Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCOCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.4 %

Procedure:
tert-Butyl 3-[2-(1-naphthyl)ethoxy]propanoate (6.19 g) was taken up in dichloromethane (30 mL) and treated with trifluoroacetic acid (5 mL). The resulting solution was stirred at room temperature for 2 hours, an additional 1 mL of trifluoroacetic acid was added and the solution stirred overnight. The mixture was concentrated, taken up in 2M sodium hydroxide solution (30 mL) and washed with ether (2×20 mL). The aqueous layer was subsequently acidified (using 1M hydrochloric acid) and extracted with ether (2×30 mL). The combined organics were washed with brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (5.66 g) as a clear oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1B(O)O.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([N:33](CC3C=CC(OC)=CC=3)[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1>COCCOC.O.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>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:20]1[C:29]2[C:24](=[CH:25][C:26]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(C)ccc1B(O)O
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A microwave vial containing Cs2CO3 (0.175 g, 0.538 mmol), (2-methoxy 4-methyl phenyl)boronic acid (27 mg, 0.175 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.06 g, 0.135 mmol) in DME (1.500 ml) and water (0.225 ml) was purged with nitrogen and Pd(PPh3)4(0.016 g, 0.013 mmol) was added and the reaction was irradiated under microwave irradiation at 125° C. for 1.5 h. The aqueous layer was discarded and the organic layer was concentrated. To this was then added DCM (1 mL) and TFA (0.5 mL) and the reaction was shaken for 2 h. The reaction mixture was purified by reverse-phase chromatography with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(2-methoxy-4-methylphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (28 mg, 51%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.87 (br. s., 1H) 8.65 (d, J=5.61 Hz, 1H) 8.51 (s, 1H) 8.05 (d, J=5.73 Hz, 1H) 7.85 (dd, J=8.88, 1.66 Hz, 1H) 7.71 (d, J=8.94 Hz, 1H) 7.27 (d, J=4.58 Hz, 1H) 7.20 (d, J=7.56 Hz, 1H) 7.04 (s, 1H) 6.93 (d, J=7.45 Hz, 1H) 6.87 (d, J=4.58 Hz, 1H) 3.63 (s, 3H) 2.43 (s, 3H); m/z (ESI) 416.0 (M+H)+.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[C:19]([CH3:25])=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(C)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN3C(=O)c4ccccc4C3=O)c2)C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN)c2)C1=O
Yield: 2.5 %

Procedure:
A solution of 500 mg (0.86 mmol) of 7-anilino-3,4-dihydro-3-(2,6-dimethylphenyl)-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of ethanol was treated with 0.8 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 10 mg (3%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3,4-dihydro-3-(2,6-dimethylphenyl)-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 128° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].[Cl-].[Li+]>CN(C=O)C.O.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>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:24]=[CH2:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Temperature: 90 °C
Yield: 75.2 %

Procedure:
To a solution of 2.48 g (7.05 mmol) of 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (Example 20, Step 2) in 30 mL of DMF was added 2.16 mL (7.40 mmol) of vinyl tributyltin, 0.898 g (21.1 mmol) of lithium chloride and 0.247 g (0.352 mmol) of tetrakis(triphenylphosphine)palladium(0). The reaction was heated to 90° C. for 3 h and then cooled to room temperature. The reaction was diluted with water and extracted with ether. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:25) to provide 1.22 g of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32].O>CN(C)C=O>[CH2:32]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH:31]=[CH2:30]
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Compound of Example 153 (191 mg, 0.5 mmol) was suspended in 2 ml dimethylformamide. 24 mg (0.5 mmol) sodium hydride was added in small portions at room temperature. After 15 minutes 72 mg (0.6 mmol) allylbromide was added and the mixture was stirred at 100° C. for 2 hours. Then the cooled solution was poured on 200 ml water and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 110 mg (52%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:33]([S:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)(=[O:32])=[O:31])[CH3:34]
Reactant: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 3 ml of a 4N solution of hydrochloric acid in dioxane. The reaction mixture is stirred at ambient temperature for 3 h. It is subsequently evaporated under reduced pressure and then a saturated aqueous sodium hydrogencarbonate solution is added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. 0.7 g of 1-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.C[O:13][C:14](=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)=[CH:17][CH:16]=1>>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:21]([CH:31]1[CH2:32][CH2:33][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=2[CH3:11])=[O:10])[CH2:35][CH2:36]1)[C:18]1[CH:17]=[CH:16][C:15]([C:14]([OH:42])=[O:13])=[CH:20][CH:19]=1)#[N:30]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4,6-dimethyl-pyrimidine-5-carboxylic acid (71 mg, 0.46 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester gave 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a brown solid (105 mg, 64% over 2 steps).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[OH:13])=[CH:2]1.O1CCCC1>CO.[C].[Pd]>[CH3:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:7]=1[OH:13]
Reactant: Cc1cccc(-c2ccoc2)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C2CCOC2)c1O
Reaction time: 48 h
Yield: 93.8 %

