Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[CH:27]=1>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[C:25]([OH:34])=[O:24])[CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccccc32)s1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 19 (part C) starting with 1.48 mmol (4.48 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)-3-piperidin-4-yl-1H-indole and 1.0 g (8.8 mmol) of 3-bromomethyl-benzoic acid methyl ester. The crude mixture was purified by flash chromatography over silica gel affording 0.29 g (14% of yield) of the pure acid.
Reaction SMILES: [CH3:1][C:2]1(O)[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]1([CH3:10])[CH3:9].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]1([CH3:10])[CH3:9]
Reactant: CC1(C)CCC(C)(C)C1(C)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=C1C(C)(C)CCC1(C)C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
30 g of 1,2,2,5,5-pentamethylcyclopentanol was dissolved in 150 ml of pyridine, and 20 ml of thionyl chloride was added dropwise thereto with ice cooling. The reaction mixture was stirred overnight and subjected to filtration. Ether and water were added to the filtrate, and the resulting layers were separated. The organic layer was washed twice with 200 ml of water, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 10.8 g of 1-methylene-2,2,5,5-tetramethylcyclopentane was obtained (b.p. 137°-140° C./760 mmHg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:4]=2[CH2:3]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1CCC(=O)CC1
Agent: N
Solvent: ClC(Cl)Cl
Product: CC1CCc2ncc([N+](=O)[O-])cc2C1
Yield: 72.7 %

Procedure:
4-Methylcyclohexanone (170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (300 mg, 1.51 mmol) in 1M methanolic ammonia (30 mL, 30 mmol). The solution was heated at gentle reflux for 3 h. Evaporation of the solvent gave an orange residue which was suspended in CHCl3 and flash chromatographed over silica gel (16 g) eluting with EtOAc/hexane (1:10) to afford a white solid (211 mg, 73% yield): mp 50-52° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[C:34]1([NH:40][S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([S:41](=[O:43])(=[O:42])[NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)Nc1ccccc1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry acetonitrile (5 mL) was treated with dry triethylamine (0.20 mL), then with phenylsulfamoyl chloride (100 mg Reference Example 44). After stirring at room temperature for a further 1 hour the reaction mixture was evaporated and the residue then treated with water and dichloromethane. The organic phase was separated, then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:1 v/v) to give 7-chloro-6-phenyl-2-phenylsulfamoyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (85 mg) as a white solid, m.p. 207–208° C. [Elemental analysis: C, 55.44; H, 4.34; N, 12.78%; Calculated for C20H19ClN4O3S: C, 55.75; H, 4.44; N, 13.00%].
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[O:50]([C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:64]=2)=[CH:59][CH:58]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(Oc5ccccc5)cc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 83% yield: LCMS (ESI) m/z 464 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].O.OS(O)(=O)=O>C(Cl)Cl>[C:10](=[O:11])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Benzyl alcohol (10.8 g, 100.0 mol) was dissolved in 100 mL of CH2Cl2. The solution was cooled down to 0° C. and phenyl chloroformate (15.7 g, 100 mol) was slowly added dropwise. The solution was stirred at RT overnight. Addition of 100 mL of H2O was followed by 2× washes with 100 mL of 2M H2SO4 each time. The organic phase was separated off and dried over Na2SO4. The solvent was removed in vacuo to obtain a colorless liquid (22.5 g, 99%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:12][NH2:13].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[C:14]1(=[O:20])[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH:2]2[CH2:12][NH:13][C:15]1=[O:16]
Reactant: NCC1CCCc2ccccc2N1
Reactant: CCOC(=O)C(=O)OCC
Product: O=C1NCC2CCCc3ccccc3N2C1=O
Reaction time: 2 h

Procedure:
A solution of Example 182E (0.282 g, 1.600 mmol) in diethyl oxalate (1.518 mL, 11.20 mmol) was heated at 140° C. for 1 hour and then at 180° C. for 2 hours. The crude mixture was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF24-40) eluting with dichloromethane, then with 2% methanol/dichloromethane, and then with 10% methanol/dichloromethane to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (s, 1H), 7.37-7.17 (m, 4H), 3.91 (dd, J=12.8, 4.2, 1H), 3.49 (d, J=11.4, 1H), 3.19-3.13 (m, 1H), 2.71 (dd, J=18.6, 12.5, 1H), 2.56 (m, 1H), 2.02 (m, 2H), 1.86 (m, 1H), 1.42 (m, 1H); MS (ESI+) m/z 248.2 (M+NH4)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:13]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(-c2n[nH]c3ncccc23)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(-c2ccc(NCCN(C)C)cc2)c2cccnc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 6 g of 3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine, 5 g of potassium carbonate and 60 ml of dimethylformamide was added dropwise 4.6 g of ethyl chloroacetate. The mixture was stirred at 50° C. for 4 hours. