Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](OC)(OC)[CH2:12][CH2:13][C:14]2(C2C=CC=CC=2OC)O)[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.FC(F)(F)C(O)=[O:40].[OH-].[Na+]>ClCCl>[C:9]1(=[O:40])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: COc1ccccc1C1(O)CCC(OC)(OC)C2CN(Cc3ccccc3)CC21
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCC2CCCCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 g of (3aRS,4RS,7aSR)-2-benzyl-7,7-dimethoxy -4-(2-methoxyphenyl)-4-perhydroisoindolol in 70 cm3 of dry dichloromethane are added 6.5 cm3 of triethylamine and 6.5 cm3 of trifluoroacetic acid. After stirring for 3 hours at room temperature, the reaction mixture, cooled to +5° C., is basified with 50 cm3 of 1N sodium hydroxide. The organic phase is separated out, washed with water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized in diisopropyl ether. The solid, washed with petroleum ether, is then drained and dried under reduced pressure at 40° C. 3.4 g of (3aRS,7RS,7aSR)-2-benzyl-7-hydroxy -7-(2-methoxyphenyl)-4)-perhydroisoindolone are obtained, in the form of a cream-coloured solid. M.p.=96C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 49.5 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (56 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-7.5% 2M NH3/MeOH in DCM) to afford 270 as a white solid (48 mg, 49%). LCMS (Method K): RT 3.07 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.80 (1H, br s), 8.65 (1H, s), 8.16-8.04 (2H, m), 7.98 (1H, s), 7.87-7.81 (1H, m), 7.79 (1H, d, J=8.01 Hz), 7.72 (1H, dd, J=8.82, 4.90 Hz), 7.56-7.49 (1H, m), 7.21-7.10 (2H, m), 6.05 (1H, s), 3.90 (2H, d, J=6.25 Hz), 3.20 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)=[CH:17][CH:16]=1)=[N:8]2.[H][H]>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1

Procedure:
A solution of tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (10) (0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged with nitrogen and 10% Pd/C (0.016 g) was added. The mixture was stirred under 1 atmosphere of hydrogen overnight. Then, the solution was filtered through Celite, with MeOH washings, and the filtrate was concentrated in vacuo. The material was purified by flash chromatography on silica gel to afford tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate (11).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:22])[C:16]=2[CH:15]=[N:14][CH:13]=1.[C:23](O)(=[O:25])[CH3:24]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:22][C:23](=[O:25])[CH3:24])[C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Reactant: CC(=O)O
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 90 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-4 [D], (+)-(R)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-amine (example 74) and acetic acid gave the title compound as off-white amorphous solid in 90% yield. MS: 353.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>CO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(Br)cc1N

Procedure:
A mixture of 4-bromo-2-nitroaniline (1 g; 4.6 mmol) and SnCl2.2H2O (6.2 g; 27.6 mmol) in MeOH (30 mL) with 5-6 drops of conc. HCl was heated at reflux for 5 hrs., concentrated, suspended in sat'd NaHCO3 (aq.) and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO4), and concentrated to provide the product of sufficient purity to carry on.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][C:23]1=2.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
150 mg (0.44 mmol) of 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 112 mg (0.48 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid and 202 mg (0.88 mmol) of tripotassium phosphate monohydrate are suspended in 6 ml of ethylene glycol monomethyl ether, degassed a number of times, and 25 mg (0.04 mmol) of bis(triphenylphosphine)-palladium(II) dichloride are added under nitrogen atmosphere. The reaction mixture is stirred at 80° C. for 16 h, cooled to RT, and 20 ml of water are added. This mixture is extracted three times with ethyl acetate, dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][CH:37]=[N:36][C:35]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:35]6[N:36]=[CH:37][O:38][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ocnc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncoc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.045 g (17.6%) 1H NMR (400 MHz, DMSO-d6): δ 1.11-1.14 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.31 (s, 3H), 2.82 (d, 3H, J=4.4 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.33 (dd, 1H, J=1.6, 8.4 Hz), 7.40 (apparent t, 2H, J=8.8 Hz), 7.49 (d, 1H, J=1.2 Hz), 7.60 (s, 1H), 7.72 (d, 1H, J=8.4 Hz), 7.97-8.01 (m, 2H), 8.04 (s, 1H), 8.46-8.48 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccccc1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.4 ml), and 2-methoxybenzoyl chloride (0.7 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: C1CCNCC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and piperidine are converted to the named compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[Cl:39]>C(O)C.O.Cl>[Cl:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1
Yield: 16 %

Procedure:
A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.1 g (0.38 mmole) of 4-amino-3-chloro-N-(1-methyl-piperidin-4-yl)-benzamide in 10 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, and then heated in a pressure tube at 130 degrees for 3 hours. After removal of the solvents under reduced pressure, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.028 g of 3-chloro-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-179) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=O)[CH:9]=[CH:8]2.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][C@@H:9]3[C@H:8]([C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:18][NH:17][CH2:16]3
Reactant: COc1cccc2ccc(=O)oc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: COc1cccc2c1OC[C@H]1CNC[C@@H]21

