Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([O:24][Si](C(C)(C)C)(C)C)[C@H:22]([O:32][Si](C(C)(C)C)(C)C)[C@@H:21]([CH2:40][O:41][CH3:42])[O:20]2)=[C:12]([NH:43][CH2:44][CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[C@H:23]([OH:24])[C@H:22]([OH:32])[C@@H:21]([CH2:40][O:41][CH3:42])[O:20]2)=[C:12]([NH:43][CH2:44][CH:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCc4ccccc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
2-[(Benzyloxy)methyl]-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-N-(2,2-diphenylethyl)-9H-purin-6-amine (65 mg, 0.08 mmol) (preparation 24) was dissolved in stirred tetrahydrofuran (10 ml) and a 1 molar solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.5 ml, 0.5 mmol) added. The reaction mixture was stirred at room temperature for 15 min. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate layer was separated, washed with brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent system of ethyl acetate:hexane (3:1) increasing in polarity to ethyl acetate:methanol (97:3). This gave the title compound (25 mg) as a gum. MS: 604 (MNa+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[Cl:8][C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(OCC)C>[Cl:8][C:9]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[O:11]
Reactant: CC(O)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(OC(=O)Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, Matrix Scientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether (10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethyl ether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. and stirred for 6 h. The flask containing the above reaction mixture was put into a refrigerator overnight and then filtered. The filtrate was concentrated in vacuo in ice both to colorless oil which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.Cl[CH2:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Br)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 4-(8-bromo-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (510 mg, 1.81 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (455 mg, 2.17 mmol) in anhydrous DMF (8 mL) was added anhydrous potassium carbonate (499 mg, 3.62 mmol). The resulting suspension was stirred under argon at 80° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional of 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (120 mg, 0.57 mmol) and anhydrous potassium carbonate (200 mg, 2.07 mmol) were added, and the reaction mixture was stirred at 85° C. for 6 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to afford a light brown solid. The solid was suspended in EtOAc/hexanes (about 1:1 ratio), then sonicated for 10 min to obtain a fine suspension. After filtration, the collected solid was washed with hexanes and dried in air to afford 500 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.44 min, [M+H]+=489.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:22])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:22])=[CH:14][CH:13]=1)[OH:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A solution of 5-(N,N-dibenzylglycyl)-o-anisamide (13.0g) in ethanol (800ml) was treated with excess solid sodium borohydride (ca.2g) and allowed to stand overnight at room temperature. The ethanol was then evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate was separated, washed with brine, dried over MgSO4 and evaporated. The residue readily crystallised on trituration with ether to afford 5-(2-dibenzylamino-1-hydroxyethyl)-o-anisamide as a white solid (11.1g) m.p. 120°-123°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4].[CH3:18][CH2:19][O:20]C(C)=O.O>CN(C1C=CN=CC=1)C.C(OC(=O)C)(=O)C.CCOCC>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19](=[O:20])[CH3:18])[CH:11]=1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)c1nc(C)sc1-c1cccc(NC(C)=O)c1

Procedure:
TEA (14.2 mmol) and DMAP (4.05 mmol) are added successively to a solution of 5-(3-amino-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (4.05 mmol) in acetic anhydride (25 mL). After stirring for 30 min EtOAc and water are added, the layers are separated and the aq. layer is extracted once with EtOAc. The combined organic layers are washed with sat. aq. NH4Cl solution, sat. aq. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo to give a crude product which is diluted with ether. The obtained suspension is filtered. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.81 min; [M+H]+=291.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Cl:19][C:20]1[CH:37]=[CH:36][C:23]2[NH:24][C:25]([C:27]3[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:37]=[CH:36][C:23]2[NH:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:1]4[CH2:5][CH2:4][CH2:3][CH:2]4[CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[O:32])=[CH:34][CH:35]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1)N1CCCC1CN1CCCC1

Procedure:
To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (11.0 mmol) and n-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add the product from 4-(5-Chloro-1H-benzoimidazol-2-yl)-benzoyl chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for two hours. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. Concentrate the organics in vacuo. Purify via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 409.3 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Cl)ccc(I)c21
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.5 %

