Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl.O>[N:21]1([CH2:2][CH2:3][C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CC=O)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CCN2CCCCC2)c1
Reaction time: 3 h

Procedure:
In 20 ml of 1,2-dichloroethane was dissolved 1.06 g of ethyl 2-(2-oxoethyl)biphenyl-4-carboxylate, and then 3.95 ml of piperidine, 589 μl of acetic acid, and 1.09 g of sodium triacetoxyborohydride were added thereto, followed by 3 hours of stirring. Water and chloroform were added to the reaction solution, and the organic layer obtained by an operation of separation was dried over anhydrous magnesium sulfate, followed by removal of the solvent by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 1.3 g of oily ethyl 2-(piperidin-1-ylethyl)biphenyl-4-carboxylate.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:30][OH:31])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH:12]([CH2:30][OH:31])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(NC(CO)C(=O)N1CCN(CCCc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC(CO)C(=O)N1CCN(CCCc2ccccc2)CC1
Yield: 104.3 %

Procedure:
10% Palladium-on-carbon (100 mg) was added to a solution of 1.12 g of 1-[2-(benzyloxycarbonylamino)-3-hydroxypropionyl]-4-(3-phenylpropyl)piperazine in 30 ml of ethanol, and the mixture was stirred under a hydrogen gas stream until cessation of hydrogen absorption. The catalyst was then filtered off, and the filtrate was concentrated under reduced pressure to give 800 mg of 1-(2-amino-3-hydroxypropionyl)-4-(3-phenylpropyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Br)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)Br)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 322 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-(t-butyl)benzoyl bromide. The compound of example 322 was used directly without isolation, for the preparation of compound of example 323.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([N:11]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)[CH2:12][CH2:13][OH:14])=[O:10].O>CC(O)(C)C>[Br:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([N:11]2[CH2:12][CH2:13][O:14][CH2:8][C:9]2=[O:10])=[CH:16][C:17]=1[CH3:23]
Reactant: Cc1cc(N(CCO)C(=O)CBr)cc(C)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(N2CCOCC2=O)cc(C)c1Br
Temperature: 25 °C
Yield: 100 %

Procedure:
Potassium t-butoxide (53 mg, 0.44 mmol) was added to a solution of 2-bromo-N-(4-bromo-3,5-dimethyl-phenyl)-N-(2-hydroxy-ethyl)-acetamide (147 mg, 0.40 mmol) in t-BuOH (2 ml), and the mixture was heated under reflux overnight. The reaction solution was cooled to room temperature and water was then added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(4-bromo-3,5-dimethyl-phenyl)-morpholin-3-one (100%).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[C:25]2([CH3:40])[CH3:39])[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:11][CH2:10]1)=O)(C)(C)C.O>O1CCOCC1>[ClH:36].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[C:25]([CH3:39])([CH3:40])[N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c3c(nn2c(C)c1Cl)C(C)(C)N(C(=O)c1ccccc1OC1CCNCC1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.55 mL; 2.21 mmol; 4 eq.) was added to a suspension of 4-[2-(6-chloro-1,1,5,7-tetramethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (306 mg; 0.55 mmol; 1 eq.) in 1,4-dioxane (6 mL) followed by water (604) and the resulting mixture was stirred at room temperature for 16 hours. A 4M solution of HCl in 1,4-dioxane (0.55 mL; 2.21 mmol; 4 eq.) was added and the resulting mixture was stirred at room temperature for 3 hours. Concentration in afforded the title compound (34 mg, quantitative) as an orange solid. 1H NMR (DMSO-d6) δ 9.09 (br s, 1H), 8.76 (br s, 1H), 7.48-7.38 (m, 1H), 7.37-7.17 (m, 2H), 7.06 (t, J=7.1 Hz, 1H), 4.85-4.67 (m, 1H), 4.41 (s, 2H), 3.05 (s, 4H), 2.84 (s, 3H), 2.54 (s, 3H), 2.06 (br s, 2H), 1.90 (s, 6H), 1.87-1.71 (m, 2H). HPLC (max plot) 99.8%, Rt 3.09 min. UPLC/MS: (MS+) 454.5 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=1.CC(O)=O>CO.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH2:19])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC[C@@H]1COc1cc(N)cc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
1-Methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (2.5 g, 8.2 mmol) was dissolved in MeOH (80 ml) and HOAc (glacial, 10 mL) and placed under N2. Pd/C was added and after blanketing with H2, the mixture was shaken under H2 for 18 h at 60 psi. The catalyst was removed by filtration through Celite® and the MeOH solution was concentrated in vacuo. The residue was purified with flash chromatography (SiO2, 90:10:1 CH2Cl2:MeOH:NH4OH) to afford the title compound as a yellow liquid.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH:9]([S:11]([CH3:14])(=[O:13])=[O:12])[OH:10])[O:7][C@@H:6]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:5]1)=[N+:2]=[N-:3].C(C(O)[C@H]1O[C@@H](N2C=C(C)C(=O)N([C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)C2=O)C[C@@H]1N=[N+]=[N-])(=O)C.C(C(O)[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1N=[N+]=[N-])(=O)C>>[N:1]([C@@H:4]1[C@@H:8]([CH:9]([S:11]([CH3:14])(=[O:12])=[O:13])[OH:10])[O:7][C@@H:6]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[N:18]([C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:16]2=[O:17])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](C(O)S(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](C(O)S(C)(=O)=O)O2)c(=O)n(C(=O)c2ccccc2)c1=O

