Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22].C.Cl>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21
Yield: 50 %

Procedure:
Prepared analogously to Example 2 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 50% of theory. Colourless crystals, m.p. 169°-170° C. (from acetonitrile, using activated charcoal); [α]D20 =+11.88° (dilute hydrochloric acid).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CCN(CC)CC.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.CCOC(C)=O>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][S:40]([C:37]5[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=5)(=[O:42])=[O:41])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(OS(=O)(=O)c5ccc(C)cc5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 100 mg of 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purin-2,6-dione (Example 13a) (0.28 mmol) in CH2Cl2 (10 ml) was added 40 μL of Et3N and the reaction mixture cooled in an ice bath. To this was added 100 mg of p-toluenesulfonyl chloride (0.52 mmol) and the reaction kept at 10° C. overnight. The reaction mixture was conc'd in vacuo and the residue taken up in EtOAc and washed 2× with dilute HCl (10 ml). The organic layer was dried over NaSO4 and conc'd. The residue was triturated in acetonitrile to afford 78 mg (54%) of pure white solid (MH+=515.10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:10])=[O:9].[F:27][C:28]([F:42])([F:41])[C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:9])=[O:10]
Reactant: O=C(O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 1, step 5, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 70, step 4) was coupled with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give the title compound as a colorless solid. MS: 628.3 ([M+H]+)
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])=[CH:25][CH:26]=1
Reactant: CCOP(=O)(COc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(COc1ccc(CCN)cc1)OCC

Procedure:
4-(2-t-Butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, diethyl ester (2.856 g, 9.95 mMol) in methylene chloride (300 ml) and trifluoracetic acid (16 ml) was stirred at room temperature for 5 h. The solution was concentrated under reduced pressure and product dried under in vacuo. The trifluoacetic acid salt was neutralized with aqueous sodium carbonate and extracted with dichloromethane containing a small proportion of methanol (5×100 ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give the title compound as a pale yellow gum.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]([C:18](=[O:36])[N:19]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH3:20])=[CH:7][N:6]=1)=[O:4].CO.O1CCOCC1.[OH-].[Na+]>O>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[CH2:21][N:19]([CH3:20])[C:18]([C:8]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)=[O:36]
Reactant: COC(=O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1cc(C(=O)O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.1 %

Procedure:
A mixture of 0.50 g (0.98 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester (Example 6), 10 ml methanol, 10 ml dioxane and 10 ml 1N aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with tert-butyl methyl ether. The aqueous layer was acidified to pH 2 with 1 M aqueous hydrochloric acid solution and extracted with four portions of dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate and concentrated to give 0.38 g (78%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C:5]1=[O:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH:1][CH2:2][CH2:3][C@@H:4]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C:5]1=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)OC(=O)[C@H](CCO)O1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: -4 °C

