Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]4)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl(R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]/[C:16]([O-])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:19])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C\C(=O)[O-])c1ccc(-c2cccc(C)c2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cccc(C)c2)cc1

Procedure:
(E)-3-(3′-Methyl-biphenyl-4-yl)-but-2-enoate (0.74 g, 2.64 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-(3′-methyl-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.63 g (85%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]#[C:18][CH3:19]>CC(C)=O>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(O)cc1
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of 4.13 g (0.038 mol) of hydroquinone in 80 mL of acetone was added 5.19 g (0.375 mol) of potassium carbonate and 5.0 g (0.038 mol) of 1-bromo-2-butyne. The resulting mixture was heated at 55-60° C. for 8 h and then stirred overnight at room temperature. The reaction mixture was then poured onto ice and extracted with ether. The combined organics were washed with 1N sodium hydroxide solution. The combined aqueous layers were acidified with 1N HCl solution and extracted with dichloromethane. The dichloromethane layers were washed with water and brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo to provide 2.0 g of the phenol as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][C@H:13]3[C:18]([O:19][CH3:20])=N[C@H](C(C)C)C(OC)=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:27].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:20][O:19][C:18](=[O:27])[C@@H:13]([NH2:14])[CH2:12][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:11][N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(-c2ccc(Cl)s2)on1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 1 (3.25 g, 8.51 mmol) in acetonitrile (183 ml) was treated with TFA (90 ml, 2 M in water) and stirred at RT overnight. After complete conversion the mixture was neutralized with sat. aq. NaHCO3-solution, the majority of the acetonitrile was evaporated and the remainder extracted with ethyl acetate. The combined organic phases were washed with brine, dried with MgSO4, filtered and evaporated to dryness. The resulting crude oil (2.5 g) was used in the next steps without further purification.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]CC1C=CC=CC=1)/[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1O
Yield: 99 %

Procedure:
E-methyl 3-methoxy(2'-benzyloxyphenyl)propenoate (5.44 g) was dissolved in ethyl acetate (50 ml) and 5% palladium on carbon (0.25 g) was added. The stirred mixture was hydrogenated at three atmospheres pressure, with stirring, until no more hydrogen was taken up, then filtered through celite and silica gel (50 g, Merck 60). Concentration of the filtrate under reduced pressure afforded E-methyl 3-methoxy-2-(2'-hydroxyphenyl)propenoate as a white crystalline solid (3.76 g; 99% yield), M.P. 125-126° C.; infrared maxima (nujol mull): 3400, 1670 cm-1 ; 1H nmr (CDCl3, 270 MHz): delta 3.80 (3H,s), 3.90 (3H,s), 6.20 (1H,s), 6.80-7.00 (2H,m), 7.10-7.30 (2H,m), 7.60 (1H,s)ppm.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].[C:20]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].O>O1CCCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH:2]([O:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:31][CH:30]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:16][CH:15]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(COC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.25 g of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole and 0.26 g of sodium hydride (50% dispersion in mineral oil) in 20 ml of tetrahydrofuran was stirred under nitrogen at room temperature for one hour, and at 60° C. for one hour. The mixture was then cooled to 0° C. and treated dropwise with stirring with 4-acetylaminobenzyl chloride in 10 ml tetrahydrofuran, keeping the temperature below 10° C. After stirring for one hour, the mixture was heated to 60° C. for 2 hours and poured into water. The product was extracted with ethyl acetate and the extracts dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-acetylaminobenzyloxy)-n-butyl]imidazole.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]2[C:5]1=[N:6][C@@H:7]1[CH2:16][CH2:15][CH2:14][C@@H:8]12.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>C1COCC1>[CH3:3][N:4]1[C:12](=[O:13])[C:11]2=[CH:26][NH:27][CH:28]=[C:10]2[N:9]2[C@H:8]3[CH2:14][CH2:15][CH2:16][C@H:7]3[N:6]=[C:5]12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C(=O)C=CN2C1=N[C@@H]1CCC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c[nH]cc2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Sodium hydride (95%, 112 mg, 4.44 mmol) is suspended in 3 mL of anhydrous THF, and then a mixture of (3aS,8aR)-7-Methyl-1,2,3,3a,7,8a-hexahydro-3b,7,8-triaza-cyclopenta[a]inden-6-one (283 mg, 1.48 mmol) and p-toluenesulfonylmethyl isocyanide (97%, 347 mg, 1.77 mmol) in 5 mL of anhydrous THF is added dropwise. The mixture is stirred at room temperature for an hour, and then quenched with water. The mixture is extracted with CH2Cl2 (5×10 mL). The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure to give crude product (320 mg, yield 94%) as brown solids, which is used for the next reaction without further purification. MS (ESI) m/z 231.1 [M+H]+.
Reaction SMILES: ClC(OC=C)=O.[CH3:7][S:8]([N:11]([CH2:23][CH2:24][Cl:25])[N:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]([O:15][CH2:16][CH2:17]Cl)=[O:14])(=[O:10])=[O:9]>>[CH3:7][S:8]([N:11]([CH2:23][CH2:24][Cl:25])[N:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]([O:15][CH:16]=[CH2:17])=[O:14])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)OCCCl)S(C)(=O)=O
Agent: C=COC(=O)Cl
Product: C=COC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(vinyloxycarbonyl)hydrazine (compound 10c) was prepared by reacting compound 2 with vinyl chloroformate using a procedure similar to that described for compound 10b. The product was recrystallized from ethanol, and the yield was about 39.4% by weight. The Mp of the product was approximately 85-86° C. 1H NMR (CDCl3): δ 7.0-7.3 (1H, m, CH=C), 4.8-5.3 (2H, m, C=CH2), 3.6-4.2 (4H, m, CH2CH2Cl), 3.5 and 3.2 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>O1CCOCC1>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Reactant: COc1cccc(C(=O)Cl)c1OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 79 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 30 minutes and then at 50° C. for 30 minutes. The reaction liquid is cooled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is allowed to stand overnight at room temperature whereby a part of the substance is crystallized. A small amount of ethanol is added to crystallize the substance wholly and the crystals are collected by filtration whereby 2.3 g (yield: 79.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained. M.P. 84.5°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[CH2:11]=[O:12]>>[OH:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Br:8])=[C:5]([Cl:9])[C:4]=1[CH2:11][OH:12]
Reactant: C=O
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Product: OCc1c(O)c(Cl)cc(Br)c1Cl