Procedure:
3'-Azido-3-benzoyl-3'-deoxy-5'-mesylthymidine was prepared from 3'-azido-3'-deoxy-5'-mesylthymidine by an analogous method to that used in Example 40 to prepare 5'-acetyl-3'-azido-3-benzoyl-3'-deoxythymidine from 5'-acetyl-3'-azido-3'-deoxythymidine; m.p.=86°-88° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc2ccccc2o1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc2ccccc2o1

Procedure:
A mixture of 1-benzofuran-2-carbaldehyde and propanedioic acid was treated with piperidine to give (2E)-3-(1-benzofuran-2-yl)prop-2-enoic acid. The resulting acid was converted to the acyl azide, then cyclized to [1]benzofuro[3,2-c]pyridin-1(2H)-one with tri-n-butylamine at 180° C. Treatment with phosphorus oxychloride provided 1-chloro[1]benzofuro[3,2-c]pyridine, which was converted to the requisite 2-aminoethanol according to the method of footnote 32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-])=O>CO.[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2ccc(N)c(N)c2)cc1C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide (0.12 g) in MeOH (5 mL) was added 10% Pd/C (0.04 g). The reaction mixture was stirred overnight under H2 balloon. The mixture was filtered through a Celite pad, washed with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc) to give 3,4-diamino-N-(3,4-dimethyl-phenyl)-benzene-sulfonamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:3]([O:23][C@H:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][O:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:22][C:16](=[O:22])[CH3:15])=[CH:8]1)(=[O:2])[CH3:4]
Reactant: COC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC[C@]12CC[C@H](OC(C)=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 8 h

Procedure:
19-Methoxyandrost-4-ene-3β,17β-diol is dissolved in a mixture of acetic anhydride and pyridine and the solution allowed to stand overnight at room temperature. The solvents are removed under vacuum and the remaining residue crystallized from acetone-hexane to yield 19-methoxyandrost-4-ene-3β,17β-diol diacetate.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>C(Cl)Cl.Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:14])=[CH:17][CH:18]=1
Reactant: CCC(CC)N1CCNCC1
Reactant: COc1ccc(OC(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)Oc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 1-(1-ethylpropyl)piperazine (156 mg, 1.0 mmol) and dry DCM (10 ml) was added 4-methoxyphenyl chloroformate (190 mg, 1.0 mmol). The mixture was stirred overnight at room temperature and then diluted with DCM (50 ml). The reaction mixture was washed with 1 N NaOH (3×20 ml) and water (3×20 ml) and dried (MgSO4). The organic solution was concentrated to yield an oil that was dissolved in a 0.5 N HCl solution (30 ml). The acidic solution was washed with diethyl ether (2×20 ml) and 4 N NaOH was added until pH 11. The resulting mixture was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried (MgSO4). The solvent was evaporated to give an oil that crystallized on standing. This afforded 185 mg (60%) of the title compound as a solid. M.p. 52–54° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1>CO.[Pd]>[CH3:11][C:5]1[CH:4]=[C:3]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1-c1cnco1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cnco2)c(C)cc1N
Reaction time: 8 h

Procedure:
The 5-(2,5-dimethyl-4-nitrophenyl)oxazole obtained in the last step was dissolved in methanol (10 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and then stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-dimethyl-4-(oxazol-5-yl)aniline as a white solid. ESMS m/z 189 (M+H+).
Reaction SMILES: [Br:1]Br.IBr.[F:5][C:6](I)([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>>[F:5][C:6]([Br:1])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]
Reactant: BrBr
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: BrI
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Temperature: 160 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
The same reactor as in Example 1 was used. Into the flask was placed 200 ml (747 mM) of perfluorooctyl iodide (PFOI), which was then heated at 160° C. and irradiated with a 400-W high-pressure mercury lamp. After the reaction mixture started to reflux, 54.5 ml (1.07M) of bromine was added dropwise to the mixture at a rate of 0.4 ml/min over a period of about 2 hours. The resulting IBr was drawn off at a suitable time through the IBr withdrawing Dimroth condenser. The reaction was continued for 3 hours, and the reaction mixture was thereafter cooled and washed with a 5% aqueous solution (200 ml) of sodium hydroxide, giving 349.0 g (93.6% in yield) of perfluorooctyl bromide.
Reaction SMILES: ClC1C=CC([NH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=1.[Cl-:19].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][C:9](=[O:18])[NH:8]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=c1ccc2c(Cl)cccc2[nH]1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(4-chlorophenyl)cinnamamide (8.3 g), and chlorobenzene (60 ml) was added portionwise aluminum chloride (21.4 g) under nitrogen at room temperature and the reaction mixture was slowly warmed up to 125° C. and kept at that temperature for 3 hours. The reaction mixture was cooled down and poured over 400 g of ice. The product crystallized out as a pink solid which was filtered and dried.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)CCC(=O)O
Yield: 77.7 %

