Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])=[CH:16][C:15]=2[O:14]1.[OH-].[K+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:22]([C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:13][O:14][C:15]=3[CH:16]=2)[CH2:23][C:24](=[O:26])[CH:25]=1
Reactant: CC(=O)C=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)CC(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl malonate (17.34 g) was added to a solution of sodium metal (2.35 g) in anhydrous absolute ethanol (40 ml). 1-(3,4-methylenedioxyphenyl)-but-1-en-3-one (20 g) was added to the solution and the volume of ethanol was made up to 80 ml. The mixture was heated under reflux with stirring for 2-4 hr. An aqueous solution of potassium hydroxide (25.0 g in 120 ml of water) was added and the mixture was heated under reflux for a further 6 hours. Subsequently, the ethanol was distilled off and the aqueous residue was acidified with dilute hydrochloric acid. After cooling to room temperature, the mixture was extracted with ethyl acetate and the organic phase was washed consecutively with water and an aqueous 10% sodium hydroxide solution. The basic extract was acidified with dilute aqueous hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 3-hydroxy-5-(3,4-methylenedioxyphenyl)cyclohex-2-en-1-one as a crystalline solid, mp 181° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[S:7][CH:6]=1)=[O:4].O.C(OC([N:27]1[C:31]([CH3:32])=[CH:30][C:29](I)=[N:28]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:29]2[CH:30]=[C:31]([CH3:32])[NH:27][N:28]=2)[S:7][CH:6]=1)=[O:4]
Reactant: Cc1cc(I)nn1C(=O)OC(C)(C)C
Reactant: COC(=O)c1csc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1csc(-c2cc(C)[nH]n2)c1
Temperature: 140 °C

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-3-carboxylic acid methyl ester (0.10 g, 0.37 mmol) was dissolved in DME (3 mL), IMS 1 mL) and water (0.5 mL) and 3-iodo-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.125 g, 0.41 mmol) was added followed by caesium carbonate (0.18 g, 0.56 mmol). The mixture was degassed and purged with nitrogen then palladium tetrakis(triphenylphosphine) (0.043 g, 0.04 mmol) was added. The reaction mixture was purged with nitrogen then heated by microwave irradiation to 140° C. for 20 minutes. The mixture was diluted with water then extracted with DCM (×3) then the organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a 5 g silica II cartridge, eluting with 10-33% ethyl acetate in cyclohexane to give the title compound as a tan semi-solid material (0.052 g). LCMS m/z 223.02 [M+H]+ R.T.=2.93 min (Analytical Method 6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Fc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (15.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.3 mg). Calcd for C21H19FN2O2: 350.1431, found 350.1438.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31]([C:35]1[O:39][N:38]=[C:37]([NH2:40])[CH:36]=1)([CH3:34])([CH3:33])[CH3:32].C1CCN2C(=NCCC2)CC1>C1COCC1.CN1C(=O)CCC1>[C:31]([C:35]1[O:39][N:38]=[C:37]([NH:40][C:16]([C:14]2[CH:13]=[CH:12][C:10]3[CH:11]=[C:3]4[C:2](=[O:1])[NH:8][CH2:7][CH2:6][CH2:5][N:4]4[C:9]=3[N:15]=2)=[O:18])[CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a solution of 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 35 mg, 0.14 mmol) in THF (2 mL) and NMP (0.5 mL) is added 1,1′-carbonyldiimidazole (58 mg, 0.36 mmol). The mixture is stirred at 60° C. for 1 h and is then cooled to room temperature. 5-tert-Butyl-3-aminoisoxazole (80 mg, 0.57 mmol) and DBU (53 μL, 0.36 mmol) are added and the mixture is stirred at 60° C. for 16 h. The mixture is cooled to room temperature and the THF is removed in vacuo. The residue is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/H2O with 0.1% TFA to afford the title compound (6 mg, 11%). LCMS: 368.20 (M+H+). (System V-med polar)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:28][NH2:29]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH2:28][C:27]([F:34])([F:26])[C:30]([F:33])([F:32])[F:31])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: NCC(F)(F)C(F)(F)F
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NCC(F)(F)C(F)(F)F)cn1
Yield: 75 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.292 mmol) was converted, using 2,2,3,3,3-pentafluoropropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (100 mg, 75%) which was obtained as a white solid. MS: m/e=460.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:33]>>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([OH:33])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(O)cc32)c(F)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a 5% aqueous solution (3 ml) of sodium hydroxide, and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with a 3% aqueous solution of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (49 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl

Procedure:
To 2-methyl-3,4,6-trifluorobenzoic acid (3.2 g) is added thionyl chloride (7 ml) and the mixture is refluxed for 1 hour. After concentrating, 2-methyl-3,4,6-trifluorobenzoyl chloride (3.3 g) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1C
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1C

