Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[CH:3][C:4]=1[O:11][CH3:12]
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(O)CC2)ccc1N
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (3.0 g, 17.5 mmol), 4-hydroxypiperidine (1.77 g, 17.5 mmol) and potassium carbonate (2.9 g, 21 mmol) in DMSO was stirred for 24 h. The reaction was diluted with water and extracted three times with Ethyl acetate. The combined organic solutions were dried over MgSO4 and concentrated. The resulting residue was stirred in ethanol and acetic acid with 10% Pd/C under 30 psi of hydrogen for 16 hr. The reaction was filtered through a pad of celite, rinsed with Ethyl acetate. The filtrate was concentrated and dissolved in methylene chloride. The organic solution was washed with saturated sodium bicarbonate, dried over MgSO4, and concentrated to give 1-[4-amino-3-(methyloxy)phenyl]-4-piperidinol (2.44 g, 63% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 6.49-6.45 (m, 2H), 6.27 (dd, J=8.4 and 2.4 Hz, 1H), 4.60 (d, J=4.0 Hz, 1 H), 4.18 (s, 2H), 3.71 (s, 3H), 3.54-3.48 (m, 1H), 3.25-3.22 (m, 2H), 2.63-2.56 (M, 2H), 1.80-1.76 (m, 2H), 1.51-1.42 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CN(C)CCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see Intermediate 18) (250 mg, 0.575 mmol) in DMF (10 mL) were successively added 3-(dimethylamino)-1-propanol (71.2 mg, 0.690 mmol), EDC (220 mg, 1.150 mmol) and DMAP (7.0 mg, 0.057 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo, dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (41 mg, 17%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.94 min, MH+=520.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]#[N:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Cl)nc1NCCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)nc1NCCOCc1ccccc1
Temperature: 55 °C
Yield: 67.2 %

Procedure:
To a solution of 2-(2-benzyloxy-ethylamino)-6-chloro-nicotinamide (3, 15.8 g, 51.7 mmol) in acetonitrile (anhydrous, 200 mL) were added pyridine (33.4 mL, 413 mmol) and POCl3 (18.9 mL, 207 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc (200 mL) was added and layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 2%-20% EtOAc/hexanes gradient, to afford 10 g (67% yield) of the title product.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[NH2:11][C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[Cl-:10].[NH:11]([CH2:8][P+:3]([CH2:1][NH:11][C:12]([NH2:14])=[O:13])([CH2:4][NH:11][C:12]([NH2:14])=[O:13])[CH2:6][NH:11][C:12]([NH2:14])=[O:13])[C:12]([NH2:14])=[O:13]
Reactant: OC[P+](CO)(CO)CO
Reactant: NC(N)=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: NC(=O)NC[P+](CNC(N)=O)(CNC(N)=O)CNC(N)=O
Yield: 101.1 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with urea (12.01 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 18.14 g (101%) of tetrakis(ureidomethyl)phosphonium chloride (I, R=R'=R"=H, X=Cl) as a colorless, brittle glass.
Reaction SMILES: [Cl:1][C:2]1[C:14]([I:15])=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:16][N:17]([CH:19](OC)OC)[CH3:18].CCOCC>C1COCC1>[Cl:1][C:2]1[C:14]([I:15])=[CH:13][C:5]2[C:6](=[O:12])/[C:7](=[CH:16]\[N:17]([CH3:19])[CH3:18])/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)c2cc(I)c(Cl)cc2N1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)/C=C1/CC(=O)Nc2cc(Cl)c(I)cc2C1=O
Temperature: 60 °C
Reaction time: 17 h
Yield: 81.5 %

Procedure:
To a suspension of 8-chloro-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (10.0 g, 29.8 mmol) in THF (44mL) was added DMF-DMA (21.1 mL, 149 mmol). The flask reaction mixture was allowed to stir 60° C. under an atmosphere of argon. A light orange solution containing a suspended solid resulted. After 17 h, the reaction mixture was allowed to cool to it. Ether (100 mL) was added and the solid was collected via suction filtration, washed with ether, and dried in a vacuum oven to yield (4Z)-8-chloro-4-[(dimethylamino)methylene]-7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (9.50g, 24.3 mmol, 82%) as a yellow solid. LCMS (FA): m/z=391 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][Si:45]([C:48]#[CH:49])([CH3:47])[CH3:46]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][CH:10]([C:4]2[CH:3]=[C:2]([C:49]#[C:48][Si:45]([CH3:47])([CH3:46])[CH3:44])[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(Br)cc(CO)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
403 mg of the ethyl (RS)-(3-bromo-5-hydroxymethyl-phenyl)-(4-cyano-phenylamino)-acetate described in Example 156.2 were suspended in 3.1 ml of triethylamine and 4 mg of triphenylphosphine were added. Argon was conducted through the reaction mixture for 30 min. Then, 7 mg of palladium(II) acetate and 0.22 ml of trimethylsilylacetylene were added and the mixture was heated for 26 hrs. to 80° C. Then, the mixture was left to cool to room temperature and the crude product was isolated by extraction and purified by column chromatography (n-hexane/ethyl acetate). There were obtained 398 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanylethynyl-phenyl)-acetate as a brown oil; MS: 406 ([M]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[Cl:37][CH2:38][CH2:39][CH2:40][N:41]=[C:42]=[O:43]>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:42]([NH:41][CH2:40][CH2:39][CH2:38][Cl:37])=[O:43])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C=NCCCCl
Product: COc1cc(-c2csc3c(NC(=O)NCCCCl)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 3-chloropropyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.69 (s, 1H), 8.19 (br, 1H), 8.13 (d, 1H), 7.94 (s, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.29 (s, 1H), 7.16 (m, 2H), 6.08 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.71 (t, 2H), 3.25 (m, 2H), 1.93 (m, 2H); MS: (MH)+563.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH:17]1([CH:20]([NH2:28])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][CH2:18]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:28][CH:20]([CH:17]2[CH2:18][CH2:19]2)[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NC(c1ccc(Cl)cc1)C1CC1
Solvent: CCN(CC)CC
Product: Clc1ccc(C(Nc2nc(Cl)nc3c2ncn3C2CCCC2)C2CC2)cc1

