Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:1][C:2]1[C:7]([C:11]#[N:12])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)c(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)c(C#N)cn1
Temperature: 120 °C
Yield: 54 %

Procedure:
A suspension of 4-chloro-5-iodo-2-methoxy-pyridine (30.5 g, 0.11 mol), zinc (II) cyanide (7.97 g, 68 mmol), Pd(PPh3)4 (6.56 g, 5.66 mmol) and DMF (450 mL) was degassed and then heated at 120° C. for 1 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM, the organic extract dried (MgSO4), filtered, then concentrated in vacuo. The resultant residue was crystallized from DCM to give the title compound (10.1 g, 54%). The mother liquors were concentrated in vacuo and the residue subjected to flash chromatography (SiO2 gradient 0 to 100% ethyl acetate in cyclohexane) then crystallization from cyclohexane to give the further title compound (5.16 g, 28%, 82% total). 1H NMR 400 MHz (CDCl3) δ: 8.45 (1 H, s), 6.90 (1 H, s), 4.01 (3 H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Br:10][C:11]1[C:12](F)=[C:13]2[C:19]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1>CCCCO>[Br:10][C:11]1[C:12]([N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4]2)=[C:13]2[C:19]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[CH:18][NH:17][C:14]2=[N:15][CH:16]=1
Reactant: CN(C)C1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Product: CN(C)C1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
N,N-Dimethylpiperidin-3-amine (115 mg, 0.895 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol) in n-BuOH. The reaction was stirred at 160° C. for 20 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-60% CH3CN/water gradient; 20 CV) to yield N-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (60 mg, 45.4% yield) as a solid. The solid was dissolved in a minimal amount of methanol, and then the solution was added to 2N HCl in ether. The resulting precipitate was filtered and dried under high vacuum to yield N-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 10.91 (d, 1H), 10.63 (br s, 1H), 9.47 (d, 1H), 8.99 (dd, 1H), 8.90 (d, 1H), 8.30 (s, 1H), 7.98 (dd, 1H), 7.59 (s, 1H), 3.67-3.59 (m, 1H), 3.27-3.06 (m, 3H), 2.76-2.67 (m, 1H), 2.68 (d, 3H), 2.65 (d, 3H), 2.14-2.04 (m, 1H), 1.74-1.66 (m, 1H), 1.59-1.32 (m, 2H); LCMS (APCI+) m/z 443, 445 (M+H)+, Retention time=1.90 minutes (Method 1).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4]O.[BrH:22].S(=O)(=O)(O)O>O>[Br:22][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Temperature: 100 °C
Yield: 84 %

Procedure:
To a mixture of 40.0 g (134 mmol) of 3,7,11,15-tetramethyl-1-hexadecanol and 400 mL of 48% hydrobromic acid was slowly added 40 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 h and poured into 1.2 L of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous NaHCO3 and dried over MgSO4. The solution was concentrated to a dark liquid, which was eluted through 3 inches (7.6 cm) of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 40.8 g (84%) of 1-bromo-3,7,11,15-tetramethylhexadecane as a clear, colorless liquid, bp 160-180° C. at 0.06 mm Hg.
Reaction SMILES: [I:1]I.[CH2:3]([C:6]1[CH:11]=[C:10]([Sn](C)(C)C)[N:9]=[C:8]([C:16]#[N:17])[N:7]=1)[CH2:4][CH3:5]>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[I:1][C:10]1[CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[N:7]=[C:8]([C:16]#[N:17])[N:9]=1
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(I)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Iodine (1.64 g, 6.5 mmol) was added at room temperature to a solution of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (2.0 g, 6.5 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 hours, then diluted with a saturated solution of sodium thiosulfate and the THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent:Cyclohexane/Ethyl acetate 5/5) to afford 4-iodo-6-propyl-pyrimidine-2-carbonitrile (1.28 g, 72%) as a colorless oil.
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[F:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](B(O)O)=[CH:34][C:33]=2[CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C@@H:1]([NH:5][C:6]1[C:7]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:40][C:33]=3[CH:34]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc2cc(F)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (390 mg, crude) in dioxane (6 mL) was added 5-fluorobenzofuran-2-ylboronic acid (353 mg, 1.96 mmol), K3PO4 (416 mg, 1.96 mmol), Pd(PPh3)4 (64 mg, 0.06 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of dichloromethane (100 mL). The resulting mixture washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 3.3% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate as a red solid (130.0 mg, 30% 2 steps).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1>CC(O)C.Br.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Brc1cccc(CCOCn2c(NC3CCNCC3)nc3ccccc32)n1
Yield: 19.7 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-[[1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (0.0026 mol) in 2-propanol (30 ml) and HBr/CH3COOH (2 ml) was stirred and refluxed for 2 hours and then cooled. The solvent was evaporated. The residue was taken up in H2O and CH2Cl2. The mixture was alkalized with a NaOH solution. The organic layer was separated, washed with H2O, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/NH3 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in petroleum ether. The precipitate was filtered off and dried. This fraction was recrystallized from a small amount of CH3CN. The precipitate was filtered off and dried, yielding 0.22 g of (±)-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine (19.6%) (compound 4).
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]1=2.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]1=2
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Temperature: 25 °C

