Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:25]=[CH:24]4)=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:10])[F:11]
Reactant: FC(F)Oc1ccc(Nc2ncc(C=Cc3ccc4c(cnn4C4CCCCO4)c3)cn2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)Oc1ccc(Nc2ncc(CCc3ccc4c(cnn4C4CCCCO4)c3)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 159.2 %

Procedure:
To a solution of N-(3-chloro-4-(difluoromethoxy)phenyl)-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)pyrimidin-2-amine (0.10 g, 0.201 mmol) in ethyl acetate (10 mL) was added Pd/C (0.214 g, 2.008 mmol). The reaction mixture was stirred at room temperature under hydrogen for 12 h. The reaction mixture was filtered through celite and the filtrate was concentrated to give N-(3-chloro-4-(difluoromethoxy)phenyl)-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)pyrimidin-2-amine (0.16 g, 80%). LCMS (ES-API), RT: 2.21 m/z 500.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12](OC(C)C)[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl[CH:22]1N([N+]([O-])=O)C=CC(Cl)=N1.CC1NN=C(N)C=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:22])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Reactant: O=[N+]([O-])N1C=CC(Cl)=NC1Cl
Agent: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 30 using 2,6-dichloro-3-nitropyrimidine and 5-methyl-1H-pyrazol-3-amine as the starting materials. LCMS: 255 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[CH2:9][CH2:10][NH2:12])=[CH:6][CH:7]=1
Reactant: CC(CC(N)=O)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CCN)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 100.7 %

Procedure:
To a solution of 3-(4-bromophenyl)butanamide (0.60 g, 2.48 mmol) in anhydrous tetrahydrofuran (15 mL) was added Lithium aluminum hydride (0.14 g, 37.2 mmol), the mixture was stirred at reflux for 1.5 hours, after the completion of the reaction, the mixture was cooled to 0° C., 1N sodium hydroxide solution (10 mL) was added slowly, after the reaction, the mixture was stirred at room temperature for 15 minutes. The mixture was filtered and the filtration was collected and extracted with ethyl acetate (10 mL×3), the organic phase was collected and dried over sodium sulfate, removed the solvent under reduce pressure to give 3-(4-bromophenyl)butan-1-amine as a pale yellow oil (0.57 g, 100%) which could be used in the next step without further purification. LR S (M+H+) m/z: calcd for 228.13. found 228.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][S:9][CH2:8][CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].[Li+].[OH-].C(OCC)(=O)C>CO>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:6]2[CH2:7][CH2:8][S:9][CH2:10][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reaction time: 48 h
Yield: 97.1 %

Procedure:
8.3 g of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid methyl ester was dissolved in 157 mL of methanol and 52.5 ml 1 mol/L of LiOH solution was added dropwise in the above solution at 0° C. The mixture was stirred for 48 h and ethyl acetate (60, 60 ml) was added into the reaction mixture and separated to collect mother liquid. The mother liquid was acidified by 100 ml 1 mol/L hydrogen chloride to adjust pH value to 2. Filtrated and collected the white solid to obtain 7.7 g product. Yield 97.0%□mp149-150° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:19])([CH3:18])[C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[S:22][C:23]([C:29]2[C:34]([F:35])=[CH:33][C:32]([C:36]([OH:39])([CH3:38])[CH3:37])=[CH:31][C:30]=2[F:40])=[CH:24][C:25]=1[C:26]([NH2:28])=[O:27]>>[F:40][C:30]1[CH:31]=[C:32]([C:36]([OH:39])([CH3:38])[CH3:37])[CH:33]=[C:34]([F:35])[C:29]=1[C:23]1[S:22][C:21]([NH:20][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([CH3:19])([CH3:18])[C:9]([NH:11][C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[O:10])[N:7]=2)=[C:25]([C:26]([NH2:28])=[O:27])[CH:24]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cn1cc(NC(=O)C(C)(C)c2cccc(Br)n2)cn1
Product: Cn1cc(NC(=O)C(C)(C)c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-2-methyl-N-(1-methyl-1-H-pyrazol-4-yl)propanamide (47 mg, 0.14 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (45 mg, 0.14 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[O:6].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH2:5][OH:6]
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCOc1cc(CO)cc(Cl)c1OCC#C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
3-Chloro-4,5-dipropargyloxybenzaldehyde (14.7 g) was added to a solution of sodium borohydride (3.6 g) in ethanol (150 ml) at a temperature below 30° C. After stirring at room temperature for 2 hours, the resultant mixture was poured into dilute hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3-chloro-4,5-dipropargyloxybenzyl alcohol (15.60 g)/. nD17.0 1.5713.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.[NH2:7][NH:8][C:9]([NH2:11])=[S:10]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[NH:7][N:8]=[C:9]([SH:10])[N:11]=1
Reactant: NNC(N)=S
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCc1nc(S)n[nH]1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Methoxyacetyl chloride (2.82 g; 0.023 mol) was added to a solution (15 ml) of 2.09 g (0.0230 mol) of thiosemicarbazide in pyridine followed by stirring for a whole day and night at room temperature. The reaction solution was concentrated and 10 ml of methanol and 8 ml of a 25 wt % methanolic solution of sodium methoxide were added thereto followed by heating to reflux for a whole day and night. After cooling to room temperature, the solvent was evaporated and concentrated hydrochloric acid was added thereto to acidify. The solid separated out therefrom was filtered, washed with distilled water and dried to give 1.0 g (yield: 33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(OC(OC1SC2CCN([C@@H](C3C=CC=CC=3Cl)C(OC)=O)CC=2C=1)=O)C(C)C>CO>[CH:27]([O:26][C:24]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:25])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Reactant: CC(C)OC(=O)Cl
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)OCC(C)C)cc2C1
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)OC(C)C)cc2C1
Yield: 94 %

