Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Hydrogenation and acetylation of (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester (25 g, 0.095 mol) in the presence of 5% Pd—C (2.5 g, 50% wet) and acetic anhydride (38 g, 0.37 mol) in toluene (200 mL) was carried out under vigorous stirring at room temperature and atmospheric pressure for about 4-5 h (reaction monitored by TLC). The catalyst was removed by filtration and washed with toluene two times. The combined organics were evaporated in vacuo to yield the product (24.8 g, 95%), which was used without further purification in the next step. A small sample was crystallized from hexane to yield the product as a yellow solid, mp 92-94° C. 1H NMR (CDCl3) 8.86 (s, 1H), 8.21 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[OH-:10].[Na+].[CH2:12]=O>>[OH:10][CH2:12][C:3]1[C:4]([OH:9])=[N:5][C:6]([OH:8])=[N:7][C:2]=1[CH3:1]
Reactant: C=O
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1nc(O)nc(O)c1CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask containing 6-methyl-1H-pyrimidine-2,4-dione (10 g, 79.3 mmol) is added NaOH (1.25 N, 95 mL) and the solution is allowed to stir for 10 min at room temperature. Formaldehyde (37%, 19.60 mL) is added dropwise over 30 min. After 30 min, a thick white precipitate forms and the reaction is allowed to proceed for 150 min. The suspension is then filtered and the filter cake is transferred to an Erlenmeyer flask to which EtOH (absolute, 200 mL) is added. The resulting suspension of white solid is stirred for 30 min. The white solid is collected by filtration, washed with EtOH (50 mL), Et2O (100 mL) and vacuum dried to provide the title compound as a white solid. [MS mass expected (156.14); mass found (156.02)].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:15][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:10]=3[C:9]2=[O:29])=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.O.[Cu]I>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:10]3[C:9](=[O:29])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:43]5[CH2:44][CH2:45][NH:40][CH2:41][C:42]5=[O:46])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:15]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(N4CCNCC4=O)cc2)CC3)cc1
Temperature: 130 °C
Yield: 35.3 %

Procedure:
To 6-(4-iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo(3,4-c)pyridin-7-one (0.55 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.35 g, 1.4 mmol), and K2CO3 (0.23 g, 1.6 mmol) was added DMSO (5 mL). The mixture was degassed with N2. CuI (39 mg, 0.21 mmol) was added and the reaction was heated to 130° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, and dried (MgSO4). Purification of the intermediate by chromatography on silica gel using 5% MeOH/CH2Cl2 was followed by deprotection in refluxing TFA. Purification by HPLC and freeze-drying afforded 175 mg (27%) of a white solid; High Resolution Mass Spec (M+H)+ for C24H26N6O5S 496.1650.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:30]2[CH2:31][CH2:32][CH:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: OCCC1CCNCC1
Product: CN1C(=O)c2ccccc2C1C(CCN1CCC(CCO)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 64.3 %

Procedure:
3-(3,4-dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.387g) was coupled to 4-(2-hydroxy-ethyl)piperidine (0.13g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.178 g); mp 119-125° C. (d); MS: m/z=461(M+1); NMR(CDCl3): 2.5-2.4(m,15), 3.1 (s,3), 3.56 (broad,2), 3.7 (broad,2), 4.7 (s,1), 6.6 (d,1, J=7.5), 6.8 (s,1), 7.13 (d,1, J=8), 7.4-7.7 (m,4). Analysis for C25H30Cl2N2O2.HCl: Calculated: C, 56.19; H, 6.03; N, 5.24; Found: C, 56.01; H, 5.77; N, 5.06.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1CCCC1>O>[CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]([OH:36])=[O:30])[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(CCOC(c2ccccc2)c2ccccc2)CC1
Reactant: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)NCCN1CCN(CCOC(c2ccccc2)c2ccccc2)CC1

