Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:46][C:47](=[O:60])[NH:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[C:52]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[CH:51]=1)([CH3:45])([CH3:44])[CH3:43].Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15](=[O:17])[NH:59][C:56]2([C:52]3[CH:51]=[C:50]([CH2:49][NH:48][C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:60])[CH:55]=[CH:54][N:53]=3)[CH2:58][CH2:57]2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C2(N)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
1-Benzyloxycarbonylamino-cyclopropanecarboxylic acid (1.251 g, 5.316 mmol) and HATU (2.527 g, 6.645 mmol) were dissolved in dry DMF (15 mL) and stirred for 5 min. This solution was added to the solution of [2-(1-Amino-cyclopropyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (2.8 g, 10.633 mmol) in dry DMF (5 mL). TEA (2.2 mL, 16 mmol) was then added and the reaction was stirred at room temperature for 25 min. The reaction was diluted with EtOAc (450 mL) and then acidified with 1N HCl (20 mL) to pH 1. Without separation of the layers, the mixture was basified with saturated NaHCO3 (140 mL) to pH 8.5. Layers were separated. The organic layer was further washed with water (3×350 mL). The organics was dried with anhydrous Na2SO4, filtered, and concentrated to afford 3.73 g of the crude product which was purified by Biotage flash column using 0-2% MeOH/DCM as the gradient to afford 1.447 g of (1-{1-[4-(tert-Butoxycarbonylamino-methyl)-pyridin-2-yl]-cyclopropylcarbamoyl}-cyclopropyl)-carbamic acid benzyl ester as a light brown foam.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.S(Cl)(Cl)=O>CC(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)C(=O)N1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room temperature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), mp 269°-272° C.
Reaction SMILES: CC(C1C=[C:6]([O:10]C2N=CC(NC(=O)[C@@H](C)N)=CC=2)C=CC=1)C.[CH3:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[O:32][C:33]1[N:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[C@@H:41]([CH3:43])[NH2:42])=[CH:35][CH:34]=1>>[CH3:43][C@H:41]1[NH:42][C:6](=[O:10])[N:39]([C:36]2[CH:37]=[N:38][C:33]([O:32][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=3[CH3:23])=[CH:34][CH:35]=2)[C:40]1=[O:44]
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Product: COc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1C

Procedure:
The title compound was made in a similar fashion to the preparation of Example 9 replacing N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide with N-(6-{[2-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 63, 200 mg) to afford the title compound (184 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[O:22][CH2:21][CH2:20][O:19]2)=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[O:19][CH2:20][CH2:21][O:22]2)=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C2OCCO2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C2OCCO2)c2ccccc12
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane (701 mg, 2.35 mmol) in ethyl acetate (15 mL) was added palladium (5% on BaCO3, 51 mg). The mixture was stirred under a hydrogen atmosphere for 16 hr, filtered by suction through Celite and concentrated to provide 689 mg (98%) of a colorless oil.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([O:16][C:17](=[O:30])[CH2:18][S:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1)[CH3:15].[CH3:31][C:32]([CH2:34][CH3:35])=[O:33]>CCCCCC.O1CCCC1>[CH2:14]([O:16][C:17](=[O:30])[CH:18]([S:19][C:20]1[N:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:32]([OH:33])([CH3:31])[CH2:34][CH3:35])[CH3:15]
Reactant: CCC(C)=O
Reactant: CCOC(=O)CSc1nc(OC)cc(OC)n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(O)CC
Temperature: -65 °C
Reaction time: 0.33 h

Procedure:
At -50° C., 16.6 ml of a 1.6 molar n-butyllithium solution in hexane are introduced into a prepared mixture of 3.1 g of N,N,N',N'-tetramethylethylenediamine and 25 ml of absolute tetrahydrofuran. 6.2 g of 2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-acetic acid ethyl ester dissolved in 15 ml of tetrahydrofuran are then added dropwise thereto at a temperature of -65° C. and the mixture is stirred for 20 minutes. 2.4 ml of ethyl methyl ketone are added at a temperature below -60° C. and the reaction mixture is heated to room temperature in the course of 1 hour. Ice-water is then added to the reaction mixture which is then extracted twice with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation. Column chromatography on silica gel, eluant ethyl acetate/hexane 1:4 yields pure 2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-hydroxy-3-methylpentanoic acid ethyl ester in the form of a yellow oil; 1H-NMR(CDCl3): 1.36/1.40, 2s, CH3 ; 3.17/3.31, OH; 3.93, s, OCH3 ; 4.2, m, OCH2CH3 ; 4.79/4.80, 2s, CH; 5.76, s, CH; 70/30 isomeric mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[S:24](Cl)(=[O:26])=[O:25])([O-:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:24]([C:16]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=3[N+:12]([O-:14])=[O:13])(=[O:25])=[O:26])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c([N+](=O)[O-])c1

