Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([C:35]1[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C1CCCC1
Yield: 106.6 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 4 using 3-cyclopentyl-4-methoxy-benzoic acid (10.00 g, 45.4 mmol, RN-59216-82-9), oxalyl chloride (4.4 mL, 50.4 mmol), N,N-DMF (5 drops), tin(IV) chloride (5.8 mL, 49.7 mmol) and 2-benzyl-4,5-dimethylfuran (10.1 g, 54.3 mmol) in CH2Cl2. The final organic extracts were concentrated to give 18.8 g of the title compound, synthetically pure. 1H NMR: consistent.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](OC)=[O:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccnc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1ccnc(CO)c1
Yield: 82.8 %

Procedure:
To a solution of methyl 4-butoxypyridine-2-carboxylate (1.20 g, 5.80 mmol, obtained from Example 18(b)) in methanol (60 mL) was added sodium borohydride (0.85 g, 23.0 mmol). The reaction was monitored by TLC (hexanes/ethyl acetate, 1:2). After the disappearance of starting material, the reaction mixture was concentrated in vacuo and the crude was dissolved in ethyl acetate/water (1:1, 60 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and solvent was removed in vacuo to give the title compound (0.87 g, 84% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30].O.Cl>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3C)cc2c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Yield: 82 %

Procedure:
A mixture of 1-bromo-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (2 g, 4.5 mmol) (prepared according to U.S. Pat. No. 7,928,120) and CuCN (0.81 g, 9.0 mmol) in DMF (30 mL) was refluxed for 1.5 h. The resulting mixture was poured into a mixture of water (200 mL) and CH2Cl2 (200 mL). 4 M HCl was added with vigorous stirring until no solid was observed. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (10-80% CH2Cl2/hexanes) to give 1.44 g of the title compound as a pale pink solid. MS: (+) m/z 391.34 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[CH:16]=[CH:17][C:18]=2[OH:19])=[CH:9][C:8]=1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C)C=O>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH2:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:53])[CH3:52])([CH3:48])[CH3:49])=[CH:9][C:8]=1[C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Yield: 99 %

Procedure:
In a manner similar to that of Example 2a, by reacting 260 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate (0.56 mmol) in 12 mL of dimethylformamide with 225 mg of caesium carbonate and 0.16 mL of 1-bromo-4-(tert-butyldimethylsilanyloxy)butane, 310 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-[1,1′;3′,1″]terphenyl-4-carboxylate (yield=99%) are obtained in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18]C)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
To a solution of methyl 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoate (0.882 g, 2.454 mmol) in THF (15 ml), LiOH 1N (2.94 ml, 2.94 mmol) was added and the mixture was stirred at RT for 24 hours. The mixture was acidified with HCl 1N and extracted with EtOAc; the organic phase was washed with brine ad dried over Na2SO4. The solvent was removed and the residue was triturated with Et2O to afford after filtration 3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-4-methoxybenzoic acid (0.487 g, 1.410 mmol, 57.5% yield, MS/ESI+ 367.9 [MNa]+).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:37][CH:38]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(C3(c4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)CCCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(C3(c4ccc(Cc5ccc(N)cc5)cc4)CCCCC3)cc2)cc1
Yield: 82.2 %

