Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(N)n1
Yield: 90.4 %

Procedure:
To a solution of 4,6-dichloro-2-amino pyrimidine (5.0 g, 30.5 mmol) in methanol (100 mL) was added 25% sodium methoxide (6.59 g, 30.5 mmol). The solution was refluxed for 20 hours, at which time the methanol was removed in vacuo. The residue was dissolved in EtOAc (350 mL), washed with H2O (100 mL) and with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 4.4 g (90%) of 4-chloro-6-methoxypyrimidine-2-ylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:19].[CH3:20][C:21]1[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH:23][N:22]=1.CN(C=O)C.[F-].[K+]>C(OCC)(=O)C.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>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[C:3]([CH3:19])=[CH:4][C:5]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc(Cl)c(C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cnc(-c2ccnc(C)c2)c(C)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction flask containing diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate 156-3 (1.00 g, 4.00 mmol), 2-methyl-4-(tributylstannyl)pyridine (1.53 g, 4.00 mmol) and Pd(PPh3)4 (440 mg, 0.4 mmol) under argon was added DMF (20 mL). The mixture was stirred at 120° C. for 10 hours. After the mixture was cooled down to room temperature, 1N KF aqueous solution was added to it and stirred for 15 minutes. The mixture was diluted with ethyl acetate and the two layers were separated. The organic layer was further washed with water and brine, dried over Na2SO4, concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give diethyl 2-(2′,3-dimethyl-2,4′-bipyridin-5-yl)malonate 156-4 as colorless oil. MS m/z 343.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][C:23]1=2.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
150 mg (0.44 mmol) of 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 112 mg (0.48 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid and 202 mg (0.88 mmol) of tripotassium phosphate monohydrate are suspended in 6 ml of ethylene glycol monomethyl ether, degassed a number of times, and 25 mg (0.04 mmol) of bis(triphenylphosphine)-palladium(II) dichloride are added under nitrogen atmosphere. The reaction mixture is stirred at 80° C. for 16 h, cooled to RT, and 20 ml of water are added. This mixture is extracted three times with ethyl acetate, dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S-:13].[K+].[CH3:15]I.O>CN(C)C=O>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[S:13][CH3:15]
Reactant: Nn1c([S-])nc2ccccc2c1=O
Reactant: CI
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccccc2c(=O)n1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution 209 mg of potassium 3-amino-3H-quinazolin-4-one-2-thiolate in 5 ml of dimethylformamide, 141 mg of methyl iodide was added, and stirred for 20 minutes at room temperature. Water was added to the solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 161 mg (86%) of 3-amino-2-methylthio-3H-quinazolin-4-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[CH2:40]([NH:42][CH2:43][CH2:44][OH:45])[CH3:41].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:42]([CH2:43][CH2:44][OH:45])[CH2:40][CH3:41])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CCNCCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Temperature: 90 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
4-Chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.4 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with 2-(ethylamino)ethanol (0.321 mL, 2.37 mmol), followed by stirring at 90° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-[N-ethyl(2-hydroxyethyl)amino]propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (79.8 mg, yield 81%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 95 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a stirred solution of 100 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone dissolved in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate, and 100 mg of 3-(trifluoromethyl)benzeneboronic acid. Then the mixture was stirred at 95° C. for 24 hours. The reaction mixture was purified according to a procedure similar to Step 4 of Example 22 to yield 35 mg of 5-{4-(aminosulfonyl)phenyl}2,2-dimethyl-4-{3-(trifluoromethyl)phenyl}-3(2H)-furanone. mp: 129-130° C. NMR: δ1.59 (s, 6H), 4.93 (br, s, 2H), 7.48 (m, 2H), 7.59 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.93 (d, J=9.0 Hz, 2H). IR (cm−1): 3343, 3265, 1691, 1593, 1329, 1262.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CO.C1COCC1>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1)[CH3:16]
Reactant: COC(=O)c1cc(CCO)cnc1Br
Reactant: CCN
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ncc(CCO)cc1C(=O)OC
Temperature: 57.5 °C
Reaction time: 2 h