Procedure:
4-Chloro-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (6.94 g, 16.2 mmol) was dissolved in nitromethane (280 mL), and the solution was added with trifluoroacetic acid (17.7 mL, 230 mmol) and triethylsilane (7.35 mL, 46.1 mmol), followed by stirring at room temperature for 23 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using diisopropyl ether to obtain 4-chloro-7-iodoisoindolinone (4.73 g, yield 99%).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Cl:15])[CH:7]=1>CO>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:1])=[O:11])=[C:8]([Cl:15])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To anhydrous methanol (45 mL) was added acetyl chloride (1.9 mL) over 2 min. The mixture, which became slightly exothermic and evolved gas, was stirred for 15 min. 4-Bromo-2-chlorobenzoic acid (3.0 g) was added in one portion and the mixture was heated at gentle reflux for 16 h. The mixture was allowed to cool to room temperature and the solvent was removed with a rotary evaporator. The residue was partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford the title compound as a white solid (2.89 g).
Reaction SMILES: C1(S(O[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)(=O)=O)C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.CCCCCC>C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH:12]=[C:13]([CH3:18])[CH:14]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1cc(C)cc(OS(=O)(=O)c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)cc(Nc2ccc3[nH]ccc3c2)c1
Yield: 74.5 %

Procedure:
Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with 5-aminoindole (100 mg, 0.75 mmol) with the reaction time of 4 h. Chromatography on silica gel column with 6:1 hexane:ethyl acetate gave 88 mg (74%) of 5-(3,5-dimethylphenylamino)indole as a pale brown solid; and 16 mg (14%) of 1-(3,5-dimethylphenyl)-5-aminoindole as a white solid.
Reaction SMILES: C(NC(C1SC(NC(N(CC(OC)OC)CC2C=CC(F)=CC=2)=O)=NC=1C)=O)C1C=CC=CC=1.C[O:36][CH:37](OC)[CH2:38][N:39]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=1)[C:40](=[O:58])[NH:41][C:42]1[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:49])=[C:45]([CH3:47])[N:46]=1>>[F:66][C:63]1[CH:64]=[CH:65][C:60]([CH2:59][N:39]2[CH2:38][CH:37]([OH:36])[N:41]([C:42]3[S:43][C:44]([C:48]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:49])=[C:45]([CH3:47])[N:46]=3)[C:40]2=[O:58])=[CH:61][CH:62]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Agent: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1cccnc1
Yield: 96 %

Procedure:
Following the procedure as described in Example 16, making variations as required to replace N-benzyl-2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methylthiazole-5-carboxamide with 2-(3-(2,2-dimethoxyethyl)-3-(4-fluorobenzyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 96% yield: mp 64-66° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.64-8.45 (m, 2H), 7.68-7.63 (m, 1H), 7.30-7.10 (m, 3H), 7.05-6.97 (m, 2H), 6.57 (br s, 1H), 6.04-5.75 (m, 2H), 4.56 (d, J=6.0 Hz, 2H), 4.48 (s, 2H), 3.62-3.56 (m, 1H), 3.29-3.25 (m, 1H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 162.4, 157.0, 153.7, 148.9, 135.7, 135.0, 133.9, 131.0, 129.9, 123.6, 117.4, 116.0, 115.7, 60.4, 49.5, 46.7, 41.4, 17.2; MS (ES+) m/z 442.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].[H][H].O.N>[Pd].O1CCOCC1>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5]
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Pd]
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 30 °C

Procedure:
In a closed glass vessel with a thermometer and a stirrer, there are charged 102.3 g (0.3 moles) of 2,4'-dichloro-5,3'-dinitro benzophenone, 5 g of 5% palladium/active carbon catalyst (from Nihon-Engelhardt Co.) and 300 ml of dioxane. At 70°-80° C., hydrogen is introduced into the vessel while the mixture being stirred, so that 42 l (1.88 moles) of hydrogen is absorbed in the mixture during ten hours. After being cooled to 30° C., the mixture is added with 55 g (0.9 moles) of 28% ammonia water and then introduced with hydrogen while being stirred at 30°-40° C. so as to absorb 13.2 l (0.59 moles) of hydrogen during 5 hours. The reaction mixture is subject to filtering at 30°-40° C. to remove the catalyst. On cooling, there is obtained 3,3'-diamino benzophenone as yellow crystals. The crystals are filtered, washed with 30 ml of 50% aqueous solution of dioxane and dried. Yield 56.5 g (89%). M.P. 149°-150.5° C. Recrystallization from ethanol gives yellow needle-like pure crystals of said benzophenone. M.P. 150°-151° C.
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:7]2[CH2:22][C:23](OCC)=[O:24].O>O1CCCC1>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[N:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:7]2[CH2:22][CH2:23][OH:24]
Reactant: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(CCO)N(c1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.7 %

