Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].I[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1CCCNC(=O)OC(C)(C)C
Yield: 26.8 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 5.00 g (28.5 mmol) of methyl 2-indolecarboxylate, 1.26 g (31.4 mmol) of 60% sodium hydroxide, 12.3 g (43.2 mmol) of tert-butyl N-(3-iodopropyl)carbamate (prepared from 3-iodopropyl-amine and di-tert-butyl dicarbonate) and 60 ml of dimethylformamide. Thus, 2.54 g (27%) of methyl 1-(3-tert-butoxycarbonylaminopropyl)-2-indolecarboxylate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([NH:21]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:29]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To 1,1-dimethylethyl(1RS,2SR)-2-(6-chloro-3-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate (880 mg, 2.04 mmol) was added trifluoroacetic acid (8 ml) at 0° C., and the mixture was stirred for 10 min. The reaction solution was concentrated, diluted with water (20 ml) and extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (602 mg, 89%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:56][C:57]1[N:62]=[CH:61][C:60]([C:63](=[N:65]O)[NH2:64])=[CH:59][CH:58]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[Cl:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]2[N:65]=[C:9]([C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:13][CH:12]=3)[O:11][N:64]=2)=[CH:61][N:62]=1
Reactant: NC(=NO)c1ccc(Cl)nc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[P-](F)(F)(F)(F)F
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
A solution of 4-isobutylbenzoic acid (19.5 g, 110 mmol), PyBOP (57.6 g, 111 mmol), diisopropylethyl amine (19 mL, 111 mmol) and dichloromethane (1.0 L) was stirred at room temperature for 15 minutes and 6-chloro-N′-hydroxypyridine-3-carboximidamide (19.0 g, 111 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours and filtered. The white solid (35.0 g) was treated with TBAF (1M in THF, 159 mL, 158 mmol) and stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, taken up in H2O (1.0 L) and filtered to provide the title compound (29.6 g, 87% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][C:19]1[C:24](=[O:25])[N:23]2[CH:26]=[CH:27][S:28][C:22]2=[N:21][C:20]=1[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C.[I-].[K+]>[N:7]1([CH:4]2[CH2:5][CH2:6][N:1]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][S:28][C:22]4=[N:21][C:20]=3[CH3:29])[CH2:2][CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: Cc1nc2sccn2c(=O)c1CCCl
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2sccn2c(=O)c1CCN1CCC(n2ccc3ccccc32)CC1
Yield: 51.4 %

Procedure:
A mixture of 1-(4-piperidinyl)-1H-indole (4.1 g), 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (3.4 g), prepared as described in EP-A-0,196,132, sodium carbonate (6 g) and potassium iodide (0.1 g) in 4-methyl-2-pentanone (250 ml) was stirred and refluxed overnight. The warm reaction mixture was filtered and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2 /C2H5OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a small amount of CH3CN. The precipitate was filtered off and dried, yielding 3 g (51%) 6-[2-[4-(1H-indol-1-yl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (compound 3; mp. 134.4° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)(=O)C.[Pt](=O)=O>[CH2:1]([C@H:5]1[CH2:13][CH2:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-isobutylbenzoic acid (1.0 g, 5.6 mmol) in acetic acid (56 ml) was purged with argon. After addition of platinum(IV) oxide (0.38 g, 1.7 mmol) the reaction flask was filled with hydrogen gas. The reaction mixture was stirred under an atmosphere of hydrogen gas for 72 h at RT. The flask was purged with argon, and the catalyst was removed by filtration over Decalite. The filtrate was concentrated to dryness to give the title compound as a (7:3) cis/trans mixture. MS m/e: 183 ([M−H]−)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.Cl.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[CH:3]=[C:4]([N:8]4[C:16]5[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=5[C:10]5[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]4=5)[CH:5]=[CH:6][CH:7]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[N:25]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cccc4[nH]ncc34)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), indazole-4-boronic acid hydrochloride (111 mg, 0.559 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(1H-indazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.18 (s, 1H), 7.82 (d, 1H), 7.78 (t, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.5 (m, 2H), 7.34 (m, 2H), 7.21 (d, 1H), 7.1 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.04-3.18 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:14][C:13]([C:4]1[C:5]2[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:2]([Br:1])[CH:3]=1)=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)cc2c1NCCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Br)cc2c1NCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To 7-bromo-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid (8.53 g) dissolved in DMF (80 ml), were added potassium carbonate (13.8 g) and benzyl bromide (4.5 ml) and the mixture was stirred for 2 hours at room temperature. After the insoluble matter was filtered off and the filtrate was concentrated, a mixed liquid of ethyl acetate-benzene (1:1, 400 ml) was added to the residue, and the mixture was washed with water, dried over anhydrous sodium sulfate and then subjected to distilling off the solvent to give the intended compound 11.35 g (99.7%) as brown oily matter.