Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]3[N:13]([CH2:17][CH2:18][N:19]=3)[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.[N:24]([O-])=[O:25].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]3[N:13]([CH2:17][CH2:18][N:19]=3)[C:14](=[O:16])[C:15]=2[N:24]=[O:25])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CC(C)CN1C(NCc2ccc(Cl)cc2)=CC(=O)N2CCN=C21
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN1C2=NCCN2C(=O)C(N=O)=C1NCc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of the product of Procedure 86 (0.1 mol) in 150 ml. 25% aqueous acetic acid is cooled to 0° C. and treated by dropwise addition of an aqueous solution of sodium nitrite (0.11 mol). After stirring at 0° C. for an hour, the mixture is warmed to room temperature, the solid collected by filtration, washed with water and air dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[CH:8]=1)=[O:6]
Reactant: Cc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ncccc32)n1
Yield: 44.8 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 0.100 g (0.359 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 17.2 mg (0.431 mmol, 60% dispersion in oil) of sodium hydride, 80.2 mg (0.431 mmol) of 2-methyl-6-bromomethyl-pyridine and 3.5 mL of N,N dimethylformamide. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 61.7 mg of 3-(3,4-Dimethyl-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H21N3O2 [M+H]: 384.2 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])=[O:5]
Reactant: CNCCO
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
2,4,5-Trifluorobenzoyl chloride (540 mg, 2.78 mmol) was added to a stirred solution of 2-methylaminoethanol (0.185 mL, 3.06 mmol) in DCM (5 mL) and 10% aqueous sodium hydroxide solution (5 mL) at 0° C. After addition was complete the icebath was removed and the reaction was allowed to warm up to RT and stirred for 3 hours. The phases were then separated and the aqueous phase extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to give the desired compound as a colourless oil (686 mg). This material was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as light yellow needles, m.p. 193–194° C. Analysis: Calculated for C17H23N5O3S: % C, 54.09; % H, 6.14; % N, 18.55. Found: % C, 54.09; % H, 5.93; % N, 18.49.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:18])[CH3:17].CO>>[CH2:16]([NH:18][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1)[CH3:17]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2nc1Cl
Reactant: CCN
Solvent: CO
Product: CCNc1nc2ccc([N+](=O)[O-])cc2cc1C

Procedure:
The product (1 g, 4.5 mmol) from Step A and a solution of 2N ethylamine in methanol (5 mL, 25 mmol) were used to prepare the product according to the procedure of Example 1, Step C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.C1C[O:17][CH2:16][CH2:15]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[CH:15][CH:16]=[O:17]
Reactant: C1CCOC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: O=CC=Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-5-trifluoromethylbenzaldehyde (300 mg) in 5 mL THF was added 40 mg of ZnBr2. With stirring, 360 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (40 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a light brown oil (220 mg): 1H NMR (CDCl3) δ 6.09 (s, 2H), 6.14 (s, 1H), 6.86-6.98 (m, 4H), 7.43 (d, 1H, J=9.6 Hz), 9.69 (d, 1H, J=4.5 Hz).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1)=[O:45]>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=1)=[O:45])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g of Boc-Ile (16 mmol) is reacted with 3.8 g of 1-hydroxybenzotriazole (2.4 mmol) and 3.7 g of N,N'-dicyclohexylcarbodiimide (18 mmol) for 1 hour at 0° C., and then the solution of Pro-Tyr-OMe in 15 cm3 of dimethylformamide, prepared earlier, is added. After stirring for 1 hour at 0° C. and then for 10 hours at 20° C., the precipitate of dicyclohexylurea is separated off by filtration and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and the solution obtained is washed successively with a 1M solution of citric acid, a solution of sodium bicarbonate and a solution of sodium chloride. The organic layer is dried over sodium sulphate. After removal of the solvent, the crude product is purified by chromatography on a column of silica gel (height 45 cm, diameter 2.5 cm), by eluting with ethyl acetate and mixtures of ethyl acetate with hexane. 3.8 g of Boc-Ile-Pro-Tyr-OMe are obtained, the properties of which are as follows:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:10]1[CH:11]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: BrBr
Reactant: CCCCCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCCc1ccc(O)c(Br)c1
Yield: 89.4 %

Procedure:
24.6 g (0.15 mol) of p-n-pentylphenol was reacted with 24.5 g (0.153 mol) bromine in glacial acetic acid to yield 32.6 g of 2-bromo-4-n-pentylphenol by vacuum distillation or a yield of 89.5%.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:29](/[CH:30]=[CH:31]/[N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=[CH:26][C:25]=1[NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH:30]([C:29]4[C:24]([CH3:23])=[C:25]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:26]=[CH:27][CH:28]=4)[CH2:31][N+:32]([O-:34])=[O:33])=[CH:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc3cc[nH]c3c2)C1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Temperature: 110 °C
Yield: 33.4 %