Procedure:
7.85 g (30.18 mmol) of methyl 2-bromo-5-(2-hydroxyethyl)pyridine-3-carboxylate (free base) were dissolved in 20 ml MeOH and added to a 250 ml 3-neck-round bottom flask with a stirrer bar, a thermocouple, a addition funnel and a cold condenser (capable for −78° C.). The solution was treated with 433 mg (3.018 mmol, 0.1 equiv.) CuBr and heated to 55-60° C. The reaction mixture was treated dropwise with 74 ml (148 mmol, 4.9 equiv.) 2M EtNH2 in THF. The reaction was kept at 55-60° C. for two hour and monitored. If the chromatogram still shows starting material the reaction was treated with additional 20 ml (40 mmol, 1.32 equiv.) 2M EtNH2 in THF and kept another 2 h at 55-60° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>ClCCl>[OH:31][CH2:30][C:29]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:33])[CH3:32]
Reactant: O=C(O)c1cc(I)cc(C(F)(F)F)c1
Reactant: CC(C)(N)CO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cc(I)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)benzoic acid (2.32 g) and triethylamine (1.13 ml) in dichloromethane (20 ml) was added dropwise a solution of ethyl chloroformate (1.4 ml) in dichloromethane (2.0 ml) over 10 minutes at −30° C., and the mixture was stirred at −30° C. for 1 hour. 2-Amino-2-methyl-1-propanol was added dropwise to the mixture over 5 minutes at −30° C., and the mixture was stirred at −30° C. for 30 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous ammonium chloride solution at 0° C., and extracted with dichloromethane (X2). The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine, and then dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=20:80) to give N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluoromethyl)benzamide (2.10 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31]O)=[CH:4][C:3]=1[F:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][Br:54])=[CH:4][C:3]=1[F:33]
Reactant: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCO)c3n2CC(C)C)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCBr)c3n2CC(C)C)o1

Procedure:
To a cold (0° C.) solution of 1.0 mmol of 4-amino-7-(4-hydroxybutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole in 20 mL of CH2Cl2 was added 3.0 mmol of PPh3 and 3.0 mmol of CBr4. After 40 min. at rt solvent was removed and the residue was subjected to chromatography to give 4-amino-7-(4-bromobutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole. CCl4 gave the corresponding chloro compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
Intermediate 5 (800 mg, 2.85 mmol) and 2-chloro-5-ethylpyrimidine (447 mg, 3.14 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (3.1 ml, 17.12 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (8:92) as eluent to afford the titled compound (80 mg) as a pale-yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.19 (s, 2H), 7.81 (s, 1H), 7.41 (dd, J 1.6, 8.6, 1H), 7.35 (d, J 8.6, 1H), 4.72 (d, J 13.6, 2H), 3.27-3.11 (m, 3H), 2.47 (q, J 7.6, 2H), 2.21 (dd, J 2.6, 13.1, 2H), 2.02-1.90 (m, 2H), 1.19 (t, J 7.6, 3H).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[CH2:9]([O:11][C:12](=[O:26])[C:13](=O)[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]>O.C(O)C>[CH2:9]([O:11][C:12](=[O:26])[C:13](=[N:7][OH:8])[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(CC)cccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NO)c1c[nH]c2c(CC)cccc12
Yield: 75.7 %

Procedure:
Solutions of sodium acetate (43.7 g, 0.53 mol) in water (100 mL) and hydroxylamine hydrochloride (37 g, 0.53 mol) in water (100 mL) were added to 7-ethyl-α-oxo-1H-indole-3-acetic acid ethyl ester 4 (17.4 g, 0.07 mol), in ethanol (250 mL) and the mixture was heated at reflux for 12 hours. The ethanol was removed by distillation and the resultant precipitate was filtered and recrystallized from hot ethanol to give the product (13.8 g, 75%), m.p. 167°-169° C. as a mixture of isomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1B(O)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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O

