Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.CC([O-])=O.CC([O-])=O.[Cu+2:33].O>CO>[C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[Cu:33]
Reactant: [Cu+2]
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: [Cu]
Reaction time: 0.33 h

Procedure:
A 1:1.1 molar solution of porphyrin compound (VIII) (50 milligrams, 36.5 millimoles) to Cu(OAc)2.H2O (8 milligrams, 40 millimoles) to Cu(OAc)2H2O was prepared by dissolving the two compounds in methanol. The resulting purple solution was stirred for 20 minutes during which time the color turned to red. The solvent was then removed by rotary evaporation. The resulting residue was dissolved in dichloromethane to make an organic phase, which was washed with water and then dried over anhydrous sodium sulfate. The solvent of the organic phase was removed by rotary evaporation, leaving a red copper porphyrin compound. The compound was re-dissolved in dichloromethane and purified on a silica pad eluting with a 3:1:1 solvent mixture of hexane to dichloromethane to acetone. The solvent of the organic phase was removed by rotary evaporation, leaving 36 milligrams of the copper porphyrin compound (IX) (70% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:12][C:4]1[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(C)c23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 95.2 %

Procedure:
In a sealed tube was added 2-chloro-4-(mesityloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (52.7 mg, 0.18 mmol), 4-aminobenzonitrile (83 mg, 0.70 mmol), TFE (1.0 mL) and TFA (0.11 mL, 1.44 mmol). The reaction mixture was stirred at 90° C. for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (5:1-2:1), to give the product as a light yellow solid (65.7 mg, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[O:16][CH2:15]1.[OH-].[Na+].O>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[O:16][CH2:15]1
Reactant: COC(=O)COc1cccc2c1OCC2CCSCCCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc2c1OCC2CCSCCCc1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
Methyl (+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetate (160 mg) was dissolved in methanol (4 ml), and a 2N sodium hydroxide aqueous solution (0.4 ml) was added to the resultant solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into water and then extracted with ethyl acetate twice. The combined organic layers were washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated. The residue was purified by Lober® column DIOL (elution solvent: hexane/ethyl acetate=1/2) to obtain (+)-3-(2-(3-(2-hydroxyphenyl)propylthio)ethyl)-2,3-dihydrobenzofuran-7-yloxyacetic acid (145 mg). This product was dissolved in chloroform, and diethanolamine was added to the resultant solution. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane/ethanol to obtain the object compound (140 mg, yield 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 84 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and aniline (93 mg, 1.0 mmol) to give 31 0 mg of the title compound (84%): mp>250° C.; 1H NMR (270 MHz, DMSO-d6) δ12.25 (s, 1H), 10.36 (s, 1H), 7.56 (d, 2H, J=8 Hz), 7.33 (t, 2H, J=8.0 Hz), 7.24 (bs, 1H), 7.22 (bs, 1H), 7.09 (t, 1H, J=8 Hz), 5.32~5.36 (m, 1H), 2.89 (dm, 1H, J=16.8 Hz), 2.58~2.81 (m, 2H), 2.05~2.22 (m, 1H).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1(N(C)C2CCCCC2)CCCCC1.Br[C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1.O1CCOCC1>O>[F:28][C:23]1[C:22]([C:3]2[CH2:4][CH2:5][C:1](=[O:6])[CH:2]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C1C=CCC1
Reactant: Fc1ncccc1Br
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: O=C1C=C(c2cccnc2F)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a round bottom flask was added bis(tri-t-butyl)phosphine palladium (0.591 g, 1.156 mmol) before sealing and evacuating and backfilling with nitrogen. Subsequently, cyclopent-2-enone (7.48 mL, 93 mmol), N-cyclohexyl-N-methylcyclohexanamine (14.73 mL, 69.4 mmol), and 3-bromo-2-fluoropyridine (4.07 g, 23.13 mmol) were added before adding dioxane (25 mL). The reaction mixture was stirred under nitrogen at 110° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/dichloromethane) to give 3-(2-fluoropyridin-3-yl)cyclopent-2-enone was afforded as an orange solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([OH:52])=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)c(C)s1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(CC)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.72 g), 4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.39 g), potassium carbonate (1.11 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, tetrahydrofuran-hexane (1:5, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.80 g, yield 28%) as crystals. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[C@H:16]2[C@H:17]([O:23][CH3:24])[O:18][CH:19]=[C:20]([CH2:21][OH:22])[C@H:15]2[CH2:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CCCCCC.C(OC(=O)C)C>[Si:3]([O:10][CH2:11][C:12]1[C@H:16]2[C@H:17]([O:23][CH3:24])[O:18][CH:19]=[C:20]([CH2:21][O:22][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C@H:15]2[CH2:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: COc1ccc(CCl)cc1
Reactant: CO[C@@H]1OC=C(CO)[C@H]2CC=C(CO[Si](C)(C)C(C)(C)C)[C@@H]12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(CO[Si](C)(C)C(C)(C)C)=CC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
0.402 g (10.04 mmol) of sodium hydride was introduced into a reaction vessel and 10ml of dried dimethylformanide was added thereto under nitrogen atmosphere. After the reaction temperature was lowered to 5° C., 3 g (8.37 mmol) of (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-methoxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran which is diluted in advance in 20 ml of dried dimethylfor- mamide was slowly added dropwise thereto. After stirring for one hour, 1.36 ml (10.04 mmol) of p-methoxybenzylchloride was added to the solution, which was then stirred for 6 hours while its temperature being slowly raised to room temperature. Saturated aqueous sodium bicarbonate solution was added to stop the reaction. The reaction solution was extracted with diethylether and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=8/1, v/v) to obtain 1.578 g (Yield 42.2%) of (1R,4aS,7aS)-7-(t-butyldimethylsilyloxymethyl)-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran as a colorless oil.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[NH2:73][C:74]([N:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1)=[S:75]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:75][C:74]([N:76]3[CH2:77][CH2:78][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:80][CH2:81]3)=[N:73][C:44]=2[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[C:47]=2[F:64])[CH:40]=[CH:39][N:38]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 38 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.00 g, 4.53 mmol), NBS (0.85 g, 4.75 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (2.22 g, 9.05 mmol) the title compound of Step A was obtained (1.16 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.30 (d, J=5.49 Hz, 1H), 7.62-7.76 (m, 1H), 7.46 (td, J=7.46, 1.28 Hz, 1H), 7.38 (t, J=6.09 Hz, 1H), 7.32 (t, J=7.78 Hz, 1H), 7.25 (t, J=9.11 Hz, 2H), 6.46 (d, J=5.40 Hz, 1H), 3.56 (br. s., 4H), 3.47 (br. s., 4H), 1.42 (s, 9H). m/z (ES+): 668 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[N:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cncc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 5-bromo-pyridine-3-sulfonic acid amide (178 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.101 g, 19%). MS (ISP) 470.3 [(M+H)+]; mp 217° C.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[C:3](=[O:6])[CH2:4][Cl:5].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.CO>[CH3:1][N:2]([CH2:7][CH:8]1[O:11][CH2:12][CH2:10][O:9]1)[C:3](=[O:6])[CH2:4][Cl:5]
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: CN(CC1OCCO1)C(=O)CCl
Temperature: 25 °C

