Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed tert-butyl 4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-carboxylate (570 mg, 0.99 mmol, 1.00 equip), dichloromethane (8 mL), and CF3COOH (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol as an off-white solid. LCMS-(ES, m/z) 478 [M+H]+
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[F:13][C:14]([F:27])([F:26])[C:15]([F:25])([F:24])[C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][C:17](=[O:18])[C:16]([F:22])([F:23])[C:15]([F:24])([F:25])[C:14]([F:27])([F:26])[F:13]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1cc2ccccc2o1
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1cc2ccccc2o1

Procedure:
The compound was synthesized according to example 1 using 2-acetylbenzofuran and ethyl heptafluorobutyrate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.74 (s, 1 H); 7.35 (ddd, 1H, J=0.9 & 7.2 & 8.0 Hz); 7.52 (ddd, 1H, J=1.3 & 7.2 & 8.4 Hz); 7.58-7.61 (m, 1 H); 7.68 (d, 1H, J=0.9 Hz); 7.71-7.74 (m, 1 H). IR (film): 1614 (C═O); 1232 (C—F).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:3]=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:26][CH2:27]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 47a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield the 2-cyclopropylamino-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=397.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[CH3:25][S-:26].[Na+].O.C(OCC)(=O)C>C1COCC1>[CH3:25][S:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH2:21][CH2:22][CH3:23])[CH2:18][C:17]3=[O:24])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(Cl)nn23)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(SC)nn23)C1
Temperature: 150 °C
Yield: 26 %

Procedure:
A mixture of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 30 (400 mg, 1.11 mmol) and sodium methanethiolate (155 mg, 2.22 mmol, 2.2 eq) in THF is heated in a microwave apparatus (300 W, Tmax 150° C.) during 15 minutes. After cooling to room temperature, hydrolysis (15 ml of water), extraction (ethyl acetate, 3×15 ml), the cumulated organic layers are dried over MgSO4, flitered and condensed under reduce pressure to afford an oil which is purified under preparative chromatography over silicagel (Gradient: CH2Cl2 to CH2Cl2/MeOH/NH4OH 99/1/0.1 (v/v/v)). Recristallization in diisopropyl ether affords 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 46.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:27](=O)[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CSC.CO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: CO
Solvent: CSC
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Temperature: 65 °C
Yield: 19.8 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Dimethylcarbamoyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (260 mg, 0.569 mmol) in dry tetrahydrofuran (6.5 mL) is added 2M toluene solution BH3.DMS (130 mg, 1.708 mmol) at 0° C. Reaction heated to 65° C. for 16 hours. Methanol is added to reaction mixture and heated at 65° C. for 2 hours. Volatiles are removed under reduced pressure to obtain crude material purified by column chromatography eluting in 5% methanol in CH2Cl2 to afford the title compound (50 mg): LC-MS (m/z): [M+H]=444.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]2[NH:22][N:23]=[CH:24][CH:25]=2)[CH:14]=1)=[O:11].