Procedure:
6-(3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indole (1.867 g, 5.90 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.5354 g, 4.92 mmol) were dissolved in THF (40 mL), concentrated in vacuo, and the mixture was heated at 110° C. for 1 hr. The reaction mixture was cooled to room temperature and purified by flash chromatography using an ISCO 220 g column eluting with 25-100% EtOAc/hexanes to give the desired product (1.0324 g, 1.642 mmol, 33.4% yield) as a tan solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([C:26]([NH:39][C:40]2[CH:41]=[C:42](/[CH:46]=[CH:47]/[CH2:48]O)[CH:43]=[CH:44][CH:45]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:51]>O1CCCC1>[C:20]1([C:26]([NH:39][C:40]2[CH:41]=[C:42](/[CH:46]=[CH:47]/[CH2:48][Br:51])[CH:43]=[CH:44][CH:45]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC/C=C/c1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC/C=C/c1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
11.54 g of triphenylphosphine was added to a solution of 7.83 g of (E)-3-(3-triphenylmethylaminophenyl)allyl alcohol and 14.59 g of carbon tetrabromide dissolved in 60 ml of tetrahydrofuran, with ice-cooling. The mixture was stirred for 1 hour at the same temperature to obtain a tetrahydrofuran solution of (E)-(3-triphenylmethylaminophenyl)allyl bromide. To this solution were added 4.45 g of triethylamine and 6.47 g of 3-nitro-5-(piperazin-1-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, with ice-cooling. The mixture was stirred for 5 hours at room temperature. To the reaction mixture was added 200 ml of water and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=3/1) to obtain 7.8 g of light yellow oily 3-nitro-5-[4-{(E)-3-(3-triphenylmethylaminophenyl)allyl}piperazin-1-yl]-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[C:11]([SH:20])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.Br[CH2:23][CH2:24][NH2:25].O>C1COCC1>[NH2:25][CH2:24][CH2:23][S:20][C:11]1[NH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1
Reactant: NCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
60% NaH in oil (0.91 g, 22.8 mmol) was added to a suspension of 4,5-diphenyl-2-imidazolethiol (2.5 g, 9.9 mmol) in dry THF (80 ml) at room temperature under stirring. After 15 minutes, 2-bromoethylamine hydrobromide (2.0 g, 9.9 mmol) was added to the mixture. The reaction mixture was refluxed for 1 hour, then poured into water (500 ml) and extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated. The residue was recrystallized (toluene) to give 2-(2-aminoethylthio)-4,5-diphenylimidazole (51.3%): mp 152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1I.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]#[C:12][CH2:11][CH2:10][OH:14]
Reactant: C#CCCO
Reactant: Clc1ccc(I)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCC#Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere 97.2 g (0.356 mole) of 2,4-dichloroiodobenzene, 3.21 g (0.0046 mole) of bis(triphenylphosphine)palladium(II) chloride, and 0.8 g (0.0042 mole) of copper(I) iodide were suspended in 50 mL of triethylamine and 100 mL of acetonitrile. This mixture was cooled in an ice/water bath to 0°-5° C., and 24.6 g (0.356 mole) of 3-butyn-1-ol dispersed in 25 mL of acetonitrile was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for approximately 16 hours. The solvent was evaporated from the reaction mixture under reduced pressure, leaving a brown oil as the residue. This oil was passed through a column of silica gel, eluting first with hexane and then with methylene chloride. Product-containing factions were combined, and the solvent was evaporated under reduced pressure, leaving 4-(2,4-dichlorophenyl)-3-butyn-1-ol as the residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O=S1(=O)CCC(NCCN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C1.[CH3:50][C@:51]12[C@@:68]3([CH3:69])[C@@H:59]([C@:60]4([CH3:81])[C@@H:65]([CH2:66][CH2:67]3)[C:64]([CH3:71])([CH3:70])[C:63]([C:72]3[CH:80]=[CH:79][C:75]([C:76]([OH:78])=[O:77])=[CH:74][CH:73]=3)=[CH:62][CH2:61]4)[CH2:58][CH2:57][C@@H:56]1[C@H:55]1[C@H:82]([C:85]([CH3:87])=[CH2:86])[CH2:83][CH2:84][C@:54]1([NH:88][CH2:89][C:90]([NH:92][CH3:93])=[O:91])[CH2:53][CH2:52]2>>[CH:85]([C@H:82]1[C@@H:55]2[C@@H:56]3[C@@:51]([CH3:50])([CH2:52][CH2:53][C@@:54]2([NH:88][CH2:89][C:90]([NH:92][CH3:93])=[O:91])[CH2:84][CH2:83]1)[C@@:68]1([CH3:69])[C@@H:59]([C@:60]2([CH3:81])[C@@H:65]([CH2:66][CH2:67]1)[C:64]([CH3:71])([CH3:70])[C@@H:63]([C:72]1[CH:80]=[CH:79][C:75]([C:76]([OH:78])=[O:77])=[CH:74][CH:73]=1)[CH2:62][CH2:61]2)[CH2:58][CH2:57]3)([CH3:87])[CH3:86]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)NC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCNC3CCS(=O)(=O)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CNC(=O)CN[C@]12CC[C@@H](C(C)C)[C@@H]1[C@H]1CC[C@@H]3[C@@]4(C)CC[C@H](c5ccc(C(=O)O)cc5)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2