Procedure:
2,5-Dichloro-4-bromo-phenol was hydroxymethylated in alkaline aqueous solution with excess formalin at 40°C, using a procedure analogous to that described in U.S. Pat. No. 2,631,169 to produce 2-hydroxy-3,6-dichloro-5-bromo-benzyl alcohol.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:30])[CH2:32][CH2:33][OH:34])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CNCCO
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 44 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylethanolamine to give the title compound in 44% yield; NMR Spectrum: 2.30 (s, 3H), 2.52-2.55 (m, 2H), 2.88 (t, 2H), 3.47-3.50 (m, 2H), 4.39 (t, 2H), 5.28 (s, 2H), 7.25 (d, 1H), 7.35-7.38 (m, 1H), 7.55-7.58 (m, 2H), 7.87 (t, 1H), 7.93 (d, 1H), 8.29 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 470 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13](=[O:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C@H:13]([OH:19])[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC(C)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-isopropyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 35, 0.667 g, 1.74 mmol) following the procedure described for Intermediate 8. The desired product was obtained as a colorless oil (0.464 g, 69%).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[C:7](Cl)=[C:6]([Cl:18])[CH:5]=[C:4]([Cl:19])[C:3]1=2.[C:20]1([CH:27]=[CH:26][CH:25]=[C:23](O)[CH:22]=1)[OH:21].C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O.O1CCCC1.C1(C)C=CC=CC=1>[Cl:18][C:6]1[CH:5]=[C:4]([Cl:19])[C:3]2[N:2]([CH3:1])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[C:8]=2[C:7]=1[C:23]1[CH:25]=[CH:26][CH:27]=[C:20]([OH:21])[CH:22]=1
Reactant: Oc1cccc(O)c1
Reactant: Cn1c2ccccc2c(=O)c2c(Cl)c(Cl)cc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c2ccccc2c(=O)c2c(-c3cccc(O)c3)c(Cl)cc(Cl)c21