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed with water. After ethyl acetate was distilled off, the residue was purified by column chromatography to give ethyl 3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate in an oily form.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:15])[F:14].[F-].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.OS([O-])(=O)=O.[Na+]>CN(C=O)C>[CH2:20]([O:17][C:3]1[C:2]([Br:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:7](=[O:12])[NH:8]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1cc(C(F)(F)F)c2c(O)c(Br)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)c2c(OCc3ccccc3)c(Br)ccc2[nH]1
Temperature: 0 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a suspension of 6-bromo-5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (9.42 g, 30.6 mmol) and CsF (13.9 g, 91.7 mmol) in 102 mL DMF was added benzyl bromide (6.54 g, 38.2 mmol) dropwise. After 24 h, the mixture was poured into 0.1 M NaHSO4 (500 mL) and extracted with EtOAc (1:1). The aqueous layer was reextracted with EtOAc (500 mL) and the combined organic layers were washed sequentially with water (500 mL), brine (300 mL), dried over MgSO4, filtered and concentrated to a slurry. The mixture was cooled to 0° C., filtered and the resultant solids washed with cold EtOAc to afford 7.26 g (60%) of 5-benzyloxy-6-bromo-4-(trifluoromethyl)-1H-quinolin-2-one, a tan solid. Rf 0.26 (7:3 hexanes:acetone); 1H NMR (400 MHz, acetone-d6) δ 11.3 (broad s, 1H), 7.91 (d, 1H, J=9.0, 1H), 7.61 (d, 2H, J=7.3), 7.43 (t, 2H, J=7.2), 7.25–7.35 (m, 1H), 7.32 (d, 1H, J=9.0), 7.06 (s, 1H), 5.10 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:52]=[O:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=C[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Yield: 101.4 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 15o (0.7 g, 0.94 mmol) in ethyl acetate (30 mL) was added 2-iodoxybenzoic acid (0.79 g, 2.81 mmol) at room temperature. The mixture was refluxed for 24 hours and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate (10 mL×2) and saturated aqueous sodium chloride (10 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15p as yellow oil (0.71 g, 100%). This material was not further purified.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([C@H:13]([NH:15][C:16]2[C:21]3[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:36]#[N:37])[N:17]=2)[CH3:14])[CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:8][C:19]1[C:20]2[N:24]=[CH:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[C:21]=2[C:16]([NH:15][C@@H:13]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH3:14])=[N:17][C:18]=1[C:36]#[N:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](Nc1nc(C#N)cc2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@@H](Nc1nc(C#N)c(Br)c2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
NBS (73.5 mg, 0.413 mmol) was added to a stirred, room temperature mixture of (R)-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (150 mg, 0.376 mmol) in degassed chloroform (3 ml) in a sealed tube. The mixture was heated to 45° C. and stirred under Ar for 1 hour. The mixture was cooled to room temperature and diluted with DCM. The mixture was then transferred to a separatory funnel, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting dark orange oil was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford (R)-7-bromo-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C21H19BrF3N5 [M+H]+ 479. found 479.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[OH:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1.B(O)O>>[OH:44][C:45]1[CH:50]=[CH:49][C:48]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:47][CH:46]=1
Reactant: OB(O)c1ccc(O)cc1
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(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: 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(c6ccc(O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-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]chrysene-3a-carboxylic acid (example 4a) using 4-hydroxyphenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (1.25 mg, 4%). LCMS: m/e 529.55 (M−H)−, 4.34 min (method 2).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=2)O)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:61](=[O:66])([O:63][CH2:64][CH3:65])[NH2:62].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:64]([O:63][C:61](=[O:66])[NH:62][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:34][CH:33]=1)[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=1)[CH3:65]
Reactant: CCOC(N)=O
