Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][OH:12])[C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]C(O)=O)=[CH:17][CH:16]=1.[C:25]([O-])(=[O:27])C.[Na+].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:27][CH3:25])[CH:7]=[C:6]2[C:3]=1[CH:4]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[C:11](=[O:12])[O:10]2
Reactant: O=Cc1c(Cl)cccc1OCO
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(-c2cc3c(Cl)cc(OC)cc3oc2=O)cc1
Yield: 60.4 %

Procedure:
A solution of 2-chloro-6-hydroxymethoxybenzaldehyde (2.85 g), 4-methoxyphenylacetic acid (2.54 g) and sodium acetate (3 g) in acetic anhydride (25 mL) was refluxed for 18 h and cooled. Cold water (200 mL) was added. The solids were filtered, washed with water (three times) and ether-hexane (1:1), and dried under high vacuum to give the title compound (2.92 g). 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.68 (d, 2H, J=8.7 Hz), 6.98 (d, 2H, J=8.7 Hz), 6.94 (d, 1H, J=1.8 Hz), 6.77 (d, 1H, J=1.8 Hz), 3.87 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:16]1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:16][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:18]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ncccc2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ncccc3O)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(3-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in step C, 1 eq.) and N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in the previous step, tris TFA salt, 1 eq.) in DCM was added TEA (3 eq.). After stirring at room temperature 30 minutes, NaBH(OAc)3 (3 eq) was added and the mixture was stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution and partially concentrated. Extraction with ethyl acetate followed by concentration of the organic layer in vacuo yielded a residue which was purified by flash chromatography (silica gel, 0-20% 7 N NH3-MeOH/Ethyl acetate) to afford the product as a solid, mixture of isomers.
Reaction SMILES: C([N:8]([CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([C:48](=[O:50])[NH2:49])[CH:42]=1)[CH2:9][CH:10]([OH:37])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[N:22]=[C:21]([CH3:31])[C:20]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:15][CH:14]=1)C1C=CC=CC=1.[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].O>C(O)(C)C>[C:48]([C:43]1[CH:42]=[C:41]([CH:46]=[CH:45][C:44]=1[OH:47])[O:40][CH2:39][CH2:38][NH:8][CH2:9][CH:10]([OH:37])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[N:22]=[C:21]([CH3:31])[C:20]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:15][CH:14]=1)(=[O:50])[NH2:49].[C:51]([O-:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([O-:56])=[O:55]
Reactant: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
11.6 g of 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(3,5-dicarboethoxy-2,6-dimethylpyridin-4-yl)-phenoxy]-2-propanol are hydrogenated and worked up analogously to Example 1. The resulting base is reacted with fumaric acid in isopropanol and the resulting salt is recrystallised from ethanol. After drying for 15 hours at 0.05 mm Hg and 80°, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(3,5-dicarboethoxy-2,6-dimethylpyridin-4-yl)-phenoxy]-2-propanol is obtained in the form of a neutral fumarate with 1/4 mole of water of crystallisation and has a melting point of 133°-135°.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20]C)=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[OH:17][C:10]1([C:13]([F:15])([F:16])[F:14])[CH2:9][C:8]([CH3:18])([CH3:19])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[OH:20])[CH:11]1[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2ccc(F)c(O)c21
Yield: 18 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (Example 3) and 520 mg of 5-aminoquinolin-2(1H)-one. 255 mg of the title compound is obtained by reaction of 300 mg of imine with 3.3 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1Cl

Procedure:
(2′-{[(2-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.27 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.7 mL) for 1 hour. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=O>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: N#Cc1ccc(F)cc1N
Reactant: O=c1ccccs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(F)ccc13)CCSC2
Temperature: 50 °C
Yield: 62.4 %