Procedure:
1,1-bis[4-(4-nitrobenzyl)phenyl]cyclohexane 98.93 g was dissolved in 1100 ml of tetrahydrofuran, a Pd--C catalyst (5% purity, water content 55.9%) 9.8 g was added, and the mixture was cooled with water at atmospheric pressure and contacted with hydrogen gas with stirring. After the absorption of hydrogen stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was recrystallized with toluene solvent to obtain 71.71 g of 1,1-bis[4-(4aminobenzyl)phenyl]cyclohexane which is a diamino compound of the present invention. The melting point was 154.4°-155.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([O:18][CH2:25][CH:24]=[CH2:23])[CH2:15][CH:16]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: C=CCC(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(CC=C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
(S)-4-(2-Hydroxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g, 8.91 mmol) was dissolved in dry tetrahydrofuran (60 mL). Sodium hydride (60% suspension in mineral oil, 360 mg) was added. The mixture was stirred at 0° C. for 5 min. Then allylbromide (1.60 mL) was added. The mixture was stirred at room temperature for 18 h. Solvents were evaporated and the residue was extracted with diethyl ether and citric acid solution. The organic layer was washed with saturated sodium chloride solution and concentrated. The crude material was purified through flash column chromatography (silica gel, 5-30% ethyl acetate/hexanes) to afford (S)-4-(2-allyloxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.38 g, 48% yield for two steps) as an oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 12H), 1.56, 1.60 (2×s, 3H), 1.64-1.77 (m, 1H), 1.80-2.07 (m, 1H), 2.32 (br. s., 2H), 3.48 (br. s., 1H), 3.79-4.23 (m, 5H), 4.98-5.19 (m, 3H), 5.26 (d, J=17.2 Hz, 1H), 5.72-5.98 (m, 2H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]2([C:24](O)=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[C:12]1([C:18]2([CH2:24][OH:25])[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(c2ccccc2)CCNCC1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
To a solution of 4-phenyl-4-piperidinecarboxylic acid 4-toluene-sulfonate (2.0 g, 5.3 mmol) in dry tetrahydrofuran (10 ml) was added 1 M lithium aluminum hydride solution in tetrahydrofuran at 0° C. The reaction mixture was heated at reflux for 90 min. After cooling to 0° C. water (0.4 ml), 2 M aqueous sodium hydroxide solution (0.6 ml) and water (0.8 ml) were added consecutively. The white suspension was stirred for 10 min and diluted with tetrahydrofuran (40 ml). After addition of anhydrous sodium sulfate (18 g) the suspension was stirred for further 10 min. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give the crude title compound (0.65 g, 64%) as white solid.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[O:38][CH3:39])[C:6]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:5]1=2)(=[O:3])[CH3:2].[ClH:46]>O1CCOCC1.CCOCC>[ClH:46].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[O:38][CH3:39])[C:6]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 80 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (255 mg, 416 μmol) in 4 M HCl in dioxane (2.08 ml) was stirred for 45 min. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (181.8 mg, 80%) as a white solid. MS m/z 514 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].I[CH3:23]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]([C:16]([F:19])([F:17])[F:18])=[N:14][N:13]=[N:12]2)[CH:5]=[C:6]2[C:10]=1[N:9]([CH3:23])[CH:8]=[CH:7]2
Reactant: CI
Reactant: FC(F)(F)c1nnnn1-c1cc(Br)c2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccc2cc(-n3nnnc3C(F)(F)F)cc(Br)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-bromo-5-(5-trifluoromethyl-tetrazol-1-yl)-1H-indole (115 mg, 0.346 mmol) in DMF (2 mL) was added sodium hydride (80% dispersion in mineral oil) (12 mg, 0.417 mmol). After gas evolution ceased, iodomethane (33 μL, 0.530 mmol) was added, and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with diethyl ether, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (MgSO4), and evaporated. Silica gel chromatography eluting with 10% diethyl ether/hexane afforded pure title compound; yield 83 mg of a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: C1COCCN1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1N1CCOCC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 5 ml of morpholine gives 800 mg of the desired product :M+ =493.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)c1