Procedure:
Using General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (4.9 g, 32.6 mmol), 2,4-dinitro-benzenesulfonyl chloride (9.8 g, 36.8 mmol), pyridine (18 mL), methylene chloride (100 ml), 0° C.-rt, 0/N. Purification: precipitation from hot H2O. The title compound was recrystallized from ethyl acetate as a light-orange solid (9.5 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.0 (s, 1H), 9.27 (s, 1H), 8.88 (d, Hz, 1H), 8.58 (dd, J=2.2, 8.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.51 (d, Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), (dd, J=1.9, 8.3 Hz, 1H), 4.91 (s, 2H); MS (ESI) m/z=378 (M−1, negative).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(CCO)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
66.0 g (436 mmol) of 2-(5-ethylpyridin-2-yl)ethanol was dissolved in 500 mL of toluene. 72.5 mL (523 mmol) of triethylamine was added to this solution, at room temperature. The resulting solution was cooled between 0 and 10° C., after which 34.0 mL (438 mmol) of methanesulphonyl chloride was added dropwise during 75 minutes. When addition was completed, it was stirred for 1 hour at room temperature. Next, the organic phase was washed with a saturated solution of sodium bicarbonate (400 mL) and with water (400 mL), and was dried over sodium sulphate, obtaining a toluene solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulphonate, a compound of formula (III) in which Z=OMs.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[OH-].[K+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Cl)Cl>O>[C:14]1([S:20]([OH:22])(=[O:1])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:5][C:4]1[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: COc1cccc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of o-vanillin (537.5 g, 3.54 mole) in water (3.6 L) containing potassium hydroxide (215 g, 3.77 mole) was treated with benzenesulfonyl chloride (360 mL, 2.83 mole) dropwise over a period of one hour. Methylene chloride (75 ml) was added and the mixture was stirred overnight. The resultant solid was collected by filtration and washed with 500 mL of 5% aqueous potassium hydroxide and 1 L of water. The solid was dried in vacuo at 70°-90° C. to give the title compound, 750 g, mp 115°-119° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:19])[CH:9](C#N)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[BrH:20]>C(=O)(O)[O-].[Na+]>[Br:20][C:2]1[CH:7]=[C:6]([C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CC(C(=O)c1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1ccc(F)cc1)c1ccnc(Br)c1
Temperature: 135 °C
Reaction time: 4 h

Procedure:
To 1-(2-chloropyridin-4-yl)-2-cyano-2-(4-fluorophenyl)ethanone (22.0 g, 80 mmol) was added 48% hydrobromic acid (75 ml) and the reaction mixture was heated at reflux in an oil bath at 135° C. After 4 h, the reaction mixture was allowed to cool to room temperature and then further cooled in an ice bath. Saturated sodium bicarbonate (100 ml) was carefully added, followed by solid portions of sodium bicarbonate until the pH of the reaction mixture was neutral. The reaction mixture was then extracted with ethyl acetate and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to a brown semi-solid (2.8 g). The crude product was purified by flash chromatography on silica gel, eluting with 1:1 mixture of ethyl acetate/hexanes to give 1-(2-bromopyridin-4-yl)-2-(4-fluorophenyl)ethanone (1.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
A mixture of 3-nitrophenol (6.95 g), ethyl bromoacetate (8.35 g) and potassium carbonate (6.9 g) in dry NHP (50 ml) was stirred at room temperature for 48 hours. The reaction mixture was partitioned between water (300 ml) and diethyl ether (75 ml). The organic layer was separated, washed with water, brine and dried (MgSO4). The residue was filtered through silica and eluted with a 3:2 mixture of hexane and ethyl acetate to give ethyl 3-nitrophenoxyacetate as a viscous oil in 98% yield;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([N+:31]([O-:33])=[O:32])=[CH:23][CH:22]=1>CS(C)=O.CO.C(O)(C(F)(F)F)=O>[N+:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[CH:3]=2)=[CH:22][CH:23]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cc(=O)[nH]cn1
Solvent: CO
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
To a solution of 6-aminopyrimidin-4(3H)-one (866 mg, 7.79 mmol) in DMSO (10.0 mL) at RT was added DBU (1.29 mL, 8.57 mmol) and after 30 min a solution of 1-fluoro-4-nitronaphthalene (1.57 g, 8.18 mmol) in DMSO (3.0 mL) was added over 2 min. The resulting mixture was maintained at RT for 2 hr and was diluted with MeOH (20 mL) and TFA (2.0 mL) was added. The solution was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 50-100%, gradient elution) to afford the title compound as a yellow solid (370 mg, 16.48%); Rt 3.82 min (Method 1 basic); m/z 283 (M+H)+ (ES+)
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[OH:23])[C:6]([C@H:8]2[C@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9]2)=[O:7])[CH2:3][CH2:2]1>C(#N)C.C(O)(C(F)(F)F)=O>[CH:1]1([CH2:4][N:5]2[C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[O:23][C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@@H:8]([OH:9])[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: O=C([C@@H]1O[C@H]1c1ccccc1)N(CC1CC1)[C@@H]1CCCC[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1[C@H](O)[C@H](c2ccccc2)O[C@@H]2CCCC[C@H]2N1CC1CC1
Yield: 80.9 %

