Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)O)cc1)C1CCC(C(C)(C)C)CC1)n2C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Example 14 Step C (0.2 mmol, 93 mg) in 2 mL of dioxane was added LiOH (2 mmol, 48 mg) in 1 mL of H2O. The reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was taken up in dilute pH 7 buffer and EtOAc, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed 2× with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford the acid as a white solid. HPLC A: 2.17 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]2[N:12]=[C:13]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4]1=[O:31])[CH3:2].[C:32]([O:36][C:37](=[O:55])[NH:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[CH3:54])([CH3:35])([CH3:34])[CH3:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=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>[C:32]([O:36][C:37](=[O:55])[NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:15]2[C:5]3[C:4](=[O:31])[N:3]([CH2:1][CH3:2])[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]=3[N:12]=[C:13]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:14]=2)=[CH:41][C:40]=1[CH3:54])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(OS(=O)(=O)C(F)(F)F)c2C1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)OC(C)(C)C)c(C)c3)c2C1=O
Temperature: 100 °C
Yield: 110.8 %

Procedure:
A mixture of 1 g (2.13 mmol) of trifluoromethanesulfonic acid 6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl ester, 711.35 mg (2.13 mmol) of [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]carbamic acid tert-butyl ester, 906.25 mg (4.27 mmol) of tribasic potassium phosphate, 149.83 mg (213.47 μmol) of bis(triphenylphosphine)palladium(II) chloride in 10 ml of dioxane and 3 ml of water is heated in a Biotage microwave machine at 100° C. for 30 minutes. The reaction medium is diluted in 250 ml of ethyl acetate and filtered through Celite. The organic phase is dried over MgSO4. The filtrate is evaporated under reduced pressure. The residue is taken up in 30 ml of heptane, brought to reflux and filtered while hot to give 1.24 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triaza benzocyclohepten-4-yl]-2-methylphenyl}carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][CH:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].[CH3:43]I>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:43])[CH:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CI
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3c[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (90 mg, 0.156 mmol) was dissolved in DMF (1 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 8 mg, 0.20 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then methyl iodide (10 μl, 0.16 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 56 mg (61%) of 2-(6-chloro-1-methyl-1H-indol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:14]=[C:15]1[CH:19]([CH2:20]OS(C)(=O)=O)[CH2:18][CH2:17][N:16]1[C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]2=[O:36])=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[N:1]1([CH2:20][CH:19]2[CH2:18][CH2:17][N:16]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:46])([F:45])[F:44])[NH:32][C:33]4=[O:36])=[CH:28][CH:27]=3)[C:15]2=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C(CN2CCOCC2)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 21.9 %

Procedure:
Morpholine (0.024 ml, 0.29 mmol) and triethylamine (0.040 ml, 0.29 mmol) were added to a THF solution (1 ml) that contained the obtained methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (14 mg, 0.029 mmol). The obtained mixture was heated to reflux for 16 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1->30:1), so as to obtain 7-(3-morpholin-4-ylmethyl-2-oxo-pyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (3 mg, 22%) in the form of a colorless oil substance.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12][C:13]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH:20]=[CH:19]3)=[S:14])=O)[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[O:28][CH3:29])[CH3:2].[OH-].[Na+].Cl>>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[N:15]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[CH:20]=[CH:19]4)[C:13]([SH:14])=[N:12][N:11]=2)[C:6]([O:26][CH3:27])=[CH:5][C:4]=1[O:28][CH3:29])[CH3:2]
Reactant: CCc1nc(C(=O)NNC(=S)Nc2ccc3c(ccn3C)c2)c(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(-c2nnc(S)n2-c2ccc3c(ccn3C)c2)c(OC)cc1OC

