Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCOC(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(Cl)c2C1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1

Procedure:
To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1.00 g, 3.44 mmol) and DIPEA (0.672 mL, 3.86 mmol) at room temperature (20° C.) in DCM (7 mL) was added morpholine (0.33 mL, 3.86 mmol). After 2 h the reaction was diluted with DCM and Sat. NaHCO3. The organic layer was rinsed (brine), dried (anhydrous Na2SO4) and concentrated in vacuo. The desired product was isolated by flash chromatography (silica, 50 g, 0-50% EtOAc in petroleum ether (40-60) over 25 min) as a white solid (0.63 g, 1.85 mmol, 54% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=O)[CH2:17][CH2:18][C:19]([O:21]C)=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25].CCCCCC.C(OCC)(=O)C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C2=NNC(=O)CC2)cc(C(C)(C)C)c1O
Yield: 85 %

Procedure:
A mixture of 22 g (0.07 mol) methyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-butanoate and 6.8 g (0.18 mol) of 85% aqueous hydrazine in 250 ml of ethanol is heated under reflux. The reaction is considered complete by the disappearance of the starting material as indicated by TLC analysis (silica gel; 7/3: hexane/ethyl acetate). Upon cooling the reaction mixture, 18.0 g (85% yield) of white crystals are collected by filtration: mp 200°-203° C.; IR (CH2Cl2) 3640, 3420, 3250 and 1680 cm-1.
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29][NH:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[CH:27][C:26]=1I>[Cu]I.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][NH:30][C@@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])=[CH:39][C:40]=1[N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: C[C@@H](NCc1ccc(Cl)c(I)c1)c1ccccc1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@@H](NCc1ccc(Cl)c(-n2cncn2)c1)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.4 %

Procedure:
To a mixture of copper(I) iodide (0.022 g, 0.12 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.027 g, 0.19 mmol), potassium phosphate (0.420 g, 2.0 mmol), 1H-1,2,4-triazole (0.078 g, 1.1 mmol), and (R)—N-(4-chloro-3-iodobenzyl)-1-phenylethanamine 77 (0.352 g, 0.95 mmol) was added DMF (1 mL). The reaction mixture was degassed by a purge/nitrogen cycle (3×) and heated in a sealed tube to 110° C. After 24 h, the reaction mixture was diluted with EtOAc and the organic phase was washed with saturated NH4Cl/NH4OH (10:1) (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 100% EtOAc in hexanes) gave (1R)—N-(4-chloro-3-(1H-1,2,4-triazol-1-yl)benzyl)-1-phenylethanamine 78 (0.031 g, 10% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.38 (d, J=6.5 Hz, 3H), 3.66 (s, 2H), 3.80 (q, J=6.5 Hz, 1H), 7.24-7.36 (m, 7H), 7.48 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 8.14 (s, 1H), 8.52 (s, 1H). Mass spectrum: calculated for C17H17ClN4 312.1. found 313.2 (M++1).
Reaction SMILES: C(O)(=O)CCC#C.C([O-])([O-])=O.[K+].[K+].CI.I[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[C:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[CH2:34][C:33]([CH3:40])([CH3:39])[CH2:32]2)[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[C:50]([O:56][CH3:57])(=[O:55])[CH2:51][CH2:52][C:53]#[CH:54].[NH4+].[Cl-]>CN(C=O)C.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.[Cu]I.O>[OH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23](=[C:31]2[CH2:32][C:33]([CH3:40])([CH3:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH2:36]2)[C:20]2[CH:19]=[CH:18][C:17]([C:54]#[C:53][CH2:52][CH2:51][C:50]([O:56][CH3:57])=[O:55])=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
4-Pentynoic acid (0.50 g, 5.0 mmol) was dissolved in DMF (15 mL). To this solution was added K2CO3 (2.76 g, 20 mmol) followed by CH3I (0.95 mL, 15 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to dissolve all solid, and the mixture was extracted with ether (2×75 mL). The organic extracts were combined and washed with saturated NaHCO3, water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude methyl 4-pentynoate as colorless oil (0.29 g, 52%). To a degassed solution of 4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144) (0.25 g, 0.56 mmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (40 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52 mmol) and methyl 4-pentynoate (0.15 g). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl (15 mL) and water (5 mL), extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc in hexanes to give a light brown solid. The solid was triturated with hot hexanes containing 1% to afford 184 mg (76%) of the title compound (243) as off-white solid. mp 159-160° C. 1H NMR (400 MHz, CDCl3): δ 0.90 (s, 6H), 0.91 (s, 6H), 1.27 (s, 2H), 1.92 (s, 2H), 1.96 (s, 2H), 2.55-2.65 (m, 2H), 2.65-2.75 (m, 2H), 3.71 (s, 3H), 4.58 (s, 1H), 6.72 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H). LCMS (ESI): m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[C:49](=[O:51])[CH3:50])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCCCC.CCOC(C)=O>C1COCC1.O>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[C:49](=[O:51])[CH2:50][Br:1])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(F)cc1OCc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(CBr)c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Phenyltrimethylammonium tribromide (1.55 g, 4.13 mmol) was added to a solution of 2′-(benzyloxy)-4′-fluoroacetophenone (1.01 g, 4.13 mmol) in THF (10 mL), and the mixture stirred at room temperature for 45 minutes, over which time the orange solution faded and a white precipitate formed. Tlc analysis (9:1 hexane:EtOAc) showed the reaction to be complete. The mixture was poured into water (20 mL) and extracted with ether (2×50 mL). The combined ethereal extracts were dried (MgSO4) and the solvents removed in vacuo to give crude 2′-(benzyloxy)-2-bromo-4′-fluoroacetophenone as a colourless oil, which was used in the following step without purification. Rf 0.47 (9:1 hexane:EtOAc); δH (CDCl3) 7.89 (1H, dd, J=9.4 and 6.9 Hz), 7.45-7.40 (5H, m), 6.77-6.74 (2H, m), 5.15 (2H, s), 4.47 (2H, s); LCMS retention time 2.75 min, M+H+ 323.3/325.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:25]=[CH:24][C:16]4[C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:37]=[CH:38][CH:39]=[N:40]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CC1>CN(C=O)C.O>[CH:39]1([NH:40][C:21]([C:17]2[C:16]3[CH:24]=[CH:25][C:13]([O:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][C:15]=3[O:19][C:18]=2[CH3:20])=[O:23])[CH2:37][CH2:38]1
Reactant: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)NC1CC1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 90-E (1.6 g, 4.8 mmol), HATU (2.1 g, 5.7 mmol) and triethylamine (970 mg, 9.6 mmol) in DMF (10 ml) was stirred at room temperature for 20 minutes. To the solution was added cyclopropanamine 90-F (547 mg, 9.6 mmol). The reaction mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. Silica gel column chromatography using 5% MeOH in CH2Cl2 yield N-cyclopropyl-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide 90-G (1.4 g, 77% yield) as a solid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[C:13]([Li])=[CH:14][O:15][CH:16]=1>>[Br:11][C:12]1[C:13]([C:1]([C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]=2[CH3:10])([OH:3])[CH3:2])=[CH:14][O:15][CH:16]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: [Li]c1cocc1Br
Product: Cc1nc(C)c(C(C)(O)c2cocc2Br)o1

