Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.B(O)(O)[C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[O:32]1[C:29]2[CH:30]=[CH:31][C:26]([C:2]3[CH:3]=[C:4]([NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:5]=[C:6]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[CH:7]=3)=[CH:27][C:28]=2[O:34][CH2:33]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(COc2cc(Nc3cccnc3)cc(-c3ccc4c(c3)OCO4)c2)cc1
Temperature: 110 °C

Procedure:
[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (MW=385.26, 193 mg, 0.5 mmol) was placed into a 10 mL microwave reaction tube and placed under a nitrogen atmosphere. 3,4-(Methylenedioxy)phenylboronic acid (MW=165.94, 124 mg, 0.75 mmol), 2-(di-t-butylphosphino)biphenyl (FW 298.41, 15 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (FW 915.75, 13 mg, 0.025 mmol), cesium carbonate (FW 325.82, 326 mg, 1 mmol) and dry dioxane (3 mL) were added to the tube. After flushing with nitrogen, the reaction tube was sealed and heated at 110° C. for 16 h. After cooling, the reaction mixture was filtered through a short pad of silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using 2% methanol in methylene chloride to give [3-benzo[1,3]dioxol-5-yl-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:12]2[O:11]C(=O)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(O)C>[SH:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:3])[C:12]=1[OH:11]
Reactant: Cc1cccc2sc(=O)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(S)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 2 N aqueous sodium hydroxide solution (15 ml) was added to a solution of 7-methylbenzo[d][1,3]oxathiol-2-one (Compound 102) (2.34 g, 14.44 mmol) in ethanol (15 ml), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was then quenched by adding concentrated hydrochloric acid thereto at 0° C., after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over sodium sulfate to afford 2-mercapto-6-methylphenol (Compound 103) (1.90 g). This compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:21]([O-])([OH:23])=[O:22]>C(OC(=O)C)(=O)C.CCCCCC>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][C:10]=1[N+:21]([O-:23])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCOc1ccc(OCCCCCC)cc1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCOc1ccc(OCCCCCC)c([N+](=O)[O-])c1
Reaction time: 0.05 h
Yield: 97 %

Procedure:
11.6 g of 1,4-di(n-hexyloxy)benzene was dissolved in a mixed solvent of 50 ml of acetic anhydride and 50 ml of n-hexane, and 4 ml of concentrated nitric acid having a specific gravity of 1.42 was dropwise added thereto at a room temperature of 20° C. over 3 minutes. The internal temperature rose to 46° C., and the reaction was completed to obtain 13.1 g of 2,5-di(n-hexyloxy)nitrobenzene (yield: 97%).
Reaction SMILES: [Cl:1]C1C=CC(N)=CC=1C.[Br:10][C:11]1[CH:16]=[C:15](C)[C:14]([CH3:18])=[CH:13][C:12]=1[N:19](C(C)C)[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>>[Br:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([CH3:18])=[CH:13][C:12]=1[NH:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: Cc1cc(N)ccc1Cl
Reactant: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Product: Cc1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl

Procedure:
Tert-butyl 4-{[(2-bromo-4-chloro-5-methylphenyl)amino]carbonyl}-piperidine-1-carboxylate 2-5 was prepared from 4-chloro-3-methylaniline 2-1 following a similar procedure to that described for 4-{[(2-bromo-4,5 dimethylphenyl)(isopropyl)amino]carbonyl}piperidine-1-carboxylate 1-12.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CN(C)c1cccc(-c2cccn3nc(Cl)nc23)c1
Product: CN(C)c1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1

Procedure:
4-{4-[8-(3-Dimethylamino-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from [3-(2-chloro-[1,2,4]-triazolo[1,5-a]pyridin-8-yl)-phenyl]-dimethyl-amine (0.250 g, 0.917 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.304 g, 1.10 mmol) in a manner analogous to Example 311a and 311b to give product (0.288 g, 61%). MP=95-98° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.57 (s, 1H), 8.74 (d, 1H), 7.82 (d, 1H), 7.62 (d, 2H), 7.50 (s, 1H) 7.32 (m, 2H), 7.15 (m, 3H), 6.80 (d, 1H), 4.05 (m, 2H), 3.00 (s, 6H), 2.80 (br m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=513 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[N:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(c2ccc(C(F)(F)F)cn2)CCN1
Yield: 13 %