Procedure:
A mixture of 4-fluoroanthranilonitrile (4.47 g) and freshly fused, pulverized ZnCl2 (6.7 g) in 20 ml of nitrobenzene was heated at 50° C. for 45 minutes. To the resulting suspension was added thiopyran-2-one (5.1 g). This was heated at 130° C. for 3 hours. The resulting precipitate was filtered, rinsed with ether and partioned between 2-butanone and NH4OH solution. The aqueous layer was extracted with 2-butanone and the combined organics were washed with water and dried (MgSO4). The resulted in 4.8 g of a tan solid, m.p. 234°-237° C. d., which was recrystallized from ethyl acetate to give 3.0 g of a white powder, m.p. 235°-237° C. d.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]2[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:28]1([S:34]([NH:37][C:25]([C:23]2[CH:22]=[CH:21][C:11]3[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][C:10]=3[CH:24]=2)=[O:26])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
N,N′-carbonyldiimidazole (0.401 g) is added all at once to an N,N-dimethylformamide (20 ml) solution of 2-benzyl-5-carboxy-1-(2-chlorobenzyl) benzimidazole (0.466 g), and the solution is stirred for one hour at room temperature. Subsequently, a N,N-dimethylformamide (5 ml) solution of benzenesulfonamide (0.389 g) and diazabicycloundecene (0.377 g) is added, and the solution is stirred for 48 hours at 100° C. The reaction solution is cooled, and the solvent is removed through evaporation under reduced pressure. This material is dissolved in a mixture solution of methanol and water. The pH is adjusted to pH 5˜6 using 10% hydrochloric acid. Precipitated crystals are separated through filtration, and are dried. Thus, 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole (0.447 g) is obtained.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[NH4+].[Cl-].CCOC(C)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:15]([NH:22][C@@H:5]1[CH2:4][O:3][CH2:2][C@H:1]1[OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: C1OCC2OC12
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: O[C@@H]1COC[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ti(OiPr)4 (1.0 mL, 3.48 mmol) was added to a solution of 3,6-dioxabicyclo[3.1.0]hexane (1.5 g, 17.4 mmol) in benzylamine (2.0 mL). The mixture was irradiated in a microwave reactor at 130° C. for 2 hours. It was cooled to room temperature, and 50 mL of saturated aqueous NH4Cl solution and 20 mL of EtOAc were added to the reaction. The mixture was stirred for 10 minutes. The resulting gummy precipitate was filtered over a celite bed, and the filtrate was extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography on a C-18 column (0-100% CH3CN/water) to afford trans-4-(benzylamino) tetrahydrofuran-3-ol. MS APCl calc'd for C11H15NO2 [M+H]+ 194. found 194.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]#[N:12].[H-].[K+].C([Li])CCC.C([O:24][B:25](OCCCC)[O:26]CCCC)CCC>C1COCC1>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:25]([OH:26])[OH:24])[CH:3]=2)[NH:7][CH:6]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(Br)cc12
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-bromo-3-cyanoindole (4.00 g, 18.1 mMol) in THF (20 mL) was added to a suspension of potassium hydride (2.28 g, 35% mineral oil dispersion, 19.9 mMol) in anhydrous THF (50 mL) at 0° C. After stirring for 15 min, the solution was cooled to −78° C., whereupon some precipitation occurred. A solution of n-butyllithium (2.5 M in hexanes, 16 mL) was slowly added via syringe. The resulting mixture was stirred at −78° C. for 15 minutes and then tributylborate (9.16 g, 39.8 mMol) was added. The mixture was removed from the cooling bath, stirred for 15 minutes, carefully quenched with water, and concentrated in vacuo. The residue was vigorously mixed with 1 N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were extracted three times with 1 N sodium hydroxide. The combined aqueous extracts were made acidic with concentrated hydrochloric acid to give 3-cyano-5-indolylboronic acid as a light tan precipitate which was collected by filtration and dried under vacuum (1.82 g, 55%). 1H-NMR (400 MHz, DMSO) δ 12.19 (1H, br s), 6.05 (1H, d, J=5.2 Hz), 8.24 (1H, d, J=2.8 Hz), 8.17 (1H, d, 6.4 Hz), 7.69 (1H, d, J=8.2 Hz), 7.49 (1H, d, J=8.2 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:2]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]([NH:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:20])[CH:2]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1
Reactant: Nc1cnc2ccccc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1cnc2ccccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 3-aminoquinoline (64 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-45% EtOAc in hexane), the title compound as a white solid. MP 196-199° C. MS (ESI, pos. ion) m/z: 420 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:11][C:12]([OH:14])=O.C(Cl)C[Cl:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([CH2:11][C:12]([Cl:17])=[O:14])[CH2:5][CH2:4]1
Reactant: O=C(O)CCl
Reactant: ClCCCl
Reactant: FC1(F)CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)CN1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1.44 g, 9 mmol) in DCM (15 mL) was added chloroacetic acid (0.94 g, 10 mmol), TEA (1.5 mL), EDC (3.82 g, 20 mmol) and DMAP (cat.). The reaction mixture was stirred at RT overnight. The contents were transferred to a separatory funnel and DCM layer was washed saturated NaHCO3 solution, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using 3:1 Pet. Ether:DCM in. 2-(4,4-difluoropiperidin-1-yl)acetyl chloride was isolated as a white solid weighing 1.57 g (yield: 88%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[CH:8][CH:9]=2)[N:4]=1.Cl>CC(O)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc2ccc(C(F)(F)F)nc2c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2ccc(C(F)(F)F)nc2c1