[Br:26]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:26][C:25]1[CH:24]=[N:23][NH:22][C:21]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccn[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1[nH]ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a cooled and stirred solution of 1-(2,4-Difluoro-phenyl)-3-[4-methoxy-3-(2H-pyrazol-3-yl)-phenyl]urea (0.6 g, 1.74 mmole) in DMF (15 mL) was added N-bromosuccinimide (0.37 g, 2.09 mmole) over a period of 15 minutes. The reaction mixture was warmed slowly to ambient temperature and stirred for another 2 hrs. The reaction mixture was poured into well-stirred ice water containing NaHCO3/Na2S2O3. The resulting solid was filtered and washed with ice water (50 mL). The solid was dried in vacuo to afford off-white solid (0.68 g, 92%). LCMS m/z (%)=425 (M+H, 79Br, 100), 427 (M+H, 81Br, 99). 1H NMR (Bruker, 400 MHz, DMSO-d6) δ: 8.96 (bs, 1H), 8.44 (bs, 1H), 8.02-8.08 (m, 1H), 7.48 (bs, 2H), 7.27-7.32 (m, 1 h), 6.99-7.08 (m, 2H), 3.73 (s, 3H) (major tautomer).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:27]=[CH:26][N:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:36]([O:40][C:41]([N:43]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(C(C)C)CC)(C)C>C1COCC1.CCOC(C)=O>[C:36]([O:40][C:41]([N:43]1[CH2:47][CH2:46][CH:45]([NH:48][CH2:28][C:24]2[CH:23]=[C:22]([O:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:4]=3)[CH:13]=[CH:14]4)[N:27]=[CH:26][N:25]=2)[CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the solution of methanesulfonic acid (±)-6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester (80 mg, 0.158 mmol) in THF (5 mL), 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (88 mg, 0.474 mmol) and diisopropylethylamine (61 mg, 0.474 mmol) are added. The resulting solution is stirred at 60° C. overnight. After cooling to rt, the reaction mixture is diluted with EtOAc and washed with water and then brine. The organic layer is dried with anhydrous Na2SO4, filtered, and condensed. The residue is purified by FCC (0-10% MeOH/DCM) to provide the title compound. MS (ESI) m/z 597.2 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](O)=[CH:20][CH:19]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1CCCCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:1][C@@H:2]2[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]3)[CH2:4][CH2:3]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](O)[C@H]2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CC[C@H](Oc3ccc(Cl)c4ccccc34)[C@H]2C1
Yield: 30.1 %

Procedure:
The process is performed according to the procedure described in Example 11, step 11.1. Starting with 0.15 g (0.66 mmol) of tert-butyl (3aR,4R,6aS)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, obtained in step 13.1., 0.130 g (0.73 mmol) of 4-chloro-1-naphthol, 0.160 g (0.79 mmol) of diisopropyl azodicarboxylate and 0.206 g (0.659 mmol) of resin-supported triphenylphosphine (triphenylphosphine, polymer-supported, 3.2 mmol/g on polystyrene), and after chromatography on silica gel, eluting with a 95/5 and then a 90/10 mixture of cyclohexane and ethyl acetate, 0.077 g (30%) of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:17]1[S:18][CH:19]=[C:20]([CH3:22])[N:21]=1)[C:13](=O)[CH2:14][CH3:15])[C:6]#[N:7].[NH2:23][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:25][C:26]#[N:27].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:13]([CH2:14][CH3:15])[NH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[C:25]2[C:26]#[N:27])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: CCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.480 mmol) of the compound from example 20A, 65 mg (0.480 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 8.1 mg (0.072 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude material is purified initially by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5) and then by MPLC (Biotage 12M cartridge, eluent: isohexane/ethyl acetate 80:20). 25 mg (12% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:47](=[O:62])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](=[O:61])[O:54]CC[Si](C)(C)C)[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1]([NH:4][CH:5]([CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)[C:47]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:61])=[O:54])=[O:62])(=[O:3])[CH3:2]