Procedure:
Following the general method of Example la but using 5-acetyl-2,4-dimethyloxazole and 4-bromo-3-lithiofuran (Liebigs Ann. Chem., 1986, 625-637), the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([Mg]Br)[CH2:13][CH3:14].[Cl-].[NH4+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1.C(OC)(C)(C)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CCC[Mg]Br
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCc1cc(Cl)ncc1C(=O)NC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 0.1 %

Procedure:
6-Chloro-N-methylnicotinamide (2.00 g, 11.7 mol) was dissolved in tetrahydrofuran (59 mL), added propylmagnesium bromide (46.9 mL, 46.9 mol) under ice-cold conditions, and stirred at room temperature for 4.5 hours. Then, propylmagnesium bromide (46.9 mL, 46.9 mol) was added under ice-cold conditions and the mixture was further stirred at room temperature for 9 hours. The reaction solution was added methanol (140 mL) and ammonium chloride (7.5 g) under ice-cold conditions, and stirred at room temperature for 0.5 hours. The reaction solution was added DDQ (3.19 g, 14.1 mmol) under ice-cold conditions, and stirred at room temperature for 2 hours. The reaction solution was added tert-butyl methylether, and filtered through a pad of celite, concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol). The title compound (1.88 g (yield 75%)) was obtained as a light brown crystal.
Reaction SMILES: [Cl:1][C:2](S(C(C1C=CC=CC=1)(Cl)Cl)=O)(Cl)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.[F:29][C:30]([F:43])([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=[O:39])[CH:31]([F:33])[F:32].CC[Mg+].[Br-]>C1COCC1>[Cl:1][CH2:2][C:38]([C:37]1[CH:40]=[CH:41][CH:42]=[C:35]([O:34][C:30]([F:43])([F:29])[CH:31]([F:32])[F:33])[CH:36]=1)=[O:39]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=S(C(Cl)(Cl)c1ccccc1)C(Cl)(Cl)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(CCl)c1cccc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of dichlorophenylmethyl sulfoxide (5.94 g, 28.4 mmol; K. C. Tin & T. Dust, Tetra. Lett. 1970, 4643) in THF (100 mL) at −78° C. was added LDA (1.8 M in THF, 20.5 mL, 36.9 mmol). The reaction mixture was stirred at −78° C. for 15 min and then was added 3-(1,1,2,2-tetrafluoro-ethoxy)-benzaldehyde (6.94 g, 31.3 mmol). After stirring at −78° C. for 45 min, EtMgBr (1.0 M solution in t-BuOMe, 60 mL, 60 mmol) was added. The reaction mixture was stirred at −78° C. for another 40 min, quenched with NH4Cl aqueous solution and acidified with 1 N HCl. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), concentrated and purified by column chromatography to give 4.13 g (49%) of A2a as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=7.6, 2.6 Hz, 1H), 7.81 (s, 1H), 7.58-7.46 (m, 2H), 5.95 (tt, J=53.0, 2.7 Hz, 1H), 4.68 (s, 2H); MS (ES) m/z: 293 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.O.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
6-Bromo-3-hydroxypyridine (2 g, 11.56 mmol) was dissolved in anhydrous DMF (20 mL); to which 1,2-dibromoethane (10 g, 57.82 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, water (100 mL) was added to it and extraction was carried out using EtOAc (30 mL×3). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography to provide Q-1-I (2.7 g, 86% yield). LCMS: m/z; 280.0 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2].OO.NC(N)=[O:25].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-:25])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2ncccc12