Procedure:
2.5 g (8.0 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.76 g (9.2 mmol) of 2,5-dichlorophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 2.3 g (77% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19](=[O:27])[N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:30])[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:20]1[C:19](=[O:27])[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:45])=[CH:3][C:4]=3[F:30])[CH:13]=2)=[CH:21]1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Agent: O=C([O-])O
Agent: Oc1cccc2[nH]nnc12
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(=O)n(CCN(C)C)c4)sc23)c(F)c1
Yield: 52.3 %

Procedure:
To a solution of compound 422 (25 mg, 0.059 mmol) in DMF (0.5 mL) was added the acid 27 (25 mg, 0.12 mmol), hydroxybenzotriazole (11 mg, 0.071 mmol), then EDC (23 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 6 hours before the addition of saturated NaHCO3 (8 mL). The mixture was then extracted with dichloromethane; the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by flash chromatography (eluent a gradient of 0 to 20% methanol in dichloromethane) to give title compound 417 as a white solid (19 mg, 53% yield). 1H NMR: (DMSO-d6) δ(ppm): 10.58 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.28 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.95 (dd, J=2.8, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.45 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 1H), 7.07-7.03 (m, 2H), 6.92-6.88 (m, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.51 (d, J=9.6 Hz 1H), 4.05 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.62 (s, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.47 (s, 6H). MS (m/z): 308.5 ([M+2H]/2), 616.1 (M+H).
Reaction SMILES: OS(O)(=O)=O.[CH3:6]C1C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH3:6][O:30][C:29]([C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)=[O:31]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1

Procedure:
To a stirred solution of H2SO4 (16 mL) in MeOH (400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methylbenzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours. Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6N NaOH. The pH was adjusted to 10-11 by adding more 6N NaOH and extracted with CH2Cl2 (3×150 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a viscous oil. The 1H-NMR showed it to be pure (20.2 g, 92%) and was used without any further purification.
Reaction SMILES: C([O-])(=O)C.[NH4+].C[O:7][C:8](=O)[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O.C([BH3-])#[N:22].[Na+]>CO>[NH:22]1[C:8](=[O:7])[CH2:9][CH:10]2[CH2:18][C:17]3[C:12]([CH:11]12)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: [BH3-]C#N
Reactant: COC(=O)CC1Cc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2Cc3ccccc3C2N1
Reaction time: 0.5 h

Procedure:
A solution of ammonium acetate (3.77 g, 48.9 mmol) was coevaporated in anhydrous methanol. Then, (1-Oxo-indan-2-yl)-acetic acid methyl ester H1 (1.00 g, 4.89 mmol) in methanol (40 mL) was added followed by molecular sieves (4.9 g). The solution was stirred for 30 min and sodium cyanoborohydride (0.92 g, 14.9 mmol) was added. The suspension was refluxed for 40 h. The solution was filtered through celite. A saturated solution of sodium hydrogenocarbonate was added and the solution was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with hydrogen chloride (1N), brine, dried and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate and then ethyl acetate/methanol (95/5) to give 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one G1 (White solid, 300 mg, 35%). LCMS (method A) RT 1.17; ES 196, 174; IR 3233, 1689 cm−1; Mp: 150-153° C.; 1H NMR (400 MHz, CD3OD) δ 7.34 (1H, d), 7.12-7.27 (3H, m), 5.04 (1H, d), 3.22-3.37 (2H, m), 2.83 (1H, d), 2.70 (1H, dd), 2.15 (1H, dd) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH2:69]>CN(C=O)C>[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:44]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)CCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N1,N1-dimethylbutane-1,4-diamine (0.177 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The crude reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. The product was purified by flash column chromatography (10% MeOH/DCM→15% MeOH/DCM/0.5% NH4OH) to give the title compound as a waxy colourless solid (0.012 g, 37%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: Nc1ccc(OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNc1ccc(OC2CCCC2)cc1)OC
Temperature: 100 °C

Procedure:
A suspension of 4-cyclopentyloxyphenylamine (8.86 g), bromo-acetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (100 ml) was heated at 100° C. for 5 hours. Cooling was followed by filtration and concentration of the filtrate. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 265.36 (C15H23NO3); MS (ESI): 266 ([M+H]+), was obtained in this way.