Procedure:
tert-Butyl 2-(2-(trifluoromethyl)quinolin-7-yl)acetate was dissolved in glacial AcOH (0.8 mL) and 6 N HCl (0.8 mL) and heated to 80° C. for 2 hr. The reaction mixture was concentrated in vacuo to afford the crude product, which was used without further purification. HPLC method [4], retention time=1.874 min; MS(ESI) 256.1 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])[NH2:8])(=[O:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([NH:8][C:30](=[O:31])[O:32][CH:33]([CH3:35])[CH3:34])[CH:9]=[C:10]([O:15][CH2:16][CH3:17])[C:11]=1[O:12][CH2:13][CH3:14])(=[O:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1cc(N)cc(OC(C)=O)c1OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1cc(NC(=O)OC(C)C)cc(OC(C)=O)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
3-Acetyloxy-4,5-diethoxyaniline (1.0 g) and N,N-diethylaniline (0.70 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-acetyloxy-4,5-diethoxyphenyl)carbamate (Compound No. 4) (1.21 g) in a yield of 88.9%. M.P., 108°-109° C.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH2:6][CH2:5]1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:23][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH2:8]1
Reactant: F[B-](F)(F)F
Reactant: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Reaction time: 4 h
Yield: 88 %

Procedure:
The mixture of 4-(4-trimethylsilyloxy-piperidin-1-yl)-3-fluoronitrobenzene (151 mmol), selectfluor (151 mmol) in acetonitrile was stirred for 4 hours. The solvent was removed under reduced pressure and to the residual mass was extracted into ethyl acetate water mixture. The combined organic layer was dried and removal of the solvent afforded title compound in 88% yield.
Reaction SMILES: C[O:2]P(OC)OC.C(N(CC)CC)C.C1(S([CH2:23][C:24]2[C@@H:25]([C@:29]3([CH3:46])[C@@H:42]([CH:43]=2)[C@H:41]2[C:32]([C@:33]4([CH3:45])[C:38]([CH2:39][CH2:40]2)=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]4)=[CH:31][CH2:30]3)[C:26](=[O:28])[CH3:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1.CO>[OH:2][C@:25]1([C@:29]2([CH3:46])[C@H:42]([C@H:41]3[C:32](=[CH:31][CH2:30]2)[C@:33]2([CH3:45])[C:38](=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]2)[CH2:39][CH2:40]3)[CH2:43][C:24]1=[CH2:23])[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)[C@H]1C(CS(=O)c2ccccc2)=C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Reactant: COP(OC)OC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
Trimethylphosphite (0.3 ml) and triethylamine (0.3 ml) are added to a solution of 16(phenylsulfinylmethyl)pregn-1,4,9(11),15-tetraene-3,20-dione (VIB, Example 18, 538 mg of the mixed isomers) in toluene (5 ml) and methanol (0.7 ml). The mixture was heated at 85° in a sealed vial until the reaction was complete. The reaction mixture was poured into a buffer solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, and concentrated to a solid which is recrystallized from ethyl acetate to give the title compound. NMR (CDCl3) 0.70, 1.36, 2.26, 5.10, 5.51, 6.00, 6.20 and 7.17 δ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C[Si](C)(C)[N-:11][Si](C)(C)C.[Li+].[CH:19]([Mg]Br)([CH3:21])[CH3:20].Cl>O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[NH2:11]
Reactant: O=Cc1ccncc1
