Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:20]3[CH:24]=[C:23]([CH2:25][CH3:26])[N:22]=[CH:21]3)[CH:14]=[C:9]12)(=[O:3])[CH3:2].[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[CH2:25]([C:23]1[N:22]=[CH:21][N:20]([C:15]2[CH:14]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][N:8]3[C:18](=[O:19])[CH2:17][N:16]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:13]=[CH:12][CH:11]=4)[CH:24]=1)[CH3:26]
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(C(C)=O)cccc4C3=C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C(C)O)C3=C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
Example 115. A solution of 9-acetyl-2-(4-ethyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (210 mg, 0.36 mmol) in MeOH (20 mL) was treated with NaBH3CN (23 mg, 0.36 mmol) and the mixture was stirred at RT for 10 min. The mixture was then concentrated in vacuo and the residue obtained was taken up in DCM and washed with H2O. The org layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and preparative TLC (SiO2, DCM/MeOH 95:5) afforded the title compound (6 mg). UPLC-MS: MS 351.2 (M+H+); UPLC rt 0.65 min. 1H NMR (400 MHz, CD3OD): δ ppm 1.16-1.27 (m, 3 H); 1.44 (d, J=6.26 Hz, 3 H); 2.58 (q, J=7.56 Hz, 2 H); 2.97-3.17 (m, 2 H); 3.80 (m, 1 H); 3.88-4.00 (m, 2 H); 4.31-4.36 (m, 2 H); 5.14 (d, J=6.65 Hz, 1 H); 6.95 (s, 1 H); 7.34 (s, 1 H); 7.37-7.49 (m, 1 H); 7.67 (d, J=7.43 Hz, 1 H); 7.77 (d, J=7.82 Hz, 1 H); 8.11 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.BrC1C=C(O)C=CC=1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][N:27]1[C:35]2[CH:34]=[C:33]3[O:36][CH2:37][CH2:38][O:39][C:32]3=[CH:31][C:30]=2[C:29](=[O:40])[C:28]1=[O:41].FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:40][C:29]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:30]2[CH:31]=[C:32]3[O:39][CH2:38][CH2:37][O:36][C:33]3=[CH:34][C:35]=2[N:27]([CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])[C:28]1=[O:41]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: COCCOCCN1C(=O)C(=O)c2cc3c(cc21)OCCO3
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COCCOCCN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol, and 6-[2-(2-methoxyethoxy)ethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained (19%): MS (ES+) m/z 441.9 (M−17).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([C:14]2([OH:25])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([C:14]2([OH:25])[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(C2CCCCC2)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 120 mg (0.47 mmol) of 3-cyclohexyl-3-hydroxy-1-(tert-butoxycarbonyl)azetidine dissolved in 3 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour and then concentrated to dryness and used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(=O)CC>[C:1]1([CH2:7][CH2:8][C@@H:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCc1ccccc1
Solvent: CCC(C)=O
Product: C[C@H](O)CCc1ccccc1