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To bis-(4-docosoxy-phenyl)-methanol (28.5 g, 34.2 mmol) were added toluene (350 mL), ethyl carbamate (6.1 g, 68.5 mmol), and methanesulfonic acid (333 μL, 5.14 mmol), and the mixture was stirred at 110° C. for 2 hours. Methanesulfonic acid (333 μL, 5.14 mmol) was added, and the mixture was stirred for 30 minutes. After stirring, the reaction mixture was cooled to room temperature, sodium carbonate (1.1 g, 8.73 mmol) was added and the solvent was evaporated. The residue was crystallized from methanol (400 mL) to give ethyl[bis-(4-docosoxy-phenyl)-methyl]carbamate (32.1 g, 100%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[C:1]([F:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzoyl chloride (141 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to bis(methoxyethyl)aminosulfur trifluoride (567 mg, 3.0 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above benzoyl fluoride (124 mg, quantitative yield) was obtained. The product was identified by g.c.m.s. M+=124
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.C(O)C.C(OCC)C>[NH2:2][CH:14]1[CH2:15][CH2:16][N:11]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: NO
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of hydroxylamine hydrochloride (3.67 g, 52.8 mmol) in water (10 mL) and ethyl alcohol (80 mL) was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at room temperature. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The resulting white solid was filtered, washed with ether and dried (8.4 g, 80%). It was added in small portions to a suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether (150 mL) at room temperature and the suspension was heated to reflux for 8 h. The reaction mixture was cooled to 0° C. and quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The white suspension was filtered and the filtrate was dried over MgSO4. The solvent was removed in vacuo after filtration. 4-Amino-1-benzyl-piperidine was obtained as a colorless oil (6.0 g). It was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH:22]=1)[O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=[O:18])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)COc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(OCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 10 ml of ethanol is dissolved 0.95 g of ethyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenoxy]acetate, to which is added 5.7 ml of 1 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried on anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.83 g of 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenoxy]acetic acid is obtained as a white solid product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][CH3:12])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:13]([OH:17])(=O)[CH2:14]O>>[CH2:9]([O:8][C:5]1[N:4]=[C:3]2[N:11]([CH3:12])[C:14]([CH2:13][OH:17])=[N:1][C:2]2=[CH:7][CH:6]=1)[CH3:10]
Reactant: CCOc1ccc(N)c(NC)n1
Reactant: O=C(O)CO
Product: CCOc1ccc2nc(CO)n(C)c2n1
Yield: 62.2 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 4.15 g 3-amino-6-ethoxy-2-methylaminopyridine (prepared as described in Preparation 97), and 5.66 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.20 g of the title compound, melting at 161° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:16])([F:15])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>>[F:6][C:7]([F:15])([F:16])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: C=CC(=O)O
Product: O=C(O)CCNc1ccccc1C(F)(F)F
Temperature: 75 °C
Reaction time: 32 h
Yield: 88 %

Procedure:
672 g of acrylic acid were added to 500 g of o-trifluoromethylaniline at 20°-25° C. with stirring while bubbling nitrogen therethrough and then 0.5 g of hydroquinone were added thereto in the dark. The mixture was heated to 75° C. over one hour and was then held at 75° C. for 32 hours. The mixture was cooled to 65°-70° C. and 500 ml of technical cyclohexane and 500 ml ofdemineralized water were rapidly added thereto. The mixture was refluxed for 10 minutes and was then slowly cooled to 2° to 4° C. andheld there for one hour. The mixture was vacuum filtered and the recovered crystals were washed and dried to obtain 636.7 g of β-(o-trifluoromethylanilino)-propanoic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1)C.O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](NC(C)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@H]1CC[C@H](CCO)CC1

Procedure:
LiAlH4 (2.10 g, 55 mmol) and THF (150 ml) were placed in a dry balloon. After cooling this mixture to 0° C. a solution of (trans-4-acetylamino-cyclohexyl)-acetic acid ethyl ester (8.42 g, 37 mmol) in little THF was added dropwise. The reaction was stirred 1 h before careful neutralization with H2O (5.6 ml), 1 N NaOH (3×5.6 ml) and more H2O (5.6 ml). The resulting mixture was stirred over night before filtering off the solids. Evaporation of the solvent and drying under high vacuum afforded 5.25 g (76%, 28 mmol) of a light brown solid. MS (m/z): 186.4 ([M+H+).