Reactant: CC(C)[Mg]Br
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(N)c1ccncc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Pyridinecarbaldehyde (0.5 mL, 5.25 mmol) in tetrahydrofuran (10 mL) was mixed with lithium hexamethyldisilazide in tetrahydrofuran (1 M, 6.3 mL, 6.3 mmol) and stirred at 0° C. for 4 hours and then stirred with isopropylmagnesium bromide in tetrahydrofuran (0.98 M, 6.3 mL, 6.3 mmol) at room temperature for 16 hours. After completion of the reaction, 1 M aqueous hydrochloric acid was added, and the reaction solution was washed with ethyl acetate. After addition of 1 M aqueous sodium hydroxide, the combined aqueous layer was extracted with chloroform. The resulting organic layer was filtered through celite, and the filtrate was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH:20][CH3:21])=[S:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:22][I:23].CO>O1CCCC1>[IH:23].[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH:20][CH3:21])[S:19][CH3:22])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CNC(=S)Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1)SC
Product: I

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-methylthioureido)thiazole (1.5 g) and methyl iodide (0.45 ml) in a solution of methanol (15 ml) and tetrahydrofuran (8 ml) was heated under reflux for 9 hours. The solvent was removed by concentration and the residue was triturated with ethyl acetate to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(methylamino)(methylthio)methyleneamino]thiazole hydriodide (1.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:23][CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:23][CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O)OCC
Temperature: 75 °C
Yield: 26.3 %

Procedure:
A solution of 5.02 g (18.00 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 140 ml of DMA was treated at RT with 0.86 g (19.80 mmol) of NaH (55% in oil) in four portions. After 1 h 3.72 ml (21.60 mmol) of 2-bromo-1,1-diethoxy-ethane were added over 30 min. The reaction was stirred over night and heated for 1 h at 75° C. The reaction was cooled and neutralized with cold aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 98:2) to yield 1.87 g (26%) of the title compound as a yellow viscous oil. MS: 395.4 (MH+, Cl).
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[N:9]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:8](=[O:37])[C@H:7]1[CH:38]([CH3:40])[CH3:39])(=[O:5])[CH3:4].C(OCC)C.Cl>C(O)C>[C:3]([N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[N:9]([CH2:26][C:27]([OH:29])=[O:28])[C:8](=[O:37])[C@H:7]1[CH:38]([CH3:40])[CH3:39])(=[O:5])[CH3:4]
Reactant: CC(=O)N1C=C(c2cccc(OCc3ccccc3)c2)N(CC(=O)OCc2ccccc2)C(=O)[C@H]1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)N1C=C(c2cccc(OCc3ccccc3)c2)N(CC(=O)O)C(=O)[C@H]1C(C)C

Procedure:
A 4 N aqueous lithium hydroxide solution (1.5 ml) is added to a solution of benzyl {(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate (276 mg, Reference compound No. 63-1) in ethanol (8 ml)/diethyl ether (2 ml), and the mixture is stirred overnight. To the reaction mixture is added 6 N hydrochloric acid to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (215 mg).