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide (19.5 grams; 0.10 mole), ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of toluene sulfonic acid (1 gram) in ether (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and distillation head. The mixture was heated at 100° to 110° C. with stirring and the methanol removed as it was formed. After no more methanol was given off the reaction mixture was cooled to room temperature and was stirred with about 2 grams of sodium carbonate for a period of about 1 hour. After this time the reaction mixture was filtered and the filtrate was distilled under reduced pressure to yield the desired product N-methyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 119° to 124° C. at a pressure of 0.15 to 0.30 mm of Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21](S(C)(=O)=O)[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1.CC1([N:35]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1.C(Cl)Cl.N>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:35])[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: COc1ccc(-c2ncn(C)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ncn(C)c2-c2cc3c(N)ncnc3s2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-methoxyphenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 106) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 17) followed by flash chromatography on silica eluting with DCM:MeOH (0-10%) then 1% NH3. Tan solid (0.91 g, 36%);
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2].O.NN>CO>[NH2:23][CH2:22][C@H:20]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:15][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:21]1
Reactant: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Agent: NN
Solvent: O
Solvent: CO
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN)O1
Yield: 99.6 %

Procedure:
To a solution of the crude cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-phthalimidomethyltetrahydropyrane (2.81 g, 6.19 mmol) in methanol (30 ml) was added hydrazine monohydrate (0.48 ml, 15 mmol) and heated under reflux for 2 hours. To the reaction mixture was added purified water (30 ml) to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (50 ml×3). The combined organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude cis-2-aminomethyl-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]tetrahydropyrane (2.0 g). This compound was used for the subsequent reaction without purification. Yield of two steps=100%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1.N1C2C(=CC=CC=2)C=C1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](OC)=[O:37])=[CH:28]1>>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[NH:12][C:36]([C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH2:2][C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:28]=1)=[O:37]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Nc1nccs1
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Cn1cc(C(=O)Nc2nccs2)c2ccccc21)Nc1ccccc1

Procedure:
R5X=2-chloro-N-phenylacetamide; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([OH:16])=[O:15])=[CH:8]2)=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[CH:8]2)=[O:2]
Reactant: O=Cc1c(O)ccc2cc(C(=O)O)ccc12
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(O)ccc2cc(C(=O)OCc3ccccc3)ccc12
Reaction time: 72 h

Procedure:
To a suspension of 5-formyl-6-hydroxy-2-naphthoic acid (1.12 g, 5.18 mmol) in 7.3 mL DMF at rt under N2 was added 569 mg (5.69 mmol) of KHCO3 and 1.11 mL (9.32 mmol) of benzyl bromide. The mixture was stirred for 3 days, at which point it was diluted with H2O and extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel, using 85:15 hexanes-EtOAc as the eluent, to give 410 mg (25%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[O:13][C:14](=[O:15])[C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+].CC(O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][OH:16])[C:6]([C:14]([OH:15])=[O:13])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1c(CO)nc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 4 h
Yield: 9.8 %

Procedure:
To a solution of 7-chloro-9-phenylfuro[3,4-b]quinoline-1,3-dione (prepared as described in example 9 step A, 250 mg, 0.81 mmol) in THF was added NaBH4 (30.5 mg, 0.81 mmol) at 15° C., then AcOH (92.4 μl, 1.61 mmol) was added drop wise and stirring was continued for 4 hr at room temperature. The reaction mixture was dissolved in water and the pH was adjusted to ca. 2 and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography, and then further triturated with ether to give the desired product as an off-white solid (25 mg, 10%). MS (ESI): 314 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([Cl:35])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:35][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([F:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([CH3:26])[C:23]=1[NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (121 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methylphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.