Procedure:
Phenyl ring-containing 2-butanone derivatives were reduced to the corresponding (S)-alcohols with excellent stereoselectivities and moderate to excellent yields (Table 4). 4-Phenyl-2-butanone (1a) was reduced stereoselectively to produce (S)-4-phenyl-2-butanol ((S)-1b) with excellent chemical and optical yields. The â-diketone 1-phenyl-1,3-butadione (2a) was reduced regio- and stereoselectively to furnish the monohydroxy ketone (S)-3-hydroxy-1-phenyl-1-butanone ((S)-2b) with excellent yield and ee, leaving the other keto group at C-1 intact. (E)-4-Phenyl-3-butene-2-one (3a) was reduced with moderate yield and excellent optical purity to produce the allylic alcohol (S)-4-phenyl-3-butene-2-ol ((S)-3b). The presence of the methoxy group at the para position of the phenyl ring in 4-(4-methoxyphenyl)-2-butanone (4a) affected the ee of the produced (S)-4-(4-methoxyphenyl)-2-butanol ((S)-4-b) (91% ee), which was lower than for (S)-1b. Phenoxy-2-propanone (5a) was reduced with very high yield and optical purity to produce the corresponding (S)-phenoxy-2-propanol ((S)-5b). When the R-chloroketone, 3-chloro-4-(4-chlorophenyl)-2-butanone (6a), was reduced with W110A TESADH, (+)-(2S,3R)-3-chloro-4-(4-chlorophenyl)-2-butanol ((+)-(2S,3R)-6b) was produced with high enantioselectivity (>99% ee) and diastereoselectivity (92:8 mixture of anti- and syn-R-chlorohydrins).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36](B(O)O)=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)#[N:25]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:36]([C:2]3[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)[C:7]=3[CH3:8])=[CH:35][CH:34]=[N:33]2)=[CH:30][CH:31]=1)#[N:25]
Reactant: CNC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: N#Cc1ccc(-n2nccc2B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CNC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 82 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
Argon was bubbled through 5-iodo-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (SM2, 200 mg, 0.46 mmol) and [1-(4-cyanophenyl)-1H-pyrazol-5-yl]boronic acid (SM3, 150 mg, 0.70 mmol) in DME (10 ml) and 2M Na2CO3 (5 ml) for 10 min. Palladium-tri-tert-butylphosphine (25 mg, 0.049 mmol) was added and the mixture was stirred under argon at 82° C. for 2 h. More SM3 (150 mg, 0.70 mmol) and palladium-tri-tert-butylphosphine (10 mg, 0.019 mmol) were added and the mixture was stirred for a further 2 h under the same conditions. The reaction mixture was then was cooled to RT, diluted with ethyl acetate (150 ml) and washed with brine (3×100 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by HPLC on a Kromasil C-18 column using a gradient of acetonitrile/water. Freeze-drying of the mixture afforded the title compound (80 mg).
Reaction SMILES: ClC1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]3[CH:41]=[C:42]([C:47]([O:49]C)=[O:48])[C:43](=[O:46])[NH:44][N:45]=3)=[CH:39][C:34]=2[CH2:33][CH2:32]1.[Cl:51][C:52]1[CH:61]=[CH:60][C:55]([CH:56]=[CH:57][CH2:58]Cl)=[CH:54][CH:53]=1>>[C:47]([C:42]1[C:43](=[O:46])[N:44]([CH2:58][CH:57]=[CH:56][C:55]2[CH:60]=[CH:61][C:52]([Cl:51])=[CH:53][CH:54]=2)[N:45]=[C:40]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)[CH:41]=1)([OH:49])=[O:48]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 44.4 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride, to thereby yield the title compound as an orange powder (yield: 44.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[Cl-].[CH:27]1([Mg]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1>S(Cl)(Cl)=O.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O)CCc1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Temperature: 25 °C

Procedure:
3-(3-Benzyloxy-phenyl)-propanoic acid (5 g, 19.5 mmol) from Example XXXX was taken up in thionyl chloride (20 mL) and refluxed for 2 hours. The excess thionyl chloride was removed under reduced pressure and carbon tetrachloride added and removed several times under reduced pressure to remove any excess thionyl chloride. The resulting oil was taken up in freshly distilled THF (50 mL), MnCl2 (0.49 g, 3.9 mmol) and LiCl (0.331 g, 7.8 mmol) were added. This was allowed to stir under nitrogen at room temperature until homogenous. The solution was then cooled to 0° C. with an ice bath and 2.0 M cyclopentyl magnesium chloride (11.0 mL, 22 mmol) in Et2O was added dropwise to the solution over 0.5 hour. The reaction was allowed to stir for 10 minutes after addition was complete and was then quenched with 1N HCl and brine until acidic. The organics were extracted into EtOAc and then washed with brine and dried with MgSO4. The solvent was removed under reduced pressure and the residue submitted to flash chromatography (3:7 EtOAc:hexane, silica gel) to yield the title compound as a viscous oil. 1H NMR (CDCl3) δ 1.54-1.80 (br m, 8 H), 2.76 (m, 2 H), 2.80 (m, obscured, 1 H), 2.86 (m, 2 H), 5.05 (s, 2 H), 6.81 (br m, 3 H), 7.21 (br m, 1 H), 7.43 (br m, 5 H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][C:32]=1[CH2:33][O:34][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH3:29])=[CH:22]/[CH:23]=[CH:24]/[C:25]([CH3:28])([OH:27])[CH3:26])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][C:32]=1[CH2:33][OH:34])[O:13][CH2:14][C:15]1[CH:16]=[C:17](/[C:21](/[CH3:29])=[CH:22]/[CH:23]=[CH:24]/[C:25]([CH3:26])([OH:27])[CH3:28])[CH:18]=[CH:19][CH:20]=1
Reactant: C/C(=C\C=C\C(C)(C)O)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C/C(=C\C=C\C(C)(C)O)c1cccc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 57(c), by reacting 120 mg (0.2 mmol) of (3E,5E)-6-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-phenyl}-2-methylhepta-3,5-dien-2-ol with 0.6 ml of a tetrabutylammonium fluoride solution (1N in THF), a colourless oil is obtained (m=30 mg; Y=41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][N:31]=1
Reactant: COc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: COCCN(C)c1ncc(N)cn1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3OC)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C20H20F3N5O4 (m/e) 451. obsd 452 (M+H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11](O)[CH2:12][CH3:13]>>[CH:11]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH:2]([CH2:4][CH3:5])[CH3:1])=[O:6])[OH:3])([CH2:12][CH3:13])[CH3:10]
Reactant: CCC(C)O
Reactant: O=C(O)CC(O)C(=O)O
Product: CCC(C)OC(=O)CC(O)C(=O)OC(C)CC
Temperature: 102 °C