Procedure:
Piperazinone (1.16 g, 11.6 mmol), 2-chloro-5-(trifluoromethyl)pyridine (2.10 g, 11.6 mmol) and i-Pr2NEt (4.6 g, 6.4 mL, 36 mmol) were heated at reflux for 40 h in acetonitrile (60 mL). The mixture was concentrated, and the residue was purified by column chromatography (40 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (370 mg, 13%) as a yellow powder: ESI MS m/z 246 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:16]=[C:15]([C:17](O)=[O:18])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl.O>[Br:10][C:11]1[N:16]=[C:15]([C:17]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1ccc(Br)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)nc1C(=O)NCc1ccc(Cl)cc1
Yield: 84.8 %

Procedure:
To a solution of (4-chlorophenyl)methanamine (610 mg, 4.31 mmol), 6-bromo-3-methoxypicolinic acid (1.0 g, 4.31 mmol) and triethylamine (1.31 g, 12.9 mmol) in DCM (10 mL) was added dropwise T3P (2.74 g, 8.61 mmol) at 0° C. Five minutes later, TLC indicated the reaction was complete, and the mixture was suspended in water and extracted with DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude 6-bromo-N-(4-chlorobenzyl)-3-methoxypicolinamide (1.3 g, yield: 87%) without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 8.98 (t, J=6.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.39˜7.43 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.22 (d, J=6.4 Hz, 2H), 3.84 (s, 3H). MS (M+H)+: 355/357.
Reaction SMILES: [C:1]([CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Na].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:11][CH2:10][CH:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(C(=O)c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
The 3-benzoyl-3-phenylpropionaldehyde residue obtained from Step B, above, (˜8.85 mmol) was dissolved in 110 mL of methylene chloride. To this solution was added 2-methoxyphenylpiperazine (10.61 mmol) and sodium triacetoxyboranehydride, NaBH(OAc)3, (10.61 mmol). The mixture was stirred at room temperature for 3 hours. Aqueous workup followed by flash chromatography gave pure product 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine (3.48 g) in 95% yield for last two steps. One equivalent of oxalic acid was added to the free base dissolved in methanol. The solvent was evaporated and the product was dried under vacuum to form the oxalate salt.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:35])=[C:8]([N:10]2[CH2:33][CH2:32][C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:16]=[CH:17][C:12]=3[C:11]2=[O:34])[CH:9]=1)=[C:2]=S.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43].CCN=C=NCCCN(C)C.Cl>C1COCC1>[O:43]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:2]1[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:35])=[C:8]([N:10]2[CH2:33][CH2:32][C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:16]=[CH:17][C:12]=3[C:11]2=[O:34])[CH:9]=1
Reactant: Cc1ccc(N=C=S)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Reactant: Nc1ccccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nc3ccccc3o2)cc1N1CCc2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2C1=O
Reaction time: 12 h
Yield: 115.6 %