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:35][CH2:36][CH3:37])[C:16]2[C:25]3[CH:24]=[C:23]([O:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:33])[C:17]=2[N:34]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:35][CH2:36][CH3:37])[C:16]2[C:25]3[CH:24]=[C:23]([O:26][CH:27]4[CH2:28][CH2:29][N:30]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:31][CH2:32]4)[CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:33])[C:17]=2[N:34]=1)[CH3:11]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(S(C)(=O)=O)CC4)cc3c21
Reaction time: 16 h
Yield: 83.3 %

Procedure:
Methanesulfonic anhydride (0.295 g, 1.69 mmol) was added in one portion to a stirred solution of 2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 411, 0.650 g, 1.69 mmol) in dichloromethane (15 mL) at room temperature, resulting in a white precipitate. After 16 hours, 2.0 M aqueous sodium carbonate was added and the reaction mixture was allowed to stir for 45 minutes. The precipitate dissolved and the mixture was transferred to a separatory funnel where the layers were separated. The aqueous layer was extracted with chloroform. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by trituration in boiling acetonitrile and isolated by filtration to yield 0.650 g of 2-(ethoxymethyl)-8-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white crystalline solid, mp 240-243.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:26]=1>>[C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[O:18])=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCCCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
8-(4-Acetyl-3-hydroxy-2-propylphenoxy)octanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by high performance liquid chromatography (HPLC) to give 8-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]octanamide, the title compound, mp 48°-51° (from ether-hexane) in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH:18]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][NH:10][C:22](=[O:23])[CH2:21][CH:18]2[CH2:20][CH2:19]2)=[N:4][CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C(Cl)CC1CC1
Reactant: NNc1nccc(I)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC1CC1)NNc1nccc(I)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To a solution of intermediate compound D7 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at 0° C., were added triethylamine (0.562 ml, 4.064 mmol) and cyclopropyl-acetyl chloride (0.385 g, 3.251 mmol). The resulting reaction mixture was stirred at r.t. for 16 h. To this mixture was then added NaHCO3 (aqueous sat. solution). The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield intermediate compound D8 (0.94 g, 99%).
Reaction SMILES: O=[C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[NH:3]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:30].O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:30][C:2]1[C:11]2[N:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncsc12
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ncsc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Methyl 4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylate (1.0 eq, 0.62 g, 2.38 mmol) was suspended in toluene. DIEA (1.5 eq, 122 ul, 3.57 mmol) and POCl3 (2.3 eq, 507 ul, 5.47 mmol) were added and the mixture vigorously stirred at 120° C. for 1 hour. Water, ice and CH2Cl2 were added and the resulting emulsion filtered through celite. The organic phase was decanted and the aqueous phase further extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4 and the solvent removed in vacuo to afford methyl 4-chlorothiazolo[4,5-c]quinoline-7-carboxylate (0.31 g, 47% yield). LCMS (ES): >90% pure, m/z 279[M+1]+.
Reaction SMILES: C([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of methyl (2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15 (20),16,18-decaen-3-yl]acetate (88 mg, 0.134 mmol) in DCM (3 mL) at room temp was added TFA (0.311 mL, 4.03 mmol) and the mixture was stirred at room temp for 16 h. Then, mixture was concentrated and purified by biotage (0-40% EtOAc/hexane) to afford methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15 (20),16,18-decaen-3-yl]acetate (60 mg, 0.100 mmol, 74.