 2.77-2.70 (m, 1H), 2.62 (t, J=4.9, 2H), 2.53 (t, J=4.9, 2H), 2.48-2.42 (m, 4H), 1.63-1.57 (m, 4H), 1.49-1.42 (m, 2H), 1.05 (d, J=6.6, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)=[N:5][CH:4]=[N:3]1.[CH3:16][N:17]1[C:21]([C:22]2C=CC=CC=2N)=[N:20][CH:19]=N1>>[NH:20]1[CH2:19][CH2:16][N:17]=[C:21]1[CH2:22][NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cn1ncnc1-c1ccccc1[N+](=O)[O-]
Reactant: Cn1ncnc1-c1ccccc1N
Product: Cn1ncnc1-c1ccccc1NCC1=NCCN1

Procedure:
In a fashion analogous to Example 90, 1-methyl-5-(2-nitrophenyl)-1,2,4-triazole was prepared, the nitro reduced, and the resulting 1-methyl-5-(2-aminophenyl)-1,2,4-triazole coupled with CMI to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH:32](O)[CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:32]4[CH2:33][CH2:34][CH2:35][N:30]([CH3:29])[CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CN1CCCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCN(C)C3)cc2)cc1
Yield: 21 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-methyl-3-hydroxypiperidine (691 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 11 to give 307 mg of the title compound. Yield: 21%. MS(FD) 487(M+). IR (CHCl3) ν max 3010, 2947, 2840, 2795, 1646, 1599, 1476, 1254, 1167.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19]C(=O)OC(C)(C)C)[C:13]2=[O:27])[CH2:10][CH2:9]1>ClCCl>[NH2:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:13]1=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCCN(CC2CC2)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate (257 mg, 0.91 mmol) in dichloromethane (10 mL). After 1 h, the mixture was concentrated and azeotroped with dichloromethane (3×) to give the crude amine.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C>O>[CH2:17]([NH:24][C:8]([NH:7][N:6]=[CH:5][C:4]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=1[Cl:2])=[NH:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: O
Solvent: CCO
Product: N=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 93.6 g of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 51.2 of benzylamine in 400 ml. of absolute ethanol is heated at reflux for 6 hours and then diluted while hot with 400 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and the nearly colorless crystals are recovered by filtration. Recrystallization from aqueous ethanol gives the desired product as pale yellow crystals, m.p. 134°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([OH:23])[C:4]=1[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27].[H-].[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([O:23][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:4]=1[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: COc1ccc(CCC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(CC=C(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Then, 30 ml of dimethylformamide was added to 5.2 g of 1-[4,6-dimethoxy-2-hydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone and 335 mg of sodium hydride, and the mixture was stirred at 0° C. for 1 hour. Then, 2.2 g of methyl α-bromoacetate was added to the mixture, and the mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours to effect reaction. After the reaction, the reaction mixture was extracted with ethyl acetate and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chrometography [230-400 mesh silica gel; eluting solvent=n-hexane/ethyl acetate (4/1)]. to obtain 5.6 g (yield=91.0%) of 1-[4,6-dimethoxy-2-methoxycarbonylmethoxy-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14]O>C(O)(=O)C>[CH2:1]([C:8]1[CH:9]=[N+:10]([O-:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Cc2ccccc2)c1
Yield: 100 %

Procedure:
A solution of 3-benzylpyridine (25 g, 0.148 tool) in hydrogen peroxide (30%, 15.1 mL) and acetic acid (100 mL) was refluxed for one day. Then more hydrogen peroxide (3 mL) was added and the resulting mixture was refluxed overnight. The reaction mixture was then evaporated and partitioned between a mixture of 3 N HCl, brine and dichloromethane. The organic layer was separated, dried and evaporated to give the desired compound (27.6 g, 100%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[BrH:34]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Br
Reactant: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CO)c2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CBr)c2)cc1

Procedure:
A mixture of 10.0 g of N-[3-(hydroxymethyl)phenyl]-N'-[4-(tetradecyloxy)phenyl]urea, 70 ml of hydrogen bromide in acetic acid and 40 ml of chloroform is refluxed for 2.5 hours, then cooled. The solid is collected and washed with carbon tetrachloride and two times with water. The collected solid is crystallized from ethyl alcohol:tetrahydrofuran followed by recrystallization from tetrahydrofuran to give 7.4 g of the desired product as a white powder, m.p. 164°-169° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([OH:26])([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:7])[CH3:6].ClC(Cl)C.C(O)(=O)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C(OCC)(=O)C.[OH-].[NH4+]>[F:28][C:2]([F:1])([F:27])[C:3]([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)([OH:26])[CH2:4][C:5]([CH3:7])([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:9]=1)[CH3:6]
Reactant: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]benzaldehyde (50 mg, 0.13 mmol), 3 mL of dichloroethane, and acetic acid (0.1 mL, 1.6 mmol) in an ice bath was added morpholine (0.28 mL, 3.20 mmol) in one batch. The solution was warmed to room temperature and stirred for 0.5 hours. Triacetoxy sodium borohyride (68 g, 0.32 mmol) was added in a single portion and the reaction stirred at room temperature for 3.0 hours. The solution was diluted with ethyl acetate and 3 mL of 3% ammonium hydroxide solution was added. The biphasic system was transferred to a separatory funnel and the aqueous layer was removed and back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The product was eluted from a flash chromatography column with dichloromethane-methanol, and evaporation of the solvent in vacuo yielded the title compound (27 mg, 45% yield).