Procedure:
To a solution of lithium borohydride (80 mg, 3.7 mmol) in tetrahydrofuran was added with stirring 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.63 g, 1.9 mmol) under ice cooling and stirred at 25° C. for 39 hrs. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.51 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-(2-hydroxyethyl)isoindolin-1-one.
Reaction SMILES: ClC(=O)C(OC)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl.CC#N>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Sc2ccccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
Methyl Chloro-oxo-acetate (1.37 g, 11.25 mmol) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (3.00 g, 7.5 mmol) and 4-(dimethylamino)pyridine (1.65 g, 13.5 mmol) in a mixture of dry CH3CN (24 ml) and CHCl3 (12 mL) at 0° C. under argon. The reaction mixture was allowed to reach room temperature and then stirred 2 h. Ethyl acetate (140 mL) was added and some salts were removed by filtration through celite. The organic phase was washed with sat. NaHCO3 (140 ml), brine (140 mL) and dried (MgSO4). The solvents were evaporated in vacuo and the crude material was dried in vacuo. This material was dissolved in dry toluen (48 mL) under argon. Bu3SnH (3.27 g, 11.25 mmol) and AIBN (0.31 g, 1.88 mmol) were added. The solution was stirred under argon at 90° C. for 2.5 h. The solvent was evaporated in vacuo, and the crude material was purified by flash chromatography on silica gel (eluent: a stepwise gradient of ethylacetat in heptane from 10:90 to 20:80) to produce 4-(2-(4-methylphenylsulfanyl)phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (1.94 g, 67%). This oil was dissolved in MeOH (9.2 mL) and HCl in diethylether (2.0 M) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The target compound was collected as its hydrochloride. M.p 229–231° C. Calculated for C18H21NS.HCl: C, 67.58; H, 6.63; N, 4.38. Found: C, 67.33; H, 6.97; N, 4.31. LC/MS (m/z) 284 (MH+); RT=2.12; purity (UV, ELSD): 96%, 100%; yield: 0.26 g (46%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25](=[CH2:27])[CH3:26].S(=O)(=O)(O)O>CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([O:18][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:17])[CH2:14][C:13]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: O=C(O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 6.6 g of (±)-4,5-dihydro-1-(benzyloxycarbonyl)-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid, 5 ml of isobutylene, 25 ml of ether and 0.25 ml of concentrated sulfuric acid is shaken in a pressure vessel for about 16 hours. The reaction vessel is vented (-10° C.) and the contents are washed with ice cold aqueous sodium hydroxide. The organic fraction is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH2:23]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:23][CH2:22][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCC(c2ccccc2)c2ccccc2)CC1
Yield: 80 %

Procedure:
To a solution of 4-(Boc-amino) piperidine (10 g, 50 mmol) in acetonitrile (200 ml) was added 3,3-diphenylpropyl bromide (15.1 g, 55 mmol), tetra-butylammonium iodide (2 g, 5 mmol) and potassium carbonate (15 g, 100 mmol) and the mixture refluxed. After 5 h the reaction mixture was cooled and poured into water. The solution was partitioned with EtOAc and the organic layer dried (MgSO4), concentrated and purified by column chromatography (toluene: EtOAc, 1:1 with 1% triethylamine) to give the title compound as an oil (15.9 g, 40 mmol); MS: 395.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]([F:17])([F:16])[F:15])([O-])=O>CC#N>[F:15][C:14]([F:16])([F:17])[O:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Solvent: CC#N
Product: Nc1ccc(OC(F)(F)F)c(N)c1

Procedure:
4-Trifluoromethoxy-benzene-1,3-diamine (D-4) was synthesized following the general scheme above starting from 2,4-dinitro-1-trifluoromethoxy-benzene. Yield (89%). HPLC ret. time 0.91 min, 10-99% CH3CN, 5 min run; ESI-MS 193.3 m/z (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([NH:16][CH2:17][CH2:18][NH2:19])(=[O:15])[CH3:14]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:19][CH2:18][CH2:17][NH:16][C:13](=[O:15])[CH3:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(=O)NCCN
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCNC(C)=O)n1
Temperature: 0 °C
Yield: 72.5 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.51 ml (0.0424 mol) of N-acetylethane-1,2-diamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 3.9 g of yellow powder are obtained, ie a yield of 72.5%.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:47][O:46][C:15]1[CH:16]=[C:17]([CH:44]=[CH:45][C:14]=1[NH:13][C:11]([C:10]1[C:4]2[N:3]=[C:2]([N:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)=[O:12])[C:18]([N:20]([CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35])=[O:19]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(Cl)nc12
Reactant: CN1CCNCC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N3CCN(C)CC3)nc12
Yield: 86 %

Procedure:
A solution of 4-[2-chloro-1H-benzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg) and N-methylpiperazine (106 mg) was heated at 80° C. for 2.5 hours. The excess of N-methylpiperazine was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-methylpiperazin-1-yl)-1H-benzimidazol-4-yl]carbonylaminobenzamide (66 mg).