Procedure:
2-(furan-3-yl)-6-methylphenol (Compound 6-9) (173 mg, 0.70 mmol) and palladium carbon (25 mg, 15%) were dissolved in methanol:tetrahydrofuran=1 mL:1 mL, followed by stirring under hydrogen balloon for 48 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=3:1) to obtain 2-methyl-6-(tetrahydrofuran-3-yl)phenol (117 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: Brc1ccc2ncc(-c3ccccc3)n2c1

Procedure:
The title compound, off-white solid (0.4 g, 68%), MS (ISP) m/z=273.4 [(M+H)+], mp 77° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available phenylboronic acid (0.29 g, 2.38 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[N:16]([CH3:28])[N:17]=[C:18]2[C:23]=1[C:22]1[C:24](=O)[CH2:25][CH2:26][C:21]=1[CH:20]=[CH:19]2>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:14][C:15]1[N:16]([CH3:28])[N:17]=[C:18]2[C:23]=1[C:22]1[C:24](=[CH:5][C:3]#[N:4])[CH2:25][CH2:26][C:21]=1[CH:20]=[CH:19]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1c2c3c(ccc2nn1C)CCC3=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c2c3c(ccc2nn1C)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a suspension of 60% sodium hydride (58.1 mg, 1.45 mmol) in tetrahydrofuran (4 mL) was added diethyl cyanomethylphosphonate (255 μL, 1.58 mmol), and the mixture was stirred at room temperature for 15 min. A solution of 1,2-dimethyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (243 mg, 1.21 mmol) in tetrahydrofuran (8 mL) was added thereto, and the mixture was stirred at 60° C. for 24 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (122 mg) as a mixture with 1,2-dimethyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one. The obtained title compound was used for the reaction of Reference Example 28 without purification.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[F:17]>CN1C(=O)CCC1.CCOCC>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:19]#[N:20])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: ClCCOCCCl
Reactant: N#CCc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2ccc(F)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
NaH (60% in mineral oil, 14.3 g, 357 mmol) was suspended in NMP (143 mL) and cooled to 0° C. A solution of 1-chloro-2-(2-chloroethoxy)ethane (20.4 g, 143 mmol) and 3-chloro-4-fluorophenylacetonitrile (24.23 g, 143 mmol) in ether was then added dropwise via addition funnel. The resulting reaction mixture was stirred at 0° C. for 3 hours and then quenched with water, acidified with 5N HCl, diluted with 400 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 3 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title (16.99 g) after flash chromatography. MS m/e=240 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([OH:15])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:15][C:6]1[C:5]2[C:16]3[C:17]([C:2]([CH3:1])([CH3:22])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=1)=[CH:18][CH:19]=[N:20][CH:21]=3)(=[O:25])[CH3:24]
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-n-pentyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-n-pentyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: C1(C)C=CC(S([N:10]([CH2:20][CH2:21][N:22](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:23][CH2:24][N:25](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:36][CH2:37][N:38](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:39][CH2:40][N:41](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:42][CH3:43])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])(=O)=O)=CC=1.[Na+].[Na+].P(=O)(O)([O-])[O-].Cl>CO.O1CCOCC1>[CH2:18]([OH:19])[CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][NH:41][CH2:42][CH3:43]
Reactant: CCN(CCN(CCN(CCCCCCCCCN(CCN(CCN(CCOCCOCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNCCNCCNCCCCCCCCCNCCNCCNCCOCCOCCO

Procedure:
A mixture of 9,12,15,25,28,31-hexa(p-toluenesulfonyl)-9,12,15,25,28,31-hexaaza-3,6-dioxatritriacontanol (1.30 g, 0.92 mmole), Na/Hg (10.85 g), and phosphoric acid disodium salt (1.96 g, 13.8 mmole) in methanol/dioxane (70 ml/40 ml) was heated to gentle reflux for 24 hours. Additional Na/Hg (2.0 g) was then added. The reaction mixture was maintained at reflux for another 24 hours, then cooled. The insoluble material was filtered and washed with CH3OH. The filtrate was concentrated to give an oily residue which was then treated with 2 N HCl (aq) and washed with CH2Cl2 (200 ml×2). The aqueous acidic solution was then made basic with 10% NaOH (aq), extracted with CH2Cl2 (250 ml×3), dried over MgSO4, filtered and concentrated to give a pale yellow oil (0.25 g, 55% crude yield) which was used further without purification. The reaction is shown schematically below:
Reaction SMILES: [C:1]([C:3]1([C:10]([O:12]CC(C)C)=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:2].C(O)C.[OH-].[K+]>O>[C:1]([C:3]1([C:10]([OH:12])=[O:11])[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:2]
Reactant: CC(C)COC(=O)C1(C#N)CC2C=CC1C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1(C(=O)O)CC2C=CC1C2