Procedure:
8 g (25.6 mmol) of N-methyl-1,2,4-trichloroacridone, 8.46 g (76.8 mmol) of resorcinol, 14.15 g (102.4 mmol) of potassium carbonate and 80 ml of NMP are stirred at 60° C. for 30 hours. The mixture is discharged into water/tetrahydrofuran/toluene. The organic phase is washed with water, dried over sodium sulfate, filtered through silica gel and evaporated. The residue is chromatographed on silica gel using methylene chloride. The fractions containing the product are evaporated, and the residue is recrystallized from 0-dichlorobbenzene: Yield 5.45 g (55%), melting point 220°-222° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:38])[C@@H:6]([NH:25][C:26](=[O:37])[C:27]1[C:32]([F:33])=[CH:31][C:30]([C:34]#[N:35])=[CH:29][C:28]=1[F:36])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3]>C(O)CC>[CH2:1]([O:4][C:5](=[O:38])[C@@H:6]([NH:25][C:26](=[O:37])[C:27]1[C:28]([F:36])=[CH:29][C:30]([CH2:34][NH:35][CH2:34][C:30]2[CH:29]=[C:28]([F:36])[C:27]([C:26](=[O:37])[NH:25][C@H:6]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:38])[CH2:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]4[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=4[CH3:20])=[CH:12][CH:13]=3)=[C:32]([F:33])[CH:31]=2)=[CH:31][C:32]=1[F:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(C#N)cc1F
Solvent: CCCO
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CNCc2cc(F)c(C(=O)N[C@@H](Cc3ccc(-c4c(C)n(C)c(=O)n(C)c4=O)cc3)C(=O)OCCC)c(F)c2)cc1F
Yield: 39.2 %

Procedure:
To a 100 mL flask containing (S)-2-(4-cyano-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)phenyl]propionic acid propyl ester (524 mg, 1.0 mmol) dissolved in n-propanol (20 mL) purged with nitrogen was added palladium on carbon (10%, 106 mg). The reaction was sealed, degassed with three exposures to nitrogen and house vacuum, and then exposed to a balloon of hydrogen overnight. The reaction was diluted with EA, degassed again, and exposed to hydrogen overnight. The reaction was filtered through celite, concentrated and purified by HPLC yielding the title compound (204 mg, 19%). ES(+)-LRMS m/e calcd. for C54H57F4N7O10 (M+H)+ 1041, obsd 1041.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C.CN(C=O)C>[CH2:19]([N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Compound 17 (2.12 g, 10 mmol) was mixed with DMF (50 ml). After stirring the mixture at room temperature for 30 minutes, NaH (1.6 g, 40 mmol) was added and stirred until the solution became clear. After that, benzyl bromide (5 ml) was added. The mixture was stirred and reacted at room temperature for 1 h. The reaction mixture was poured into cold water (200 ml) and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with water and brine, then the organic phase was evaporated in reduced pressure, the residue was dissolved in anhydrous ethanol, and then the mixture was adjusted to pH 4 with concentrated HCl, and evaporated and recrystallized with acetone/ethyl ether, light yellow solids were obtained. The light yellow solids were dissolved in a mixed solution of water and ethyl acetate. The pH was adjusted to 8 with saturated NaHCO3 solution. The organic phases were isolated. The aqueous layer was extracted with ethyl acetate. After drying, decolorization with activated carbon, filtration, concentration, and recrystallization with ethyl ether, white solids (2.3 g, 57%) were obtained, mp 169-170° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC=CC=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (8.6 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-5-(pyrimidin-2-yl)benzoate (1.4 g) in dioxane (10 mL) and methanol (5 mL), followed by stirring at room temperature for 4 hours. Toluene was added to the reaction mixture, and the aqueous layer was separated. After adjusting the pH to 1 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.65 g of 2-(benzyloxy)-5-(pyrimidin-2-yl)benzoic acid as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH3:24][N:21]1[CH2:20][CH2:19][CH:18]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=3)[NH:14][CH:13]=2)[CH2:23][CH2:22]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Yield: 51.1 %

Procedure:
A mixture of 5-benzyloxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (16.4 g, 51.5 mmol) and 5% palladium on carbon (4.0 g) in ethanol (125 mL) and tetrahydrofuran (125 mL) was hydrogenated with an initial hydrogen pressure of 60 psi (413 kPa) at ambient temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol and THF to give 6.06 g (51%) of the title compound as white crystals: mp=234-237° C.; MS(m/e): 230 (M+); Calculated for C14H18N2O: Calcd: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.79; H, 8.17; N, 12.33.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:39]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and N,N-dibenzylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:36])([F:34])([F:35])([F:37])[F:38])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 73 mg (0.276 mmol) of the compound of Example 34A gave 101 mg (61% of theory, 90% pure) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[NH:26][CH:27]=[N:28][C:29]=2[CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3[nH]cnc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.80 minutes; C23H20Cl2N6O2 (483.36); mass spectrum: (M−H)−=482/484/486 (chlorine isotope).