Procedure:
Following the method described in Example 18, (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (85 mg) was reacted with isopropyl chloroformate (0.23 ml), to prepare (S)-methyl 2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-15) (100 mg). Yield: 94%, ee=97.5% (chiral HPLC analysis conditions were the same as those in Example 4), [α]D20=+34.00° (c 0.50, MeOH); 1H-NMR (300 MHz, CDCl3) δ 1.36 (d, 6H, J=6.2 Hz), 2.77-2.78 (m, 2H), 2.86-2.89 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.90 (s, 1H), 4.93-5.01 (m, 1H), 6.30 (s, 1H), 7.24-7.68 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 21.6, 25.4, 48.1, 50.3, 52.1, 67.8, 73.9, 112.2, 125.7, 127.1, 129.4, 129.8, 129.9, 130.3, 133.7, 134.7, 150.5, 152.0, 171.2; ESI-MS m/z 424.1 [M+H]+; HRMS Calcd for C20H23NO5SCl [M+H]+ m/z 424.0989. found 424.0985.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[C:15]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(N)cccc1NC1=NCCC1
Agent: Cl
Product: CCOC(=O)Nc1cccc(NC2=NCCC2)c1C

Procedure:
The title compound (2.2 g) was prepared by the method of Example 23 using ethyl chloroformate and 3.0 g of the product aniline of Example 45. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Yield: 95.4 %