Procedure:
A solution of (2R,3S)—N-(cyclopropylmethyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-3-phenyloxirane-2-carboxamide (117b) (1.05 g, 3.33 mmol) in 125 mL acetonitrile/TFA (0.4%) was stirred for 6 hours. After evaporation the crude oil was purified by chromatography (CHCl3) to afford the title compound (850 mg, 81%). HPLC: 4.54 min (Method B). 1H NMR (300 MHz, CDCl3) δ0.37-0.44 (m, 2H), 0.49-0.57 (m, 2H), 0.85 (m, 1H), 1.03 (m, 1H), 1.14-1.50 (m, 2H), 1.66-1.80 (m, 2H), 1.83-2.02 (m, 1H), 2.03-2.16 (m, 2H), 3.32 (dd, 1H, J=7 Hz, J=14 Hz), 3.60 (in 1H), 3.74 (m, 1H), 3.85 (dd, 1H, J=7 Hz, J=14 Hz), 4.34 (m, 1H), 4.60 (m, 1H), 7.27-7.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](S(O)(=O)=O)=[CH:29][CH:28]=2)[C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=4)=[CH:12][C:11]([CH3:24])=[N:10][C:9]=3[C:4]=2[N:3]=1.[Na][Na]>>[CH3:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:12][C:11]([CH3:24])=[N:10][C:9]=3[C:4]=2[N:3]=1
Reactant: Cc1cc(-c2ccc(S(=O)(=O)O)cc2)c2ccc3c(-c4ccc(S(=O)(=O)O)cc4)cc(C)nc3c2n1
Agent: [Na][Na]
Product: Cc1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(C)nc3c2n1

Procedure:
Bathocuproinedisulfonic acid, disodium salt
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a mixture of 2-(3-bromo-5-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.3 g, 7.9 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×20 mL), washed with saturated aqueous sodium bicarbonate solution (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 16%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.2, 408.2.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>OO.C([O-])(O)=O.[Na+]>[CH3:33][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:6]=[C:5]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:26]=[CH:25][N+:24]=3[O-:42])[CH2:21][CH2:22]2)[N:4]=1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: Cc1ccc(Nc2cc(N(C)C)nc(N3CCN(c4c(C(F)(F)F)ccc[n+]4[O-])CC3)n2)cc1
Yield: 8 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2-{4-[3-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl}-4,6-pyrimidinediamine (150, mg, 0.33 mmol), m-chloroperbenzoic acid (56 mg, 0.33 mmol) and 30% H2O2 (2 drops) were stirred at 0° C. for 24 hours. The crude product was then treated with saturated NaHCO3 solution (2×100 mL). The organic layer was separated, dried over MgSO4, concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (eluent: EtOAc), giving the desired product (12 mg, 8%).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(C#CCN2CCCCC2)=C(F)C=1.[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)[CH:43]=[CH:44][C:45]=1[C:46]#[C:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[F:39][C:40]1[CH:41]=[C:42]([NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)[CH:43]=[CH:44][C:45]=1[CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(C#CCN3CCCCC3)c(F)c1)C2
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Fc1cc(Br)ccc1C#CCN1CCCCC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(CCCN3CCCCC3)c(F)c1)C2
Yield: 83 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[3-(4-bromo-2-fluorophenyl)prop-2-ynyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(3-piperidin-1-ylprop-1-ynyl)phenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (281 mg) was used according to an analogous synthetic method to Example 22 to provide [3-fluoro-4-(3-piperidin-1-ylpropyl)phenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (235 mg). This compound (233 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (122 mg).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][NH:9][C:10](=[O:33])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:23]1[CH2:22][CH2:21][CH:20]([CH2:19][C:15]2[CH:14]=[C:13]([CH2:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])=[O:33])[CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)CCc1cccc(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)CCc1cccc(CC2CCNCC2)c1