Procedure:
2-Hydroxyethyl methacrylate (25 g, 0.195 mol) and succinic anhydride (19.5 g, 0.195 mol) were added to dichloromethane (200 mL) under nitrogen. Triethylamine (28.5 ml, 20.72 g, 1.05 equiv.) was then added dropwise over 20 minutes and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 2 M HCl (150 mL) and then finally with brine (100 mL). The organic phase was separated from the aqueous phase, dried (MgSO4 and Na2SO4) and evaporated to dryness, yielding a viscous, colourless liquid (34.9 g, 77.8% yield). 1H NMR δ 1.89 (s, 3H, CH3), 2.59-2.67 (m, 4H, 2×CH2CO), 4.31 (br. s, 4H, 2×CH2OCO), 5.55 (s, 1H, vinyl CH), 6.08 (s, 1H, vinyl CH). 13C NMR δ 17.96, 28.64, 28.73, 62.15, 62.29, 126.12, 135.79, 167.11, 171.90, 177.73.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@@H:38]1[CH2:41][C@H:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:50])[CH3:49]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@@H:38]4[CH2:41][C@H:40]([C:42]([N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:50])[CH3:49])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.336 g, 0.674 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.58 ml, 6.746 mmol) in DCM (3.15 ml) was added at 0° C. and stirred at room temperature for about 3 hours and completion of the reaction monitored by TLC then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to the above stirred solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-1-yl)methanone (step 2, 0.264 g, 1.349 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous 1N HCl, then washed with water and brine, and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.350 g: Yield: 76.7%; 1H NMR (300 MHz, CDCl3): δ 6.28 (d, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.51-4.06 (m, 2H), 3.56-3.27 (m, 8H), 3.18-3.08 (m, 1H), 2.91-2.74 (m, 2H), 2.60-2.46 (m, 2H), 2.37-2.20 (m, 3H), 2.08 (s, 3H), 1.99-1.11 (m, 26H), 1.00-0.75 (s, 18H); Mass: [M+Na]+ 699 (100%); IR (KBr, cm−1): 3268, 3077, 2955, 2873, 1734, 1716, 1618, 1549, 1455, 1452, 1371, 1344, 1242, 1180, 1150, 1033, 980, 869; M.R: 94.9° C.-101.2° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>[Pd].C(O)C>[OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)ccc(C(N)=O)c1O
Yield: 0.7 %

Procedure:
2,4-Dihydroxy-3-(2-propenyl)benzamide (575 mg) and 125 ml of ethanol was hydrogenated at 5 psi, room temperature, using 4% Pd/C catalyst for 3 hours. The solvent was removed under vacuum to give the product as an oil (4.25 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][C:6](=O)[NH:5][C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][NH:5][CH2:3]1
Reactant: CCCC1(C)CC(=O)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(C)CCNC1
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
α-Methyl-α-propyl-succinimide (310 mg, 2 mmol) was dissolved in THF and to the solution was added 84 mg LiAlH4 (2.2 mmol) in three small portions. The reaction was proceeded at 0° C. for 5 min, then room temp for 2 h. Cold water was added to quench the reduction. The solution was filtered through celite. The filtrates were combined and evaporated under vacuum. The product (160 mg, Yield 63%) was ready for use.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:21])([F:20])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][C:11](O)=[O:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[F:7][C:8]([F:20])([F:21])[CH:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11][OH:12]
Reactant: CCCCCCC(CC(=O)O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCC(CCO)C(F)(F)F
Reaction time: 4 h
Yield: 75.4 %

Procedure:
In a two-necked round-bottomed flask replaced with nitrogen, 67 mg of lithium aluminum hydride and dry ether were placed and cooled with ice, and a solution of 0.41 g of (+)-3-trifluoromethyl-1-nonanoic acid in 2 ml of dry ether was added dropwise thereto. The mixture was stirred for 4 hours on an ice bath for reaction, and a saturated sodium sulfate aqueous solution was added thereto, followed by decantation to recover the ether layer. The ether solution was dried on sodium sulfate, followed by distilling-off of the solvent and distillation by means of a Kugelrohr distiller at 110° C./28 mmHg to obtain 290 mg (yield: 66%) of (+)-3-trifluoromethyl-1-nonanol. [α]D28 +1.82 (c 6.03, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.CO.[Pd]>[O:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:20]=[CH:21][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Reaction time: 3 h
Yield: 103.4 %

Procedure:
A slurry of 2-[4-(4-nitrophenoxy)phenyl]oxazole (2.6 g, 9.2 mmol) in a mixture of ethyl acetate (20 mL) and methanol (100 mL) was placed under a nitrogen atmosphere before the addition of catalyst palladium (10% on C, 0.65 g). The reaction mixture was placed under a hydrogen atmosphere at atmospheric pressure. After 3 hours, the reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated to give the 2.4 g of 4-[4-(2-oxazolyl)phenoxy]benzenamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[C:26]([C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: C=Cc1ccc(C(=O)O)nc1
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, 5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.