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)OCC[Si](C)(C)C)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 97.4 %

Procedure:
A solution of benzhydryl 2-{4-[2-(acetylamino)-3-oxo-3-({5-oxo-5-[2-(trimethylsilyl)ethoxy]pentyl}amino)propyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoate (356 mg, 0.41 mmol) and tetrabutylammonium fluoride-1M in THF (4 mL) was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N HCl (3×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (305 mg). MS (APCI(+)) m/e 764 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.31-7.90(m, 2H), 7.73-6.85 (m, 16H), 4.43-4.33 (m, 1H), 3.22-2.48 (m, 6H), 2.22-2.15 (m, 2H), 1.80-1.72 (m, 3H), 1.62-1.25 (m, 4H), 1.05, 1.04, 1.00 (s, s, s, 9H), 1.25-0.78 (m, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C@H:6]1[C@@H:10]2[C@@H:11]3[C@@:24]([CH3:27])([CH2:25][CH2:26][C@@:9]2([CH2:33][OH:34])[CH2:8][CH2:7]1)[C@@:23]1([CH3:28])[C@@H:14]([C@:15]2([CH3:32])[C@@H:20]([CH2:21][CH2:22]1)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]2)[CH2:13][CH2:12]3)=[CH2:5].O.[O:36]1[CH2:40]CC[CH2:37]1>IC>[CH3:5][C:4]([C@H:6]1[C@@H:10]2[C@@H:11]3[C@@:24]([CH3:27])([CH2:25][CH2:26][C@@:9]2([CH2:33][OH:34])[CH2:8][CH2:7]1)[C@@:23]1([CH3:28])[C@@H:14]([C@:15]2([CH3:32])[C@@H:20]([CH2:21][CH2:22]1)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]2)[CH2:13][CH2:12]3)=[CH2:3].[CH3:37][O:36][CH3:40]
Reactant: C1CCOC1
Agent: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COC

Procedure:
The alkylated betulinol derivatives can be prepared in a variety of ways. Keto-derivatives can be acquired by treating betulinol with suitable oxidizing reagent, such as Jone's reagent or pyridinium chlorochromate (PCC) (Kim et al., Synthetic Communications 27:1607-1612 (1997); Komissarova et al., Chemistry of National Compounds 38:58-61 (2002); Ito et al., J. Nat. Prod. 64:1278-1281 (2001), which are hereby incorporated by reference in their entirety). In a preferred method, betulinol is first dissolved in acetone, and then oxidized with oxidizing reagent at 0° C. to synthesize carbonyl derivatives of betulinol, such as betulone aldehyde, betulin aldehyde, betulonic acid, and betulonic acid. Betulin acetate derivatives betulin diacetate, 3-acetoxy betulin, and 28-acetoxy betulin were prepared by acylation reaction (Kim et al., Bioorg. Med. Chem. Lett., 8:1707-1712 (1998); Hiroya et al., Bioorg. Med. Chem. 10:3229-3236 (2002), which are hereby incorporated by reference in their entirety). In particular, a dry pyridine solution of betulinol was treated with anhydrous acetic anhydride and stirred for 6 hrs. The workup of the resulting mixture was done by diluting with ethyl acetate and washed with 10% HCl and saturated NaHCO3 to yield betulin diacetate, 3-acetoxy betulin, and 28-acetoxy betulin. Betulin dimethyl ether was prepared by alkylation. To a solution of NaOH and betulinol in dry tetrahydrofuran, iodomethane was added and the resulting mixture was refluxed for 40 hrs. Distilled water was added drop wise to stop the reaction. Betulin dimethylether was obtained after column chromatography. Chlorocarbonyl betulin was obtained by treatment with oxalyl chloride (Sun et al., J. Med. Chem 45:4271-4275 (2002), which is hereby incorporated by reference in its entirety). A solution of oxalyl chloride was added to betulinic acid and stirred for 2 hrs. Most of the solvent was removed under vacuo. Additional dry CH2Cl2 was added and subsequently concentrated to yield chlorocarbonyl betulin.