Procedure:
Dried (S)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one (9.0 g, 59.2 mmol) was dissolved in 100 mL of anhydrous pyridine under argon and cooled to -4° C. To this solution maintained at approximately 0° C. was added dropwise 11.3 g (59.22 mmol) of p-toluenesulfonyl chloride dissolved in 100 mL of pyridine. Following addition, the mixture was placed in the refrigerator (0°-4° C.) overnight. Water (150 mL) was added, and the aqueous mixture extracted with 4×200 mL of ether. The ether layers were combined, washed with 3 ×150 mL of water, 3×150 mL of saturated copper sulfate solution (until no dark blue color remained), 2×100 mL of water, 3×150 mL of brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude tosylate was purified by column chromatography using ethyl acetate:hexanes (1:1) to provide the title compound, 16.7 g (95%) as white solid: mp 48°-49° C.; α!D25 -3.7° (c=0.3, CH3OH); IR (KBr, cm-1) 2989, 1785, 1390, 1357, 1278 1H NMR (CDCl3) δ 7.80 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 4.43 (dd, J=4.4, 8.1 Hz, 1H), 4.27-4.14 (m, 2H), 2.46 (s, 3H), 2.3-2.17 (m, 1H), 2.09-1.92 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H); HRMS calculated for C14H18O6S (M+), 314.0824, found 314.0817.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:12]=2[C:13]=1[CH3:14]>N1C=CC=CC=1>[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(N)cc12
Solvent: c1ccncc1
Product: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(NS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methanesulphonyl chloride (0.21 g, 1.85 mmole) was added dropwise to a solution of N-methyl-N-(3-methyl-5-aminobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine (see Preparation 10B - 0.78 g, 1.68 mmole) in pyridine (7 ml) and the solution was then stirred at room temperature for 60 hours. The solvent was evaporated and the residue triturated with toluene. The toluene was decanted, the residue stirred with aqueous sodium bicarbonate, and the precipitate collected by filtration and recrystallised from methanol to give the title compound, yield 0.38 g, m.p. 142°-143.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:24])[S:12][C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])=[N:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([O-:47])(=[O:46])C.[K+].[C]=O>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([NH:13][C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:44]([O:47][CH3:25])=[O:46])=[CH:3][CH:4]=3)([CH3:24])[C:9](=[O:23])[N:10]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(=O)[O-]
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(Br)cc2)S1)c1ccc(F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: [C]=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C2(C)SC(N[C@@H](C)c3ccc(F)cc3)=NC2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-(4-bromophenyl)-2-((S)-1-(4fluorophenyl)ethylamino)-5-methylthiazol-4(5H)-one (0.79 g, 1.9 mmol), triphenylphosphine (Aldrich, 0.15 g, 0.58 mmol), palladium acetate (Aldrich, 0.11 g, 0.48 mmol), potassium acetate (Aldrich, 0.24 g, 2.4 mmol), in MeOH (3 mL) and DMF (3 mL) was pressurized with carbon monoxide, purged twice with CO and then heated to 100° C. overnight at 40-50 psi of CO. After the reaction mixture was cooled to ambient temp., then contents were filtered through Celite. The Celite pad was washed with CH2Cl2, and the organic phase was dried over Na2SO4, concentrated in vacuo. The crude material was purified using silica gel chromatography. MS: 387 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH2:7][C:6]2=[O:14])#N.C(C1C=C2C(=CC=1)N=C(C)C=C2[OH:28])#N.C(=O)(O)[O-].[Na+]>[Ni].C(O)=O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH2:7][C:6]2=[O:14])=[O:28]
Reactant: Cc1cc(O)c2cc(C#N)ccc2n1
Reactant: CC1=Nc2ccc(C#N)cc2C(=O)C1
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CC1=Nc2ccc(C=O)cc2C(=O)C1

Procedure:
A mixture of 6-cyano-2methyl-4-quinolone (9.2 g, Chem. Abs., 51, 11347h; known therein as 6-cyano-4-hydroxyquinaldine), Raney nickel (10 g) and 75% formic acid (150 ml ) was heated at reflux for 3 hours. The mixture was cooled, neutralised with a saturated aqueous solution of sodium bicarbonate and filtered. The solid residue was washed with warm methanol (3×50 ml). The combined filtrates were extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (100 ml), dried over sodium sulphate and evaporated to give 6-formyl-2-methyl-4-quinolone as a fawn coloured solid (9.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15](O)[CH:16]=[CH2:17].S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH:16]=[CH2:15])=[O:7])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CCO
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
Into a round bottom flask, there are introduced 9.71 g (50 mmoles) of 4-hydroxy-3-tert.butyl benzoic acid and 55 ml of allyl alcohol. 1.3 ml of concentrated sulfuric acid are added and the mixture in heated at 100° C. for 18 hours. The reaction mixture is then evaporated to dryness and 200 ml of water are added. The mixture is then neutralized with sodium bicarbonate and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column by eluting with dichloromethane. After evaporation of the solvents, 9.78 g (83% yield) of the expected ester whose melting point is 131°-132° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:24]3[O:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cccc2c1OCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.396 g (2.24 mmol) 6-chloropyrimidin-4-carboxylic acid chloride and 0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM were stirred for 20 min at RT. Then 0.300 g (2.24 mmol) 7-methyl-2,3-dihydro-benzofuran in DCM were added dropwise to the reaction mixture and this was stirred for 1.5 h at RT. After the addition of water and DCM to the reaction mixture the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, dried on sodium sulphate, filtered and evaporated down i.vac.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:31]([CH:33]=O)C>>[NH:31]([C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=2)=[CH:7][CH:6]=1)[C:33]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccccc3)cc2)ccn1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)propanoic acid (10.7 g, 64.5 mmol), 4-chloro-N-methylpicolinamide (10.0 g, 58.6 mmol) and cesium carbonate (57.3 g, 175.8 mmol) was stirred in DMF and heated at 100° C. overnight. After cooling to rt, the mixture was filtered and washed with EtOAc to remove cesium carbonate. The remaining solid was dissolved in a minimal amount of water and the pH of the solution was adjusted to 4 by the dropwise addition of a sat. oxalic acid solution. The solution was extracted with DCM, the organic solutions washed with water and brine, dried over MgSO4, filtered, and concentrated. The resulting solid was recrystallized from EtOAc to give the desired product as a pale cream solid (5.07 g, 37%). 1H NMR (400 MHz, d6-DMSO) δ: 12.13 (s, 1H), 8.70-8.78 (m, 1H), 8.49 (d, J=5.6 Hz, 1H), 7.34-7.39 (m, 3H), 7.11-7.14 (m, 3H), 2.87 (br t, J=7.6 Hz, 2H), 2.77 (d, J=4.8 Hz, 3H), and 2.57 (br t, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>C1COCC1.O>[CH2:1]([N:8]([CH2:21][C:22](=[O:24])[CH3:23])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(C)=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-(benzylamino)acetate (40 g, 207 mmol) and NaHCO3 (20.9 g, 248 mmol) in THF (400 mL) and water (30 mL) was heated to 50° C. 1-chloropropan-2-one (23.9 g, 259 mmol) was added and the reaction was stirred at 50° C. for 2 d. Water was added the solution extracted with hexanes. The organic layer was separated, dried, filtered, and concentrated to afford crude ethyl 2-(benzyl(2-oxopropyl)amino)acetate (118) which without further purification
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:12].CO>>[NH2:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCC2CO2)cc1
Reactant: N
Solvent: CO
Product: NCC(O)CCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-(2-phenylethyl)oxirane (8.0 g, 54 mmol) was placed in a sealed tube with 7N NH3-MeOH (130 mL) and stirred 2 hours at 70° C. followed by concentration to a clear oil (and was used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12](Cl)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH3:25])[C:21]([OH:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=1[CH3:25])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Yield: 78.8 %