Procedure:
To a solution of 250 g (1.14 moles) isobutyl 2-cyano-5-norbornene-2-carboxylate (IBC/CPD adduct) in 1000 ml. 95% ethanol is added a solution of 112 g (1.71 moles) of potassium hydroxide (86%w) in 1000 ml. water. The solution is refluxed on a steam bath for one hour, diluted with 3500 ml. water, and extracted with 2 × 400 ml. benzene to remove any unreacted ester. The aqueous phase is acidified to pH 1 with 6 N HCl and the oily product extracted into 4 × 200 ml. chloroform. The combined extracts are backwashed with 3 × 200 ml. water (which removed the orange color), dried over anhydrous sodium sulfate, and solvent stripped to give 182.3 g (98% theory) of the crude adduct, a pale orange syrupy liquid. Crystallization from benzene/hexane gives three crops of purified 2-cyano-5-norbornene-2-carboxylic acid: (1) 89.7 g, mp 87.5°-92° C, (2) 34.2 g, mp 87.5°-96.5° C, and (3) 15.9 g, mp. 85°-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8](=[O:12])[CH:9]([CH3:11])[CH2:10]2
Reactant: C=C(C)C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Fifty grams (0.30 moles) of 4'-fluoro-2-methylacrylophenone is added to a slurry of 60.1 g. (0.45 moles) of anhydrous aluminum chloride in 27 ml. of carbon disulfide at 20°-25°C over one hour. The mixture is heated to 45°C over one hour and stirred at 45°C for one hour. The reaction is quenched in ice. The oily aqueous layer is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1[C:17]([N+:18]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:17][NH:18][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CNC(=O)Cc1ccc(O)cc1
Yield: 48.5 %

Procedure:
To a solution of 7.6 g of p-hydroxyphenylacetic acid in 100 ml of acetonitrile were added 8.4 g of p-nitrophenol and 10.3 g of dicyclohexylcarbodiimide at room temperature with stirring, and the resulting crystals of dicyclohexylurea were filtered out. An ethereal solution of 7.8 g of methylamine was added to the filtrate containing p-nitrophenyl p-hydroxyphenylacetate, the mixture was allowed to stand to precipitate crystals. The crystals obtained were filtered out and washed with diethyl ether to obtain 4.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[N:10][C:11]([O:18]C)=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Si](Cl)(C)(C)C>C(#N)C>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[N:10][C:11]([OH:18])=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(OC)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Product: COC(=O)c1nc(O)c(C(F)(F)F)cc1-n1c(C)ccc1C

Procedure:
Methyl 3-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methoxy-5-(trifluoromethyl)picolinate (100 mg, 0.305 mmol) in acetonitrile (3.05 ml) was treated with KI (202 mg, 1.218 mmol) and TMS-Chloride (0.156 ml, 1.221 mmol) and heated at reflux for 6 hours. The solvent removed was in vacuo and the crude product was dissolved in EtOAc (20 ml) and washed with water (2×10 ml) and brine (10 ml), dried over a phase separator and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with iso-hexane: EtOAc (gradient of 0 to 30% EtOAc) afforded the title compound as an yellow powder. LC-MS Rt=1.11 mins [M+H]+ 315.4 (Method 2 minLC_v003).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@H:31]([CH2:33][C:34]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:8](=[O:17])[NH:9][C:10]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][N:11]=5)[CH2:5][CH2:6]3)=[O:52])[CH2:32][C:21]=2[CH:20]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c2ncccc2cc1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccnc4[nH]c3=O)CC2)C1=O
Yield: 64 %

Procedure:
3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one (57 mg, 0.19 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (60 mg, 0.16 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 64% yield. High resolution MS m/e (M+H)+=575.2538.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[N:42][C:41]=1[CH3:50]>>[CH3:38][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH:43]=[N:42][C:41]=4[CH3:50])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: Cc1ncc2ccccc2c1Br
Product: Cc1ncc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 4-bromo-3-methylisoquinoline were reacted to give 228. LCMS m/z: 503.7 (MH+)