Procedure:
Following General Procedure F and using 2-fluoro-4-hydroxy-benzonitrile (11.37 g, 83 mmol), acetone (100 mL), potassium carbonate (30 g, 165.8 mmol) followed by benzyl bromide (10.84 mL, 91 mmol) the title product (18 g, 96%) was obtained.
Reaction SMILES: [B-](Cl)(Cl)(Cl)[S+](C)C.[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:43])[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35]CC2C=CC=CC=2)=[CH:31][CH:30]=1)[C:24]1[CH:28]=[CH:27][O:26][N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:43])[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:24]1[CH:28]=[CH:27][O:26][N:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[S+](C)[B-](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
Boron trichloride methyl sulfide complex (51 mL, 2.0 M solution in DCM) was added to 6.4 (8.2 g, 17 mmol) in DCM (100 mL) at 0° C. After addition, the ice bath was removed, and the mixture was stirred at room temperature for 7 hours. The mixture was cooled in an ice bath and quenched by adding saturated sodium bicarbonate until the mixture was neutralized. More DCM (400 mL) was added, and the organic layer was separated, washed with brine, dried, and concentrated under vacuum. The crude product (6.5 g) was dissolved in 50 mL of hot MeOH. After cooling, the crystallized product was collected by filtration and washed once with MeOH to give 6.5 (4.2 g). The filtrate was concentrated, and the solid that formed was collected and washed to give an additional 1.2 g of compound 6.5. MS ESI (pos.) m/e: 393 (M+H). 1H NMR (CDCl3) δ 8.29(d, 1H), 7.30 (m, 3H), 7.20 (d, 2H), 7.15 (d, 2H), 6.95 (d, 2H), 6.14 (d, 1H), 4.71 (dd, 1H), 4.63 (m, 1H), 4.16 (d, 2H), 4.00 (dd, 1H), 3.54 (dd, 1H), 3.21 (dd, 1H), 2.76 (dd, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O[NH:53][C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)=[NH:55]>CN(C=O)C.O1CCOCC1>[N:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:54]1[N:55]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:9][N:53]=1
Reactant: N=C(NO)c1ccccn1
Reactant: O=C(O)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2noc(-c3ccccn3)n2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a solution of the appropriate pyridine carboxylic acid (1 eq.) and DIPEA (3 eq.) in DMF is added PyBOP (1.05 eq.) at 0° C. The mixture is stirred for 15 min at 0° C. The appropriate N-hydroxy pyridine-carboxamidine (1.05 eq.) is added and stirring is continued for 1 to 8 h at 0° C. to rt. The reaction is monitored by LC-MS. Upon complete conversion, the reaction is quenched with water and sat. aq. NaHCO3-solution. The mixture is extracted with diethyl ether, EA or DCM. The org. extracts are dried over MgSO4, filtered and evaporated to give the crude hydroxyamidine ester. This material is dissolved in dioxane and the resulting solution is stirred at 70-90° C. for 4 to 24 h. The solvent is removed in vacuo and the crude product is purified by either CC on silica gel, chromatography on prep. TLC plates or by HPLC to give the desired 3,5-dipyridyl-[1,2,4]oxadiazol in 30-80% yield.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([OH:5])[CH3:4].N1C=CC=CC=1.O=S(Cl)Cl.[F:27][C:28]([F:38])([F:37])[CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>O.C1COCC1>[CH:31]1([N:30]([CH2:29][C:28]([F:27])([F:37])[F:38])[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:16])[F:15])=[CH:14][CH:13]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: C[C@](O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Reactant: FC(F)(F)CNC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@](O)(c1ccc(C(=O)N(CC(F)(F)F)C2CCCCC2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a solution of (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (0.10 g, 0.43 mmol), pyridine (0.069, 0.86 mmol), and THF (1 mL) was added SOCl2 (0.046 mL, 0.64 mmol). The reaction was stirred at 80° C. for 2 h. After cooling to room temperature, half of the acid chloride was sequestered for reaction. To this material was added 2 equiv. of N-(2,2,2-trifluoroethyl)cyclohexylamine (0.077 mg, 0.43 mmol). The amide forming reaction was stirred at room temperature overnight. The reaction mixture was poured into water (5 mL), acidified with 5 N HCl and extracted with CH2Cl2 (2 mL). The organic extracts were washed with 1 N NaOH (4 mL), dried with Na2SO4, and removed in vacuo. Silica gel chromatography (gradient 20 to 30% ethyl acetate in hexanes) afforded 21 mg of (S)—N-cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide. 1H NMR (400 MHz, CDCl3) δ 1.10-1.20 (m, 3H), 1.42-1.65 (m, 3H), 1.74-1.85 (m, 7H), 2.68 (bs, 1H), 3.68 (bs, 1H), 4.02-4.19 (m, 2 H), 7.44 (d, J=8 Hz, 2H), 7.66 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2](O)=[O:3].C1CO[C:14]23OCCO[C:9]2([C@:10]2([CH2:32][C@H:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C@H:30]4[C@@H:21]([CH2:22][CH:23]=[C:24]5[C@@H:29]4[CH2:28][CH2:27][CH2:26][CH2:25]5)[C@@H:12]2[CH2:13]3)[CH3:11])[O:8]1.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:2]1[CH2:1][O:6][C:26]2([CH2:27][CH2:28][C@H:29]3[C:24](=[CH:23][CH2:22][C@@H:21]4[C@@H:30]3[C@@H:31]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[CH2:32][C@@:10]3([CH3:11])[C@H:12]4[CH2:13][CH2:14][C:9]3=[O:8])[CH2:25]2)[O:3]1
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CC=C4CC5(CC[C@@H]4[C@H]32)OCCO5)cc1