Procedure:
645 ml of anhydrous ethanol and 52 ml of a 4 N solution of hydrogen chloride in dioxane were added to 25.8 g (82.59 mmol) of 5-{[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. Subsequently, the organic phase was separated off, dried over sodium sulphate, filtered and concentrated to dryness. This gave 23.9 g (70.21 mmol, 85% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[C:8]([Cl:30])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8]([Cl:30])[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 50 °C

Procedure:
To a suspension of EXAMPLE 34B (2.15 g, 4.87 mmol) in 60 mL ethanol/water (5:1) was added powdered potassium hydroxide (1.09 g, 19.46 mmol). The suspension was heated at 50° C. for 3 hours, at which time the reaction was homogeneous. The solvent was removed and the crude material was dissolved in ethyl acetate, washed with water, and brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (Analogix280, gradient elution, 20-100% ethyl acetate/hexane) to give the title compound. MS (ESI) m/e 301.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: Fc1ccc(OCCBr)cc1
Product: O=C(NCC1CN(CCOc2ccc(F)cc2)CCO1)Nc1ccc(Cl)cc1
Yield: 46.3 %

Procedure:
Example 40 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(2-bromoethoxy)-4-fluorobenzene (0.0089 g) to give the title compound (0.007 g). LC-MS (System A): Rt 2.69 mins, Mass Spectrum m/z 408 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([CH:30]([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([CH:30]([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.17 g of 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.20 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (2)) (optical purity: 99% ee).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:12]2[O:11][C:5]3[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=3[N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(N)c1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: O
Product: Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 180 °C
Yield: 96.9 %

Procedure:
To polyphosphoric acid at 110° C. were added simultaneously 2,4-diaminophenol dihydrochloride (7.88 g, 40 mmol) and benzoic acid (4.88 g, 40 mmol). The resulting mixture was then heated to 180° C. for 3 h. The solution was then poured into water. The resulting precipitate was collected by filtration and washed with saturated sodium bicarbonate solution. The crude product was recrystallised from ethanol/water to afford 8.15 g (97%) of the title compound (LCMS RT=5.17 min, MH+ 211.1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[CH:33]1.C(=O)=O>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1cncc1C=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (3.0 g, 6.97 mmol, Intermediate 5: step d) was added THF (40 mL) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 2.8 mL, 7 mmol) was then added dropwise. After 2 minutes, 1-methyl-1H-imidazole-5-carbaldehyde (1.2 g, 9 mmol, in 10 mL THF) was introduced. After 15 minutes, the dry-ice bath was replaced with a 0° C. bath. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc:THF (10:2, 5×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. Chromatography on silica gel (30% acetone-DCM increasing to 5% MeOH) provided the title compound.
Reaction SMILES: CO[C:3](=[O:27])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:28]1([CH2:40][C:41]([NH2:43])=[O:42])[C:38]2=[C:39]3[C:34](=[CH:35][CH:36]=[CH:37]2)[CH2:33][CH2:32][CH2:31][N:30]3[CH:29]=1>>[CH:24]([Si:17]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[O:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:27])[NH:43][C:41](=[O:42])[C:40]=1[C:28]1[C:38]2=[C:39]3[C:34](=[CH:35][CH:36]=[CH:37]2)[CH2:33][CH2:32][CH2:31][N:30]3[CH:29]=1)([CH3:26])[CH3:25]
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2c(CO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Product: CC(C)[Si](OCc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)methyl)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:43])(=[O:42])[NH:15][C:16](=[O:41])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH3:28])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:15][C:16](=[O:41])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH3:28])=[CH:21][CH:20]=2)(=[O:43])=[O:42])=[CH:10][CH:9]=1
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(N)cc2)cc1)c1ccccc1

Procedure:
Prepared by treating 1y with trifluoroacetic acid (50% in CH2Cl2). Yield (92%); 1H NMR (d6-DMSO) δ 11.71 (br s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.38-7.07 (m, 13H), 6.83 (d, J=8.1 Hz, 2H), 6.55 (d, J=8.7 Hz, 2H), 6.37 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 1.44 (s, 9H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 507 (M−H−).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1>O1CCCC1.CO.[Pd]>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:17]=[CH:18][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.4 %

Procedure:
To a round bottom flask, Pd/C (100 mg, 40%) was added to a solution of methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (230 mg, 0.81 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The resultant mixture was allowed to stir at room temperature for 10 hours under H2 pressure. Filtered and concentrated to provide methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid (190 mg). MS (ES+APCI) M+1=389.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26](I)[CH3:27].CCN(C(C)C)C(C)C>CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[CH2:26][CH3:27])=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3CC)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A portion of the solution (3 ml) containing 2-(butyloxy)-8-(methyloxy)-9-[2-(2-piperidinyl)ethyl]-9H-purin-6-amine (approx 140 mg, 0.402 mmol) was treated with ethyl iodide (0.032 ml, 0.402 mmol) and DIPEA (0.140 ml, 0.804 mmol). The reaction was stirred at ambient temperature in a capped vial overnight. Methanol was added to give solution and this was purified by MDAP (Method A). Product fractions were evaporated under N2 in a Radleys blow down unit. The title compound was obtained as a white solid (103 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:24][CH2:25][CH3:26])[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1.Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.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>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:23])[N:2]([CH3:1])[CH2:24][CH2:25][CH3:26])=[CH:9][CH:8]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N(C)CCC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCN(C)C(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 54.3 %

Procedure:
N-Methyl-N-propyl-4-tributylstannylbenzamide (2.36 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.02 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.15 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.72 g of the free compound of the title compound as a pale yellow powder.