Procedure:
The title compound was prepared following the method described above for the synthesis 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1,1-dioxidotetrahydrothiophen-3-yl)amino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylamino)-2-oxoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as the starting material. The product was isolated as a white solid (3 mg, 28%). LCMS: m/e 605.45 (M+H)+, 2.58 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 4.22 (d, J=15.6 Hz, 1H), 3.85 (d, J=15.6 Hz, 1H), 2.87 (s, 3H), 2.50 (dd, J=13.1, 2.4 Hz, 1H), 2.35-1.02 (m, 26H), 1.28 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 0.95 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.84 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)(=O)C.[Pt]=O>[CH2:1]([O:3][P:4]([CH2:9][C@@H:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOP(=O)(C[C@@H]1CCN[C@@H](C(N)=O)C1)OCC
Reaction time: 6 h

Procedure:
A mixture of 1.19 g of 4-(diethylphosphonomethyl)-2pyridinecarboxamide and 0.75 g of platinum oxide in 30 ml of acetic acid is hydrogenated at 3 atmospheric pressure for 6 hours at room temperature. The reaction mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in methylene chloride and washed with a small volume of saturated sodium bicarbonate solution. After drying over magnesium sulfate, a methylene chloride solution of a 2:1 mixture of cis and trans 4-(diethylphosphonomethyl)-2-piperidinecarboxamide is obtained. After 3 days at room temperature this mixture isomerizes to the more stable cis isomer. Removal of the solvent in vacuo affords cis-4-(diethylphosphonomethyl)-2-piperidinecarboxamide as an oil, which is converted to the hydrochloride salt, melting at 155°-158°.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].CCOCC>O1CCCC1>[CH3:1][NH:3][C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Yield: 94 %

Procedure:
3α-Aminocholestane (2.00 g, 5.15 mmol) was dissolved in 98-100% formic acid (10 ml) and acetic anhydride (3.6 ml) was added under ice cooling. After the mixture was stirred for 18 hours at room temperature, the precipitated solid was filtered off and recrystallized from methanol to obtain N-formyl-3α-aminocholestane (1.14 g, yield=53%). The N-formyl-3α-aminocholestane was dissolved in tetrahydrofuran (50 ml) and lithium aluminum hydride (415 mg) was added. The mixture was heated under reflux for 1.5 hours. After the completion of the reaction, saturated aqueous solution of sodium sulfate was added to the mixture to decompose an excess of lithium aluminum hydride. Ether (100 ml) was added, and the mixture was stirred and allowed to stand. After the organic layer was collected by decantation, ether (50 ml) was added to the aqueous layer. After the mixture was stirred and allowed to stand, the ether layer was collected again. The organic layers were combined, washed with saturated saline solution, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and 4N hydrochloric acid-ethyl acetate (0.7 ml) was added. The resulting precipitate was filtered off. The precipitate was suspended in ether (500 ml) and 40% aqueous solution of potassium hydroxide (100 ml) was added. The suspension was vigorously stirred until the precipitate was dissolved. The ether layer was washed with saturated saline solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.04 g, yield=94%).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.69 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (322 mg, 1.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (487 mg, 2.54 mmol) and 1-hydroxy-1H-benzotriazole (259 mg, 1.69 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (650 mg, 84%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:31])([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9 mmol) and triethylamine (1.3 mL, 9.5 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with a solution of 3-nitrobenzoyl chloride (1.8 g, 9.5 mmol) in tetrahydrofuran (7.3 mL) and stirred at 20° C. for 1 h. The reaction mixture was treated with saturated sodium bicarbonate and the aqueous layer was separated and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (3.5 g, 105%) as a crude off-white solid that was used without further purification. LCMS for C15H14N3O5 ([M-(t-Bu)+H]+H)+: m/z=316.0.