Procedure:
6-Chloro-N-(3,4-dimethyl-phenyl)-nicotinamide was prepared from 3,4-dimethyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2OCl [M+H]+: 261.0789. Found: 261.0788
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1
Yield: 90.9 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.17 g (91%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 188°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[CH3:9]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccccc1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(-c2ccc(N3CCN(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.324 mmol) in dmf (0.025 mL, 0.32 mmol) was added 1-methylpiperazine (0.036 g, 0.356 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 80° C. and stirring continued for 19 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc, dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=389.1 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10](C2CCC(CC(OCC)=O)CC2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C([CH:66]2[CH2:71][CH2:70][CH2:69][CH:68]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:67]2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:47][Si:2]([CH3:1])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:70]2[CH2:71][CH2:66][CH2:67][CH:68]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:69]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)[CH:15]=[CH:14][N:13]=[CH:12]1>[OH-].[K+].CCO>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[C:24](=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:23][CH2:22]3)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: CSc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Methylthio)benzaldehyde (0.114 g, 0.75 mmol) was added to a stirring solution of (1) (0.25 g, 0.98 mmol) in 2 mL 4% KOH in EtOH (wt/vol). The reaction stirred at room temperature for 2 hours and the resulting precipitate was collected and washed well with water and then cold iPrOH. The solid was dried in vacuo at 40° C. for 3 hours affording the title compound, 0.277 g (95%) as an off-white solid, mp 161-161.5° C.; CI-MS m/e 390 (M+), 391 (M++1);
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[H-].[Na+].C(OC([N:38]([CH2:51][CH3:52])[C:39](=[N:43]C(OC(C)(C)C)=O)SCC)=O)(C)(C)C.CC(OC(=O)N)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.ClCCl>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([NH:1][C:39]([NH2:43])=[N:38][CH2:51][CH3:52])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CCSC(=NC(=O)OC(C)(C)C)N(CC)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(N)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCN=C(N)Nc1nc2nc(NCCCN(CC)CC)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a solution of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (42 mg) from Example 20 in DMF (1 mL) was added 60% sodium hydride suspension (5 mg), and the mixture was stirred at room temperature for 0.5 hour. To the reaction mixture was added N,N'-Bis(tert-butoxy-carbonyl)-N-(ethyl)-S-(ethyl)isothiourea (37 mg), and the mixture was stirred for 18 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×15 mL). The organic layer was dried with sodium sulfate and concentrated. The resulting oil was purified on silica gel, eluting with methanol:ethyl acetate:triethylamine (8.5:1.5:0.3) to afford a mixture of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (40 mg) and [[[6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]imino[[1,1-dimethylethoxy)carbonyl]amino]methyl]-ethylamino]carbamic acid-1,1-dimethylethyl ester. This mixture was dissolved in anhydrous dichloromethane (0.5 mL) containing 2.6-lutidine (8 mg). Trimethyl-silyl trifluoromethanesulfonate (6 mg) was added, and the mixture was stirred at room temperature for 30 hours. The mixture was poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate, and concentrated. The resulting oil was chromatographed on silica gel, eluting with methanol:ethyl acetate: triethylamine (8.5:1.5:0.3) to afford the title compound (7 mg), ESMS (1/4 MeOH/CH3CN+0.1% AcOH): m/z (relative intensity) 490.5 (MH+, 100), 491.5 (MH+ +1, 27), 492.5 (MH+ +2, 64).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[C:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17]3)[C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3cccc(CO)c3)cc2)CC(C)(C)C1
Temperature: 160 °C
Yield: 65.6 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.20 g, 0.50 mmol), 3-(hydroxymethyl)phenyl boronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 minutes. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 30% EtOAc in hexanes to give 0.14 g (66%) of the title compound (247) as pale yellow solid. mp 197-198° C. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 12H), 1.25 (s, 2H), 1.93 (s, 4H), 4.52 (d, J=5.9 Hz, 2H), 5.20 (t, J=5.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.52-7.58 (m, 3H), 9.27 (s, 1H). LCMS (ESI): m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13]C3C=CC(OC)=CC=3)[C:11](=[O:22])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.CO[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[NH4+]>[C:31]([C@H:10]1[CH2:9][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:2][CH:3]=2)[N:12]([CH2:13][N:12]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:11]1=[O:22])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccccc1
Reactant: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Reaction time: 8 h

Procedure:
Under N2, the mixture of (S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (3a, R1=pyrrolidinylmethyl) (6.68 g, 20 mmol) and benzoic acid methyl ester (3.0 g, 22 mmol) in 20 mL toluene is heated to reflux, sodium hydride (55% in mineral oil, 1.14 g, 26 mmol) is added, and stirred overnight at reflux. The reaction mixture is diluted with 20 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. the organic phase is concentrated to dryness, the residue was purified by column chromatography (ethyl acetate/heptane=1/1) to give (R/S)-3-Benzoyl-(R)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethyl-pyrrolidin-2-one (4a, R1=pyrrolidinylmethyl, R4=phenyl), the ratio of (3S,5R) and (3R,5R) is 60:40 as determined by HPLC. 1HNMR (400 MHz, CDCl3): 1.68 (m, 4H, 2×CH2CH2), 1.98 (m, 1H, 3-CHH), 2.23 (m, 1H, 3-CHH), 2.51 (m, 4H, 2×NCH2), 2.65 (dd, 1H, N—CHH), 3.15 (dd, 1H, N—CHH), 2.67 (d, 1H, 5-CHH), 2.92 (d, 1H, 5-CHH), 3.73 (m, 1H, 2-CH), 3.78 (m, 1H, 4-CH), 7.20-8.00 (14H, m, aromatic).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][C:4]1[N:5]=[C:6]([CH:15]([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[N:7](S(N(C)C)(=O)=O)[CH:8]=1.[OH-].[Na+]>Cl.C1COCC1>[CH3:1][C:2]([CH3:31])([CH3:32])[CH2:3][C:4]1[N:5]=[C:6]([CH:15]([CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[NH:7][CH:8]=1
Reactant: CC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)c[nH]1

Procedure:
A solution of 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide in 1.5 N hydrochloric acid (1 mL) and THF (1 mL) was heated at 70° C. in a sealed tube overnight. The reaction mixture was basified with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification of the resulting crude product by silica preparatory plate chromatography eluting with 10% methanol/ethyl acetate afforded the title compound. LCMS: (M+H) found 352.