Reaction SMILES: S(O[CH2:9][C:10]([CH3:23])([N+:20]([O-:22])=[O:21])[CH2:11]OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(N(C(C)C)C(C)C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[CH3:23][C:10]1([N+:20]([O-:22])=[O:21])[CH2:9][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1
Reactant: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol ditriflate [the product of step 1] (4.0 g, 10 mmol) in acetonitrile (70 ml) is cooled to 0° C.-5° C. and N-ethyl-diisopropylamine (3.23 g, 25 mmol) is added, followed by benzylamine (1.60 g, 15 mmol) and the mixture is stirred at a temperature of 80° C. for 12 hours. The cooled reaction mixture concentrated under reduced pressure, dissolved in ethyl acetate and transferred to a separating funnel. This is then washed with water (2×) and brine, dried (Na2SO4), filtered, and concentrated. The crude liquid product is used in the next step without further purification. The crude product is purified by chromatography using a 3:1 mixture of Hexane:Ethyl acetate as eluant; the product is obtained as an oil. 1H-NMR (CDCl3): 7.3 (m, 5H), 3.75 (d, 2H), 3.68 (s, 2H), 3.42 (d, 2H), 1.88 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:3]1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Cl)cc1
Reactant: c1ccc2[nH]c(C3CCCNC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCC(c2nc3ccccc3[nH]2)C1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a flask containing 2-(piperidin-3-yl)-1H-benzo[d]imidazole hydrochloride (200.0 mg, 0.841 mmol) and (R)-3-(tert-butoxycarbonylamino)-4-(4-chlorophenyl) butanoic acid (282.5 mg, 0.900 mmol) was added dichloromethane (5 mL) and triethylamine (0.23 mL, 1.683 mmol); the reaction mixture was stirred at room temperature until all the components dissolved. To the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193.5 mg, 1.010 mmol) followed by N-hydroxybenzotriazole (142.1 mg, 1.052 mmol). The solution was stirred at ambient temperature for 12 hrs and diluted with excess DCM (5 mL). The solution was washed with water (2×8 mL) and brine (lx 5 mL), and then the organic layer was collected, dried with Na2SO4, and concentrated to yield tert-butyl (2R)-4-(3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(4-chlorophenyl)-4-oxobutan-2-ylcarbamate (3A) as an amorphous solid (415.9 mg, 99.5% yield). ESI-MS: m/z 497.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.FC1(F)C2C(=CC=CC=2)N(C2CCNCC2)C1=O.[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][NH:38][C:39]([C:41]1[N:42]=[N:43][C:44](Cl)=[CH:45][CH:46]=1)=[O:40]>CN(C=O)C>[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][NH:38][C:39]([C:41]1[N:42]=[N:43][C:44]([N:13]2[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:45][CH:46]=1)=[O:40]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use (4-fluorophenyl)piperidin-4-ylmethanone to replace 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one to react with 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in DMF, the title compound was obtained as a white powder in 36% yield. 1H NMR (300 MHz, CDCl3) δ 7.99-8.03 (m, 3H), 7.85-7.87 (m, 1H), 7.15-7.19 (m, 2H), 7.02 (d, J=9.6 Hz, 1H), 4.50-4.54 (m, 2H), 3.47-3.60 (m, 3H), 3.26-3.31 (m, 2H), 2.00-2.04 (m, 2H), 1.85-1.93 (m, 2H), 1.73-1.72 (m, 1H), 1.48-1.53 (m, 2H), 0.94 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CCO.O.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])/[CH:9]=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1O
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (20 g, 93.4 mmol) in EtOH (114 mL) and H2O (6 mL) was added 4-(trifluoromethoxy)benzaldehyde (17.75 g, 93.4 mmol) and NaOH (33.6 g, 840.6 mmol). The reaction mixture was stirred overnight. Ethoxyethane was added to the mixture and filtered to give a residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (30 g, 80%). 1H-NMR (CDCl3): 6.87 (d, 1H), 7.21 (d, 2H), 7.49 (m, 1H), 7.52 (m, 1H), 7.59 (d, 2H), 7.84 (t, 1H), 7.92 (s, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:18]=2)[N:3]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH:34]2[CH2:36][CH2:35]2)[NH:31][N:30]=1>>[CH:34]1([C:32]2[NH:31][N:30]=[C:29]([NH:28][C:2]3[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=[C:4]([N:12]4[CH2:16][CH2:15][CH2:14][CH:13]4[C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[CH:18]=4)[N:3]=3)[CH:33]=2)[CH2:36][CH2:35]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Oc1cc(C(F)(F)F)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: FC(F)(F)c1cc(Nc2cc(C3CC3)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-trifluoromethyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 37) and 3-amino-5-cyclopropyl-1H-pyrazole (Method 7 of WO-03/048133).