Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[O:15][CH:16]([C:22](=O)[CH2:23][CH3:24])[C:17](OCC)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35]>C(O)C>[NH2:36][C:34]1[N:35]=[C:17]([OH:18])[C:16]([O:15][C:14]2[CH:26]=[CH:27][CH:28]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:13]=2)=[C:22]([CH2:23][CH3:24])[N:33]=1
Reactant: N=C(N)N
Reactant: CCCCCCCCCCCc1cccc(OC(C(=O)CC)C(=O)OCC)c1
Agent: O=C(O)O
Solvent: CCO
Product: CCCCCCCCCCCc1cccc(Oc2c(O)nc(N)nc2CC)c1
Yield: 15.7 %

Procedure:
A stirred solution of 8.9 grams (0.028 mole) of ethyl 2-(3-undecylphenoxy)-3-oxopentanoate and 2.5 grams (0.028 mole) of guanidine carbonate in 30 mL of ethanol was heated at reflux for about 6 hours. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was taken up in 50 mL of water and 5 mL of acetic acid, and the mixture was extracted with 50 mL of diethyl ether. The ether layer was extracted with 20 grams of aqueous 10% sodium hydroxide and then with 100 mL of water. The water extract was made acidic with acetic acid, and then it was extracted with 50 mL of diethyl ether. The ether extract was concentrated under reduced pressure to a residue. The residue was then taken up in 25 mL of heptane, and the mixture was again concentrated under reduced pressure to a residual solid. The solid was slurried in an additional 25 mL of heptane, and then it was collected by filtration. The solid was dried under reduced pressure, yielding 1.7 grams of 2-amino-6-ethyl-4-hydroxy-5-(3-undecylphenoxy) pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Br:15])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[F:16][C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([Br:15])=[C:2]([Br:1])[CH:3]=3)[CH2:7][CH2:8]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Brc1ccc(CN2CCNCC2)cc1Br
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Reaction time: 16 h

Procedure:
A solution of 1-(3,4-dibromo-benzyl)-piperazine (167 mg) in DCM (2 mL) was treated with 3-fluorophenyl isocyanate (0.07 mL). After 16 h, the resulting mixture was chromatographed, giving the title compound as a white foam (188 mg). 1H NMR (400 MHz, CDCl3): 7.61 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.31-7.12 (m, 3H), 7.01-6.97 (m, 1H), 6.75-6.99 (m, 1H), 6.47 (br m, 1H), 3.51-3.47 (m, 4H), 3.45 (s, 2H), 2.48-2.43 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O.[Na]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cl)n1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: ClCc1cccc(Cl)n1

Procedure:
6-Chloro-2-pyridylmethanol, 0.982 g (6.84 mmole) in 10 ml methylene chloride was treated with 0.814 g thionyl chloride at room temperature for one hour. The mixture was neutralized with saturated sodium bicaronate solution, extracted with methylene chloride, the extracts dried and solvent evaporated to give 815 mg of product as colorless crystals. 1H--NMR(CDCl3)ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[CH3:18][S-:19].[Na+]>CO.ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:19][CH3:18])[CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CSc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a mixture of compound 2,4-difluoro-1-nitro-benzene (10 g, 62.9 mmol), pyridine (10 ml, 124 mmol) in MeOH (30 ml) was added the solution of sodium thiomethoxide(20%, 300 mmol) in methanol drop-wise at 0° C. The mixture was stirred for 2 hour and then diluted with dichloromethane. The mixture was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give titled compound (10 g, yield 85%)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[NH:4][N:3]=1.CC(C)([O-])C.[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>C1COCC1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[N:4]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1n[nH]c2ccc(C3OCCCO3)cc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(Cl)c2cc(C3OCCCO3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.7 g (11.3 mmol) 3-chloro-5-(1,3-dioxan-2-yl)-1H-indazole (Example 44A) in anhydrous THF (60 ml) were added 1.31 g (13.6 mmol) sodium tert-butoxide at room temperature. The solution was cooled to 0° C., and 2.26 g (13.6 mmol) 2-(trimethylsilyl)ethoxymethyl chloride were added at this temperature. The resulting mixture was stirred at 0° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (silica gel; cyclohexane/ethyl acetate 5:1 v/v) to give 1.73 g (41% of th.) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1>[Pd].CCOC(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1=Cc2ccc(C#CCCOC3CCCCO3)cc2Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1=Cc2ccc(CCCCOC3CCCCO3)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of ethyl (±)-3-[4-(2-tetrahydropyranyloxy)-1-butyn-1-yl]-5H-dibenzo[a,d]cycloheptene-10-acetate (1.2 g, 2.77 mmole), 10% Pd/C (0.3 g, 0.28 mmole), and EtOAc (28 mL) was shaken at RT under hydrogen (50 psi) on a Parr apparatus. After 3 hr, the reaction was filtered through celite® and the filtrate was concentrated. Silica gel chromatography (10% EtOAc/hexanes) gave the title compound (1.06 g, 88%) as a colorless oil: TLC (20% EtOAc/hexanes) Rf 0.51; 1H NMR (400 MHz, CDCl3) δ 7.05-7.20 (m, 4 H), 6.92-7.03 (m, 3 H), 4.53-4.60 (m, 1 H), 4.34 (d, J=15.1 Hz, 1 Hz, 1 H), 4.12-4.26 (m, 2 H), 3.80-3.90 (m, 3 H), 3.71-3.80 (m, 1 H), 3.44-3.53 (m, 1 H), 3.35-3.44 (m, 1 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.65 (dd, J=15.5, 4.9 Hz, 1 H), 2.49-2.61 (m, 3 H), 1.77-1.90 (m, 1 H), 1.45-1.77 (m, 9 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 459 (M+Na)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](SC)=[N:7][C:8]#[N:9]>C(#N)C>[C:8]([N:7]=[C:6]([N:2]([CH3:1])[NH2:3])[S:5][CH3:4])#[N:9]
Reactant: CSC(=NC#N)SC
Reactant: CNN
Solvent: CC#N
Product: CSC(=NC#N)N(C)N
Reaction time: 16 h