Procedure:
25.1 g of diethyl-2-chloro-propionyl-malonate and 14.2 g of 4-chloro-o-cresol are dissolved in 100 ml dimethyl formamide. The mixture is stirred at 60° C. for 48 hours in the presence of 13.8 g of potassium carbonate. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed successively with 100 ml of a saturated aqueous sodium bicarbonate solution and 100 ml of water. The benzene phase is evaporated to yield 28 g of the desired compound, yield 80%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[O:29]=[C:30](C)[CH2:31][CH2:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:30](=[O:29])[CH2:31][CH2:32][CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)CCCc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)CCCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), 4-(4-oxo-pentyl)-benzoic acid (58.3 mg, 0.30 mmol), HATU (114.0 mg, 0.30 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-4-oxo-butyl}-benzoic acid (28.9 mg, 48.2%). HRMS (ES+) m/z Calcd for C33H30Cl2F2N2O3+H [(M+H): 599.1675; Found: 599.1674.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH2:10]([Br:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>S1(CCCC1)(=O)=O.O>[Br-:17].[CH2:10]([N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH:8]=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccnc(C=O)c1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Cc1cc[n+](Cc2ccccc2)c(C=O)c1
Product: [Br-]

Procedure:
A mixture of 1 g (8.26 mmol) of 4-methylpyridine-2-carboxaldehyde, and 1.41 g (8.3 mmol) of benzyl bromide in 10 mL of sulfolane was stirred and heated on a steam-bath overnight. The resulting mixture was triturated (repeatedly) with ethyl acetate and the solvent was decanted to isolate a dark gum. This residue was dissolved in water, and washed with ether, and the aqueous solution was concentrated in vacuo to afford 1-benzyl-4-methyl-2-formyl-pyridinium bromide, which was used without additional purification.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH2:28]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:38])[CH2:33][CH2:32]1)[C:29]#[CH:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([CH2:28][C:29]#[C:30][C@@:9]2([N:8]3[C:18]4[N:19]=[CH:2][N:3]=[C:4]([NH2:20])[C:5]=4[N:6]=[CH:7]3)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35]1)=[O:38]
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1ncn2[C@]1(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoadenosine (0.602 g, 1.531 mmol) in freshly degassed DMF (20 mL) was added degassed triethylamine (1.20 mL, 8.54 mmol), Pd(PPh3)4 (85 mg, 0.074 mmol), CuI (catalytic), and 2-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.588 g, 2.117 mmol). The mixture was stirred at room temperature under and inert atmosphere for 20 h. Silica bound Pd(II) scavenger Si-thiol (400 mg) and Pd(0) scavenger Si-TAAcOH (619 mg) were added and stirring continued a further 72 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-4%) to afford the pure product as a white solid: yield 0.733 g, 88%.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>ClCCl.CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[C:26]([N:30]=[C:1]=[S:2])[N:27]=[CH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2cccc(Cl)c2)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C=Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 60 °C

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.486 g, 2.091 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(3-chlorophenyl)pyrimidin-4-amine (0.43 g, 2.091 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484 mmol, 23% yield) as an orange oil. LCMS R.T.=2.15; [M]+=248.31.