Procedure:
Di-sec-butyl-DL-malate was prepared using a procedure similar to Example 3. This compound was isolated as a bottoms product. To the reaction flask, DL-malic acid (80.23 g), 2-butanol (220 mL) and Amberlyst®15 ion exchange resin (11.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 102° C., one phase started to collect in the Dean-Stark trap. The reaction was maintained at 102° C. for 4 hr. During this time, the water/alcohol azeotrope was removed as fresh alcohol was added. The product was dissolved in diethyl ether, separated from the catalyst via filtration over a bed of silica, washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Di-sec-butyl-DL-malate was obtained as a low viscosity, clear light yellow liquid with no detectable odor (46 g, 31% yield) after pumping on the sample in vacuo to remove residual 2-butanol.
Reaction SMILES: N([C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)N>CO.[Ag]=O>[O:13]=[C:12]1[C:6]2[C:7](=[N:8][CH:3]=[N:4][CH:5]=2)[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH3:23])[NH:11]1
Reactant: CCCOc1ccccc1-c1nc2nc(NN)ncc2c(=O)[nH]1
Agent: O=[Ag]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2ncncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7-hydrazino-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.40 g) and silver oxide (0.32 g) in methanol (40 ml) was stirred at ambient temperature for 18 hours and at 45°-50° C. for 24 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to yield a white solid which together with another sample (27 mg), similarly prepared, was recrystallised from 2-propanol to yield the title compound, 136 mg, m.p. 142°-143° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:19])=[O:20])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 66.33 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-05) (410.0 mg, 66.33%) was synthesized as a white solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (600.0 mg, 1.299 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][O:5][CH2:6][CH2:7][CH:8]=1.[Cl:9][C:10]1[N:11]([C:19]2[CH:24]=[C:23]([OH:25])[C:22]([Cl:26])=[CH:21][C:20]=2[F:27])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[Cl:9][C:10]1[N:11]([C:19]2[CH:24]=[C:23]([O:25][CH2:2][C:3]3[CH2:4][O:5][CH2:6][CH2:7][CH:8]=3)[C:22]([Cl:26])=[CH:21][C:20]=2[F:27])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: ClCC1=CCCOC1
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Cl)c(OCC2=CCCOC2)cc1-n1nc2c(c1Cl)CCCC2
Reaction time: 12 h
Yield: 83.9 %

Procedure:
2.1 g (16 mmol) of 3-chloromethyl-5,6dihydro-2H-pyran were added at 25° C. to a mixture of 4.5 g (15 mmol) of 3-chloro-2-(4-chloro-2fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydroindazole, 2.5 g (18 mmol) of potassium carbonate and 0.5 g (3 mmol) of sodium iodide in 50 ml of dimethylformamide, and the reaction mixture was stirred for 12 hours. 100 ml of water were added, and the precipitate was isolated, washed with water and dried, resulting in 5 g (84%) of the title compound [melting point 90° to 92° C⟧ Compound No. 1.002.
Reaction SMILES: C1(S([C:10](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]#[N:12])(=O)=O)C=CC=CC=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:21]=[N:22][NH:23][C:10]=2[C:11]#[N:12])=[CH:15][CH:16]=1
Reactant: N#CC(=Cc1ccc(O)cc1)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1[nH]nnc1-c1ccc(O)cc1