Procedure:
14 g of silica gel is suspended in 30 ml of methylene chloride, mixed with 1.4 ml of saturated oxalic acid solution and stirred for 15 more minutes. 4.67 g (10 mmol) of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estrene is added to this suspension and the reaction mixture is stirred at room temperature for 4 more hours. Then, it is suctioned off on a frit, the frit residue is rewashed with methanol/methylene chloride and the thus obtained filtrate is shaken out with saturated sodium bicarbonate solution. The organic phase is dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 3.28 g of 3,3-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estren-17-one is obtained as white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](O)=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:43][O:44][C:45](=[O:54])[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C(N(CC)CC)C>O>[CH:24]1([NH:23][C:21](=[O:22])/[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([NH:53][CH2:52][C:49]3[CH:50]=[CH:51][C:46]([C:45]([O:44][CH3:43])=[O:54])=[CH:47][CH:48]=3)=[O:19])=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)C=Cc2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a suspension of (1E)-3-(4-(2-(4-fluorophenyl)-3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (prepared according to the procedure described in Example 59, step-II, 0.35 g, 1 mmol) in DMF (15 mL) EDCI (0.83 g, 2 mmol), HOBt (0.13 g, 1 mmol) and methyl-4-aminomethylbenzoate hydrochloride salt (0.18 g, 0.9 mmol), were added, followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl acetate (1×150 mL) and washed with water (2×50 mL), 10% dilute HCl (50 mL) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound (0.225 g, 53.5% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[NH2:8][C@@H:9]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.O>[C:1]([NH:8][C@@H:9]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([OH:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: C=CCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
Pent-4-enoyl chloride (0.915 ml, 8.25 mmol) was added to a solution of (R)-2-amino-3-(tritylthio)propanoic acid (1.50 g, 4.13 mmol) and sodium carbonate (1.31 g, 12.4 mmol) in tetrahydrofuran (3.5 ml) and water (7 ml), and the mixture was stirred at room temperature for one hour. The reaction mixture was then adjusted to pH 2 by adding concentrated hydrochloric acid thereto at 0° C. After dilution with ethyl acetate, salting-out extraction was carried out by adding an appropriate amount of NaCl. The resulting organic extract was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-2-(pent-4-enamido)-3-(tritylthio)propanoic acid (Compound 2h) (1.14 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14]I.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH3:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(C)C2=O
Temperature: 80 °C

Procedure:
A mixture of 6-methoxy-1-tetralone (5.0 g, 28.4 mmol), methyl iodide (20 mL, 262 mmol) and sodium hydride (60%, 5.5 g, 138 mmol, prewashed twice with hexanes) in toluene is heated at 80° C. for 3 days. The mixture is quenched carefully with water and is partitioned between EtOAc and brine. The organic extract is dried with MgSO4, concentrated and purified via column chromatography to give the title compound as a light yellow oil: 1H NMR (CDCl3) δ 1.27 (d, J=7 Hz, 3H), 1.83-1.89 (m, 1H), 2.10-2.15 (m, 1H), 2.51-2.60 (m, 1H), 2.90-3.00 (m, 2H), 3.85 (s, 3H), 6.68 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H).
Reaction SMILES: C(O)(=O)C=[CH:3][C:4]([OH:6])=O.[Na].C=CC=C.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15].O1C(=O)C=CC1=O.CC(C)=C>>[O:6]1[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:16][CH:14]=[CH2:15])[CH2:3]1
Reactant: C=Cc1ccccc1
Reactant: O=C(O)C=CC(=O)O
Agent: C=C(C)C
Agent: C=CC=C
Agent: O=C1C=CC(=O)O1
Product: C=CCCCCCCC1CO1

Procedure:
2-Butenedioic acid (2Z)-, sodium salt, polymer with 1,3-butadiene, ethenylbenzene, 2,5-furandione, 2-methyl-1-propene and 2,2′,2″-[1,2,3-propanetryltris(oxymethylene)]tris[oxirane], block(9Cl)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: CCCCCN
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(Cl)c1
Yield: 65.7 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.038 g, 0.140) mmol) and amylamine (0.012 g 0.140 mmol) gives the title compound (0.0314 g, 64.3%): TOF MS ES+ 348.1 (M+H)+, HRMS calcd for C18H23N3O2Cl 348.1479 (M+H)+, found 348.1456, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:49][CH:50]3[CH2:55][CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:49][CH:50]3[CH2:55][CH2:54][CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([OH:42])=[O:41])[CH2:34][CH2:33]1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)C1
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)O)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 332 Step 6 and making non-critical variations to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoate, the title compound was obtained as a beige solid (0.87 g, 80%): MS (ES+) m/z 307.10 (M+1).