Procedure:
A mixture of methyl hydrazine (0.48 ml) and cyanocarbonimidodithioic acid dimethyl ester (1.3 g) in acetonitrile was stirred at 25° for 16 hours. The resulting solution was evaporated to a gum which was crystallized from acetonitrile/ether to give the title compound as colourless granules (210 mg) m.p. 69°-71°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=2[N:11]=[C:10]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[OH:27].Br[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=2[N:11]=[C:10]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[O:27][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)CCCCCn1c(-c2ccc(Cl)cc2O)nc2cc(F)c(F)cc21
Reactant: BrCC1CCCC1
Product: COC(=O)CCCCCn1c(-c2ccc(Cl)cc2OCC2CCCC2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 6-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-hexanoic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (65%). MS (Turbo Spray): m/z=505.3 (M+H).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[N:11]=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[N:11]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(CCl)n1
Solvent: ClCCl
Product: CCCN(CCC)Cc1nc(CN2C(=O)c3ccccc3C2=O)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
35.6 ml (260 mmol) of dipropylamine were added dropwise at room temperature to a solution of 36 g (130 mmol) of 2-(5-chloromethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in 300 ml of methylene chloride, whereupon the mixture was stirred at room temperature for 24 hours. The yellow solution was washed with sat. sodium hydrogen carbonate solution, dried with sodium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/aqueous ammonia 19:1). There were obtained 38 g (85%) of 2-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindol-1,3-dione as a beige oil, Rf=0.12 (silica gel, methylene chloride/aqueous ammonia 19:1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][S:15]([CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)(=[O:17])=[O:16]>>[CH3:14][S:15]([CH:18]1[CH2:22][CH2:21][N:20]([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19]1)(=[O:17])=[O:16]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)C1CCNC1
Product: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)C1
Yield: 44.1 %

Procedure:
The title intermediate is prepared from 4-(chlorosulfonyl)benzoic acid (CAS 10130-89-9) (375 mg, 1.7 mmol) and 3-(methylsulfonyl)pyrrolidine (CAS 433980-62-2) (343 mg, 2.3 mmol) in a manner substantially similar to Procedure F to provide 250 mg (44%) of the title compound. MS (ES−) 332.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][F:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][F:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: FCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCF)CC4)cn3)nc2n1C1CCCC1
Yield: 46.3 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 1-bromo-2-fluoroethane (88 mg, 0.687 mmol) gave 7-cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (51 mg, 80%). MS(ESI) m/z 481.3 (M+H)+
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].CC(C)([O-])C.[Mg+2].CC(C)([O-])C.CC(C)[O-].[Mg+2].CC(C)[O-].C1(C)C=CC(S(O[CH2:45][P:46](=[O:53])([O:50]CC)[O:47]CC)(=O)=O)=CC=1.Br[Si](C)(C)C>CN(C=O)C>[P:46]([CH2:45][O:1][C@H:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13])([OH:53])([OH:50])=[O:47]
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Reactant: C[C@@H](O)Cn1cnc2c(N)ncnc21
Agent: CC(C)(C)[O-]
Agent: CC(C)[O-]
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
(R)-9-[2-(hydroxy)propyl]adenine (HPA) (20.0 g, 0.104 mol) was suspended in DMF (44.5 ml) and heated to 65° C. Magnesium t-butoxide (14.2 g, 0.083 mol), or alternatively magnesium isopropoxide, was added to the mixture over one hour followed by diethyl p-toluenesulfonyloxymethylphosphonate (66.0 g, 0.205 mol) over two hours while the temperature was kept at 78° C. The mixture was stirred at 75° C. for 4 hours. After cooling to below 50° C., bromotrimethylsilane (73.9 g, 0.478 mol) was added and the mixture heated to 77° C. for 3 hours. When complete, the reaction was heated to 80° C. and volatiles were removed via atmospheric distillation. The residue was dissolved into water (120 ml) at 50° C. and then extracted with ethyl acetate (101 ml). The pH of the aqueous phase was adjusted to pH 1.1 with sodium hydroxide, seeded with authentic (R)-PMPA, and the pH of the aqueous layer was readjusted to pH 2.1 with sodium hydroxide. The resulting slurry was stirred at room temperature overnight. The slurry was cooled to 4° C. for three hours. The solid was isolated by filtration, washed with water (60 ml), and dried in vacuo at 50° C. to yield 18.9 g (63.5%) of crude (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) as an off-white solid.
Reaction SMILES: Cl.[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[ClH:31].[C:2]1([C@H:12]([NH:14][CH2:15]/[CH:16]=[CH:17]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 45 °C
Reaction time: 4.5 h