Procedure:
2-Chloro-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, α-cyclopropyl-4-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([BH3-])#N.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)CCNCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 3-nitrobenzaldehyde (127 mg, 0.84 mmol), N,N-dimethylethylenediamine (184 μL, 1.7 mmol), and HOAc (5 drops) in DCM (10 mL) was stirred at rt for 6 h and then heated to 40° C. for 1 hour. The reaction was cooled to 0° C., and sodium cyanoborohydride (360 mg, 1.7 mmol) was added in one portion. The reaction was stirred overnight at rt. After 16 h, the reaction mixture was washed with 4 N NaOH, dried over Na2SO4, and concentrated. The crude product was used in the next reaction without further purification. ES-LC/MS m/z=224 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12]OC(C)(C)C>C1(C)C=CC=CC=1.O>[Cl:12][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CC(C)(C)OCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Yield: 80.6 %

Procedure:
2-methyl-4-nitroaniline (56.0 g, 0.368 mol) was dispersed in toluene (430 ml) in a 1 liter four-neck flask. Tertiary butyl hypochloride (46.0 g, 0.423 mol) was added dropwise thereto, while cooled in iced water and stirred. The mixture was stirred at room temperature for 3 hours. The solids were filtered and washed three times with 200 ml of a 50% aqueous ethanol three times. They were then dried at 40° C. at a reduced pressure to obtain 55.33 g of a yellow solid (production yield 80%). The yellow solid was used in the subsequent step without purification.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[OH-].[Li+].[C:10](#[N:13])[CH:11]=[CH2:12]>C(O)(=O)C>[C:10]([CH2:11][CH2:12][C:1]([OH:7])([CH2:12][CH2:11][C:10]#[N:13])[CH2:2][O:3][CH2:4][CH2:5][OH:6])#[N:13]
Reactant: C=CC#N
Reactant: OCCOCCO
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CCCC(O)(CCC#N)COCCO

Procedure:
In a 5000 cc three necked flask equipped with an overhead stirrer, reflux condenser, nitrogen purge, dropping funnel and thermometer was charged 1978.1 gm. (18.64 moles) of diethylene glycol and 3.0 gm. of anhydrous lithium hydroxide. The overhead stirrer was then adjusted to high speed. Acrylonitrile was then added through the dropping funnel. Over the course of 5 hours a total of 2880 cc of acrylonitrile was added and reaction temperature reached a maximum of 66° C. with a water bath being maintained above 52° C. The reaction flask was then post-heated at 52°-72° C. for an additional 40 minutes. The reaction contents were cooled to room temperature and neutralized with glacial acetic acid. The reaction contents were filtered and the crude reaction product was stripped of all excess acrylonitrile under vacuum (15-30 mmHg) at a temperature not exceeding 60° C. to give the liquid bis-(-2-cyanoethyl)diethylene glycol. A GLC analysis showed the product to contain 99 percent dicyanoglycol and about 1 percent monocyanoglycol. This dicyanoglycol was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[C:22](B(O)O)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:22]2[NH:18][N:19]=[CH:20][CH:21]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide (2.0 g, 6.43 mmol) in toluene (30 mL), water (10 mL) and ethanol (10 mL) was added 1H-pyrazole-5-boronic acid (1.44 g, 12.9 mmol), Pd(PPh3)4 (0.74 g, 0.643 mmol), and potassium carbonate (2.67 g, 19.3 mmol). The resulting mixture was degassed three times and heated to 100° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (ethyl acetate:hexane, 1:1) to provide 4-methyl-2-(2H-Pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (1.25 g, 66% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.31-7.36 (m, 4H), 7.24-7.27 (m, 1H), 6.78 (d, J=4.0 Hz, 1H), 4.44 (d, J=4.0 Hz, 2H), 2.60 (s, 3H); MS (M+H)+=299.1; Rt=1.06 min; HRMS (M+H)+=299.10.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(OCC)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCCCCCc1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCCCCCC1CCCCC1