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate (500 mg), urea hydrogen peroxide (239 mg) and CH3CN (8 mL) was added TFAA (0.353 mL) at room temperature. The mixture was stirred at room temperature for 4 h and at 70° C. overnight. To the mixture were added urea hydrogen peroxide (80 mg) and TFAA (0.118 mL). The mixture was stirred at 70° C. for 2 h. After cooling, to the mixture was added saturated aqueous NaHCO3. The resulting precipitate was collected by filtration to give the title compound (246 mg). The filtrate was concentrated. The residue was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (85.1 mg). Total yield: 331 mg.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[N:39]1([CH2:45][CH2:46][NH2:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[N:39]1([CH2:45][CH2:46][NH:47][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: NCCN1CCOCC1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCN6CCOCC6)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and 2-(morpholin-4-yl)ethylamine in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ 8.57 (1H, d, J=5.1 Hz), 8.06 (1H,s), 7.97 (1H, bs), 7.83 (1H, d, J=8.6 Hz), 7.66 (1H, s), 7.27 (1H, d, J=8.3 Hz), 6.71 (1H, d, J=5.3 Hz), 4.20–3.95 (4H, m), 3.70–3.35 (10H, m), 3.25 (3H, d, J=12.6 Hz), 2.64 (3H, s), 2.41 (3H, s), 2.06 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:20][C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:23][N:22]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(Oc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 6) (0.03 g, 0.108 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.046 g, 0.108 mmol), PdCl2(dppf)-CH2Cl2Adduct (8.79 mg, 10.76 μmol) and sodium bicarbonate (0.215 ml, 0.215 mmol) in dioxane (0.538 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (EtOAc:MeOH=10:1) to give N-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzene-sulfonamide (0.02 g, 34%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.10-2.22 (2H, m), 2.37 (2H, s), 2.62 (3H, s), 2.88-2.95 (2H, m), 3.13-3.17 (2H, m), 5.64 (1H, brs), 6.86-6.94 (2H, m), 7.86-7.92 (1H, m), 8.21 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.79 (1H, d, J=2.0 Hz), 8.82 (1H, s), 8.91 (1H, brs). m/z=547.4 [M+1]+.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[OH:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:20])[C:14]=1[CH:21](O)[C:22]([F:25])([F:24])[F:23].CCN(CC)CC.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>C(#N)C>[OH:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:20])[C:14]=1[CH:21]([N:35]([CH3:34])[CH2:36][C:37]#[CH:38])[C:22]([F:25])([F:24])[F:23]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: C#CCNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCN(C)C(c1c(O)c(=O)ccn1C)C(F)(F)F
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To 20 mL acetonitrile cooled in an ice-water bath was added DMF (0.42 mL, 5.4 mmol) followed by oxalyl chloride (0.47 mL, 5.4 mmol) dropwise. To this resulting suspension was added 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) in one portion. The mixture was then stirred for 2 h. Then, Et3N (2.50 mL, 17.9 mmol) was added to this reaction mixture followed by N-methyl propargylamine (0.75 mL, 9.0 mmol). The reaction mixture was stirred at RT for overnight. The solid was filtered off, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (5% MeOH in CH2Cl2 as eluant) to afford the title compound, Apo7057 (570 mg) as an orange powder. Yield=46.4%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.6 (br. s., 1H), 6.25 (d, J=7.1 Hz, 1H), 5.15 (br. s., 1H), 3.87 (s, 3H), 3.37-3.67 (m, 2H), 3.23 (br. s., 1H), 2.32 (br. s., 3H); MS m/z 275 [M+1]+, 206 (100%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[S:54]1[CH:58]=[CH:57][N:56]=[C:55]1[C:59](Cl)=[O:60]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:55]2[S:54][CH:58]=[CH:57][N:56]=2)=[O:60])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2nccs2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 83 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as the starting materials in 83% yield. LCMS for C27H26ClN8O2S (M+H)+: m/z=561.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[S:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[S:35][C:31]=6[CH:30]=5)[CH:23]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)sc5c4)ncn3)CC1)C(=O)N2
Reaction time: 0.5 h

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 110 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 140 μL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60° C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered and dried.