Procedure:
20 g of 1-[2-(benzhydryloxy)ethyl]-4-[2-(phthalimido)ethyl]piperazine and 200 ml of tetrahydrofuran were placed in a reactor. A solution of 20.4 g of Na2S.9H2O in 80 ml of water was added dropwise at 0° C. After decantation, the solvents were evaporated off. The solid was taken up in 50 ml of water and 100 ml of methylene chloride. After the solution had cooled, the pH was adjusted to 3.7 and extraction was carried out with 2 times 50 ml of methylene chloride. After drying, the solvents were evaporated off to give 17 g of a solid (m.p.=45° C.) of the empirical formula: C29H33N3O4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[CH:17]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:16][CH:11]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:17][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: COc1ccc(N)c(CC(O)C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNc2ccc(OC)cc2CC(O)C(C)(C)C)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 1-(2-amino-5-methoxyphenyl)-3,3-dimethylbutan-2-ol (155 mg) and methyl 3-formylbenzoate (137 mg) in acetic acid (2 mL) was added sodium triacetoxyborohydride (294 mg) at room temperature, and the mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (205 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cccc(-c3ccccc3)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1Cc2cccc(-c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 0.30 g (0.0014 mole) of 4-phenyl-2-indanone in 10 ml of ethanol was added portionwise 0.03 g (0.0008 mole) of sodium borohydride. The resulting yellow colored solution was stirred at ambient temperature for 1.5 hours, then concentrated, and 50 ml of water was added. The mixture was extracted with two portions of 50 ml each of diethyl ether. The extracts were combined, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give, after recrystallization from hexane, 0.13 g of 4-phenyl-2-indanol. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(C1C=C(C)C=C(C)C=1O)(C)(C)C.[C:39]([O-:44])(=[O:43])[C:40]([CH3:42])=[CH2:41].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH2:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:44][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCBr)cc2)cc1
Reactant: C=C(C)C(=O)[O-]
Agent: Cc1cc(C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCOC(=O)C(=C)C)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
118.4 g (0.29 mol) of this ester were dissolved in 50 ml of dimethylformamide at 70° C., 0.3 g of 2-tert-butyl-4,6-dimethylphenol was added as stabilizer, 111.7 g (0.9 mol) of dry potassium methacrylate salt were added, and the mixture was diluted with 70 ml of toluene. The reaction mixture was stirred at 100° C. for 6 h, then cooled and diluted with 800 ml of methyl tert-butyl ether. The precipitate was filtered off with suction, and the washing solution and the filtrate were combined and washed three times with water. They were then concentrated, and the crude product obtained was recrystallized from isopropanol. 4-(4-Methacryloyloxybutoxy)phenyl 4-allyloxybenzoate of m.p. 62-63° C. was obtained in a yield of 83%. Between 41 and 45° C. the ester has a nematic phase which occurs only on supercooling.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2cc(Cl)cnc2N)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.2 %

Procedure:
To a solution of 4-(2-aminopyridin-3-yloxy)benzonitrile (5.6 g, 26.5 mmol) in DMF (100 mL) was added N-chlorosuccinimide (4.25 g, 31.8 mmol) and stirred at 80° C. for 14 h. The reaction mixture was cooled to ambient temperature and poured into water (100 mL). The aqueous suspension was extracted with EtOAc and the combined organic layers were washed with water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on silica gel (20% EtOAc/hexanes) and triturated with methanol to afford 4-(2-amino-5-chloropyridin-3-yloxy)benzonitrile (2.75 g, 42.2% yield) as a bright yellow solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05 mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400 g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.260 g (35%) as an orange foam. mp 99°-103° C. (dec). FDMS m/e=401 (M+ of free base). α[D]589 =+5.1 (c=0.98, dimethylsulfoxide).
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:3]1[C:4]2[C:12](=[C:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: c1c2c(cc3c1CCC3)CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2,3,5,6,7-Hexahydro-s-indacene (30 grams) and acetyl chloride (14.2 mL) in 120 mL of benzene at 0° C. was added 30 grams of aluminum chloride over a period of 1 hour. The cooling bath was removed and the solution was warmed to room temperature and stirred for 4 hours. The deep red mixture was then poured onto a mixture of 270 grams of ice and 50 mL of concentrated hydrochloric acid. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange solid which was recrystallized from hexane to give 34 grams of the title compound, m.p. 69.1-76.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:5][CH:4]=1.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:22]([N:21]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:11]([OH:13])[CH2:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COc1ccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 102.5 %