Procedure:
A solution of 11-8 (225 mg, 0.48 mmoles), TFA (2.5 mL), and CH2Cl2 (2.5 mL) was stirred at ambient temperature for 1.0 h. Concentration followed by flash chromatography (silica, 10:1:1 ethanol/H2O/NH4OH) gave 11-9 as a white solid. Rf 0.44 (silica, 10:1:1 ethanol/H2O/NH4OH).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 37.7 g of 17β-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one in 160 ml of pyridine is slowly mixed with 80 ml of acetic anhydride and stirred for 16 hours at 25° C. Then, it is diluted with ethyl acetate, and the organic phase, after washing with sodium bicarbonate solution, is dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 26.6 g of 17β-acetoxy-7α-(5-acetoxypentyl)-estr-4-en-3-one is obtained as oil. [α]D22 =+20.0° (c=0.51% in chloroform)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]2[CH2:19][NH:20][CH2:21][CH2:22][C@@:23]34[C@@H:28]([O:29][C:16]=1[C:17]=23)[CH2:27][C@@H:26]([OH:30])[CH:25]=[CH:24]4>>[Cl:1][CH2:2][C:3]([N:20]1[CH2:21][CH2:22][C:23]23[CH:24]=[CH:25][C@H:26]([OH:30])[CH2:27][CH:28]2[O:29][C:16]2=[C:15]([O:14][CH3:13])[CH:32]=[CH:31][C:18](=[C:17]32)[CH2:19]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Solvent: CCN(CC)CC
Product: COc1ccc2c3c1OC1C[C@@H](O)C=CC31CCN(C(=O)CCl)C2
Yield: 7.7 %

Procedure:
0.82 g of chloroacetyl chloride (7.3 mmol) and 0.81 g (8.0 mmol) of triethylamine were added to a solution of (+/−)-norgalanthamine (2.0 g, 7.3 mmol) in dry TRF (100 ml). The reaction mixture was refluxed for 3 hours and concentrated by evaporation. The residue was diluted with 2N hydrochloric acid (100 ml) and extracted with EtOAc (3×75 ml). The aqueous phase was set at pH>8.5 with concentrated ammonia and extracted with 3×75 ml of CH2Cl2. The combined, organic phases were washed with common salt solution, dried on sodium sulfate and concentrated by evaporation. Flash chromatography yielded 0.20 g (7.7% of compound 4j): 1H-NMR (CDCl3) δ 6.78 (b, 1H), 6.12 (m, 2H), 5.30 (d, J=11.0 Hz, 1H), 4.65 (m, 2H), 4.32–4.01 (m, 3H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H), 13C-NMR (CDCl3) δ 166.0 (s) 146.2 (s), 144.9 (s), 132.3 (d), 128.3 (s), 127.3 (s), 126.0 (d), 120.2 (d), 111.2 (d), 88.2 (d), 61.7 (d), 55.8 (q), 52.8 (t), 48.1 (s), 45.5 (t), 41.4 (t), 35.4 (t), 29.6 (t).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])C.C(O)(=O)C(O)=O>CC(C)=O>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH:12]=1)[O:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(COc1cc(F)ccc1OC)OCC
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: COc1ccc(F)cc1OCC=O
Yield: 30.4 %

Procedure:
To a solution of 23.0 g of 2-(5-fluoro-2-methoxyphenoxy)acetaldehyde diethylacetal in 130 ml of acetone were added 100 ml of 10% aqueous oxalic acid and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated, and the residue was diluted with water and extracted with ether. The extract was washed with water, dried and evaporated. Isopropyl ether was added to the residue and the precipitate was filtered to give 4.99 g of the desired compound as pale brown crystals, which were recrystallized from a mixture of isopropanol and isopropyl ether as pale brown crystals, m.p. 92.5°-95° C.