Procedure:
To a clear solution of 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (75 mg, 0.169 mmol) in the DCM (5 ml) was added Di(2-pyridyl)thionocarbonate (47 mg, 0.203 mmol) all at once, and the reaction mixture was allowed to stirred for 3 hours at room temperature. After 3 hours, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was given a brine wash, dried over sodium sulphate and concentrated to dryness to get sticky mass which was given a hexane wash to get 70.3 mg of 6-(5-Isothiocyanato-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [53] [Yield: 85.6%] as light brown coloured. To a solution of 6-(5-Isothiocyanato-2-methyl-phenyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (50.0 mg, 0.089 mmol), and 2-Amino-phenol (9.73 mg, 0.089 mmol) in THF (5 ml) was added EDC.HCl (25.6 mg, 0.133 mmol), and the reaction mixture was refluxed for 12 hour under nitrogen atmosphere. After 12 hrs, the reaction mass was concentrated to dryness to get crude compound. The crude obtained was subjected to preparative HPLC. The desired compound i.e., 6-[5-(Benzooxazol-2-ylamino)-2-methyl-phenyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one was obtained as brown solid [54] [Yield: 57.7 mg, 63.2%]
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([CH2:31]OS(C)(=O)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:38]#[N:39].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([CH2:31][C:38]#[N:39])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(CC(CC#N)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-methanesulfonyloxymethylethylcarbamic acid benzyl ester 1.93 g, 4.23 mmol) in DMSO (11 ml), potassium cyanide (827 mg, 12.7 mmol) was added and heated at 70° C. After stirring for 4 hours, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1), giving the titled compound (1.42 g, 74%).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=O)[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[F:1][C:2]([F:40])([F:39])[CH:3]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=1)/[CH:4]=[CH:5]/[C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][C:13]2([C:16](=[S:42])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]2)=[O:11])=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1
Reactant: O=C(NC1(C(=O)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=S)NCC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a stirred solution of (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-N-(1-(2,2,2-trifluoroethylcarbamoyl)cyclopropyl)-2-(trifluoromethyl)benzamide (200 mg, 0.31 mmol) in CH2Cl2 (20 mL) was added P4S10 (34 mg, 0.155 mmol) and hexamethyldisiloxane (HMDO, 0.1 mL, 0.517 mmol) and the reaction mixture was refluxed for 4 h. The reaction mixture was cooled to room temperature and another portion of P4S10 (34 mg, 0.155 mmol) and HMDO (0.1 mL, 0.517 mmol) were added and the reaction mixture was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica (100-200 mesh) eluting with 10% EtOAc in hexane to give the title compounds as yellow gum (37 mg, 18%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: C12N(C(=O)C(C3C=C4C(=CC=3)NC(C3C=C(C)C=C(C)C=3)=C4CCN[C:32]([CH3:44])([CH3:43])[CH:33]=[CH:34][CH:35]([OH:42])[C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)(C)C)C(CC1)CC2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.[H][H]>O1CCCC1.C(OCC)(=O)C.[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH3:43][C:32]([CH3:44])=[CH:33][CH:34]1[O:42][CH:35]1[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(C)(C)C=CC(O)c2ccncc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)=CC1OC1c1ccncc1
Reaction time: 0.25 h

Procedure:
To a solution of 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(4-hydroxy-1,1-dimethyl-4-pyridin-4-yl-but-2-enylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one (27 mg in a mixture of 2 mL dry tetrahydrofuran and 2 mL ethyl acetate) at 0° C. was added 0.010 mL trifluoroacetic anhydride followed by 0.009 mL triethylamine and the mixture stirred at low temperature. After 15 minutes, 0.030 mL acetic acid was added and along with 28 mg palladium hydroxide on carbon. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 8 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 94:6:1) gave the title compound (15 mg). m/e=591 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][C:8]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]3[CH:29]=[CH:30][C:3]([CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:4][C:5]=3[N:9]=2)[C:12]1=[O:23])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CO)ccc21
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Yield: 33.7 %

Procedure:
To a solution of 1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (155 mg, 0.38 mmol) and TEA (130 mg, 1.14 mmol) in DCM (5 mL) was added methanesulfonyl chloride (87 mg, 0.76 mmol) at 0° C. The final solution was stirred at ambient temperature for 12 h then washed with sat. NaHCO3 and brine. The organic layer was dried with MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 2:1 to 1:1) to give 62 mg (33%) of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[Cl:13][C:14]1[N:19]=[N:18][C:17]([NH2:20])=[CH:16][CH:15]=1>CCO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[N:20]=2)[N:19]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CCO
Product: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
1 mmol 3-(2-bromoacetyl)benzonitrile and 1 mmol 6-chloropyridazin-3-amine in 10 ml EtOH were heated to reflux for 12 h, then cooled to room temperature. The orange-red precipitate was collected by filtration, washed with cold EtOH, and air-dried to give the 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (125 mg, 50%).
Reaction SMILES: [OH-].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N+:8]3[C:15]([OH:16])=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)C(=O)N(C)[C:9]=32)=[CH:5][CH:4]=1.[C:25]([O:29][CH3:30])(=[O:28])[C:26]#[CH:27]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:27][C:26]([C:25]([O:29][CH3:30])=[O:28])=[C:9]32)=[CH:5][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: Cn1c2[n+](c(O)c(-c3ccccc3)c1=O)Cc1ccc(Cl)cc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1C2
Yield: 48.3 %