Procedure:
To a solution of 5-phenylpentanol (2.21 g., 13.5 mmol) in ten ml glacial acetic acid was added amorphous platinum oxide (0.40 g., 1.76 mmol, oxygen activated). This mixture was subjected to three atm. of hydrogen with agitation (Parr hydrogenator) at room temperature for four hours. The reaction mixture was diluted with ethyl ether, filtered through celite, washed repeatedly with saturated sodium bicarbonate, followed by water and saturated sodium chloride solution. The organic portion was filtered, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[H-].[Na+]>CN(C=O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of dimethyl malonate (13.2 g), 4-bromobenzylbromide (5.4 g) in DMF (200 mL) was treated with NaH (4 g, 60% in mineral oil). The mixture was stirred for 5 min at 0° C. and 20 min at room temperature and then quenched with 10 mL of AcOH slowly. The mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated and the excess dimethyl malonate was removed under vacuum at 70° C. to provide the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P([N:76]=[N+:77]=[N-:78])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:76]([C@@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1)=[N+:77]=[N-:78]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 67 %

Procedure:
Cholesterol (7.76 mmol, 3.0 g) and triphenylphosphine (7.76 mmol, 2.04 g) were dissolved in 77.6 mL of anhydrous tetrahydrofuran. Diisopropyl azodicarboxylate (7.76 mmol, 1.5 mL) was then added dropwise. After stirring the orange mixture for a few minutes, diphenylphosphoryl azide (7.76 mmol, 1.68 mL) was added dropwise. After 24 hours, the pale yellow reaction mixture was concentrated. Purification by silica gel chromatography (100% hexanes) afforded 3α-azidocholest-5-ene (2.14 g, 67%) as a white solid. mp 110-112° C.; TLC Rf=0.87 (20% ethyl acetate/hexanes); IR (thin film) 2946, 2914, 2845, 2083 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.42-5.40 (m, 1H), 3.89 (t, 1H, J=2.9 Hz), 2.58-2.49 (m, 1H), 2.23-2.16 (m, 1H), 2.16-1.93 (m, 2H), 1.89-1.05 (m, 24H), 1.02 (s, 3H), 0.93 (d, 3H, J=6.5 Hz), 0.88 (d, 6H, J=6.6 Hz), 0.69 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23]([CH3:30])=[N:22]1>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:28])[C:23]([CH3:30])=[N:22]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Product: Cc1nn(C)c(C)c1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 69 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,3,5-trimethyl-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 75°-77° C., in a 69% yield.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37])([O-:33])=[O:32]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[N+:31]([O-:33])=[O:32])=[O:37])=[CH:27][CH:28]=3)=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc3)C(=O)O)CCCC2)cc1
Yield: 51 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (32.3 mg, 0.079 mmol) and 2-nitrobenzoic acid (17 mg, 0.10 mmol) were reacted as described in example 40 to give 22 mg of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR—FAB—MS: obs. mass 546.2235. Calcd. mass 546.2240 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:28]=[CH:27][C:26]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)=[CH:25][CH:24]=1)[CH3:19]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-ethoxycarbonyl-phenylboronic acid gives “A71”; method 1: HPLC/MS: 1.46 min, [M+H]=363;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4]/[C:5](=[N:19]/[S@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1.C([BH-](CC)CC)C.[Li+].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:22]([S@@:20]([N:19]1[CH2:2][CH2:3][CH2:4][CH:5]1[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][C@@H:14]1[CH2:18][CH2:17][O:16][CH2:15]1)=[O:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[S@](=O)/N=C(/CCCCl)c1cc(F)ccc1O[C@@H]1CCOC1
Agent: CC[BH-](CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N1CCCC1c1cc(F)ccc1O[C@@H]1CCOC1
Reaction time: 3 h
Yield: 59.1 %

Procedure:
(S,Z)—N-(4-chloro-1-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)butylidene)-2-methylpropane-2-sulfinamide (7.6 g, 19.5 mmol) in THF (100 mL) was cooled to −78° C. and to which was added cold (−78° C.) Lithium triethylborohydride (1M in THF) (21.48 ml, 21.5 mmol) drop wise and stirring was continued at −78° C. for 3 h. LiHMDS (1M in THF) (19.53 ml, 19.5 mmol) was then added and stirring was continued at −78° C. to 0° C. for 2 h. The resultant reaction mixture was quenched with saturated NH4Cl solution, diluted with ethyl acetate. The ethyl acetate layer separated was washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to afford the crude residue. The residue thus obtained was purified by column chromatography twice (using initially with 60-120 silica gel and 15% EtOAc in Hexane as elute and again with 230-400 silica gel and 12-14% EtOAc in Hexane as elute) to afford 4.1 g of the title compound as crude, which was used as such for the next step.