Procedure:
The title compound, white solid (69 mg, 88%), MS (ISP) m/z=313.4 [(M+H)+], mp 253° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)ccc3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-bromobenzoxazole (576 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[F:24][C:25]([F:39])([F:38])[C@H:26]([O:36][CH3:37])[CH2:27][NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.N1C(C)=CC=CC=1C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:35][C@H:32]3[CH2:31][CH2:30][C@H:29]([NH:28][CH2:27][C@@H:26]([O:36][CH3:37])[C:25]([F:38])([F:39])[F:24])[CH2:34][CH2:33]3)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CO[C@H](CN[C@H]1CC[C@H](N)CC1)C(F)(F)F
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Solvent: CS(C)=O
Solvent: Cc1cccc(C)n1
Product: CO[C@H](CN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1)C(F)(F)F
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (36 mg, 0.10 mmol) in DMSO (0.4 mL) was added trans-N1-((R)-3,3,3-trifluoro-2-methoxypropyl)cyclohexane-1,4-diamine (48 mg, 0.20 mmol) and 2,6-lutidine (0.023 mL, 0.20 mmol). The mixture was stirred at 120° C. for 20 hr. The cooled reaction mixture was purified by reverse phase HPLC and lyophilized to give 11.4 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-3,3,3-trifluoro-2-methoxypropylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 576.2 (MH+), retention time=0.68 min.
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphthyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: C(N1CCN(C2C=CC(N)=CC=2)CC1)CC(C)C.[CH:19]1([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>[Pd]>[CH:19]1([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CCCCC3)CC2)cc1
Agent: [Pd]
Agent: CC(C)CCN1CCN(c2ccc(N)cc2)CC1
Product: Nc1ccc(N2CCN(C3CCCCC3)CC2)cc1
Yield: 99.2 %

Procedure:
Using the method described above for the synthesis of 4-(4-isopentylpiperazin-1-yl)aniline, treatment of 1-cyclohexyl-4-(4-nitrophenyl)piperazine (1.0 g, 3.46 mmol) with H2 and 10% Pd/C provided crude 4-(4-cyclohexylpiperazin-1-yl)aniline (0.89 g, 89% recovery, 78% purity as determined by LC/MS analysis @ UV 254 nm detection). The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C16H25N3, 259; [M+H]+ found, 260.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14]([NH:16][CH3:17])=O)=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][NH:16][CH3:17])=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2
Reactant: CNC(=O)CC(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 3-(7-methoxy-1H-Indol-4-yl)-N-methyl-3-phenyl-propionamide LV (0.315 mmol) in THF (3 ml) was added a suspension of LiAlH4 (46.6 mg, 1.26 mmol) in THF (4 ml). The resulting mixture was stirred at 0° C. for 5 minutes, at reflux for 5 hours, then cooled to room temperature, and additional suspension of LiAlH4 (46.6 mg, 1.26 mmol) in THF (4 ml) was added. The reaction was refluxed for additional 45 minutes, cooled to 0° C. and freshly ground Na2SO4.10H2O (1 g) was added. The mixture was stirred at room temperature over the weekend. The solid was filtered and washed with EtOAc. The filtrate was concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) to provide the amine compound LVI as a yellow film (37 mg). The free amine was dissolved in Et2O (3 ml), cooled to 0° C., and HCl (1 M in Et2O, 126 μl) was added. The precipitate was filtered affording the hydrochloride salt of [3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-propyl]-methyl-amine LVI as an off-white hygroscopic powder. MS (M+H)=295.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([OH:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4,6-trifluoronitrobenzene (10 g) in dimethyl sulphoxide(50 mL) was treated with 10N sodium hydroxide(12 mL) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water and washed with ether. The aqueous phase was then acidified and extracted with ether. The extract was washed with brine, dried and evaporated to dryness and the residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(8.3 g) [m/e 174, MH−].
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[CH:13]=[C:14]([CH2:18][C:19]([O:21]C)=[O:20])[CH:15]=[CH:16][CH:17]=3)[S:10][C:6]=2[C:5]([F:23])=[CH:4][C:3]=1[F:24].[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)[S:10][C:6]=2[C:5]([F:23])=[CH:4][C:3]=1[F:24]
Reactant: COC(=O)Cc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of methyl 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetate (231 mg, 0.66 mmol) in a mixture of water (5 ml) and dioxane (5 ml) was added dropwise 2N sodium hydroxide (2 ml, 4 mmol). After the addition was complete, the mixture was stirred for 2 hours, then diluted with water, washed with ether, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried, then evaporated to yield a residue, which was recrystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetic acid (134 mg, 90%) as a colorless powder. m.p. 132° to 134° C.