Procedure:
From 8-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:26])[C:22]=1[N+:23]([O-:25])=[O:24])[C:17](O)=[O:18].CNC>O1CCCC1>[CH3:1][N:3]([CH3:4])[C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([CH3:26])[CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C)C)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (914 mg) is added to a solution of 3,5-dimethyl-4-nitrobenzoic acid (1 g) in tetrahydrofuran (10 mL). The mixture is stirred for 3 hours at room temperature, dimethylamine (7.7 mL, 2 M in tetrahydrofuran) is added and the mixture is stirred for further 30 minutes. After concentration the mixture is diluted with ethyl acetate and washed with hydrochloric acid (0.2 M), saturated aqueous NaHCO3 solution and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 1 g; LC (method 20): tR=5.11 min; Mass spectrum (ESI+): m/z=223 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C.[F:39][C:40]([F:45])([F:44])[CH2:41][CH:42]=O>ClCCCl>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:42][CH2:41][C:40]([F:45])([F:44])[F:39])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=CCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C2=CCN(CCC(F)(F)F)CC2)cc1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
Sodium triacetoxyborohydride (6.2 g, 29.4 mmol, 2 eq.) was added to a solution of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.), DIEA (2.5 mL; 14.7 mmol; 1.0 eq.) and 3,3,3-Trifluoropropanal (2.4 mL; 29.4 mmol; 2.0 eq.) in DCE (60 mL). The reaction mixture was heated at 50° C. for 2 h and quenched by addition of a saturated solution of NH4Cl (50 mL). The phases were separated and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give a brown crude. Purification by flash chromatography on silica (EtOAc:heptane) afforded the title compound as a yellow solid (2.0 g, 45%). UPLC/MS: (MS+) 301.4.
Reaction SMILES: [Si]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CN(c2ccncc2)c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.3 %

Procedure:
Then, 31 mg of 4-[N-[4-(tert-butyldimethylsilyloxy)benzyl]-N-(4-pyridyl)amino]benzonitrile was dissolved in 0.33 ml of tetrahydrofuran, and 0.15 ml of a 1 M tetrahydrofuran solution of tetrabutyl-ammonium fluoride was added thereto, followed by stirring at room temperature for 45 minutes. After water was added to the reaction mixture, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 14 mg of 4-[N-(4-hydroxybenzyl)-N-(4-pyridyl)amino]benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([NH:18][C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=4)=[O:20])[CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[NH2:31][NH2:32]>C(O)C>[NH:31]([C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[NH:13][C:12]=3[CH:14]=2)=[O:20])=[CH:30][CH:29]=1)=[O:26])[NH2:32]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3nc(-c4ccc(OC)cc4)[nH]c3c2)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(NC(=O)c4ccc(C(=O)NN)cc4)cc3[nH]2)cc1
Temperature: 70 °C

Procedure:
In a 15-mL sealed tube, methyl 4-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)carbamoyl)benzoate (28 mg, 0.07 mmole) was dissolved in 2 mL absolute ethanol and hydrazine (1 mL) was added. The reaction mixture was heated in an oil bath at 70° C. for overnight. In the morning the reaction mixture was evaporated to dryness to provide the title compound (28 mg, 99%, >95% pure by 1H-NMR). This compound was used for next step without any further purification.
Reaction SMILES: [CH2:1]([Si:8]([CH2:11]Br)([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:13].[Na+]>CC(C)=O>[CH2:1]([Si:8]([CH2:11][I:13])([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CBr)Cc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CI)Cc1ccccc1
Yield: 94412.4 %

Procedure:
Benzyl(bromomethyl)dimethylsilane [Colm, Earborn and Foad M. S., Malmond J. Organomet. Chem., 209, 13 (1981)] (12 g, 0.05 mmol) and sodium iodide (45 g, 0.3 mmol) are refluxed with stirring in acetone (500 ml) during 24 hours. The reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ether and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl(iodomethyl)dimethylsilane (13.7 g, 5%) as a slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[C:11](Cl)(=[O:18])[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=2)=[O:16])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Product: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1

Procedure:
N,N'-bis(3,5-diacetylphenyl)(isophthalic acid diamide), mp 283-4° C. Also analogously, N,N'-bis(3-acetylphenyl)pentanediamide, mp 174-5° C. was prepared from 3-aminoacetophenone and glutaryl dichloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:34]O)[CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:34][O:24][C:23]([C:18]2([C:20]([O:22][CH2:34][CH:30]3[CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32][CH2:31]1
Reactant: OCC1CCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CCC1)(C(=O)OCC1CCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 30 as an off-white solid (HCl salt); 1H NMR (CDCl3) δ 1.32 (d, J=6.5 Hz, 3H), 1.85 (m, 8H), 2.05 (m, 4H), 2.69 (m, 2H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.10 (s, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1759, 1779 cm-1 (C=O); MS (ES) m/z 558 (MH+); [α]D25 -27° (c, 1.0, CHCl3). Anal. Calcd. for C30H36ClNO7 ·HCl: C, 60.61; H, 6.10; N, 2.36; Cl, 11.94. Found: C, 60.68; H, 6.30; N, 2.31; Cl, 11.71.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[O:30][N:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:31]5[O:30][N:29]=[C:28]([CH3:27])[CH:32]=5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: Cc1cc(C(=O)O)on1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (89 mg, 82%), MS (ISP) m/z=438.3 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-isoxazole-5-carboxylic acid.