Procedure:
A mixture of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile (2.08 g, 7.3 mmol) and sodium azide (0.47 g, 7.3 mmol) in DMF (50 mL) was heated at reflux temperature 2 hours. After cooling, the mixture was poured on ice. The mixture was evaporated in vacuo to almost dryness and toluene was added. After filtration, the organic phase was evaporated in vacuo. The residue was purified by silicagel chromatography eluting with a mixture of ethyl acetate and heptane (1:2). This afforded 1.2 g (76%) of the title compound.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([CH3:47])([O:18][C:19]2[CH:20]=[C:21]3[C:30](=[CH:31][C:32]=2[C:33]([F:36])([F:35])[F:34])[O:29][CH2:28][C:27]2[N:22]3[CH:23]([CH3:46])[C:24](=[O:45])[N:25]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:26]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:46][CH:23]1[N:22]2[C:27]([CH2:28][O:29][C:30]3[C:21]2=[CH:20][C:19]([O:18][C:16]2([CH3:47])[CH2:15][NH:14][CH2:17]2)=[C:32]([C:33]([F:35])([F:34])[F:36])[CH:31]=3)=[N:26][N:25]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:24]1=[O:45]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(OC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(OC4(C)CNC4)cc3N21
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A suspension of 6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.031 g, 0.046 mmol) and Pd(OH)2/C (10%, 0.030 g) in EtOH (10 mL) was stirred at 50° C. under an atmosphere of H2 (50 psi) overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.021 g crude) as an oil, which was used directly without purification. To a solution of 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.021 g, 0.042 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at ambient temperature for 1.5 h then the solvent was removed in vacuo and the residue was diluted with dioxane (1 mL). Aqueous ammonium hydroxide (25%, 1 mL) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 15) to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.0039 g, 25%). LC/MS (Table 1, Method 5) Rt=2.088 min; MS m/z: 371 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)[CH2:5][CH2:4]1>O1CCCC1>[CH:3]1([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=3)=[CH:14][C:13]=2[C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCCNC3CC3)ccc21
Yield: 61.9 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 130 mg (3 mmol) of sodium hydroxide with 180 mg (0.3 mmol) of ethyl 4′-(4-cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 11) in 30 ml of tetrahydrofuran. 95 mg of 4′-(4-cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=160° C., yield=62%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][O:9][CH2:10]CO.[C-]#N.[K+].COC1C=CC(O)=CC=1.C(OC)(=O)C(C)=C.CO>>[C:1]([O:6][CH2:7][CH2:8][O:9][CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COCCO
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C=C(C)C(=O)OCCOC
Temperature: 75 °C
Reaction time: 4 h

Procedure:
400 g of methyl methacrylate (4 mole), 152 g of ethylene glycol monomethyl ether (2 mole), 2.75 g of KCN (0.5%) and 0.14 g of hydroquinone monomethyl ether (250 ppm) are added to a 1 liter round-bottomed flask. The batch is heated to about 75° C. and the methyl methacrylate/methanol-azeotrope is distilled-off by way of a 1 m vigreux column at 65° C. temperature at the head of the column. After 4 hours, the trans-esterification is completed. After cooling of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A residue of ethylene glycol monomethylether methacrylate of 260 g = 90% results.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:23])[C:6](=[O:24])[CH:5]=[CH:4][C:3]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:42][C@@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40]([O:39][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:47])[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:23])[C:6](=[O:24])[CH:5]=[CH:4][C:3]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC(=O)CC2)cc1F
Product: CC(C)C[C@H](NC1CCC(Oc2cc(F)c(-n3c(N)c(C(=O)c4ccc(F)cc4)ccc3=O)c(F)c2)CC1)C(=O)OC1CCCC1

Procedure:
From Intermediate 5 (120 mg, 0.263 mmol) and L-Leucine cyclopentyl ester (Intermediate 8). LCMS purity 100%, m/z 640 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 0.95-1.05 (6H, m), 1.50-2.00 (16H, m), 2.10-2.35 (3H, m), 3.15-3.20 (1H, m), 4.00-4.15 (1H, m), 4.40 and 4.75 (0.5H each, m), 5.25-5.35 (1H, m), 5.75 (1H, d), 6.85-6.95 (2H, m), 7.15-7.25 (2H, m), 7.55-7.65 (2H, m), 7.65-7.70 (1H, m).