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 8.53-8.42 (m, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.16-7.11 (m, 2H), 6.96-6.85 (m, 2H), 5.56 (s, 1H), 4.62-4.38 (m, 2H), 4.15 (q, J=7.1 Hz, 1H), 3.89-3.83 (m, 1H), 3.81 (s, 3H), 3.47 (br. s., 1H), 3.41-3.29 (m, 1H), 3.18 (d, J=10.9 Hz, 1H), 2.76 (d, J=11.8 Hz, 1H), 2.66 (s, 2H), 2.36 (s, 3H), 2.05-1.96 (m, 1H), 1.90 (t, J=12.5 Hz, 2H), 1.82-1.72 (m, 2H), 1.68-1.56 (m, 2H), 1.50 (br. s., 2H), 1.29 (t, J=7.1 Hz, 2H), 1.24 (s, 3H), 1.15 (d, J=6.0 Hz, 3H). LCMS (M+H)=599.4.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:16][CH:17]=2)[C:12]1=[O:30].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:43][C:44]1[CH:48]=[CH:47][O:46][N:45]=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[O:46]1[CH:47]=[CH:48][C:44]([NH:43][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:16][CH:17]=4)[C:12]3=[O:30])[CH:4]=2)=[N:45]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCN3CCOCC3)cc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1ccc2ccc(OCCN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methyl-3-[7-(2-morpholin-4-ylethoxy)-1-oxoisoquinolin-2(1H)-yl]benzoic acid (708 mg) was dissolved in methylene chloride (5 ml) and DMF (3 drops) and cooled to 0° C. under an argon atmosphere. Oxalyl chloride (0.33 ml) was added and the reaction mixture stirred at room temperature for 2 hours. Pyridine (1.45 ml) and 3-aminoisoxazole (0.64 ml) were added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N NaOH, dried (magnesium sulfate) and concentrated. Purification by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give an oily solid. The solid was triturated with ethyl acetate to give N-Isoxazol-3-yl-4-methyl-3-[7-(2-morpholin-4-ylethoxy)-1-oxoisoquinolin-2(1H)-yl]benzamide as a white solid (70 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.50 (m, 4H), 2.75 (m, 2H), 3.55 (m, 4H), 4.20 (m, 2H), 6.75 (m, 1H), 7.05 (m, 1H), 7.25 (m, 1H), 7.45 (m, 1H), 7.60 (m, 1H), 7.70 (m, 2H), 8.00 (m, 2H), 8.85 (s, 1H), 11.45 (s, 1H); Mass Spectrum: M+H+ 475.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:30][C:19]1[N:20]=[N:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:23][C:18]=1[C:3]1[NH:4][C:5]2[C:10]([C:2]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:9][CH:8]=[C:7]([CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1I
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1-c1ccccc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
68 mg 3-Iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole, 17 mg phenylboronic acid, 86 mg potassium phosphate tribasic n-hydrate, and 12 mg tetrakis(triphenylphosphine)palladium(0) are dissolved in a mixture of 2.0 mL toluene and 72 μL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to 90° C. for 2.5 hours. Concentration in vacuo affords 62 mg crude product.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:35]=[CH:34][O:33][C:32]=2[CH3:36])O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>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>[CH3:22][C:3]1[C:2]([C:31]2[CH:35]=[CH:34][O:33][C:32]=2[CH3:36])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
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: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccoc1C
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 36.5 mg, 0.117 mmol), 4,4,5,5-tetramethyl-2-(2-methylfuran-3-yl)-1,3,2-dioxaborolane (Maybridge, Tintagel, UK; 0.040 mL, 0.175 mmol), Na2CO3 (37.1 mg, 0.350 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 6.74 mg, 5.84 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.500 mL) was stirred under argon at 100° C. for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(2-methyl-3-(2-methylfuran-3-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (35.1 mg, 0.098 mmol, 84% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (1H, br. s.), 8.03 (1H, dd, J=7.3, 1.5 Hz), 7.83 (1H, dd, J=8.2, 1.2 Hz), 7.78 (1H, d, J=7.4 Hz), 7.74 (1H, d, J=2.0 Hz), 7.30 (1H, d, J=2.2 Hz), 7.00 (2H, d, J=1.8 Hz), 3.41 (2H, td, J=6.8, 2.4 Hz), 2.88 (2H, t, J=6.8 Hz), 2.75 (3H, s), 2.48 (3H, s). m/z (ESI, +ve) 359.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([O:17]C)=[O:16])[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].OO.[O-2].[Mg+2]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([OH:17])=[O:16])[NH:12][CH:13]=2)=[CH:7][CH:8]=1)(=[O:27])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(Cc1ccccc1)c1nc(-c2ccc(C#N)cc2)c[nH]1
Agent: OO
Agent: [K+]
Agent: [Mg+2]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2c[nH]c(C(Cc3ccccc3)C(=O)O)n2)cc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
The product from Example 56 Part A (0.99 g, 3.0 mmol) was dissolved in 10 mL of DMSO. Potassium carbonate (1.24 g, 9.0 mmol) was added. The mixture was cooled to 0-5° C. and 30% H2O2 (3.18 mL of 30% aqueous solution) was added, followed by magnesium oxide (0.24 g, 15 mmol). The cooling bath was removed and the mixture was stirred at RT under N2 for 4 h. The mixture was filtered to remove inorganic material. Water (30 mL) was added to the filtrate and the resulting mixture was stirred at rt for 40 min. The mixture was acidified with 1N HCl to pH 5. The precipitate formed was filtered and dried to afford 0.67 g of the acid (67%). MS 336.30 (M+H)+.