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (35.0 g, 85.393 mmol) is suspended in toluene (150 ml) at 20° C. and thionyl chloride (11.2 g, 94.141 mmol) is added slowly. The reaction mixture is stirred at 30°-40° C. for 4-5 hrs and then the solvent is distilled off under vacuum. The residual toluenic slurry is flushed with isopropanol, upon several distillation/refill cycles. The resulting isopropanol solution is refluxed for 1 hr, then cooled down to 45° C. and added with methyl tert-butyl ether (MTBE) (70 ml). The so-obtained suspension is stirred at 45° C. for 1 hr, then cooled down to 0° C. and aged 1 hr. 29.6 g of a 95.8:4.2 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydro-chloride (XI) is obtained as a white powder after filtration, washing with a 3:1 vol/vol isopropanol/MTBE mixture (2×20 ml) end exsiccation at 55° C. under vacuum.
Reaction SMILES: [CH2:1]([N:5]([C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:18]=1[NH2:19]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[CH:13]=[C:12]([NH:19][C:18]2[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH3:16])[N:11]=[C:10]([CH3:15])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1cc(Cl)nc(C)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Product: CCCCN(CC)c1cc(Nc2c(C)cc(C)cc2C)nc(C)n1

Procedure:
A mixture of butyl-(6-chloro-2-methyl-pyrimidin-4-yl)-ethylamine (1.006 g, 4.42 mmol), and 2,4,6-trimethylaniline (3 ml) was heated at reflux overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 2.862 g of a brown oil. The oil was purified through silica gel column chromatography to give 981 mg (68%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.80 (t, 3H), 1.1–1.3 (m, 2H), 1.3–1.5 (m, 2H), 2.17 (s, 6H), 2.27 (s, 3H), 2.41 (s, 3H), 3.2 (m, 2H), 3.36 (m, 2H), 4.66 (s, 1H), 6.90 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(OCC)(SCC)=[S:38].C(O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[S:38])[NH2:29])=[CH:26][CH:27]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C#N)cc1)C(=O)OCC
Reactant: CCOP([O-])(=S)SCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C(N)=S)cc1)C(=O)OCC

Procedure:
1.7 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-cyano-phenylamino)-acetate, 1.13 ml of diethyl dithiophosphate and 4 ml of ethanol were heated for 2 hrs. to 60° C. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel gave 1.6 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-thiocarbamoyl-phenylamino)-acetate, m.p. 166° C., MS: 523 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][CH2:23]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1

Procedure:
1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate 2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH:17]=[CH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)([CH3:4])[CH3:3].N.[Cl-].[NH4+]>O1CCCC1>[NH:23]1[C:24]2[C:20](=[C:19]([CH2:18][CH2:17][CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: CC(C)(C)NCCCOc1ccccc1C(O)C=Cc1cccc2[nH]ccc12
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NCCCOc1ccccc1CCCc1cccc2[nH]ccc12
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
A solution of 3.38 g of the product of Example 6 and 25 ml of tetrahydrofuran was added at -78° C. to 30 ml of ammonia and after adding 3 g of sodiunm at -40° C., the mixture was stirred for 90 minutes under an inert atmosphere. 24 g of ammonium chloride were added at -40° C. and the ammonia evaporated. The residue was diluted with water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, aqueous sodium chloride, dried over a deshydrant, filtered and evaporated to dryness to obtain 2.86 g of N-[3-{2-(3-[1H-indol-4-yl]-propyl)-phenoxy}-propyl]2-methyl-2-propanamine.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.NC[C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C.O>C1COCC1.CC(O)=O>[C:25]([C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:1][N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[CH2:20][CH2:21]1)([OH:27])=[O:26]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
N-carboethoxyphthalimide (21.9 g, 0.10 mol), trans-4-(aminomethyl)cyclohexane carboxylic acid (15.7 g, 0.10 mol) and triethylamine (14 mL) were stirred in 100 mL THF and the mixture refluxed 18 h. The nearly clear solution was poured into 400 ml water containing 10 mL glac. HOAc with rapid stirring and the precipitated product collected by suction and dried in a vacuum oven at 80° C., mp 190°-192°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH2:39][CH3:40])=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH2:39][CH3:40])=[CH:36][C:37]=4[CH3:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(CC)cc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnc(CC)cc3C)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M235) (151 mg, 0.26 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (84 mg, 69%).