Procedure:
A mixture of 333 mg of 9-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-phenyl-6 H-pyrimido[2,1-a]isoindol-5-ium hydroxide (internal salt) and 41 ml of toluene was treated with 0.86 g of methyl propiolate and heated to boiling under reflux for about 6.5 days, and 0.86 ml of methyl propiolate was added thereto every 24 hours. The reaction mixture was then cooled in an ice bath and the separated crystals were filtered off under suction. After recrystallization from N,N-dimethylformamide there was obtained 165 mg of methyl 9-chloro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 269°-273°.
Reaction SMILES: CN1C=CC(=O)NC1=S.[Br:10]Br.[CH3:12][N:13]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]=[C:14]1[S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:29]>ClCCl>[CH3:12][N:13]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]=[C:14]1[S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)=[O:29].[CH3:12][N:13]1[CH:18]=[C:17]([Br:10])[C:16](=[O:19])[N:15]=[C:14]1[S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)=[O:29]
Reactant: BrBr
Agent: Cn1ccc(=O)[nH]c1=S
Agent: Cn1ccc(=O)nc1SCCCCCCCC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1cc(Br)c(=O)nc1SCCCCCCCC(=O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
1-Methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one was prepared from 1-methyl-2-thiouracil by general method A4. A solution of bromine (0.05 ml) in dichloromethane (1 ml) was added to a slurry of 1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thiopyrimidin-4-one (0.38 g) in dichloromethane (20 ml), and the mixture was stirred for 24 hours. The solution was washed with aqueous sodium carbonate, dried and evaporated. Chromatography (silica, 1-4% methanol in dichloromethane) gave 1-methyl-2-(8-(4-chlorophenyl)-8-oxooct-1-yl)thio-5-bromopyrimidin-4-one (0.18 g), as a white solid. 1H-NMR (CDCl3) δ 1.3-1.5 (6H, m), 1.65-1.8 (4H, m), 2.94 (2H, t), 3.26(2H, t), 3.56(3H, s), 7.45(2H, d), 7.56(1H, s) and 7.90(2H, d); MS (APCI+) found (M+1)=459; C19H22BrClN2O2S requires 458.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][NH:7]1)[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([CH3:25])=[N:22][C:21]=2[C:26](O)=[O:27])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][O:10][CH2:9][CH2:8][N:7]1[C:26]([C:21]1[N:22]=[C:23]([CH3:25])[S:24][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[O:27])[CH3:2]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CCOC(=O)CC1COCCN1
Product: CCOC(=O)CC1COCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Yield: 66 %

Procedure:
The title compound (1.48 g, 66%) was prepared from (RS)-morpholin-3-yl-acetic acid ethyl ester, D43 (1.37 g, 5.8 mmol) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 5.8 mmol) according to a procedure similar to that described for D16.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S([N:46]=[N+:47]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[N+:46]=[N-:47])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reaction time: 4 h
Yield: 114 %

Procedure:
tert-Butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)acetate (0.400 g) and 4-methylbenzenesulfonyl azide (0.193 g) were dissolved in 5 ml of acetonitrile and treated with DBU (0.152 ml). The reaction was stirred for 4 hours, then concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered, concentrated onto silica gel and purified by silica gel chromatography to provide tert-butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-diazoacetate (0.48 g) as a bright yellow solid.