Procedure:
A solution of glycidyl 4-methoxyphenyl ether (1.10 g, 6.10 mmol), dibenzylamine (1.25 g, 6.33 mmol), and anhydrous ethyl alcohol (20 mL) was heated at 80° C. for 2 days. The solvent was evaporated under reduced pressure to give the title compound as a clear oil (2.36 g, 100%). 1H NMR (CDCl3) δ7.35-7.30 (m, 7 H), 7.28-7.25 (m, 3 H), 6.82-6.76 (m, 4 H), 4.10-4.07 (m 1 H), 3.83-3.81 (m, 3 H), 3.78-3.76 (m, 1 H), 3.76 (s, 3 H), 3.53 (d, 2 H, J=13.4 Hz), 2.66 (d, 2 H, J=6.5 Hz). Mass spectrum (LCMS, ESI) calcd. for C24H27NO3: 378 (M+H). Found: 378.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added oxalylchloride (10.3 mL, 114.74 mmol) at 0° C. followed by DMF (0.9 mL). After complete addition, the reaction mixture was stirred at room temperature for 3 h. Volatiles were evaporated under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride (26.4 g). The crude product was used for the next step immediately.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>COCCOC.O.[Pd].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>[CH:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C(C)C)cc1
Yield: 72.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 4-isopropylphenylboronic acid (0.082 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.074 g (71%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([F:42])[CH:35]=1.[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:8][CH:7]=2)=[O:20])=[CH:35][C:36]=1[F:42])#[N:39]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (70 mg, 158 μmol, example 88) in MeCN (0.5 mL) was added 4-amino-2-fluorobenzonitrile (65 mg, 475 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, sodium hydride, 60% dispersion in mineral oil (22 μL, 475 μmol) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the solvents were removed. The residue was then dissolved in a solution of MeOH and DMSO (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [NH2:1][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.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.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]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])([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: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(NS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a solution 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20), (0.28 mmol) in 2 ml of pyridine chilled in an ice/water bath was added 22 μL of methanesulfonyl chloride (0.28 mmol), 30% completion after 24 h at 10° C. Two more aliquots (22 μL and 50 μL) of methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was concentrated in vacuo to afford a yellow oil which was taken up in EtOAc (10 ml) and washed twice with sat'd NaHCO3 (5 ml), once with 0.5N HCl and once with brine. The organic layer was dried over NaSO4 and conc'd to an oil. Crystallized from acetonitrile to afford 27 mg (22%) as a white solid (MH+=438.08). The following compounds were prepared in an analogous manner:
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1>CO>[Br:11][C:9]1[CH:10]=[C:5]([O:2][CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: C[O-]
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 2.20 ml, 10.0 mmol) was added dropwise to a stirred solution of 1-fluoro-3-chloro-5-bromobenzene (1.00 g, 4.77 mmol) in methanol (28 ml) at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 3 days and then cooled to room temperature. The mixture was evaporated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with water (2×20 ml) dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with cyclohexane to provide the title compound as a colourless oil (302 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC([O-])(C)C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a suspension of N-(3-chloro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.074 g, 3.0 mmol) in DMF (12 mL) was added t-BuOK (539 mg, 4.8 mmol). The mixture was stirred at rt for 30 minutes, then 4-chloropicolinamide (517 mg, 3.3 mmol) was added. The mixture was stirred at 120° C. for 36 hours, then cooled to rt, quenched with 50 mL of water and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=3/1) to give the title compound as a white solid (580 mg, 40.4%).