Procedure:
A flask was charged with N-[6-ethyl-3,5-dimethoxy-pyridine-2-carboxamidyl]-N′-(1-Methyl-1H-indol-5-yl)-thiourea (41 mg; 0.10 mmol), and one normal aqueous sodium hydroxide (2 mL), and the reaction was stirred at reflux under nitrogen for three hours. The reaction was then cooled, adjusted to pH=7 with one normal hydrochloric acid, and the precipitate was extracted with dichloromethane (2×6 mL). The organic layers were dried with sodium sulfate, and evaporated to give quantitative yield of 5-(6-Ethyl-3,5-dimethoxy-pyridin-2-yl)-4-(1-methyl-1H-indol-5-yl)-4H-[1,2,4]triazole-3-thiol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:35][C:36]1[C:41]2[N:42]=[C:43](I)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Br:35][C:36]1[C:41]2[N:42]=[C:43]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: FC(F)(F)Oc1cc(Br)c2nc(I)sc2c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Br)cc(OC(F)(F)F)cc2s1
Temperature: 80 °C

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (75 mg, 0.16 mmol), 4-bromo-2-iodo-6-trifluoromethoxy-1,3-benzothiazole (81 mg, 0.19 mmol), potassium carbonate (66 mg, 0.48 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) in DME (3 mL) and H2O (1 mL) was evacuated and refilled with N2 (3×), then it was heated at 80° C. for 2 h. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give the Boc-protected title compound as a yellow solid, MS (ES+): m/z=639/641 (1/1) [MH+]. This material was dissolved in DCM (1 mL) and treated with 1M HCl in diethyl ether (3 mL, 3 mmol). The resulting mixture was stirred at room temperature overnight. The solid that formed was filtered off, washed with DCM, and dried in vacuo to give the title compound as yellow solid. MS (ES+): m/z=538.98/540.96 (1/1) [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[S:22]([NH2:25])(=[O:24])=[O:23])[NH2:18]>>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([NH:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][C:21]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: Nc1ccc(S(N)(=O)=O)c(F)c1
Reactant: CNc1cc(C(=O)O)ccc1OC
Product: CNc1cc(C(=O)Nc2ccc(S(N)(=O)=O)c(F)c2)ccc1OC
Yield: 52 %

Procedure:
Using 3-methylamino-4-methoxybenzoic acid and 3-fluoro-4-aminosulfonylaniline as materials, compound 98 is synthesized following a similar method as in Example 28. Yield: 52%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[BrH:10]>>[Br:10][CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1
Reactant: Br
Reactant: O=c1cc(CO)cc[nH]1
Product: O=c1cc(CBr)cc[nH]1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 4-(hydroxymethyl)pyridin-2(1H)-one (150 mg, 1.2 mmol) and aqueous hydrogen bromide (48%, 10 mL) was heated to 100° C. for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to afford 4-(bromomethyl)pyridin-2(1H)-one as a brown solid (225 mg, 100%), which was directly used for next step without further purification. MS (ES+) C6H6BrNO requires: 188. found: 189 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=NCCCN(C)C)C.[C:12]([C:16]1[N:17]=[C:18]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH2:41][C:42]([OH:44])=O)=[CH:37][CH:38]=5)[C:33]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:32]4)=[CH:26][C:24]=3[CH:25]=2)[S:19][CH:20]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CNC>ClCCl>[C:12]([C:16]1[N:17]=[C:18]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH2:41][C:42](=[O:44])[N:3]([CH3:4])[CH3:1])=[CH:37][CH:38]=5)[C:33]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:32]4)=[CH:26][C:24]=3[CH:25]=2)[S:19][CH:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCC(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCC(=O)N(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide (46.5 mg) was added to a mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(carboxymethoxy)indole-3-acetate (145 mg), dimethylamine hydrochloride (24.4 mg) and 1H-hydroxybenzotriazole hydrate (40.4 mg) in dichloromethane (2 ml) and then the mixture was stirred at room temperature for 2 hours. After removal of solvent, the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(N,N-dimethylcarbamoylmethoxy)-indole-3-acetate (0.16 g).
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18]C(OC(C)(C)C)=O)=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH3:27][N:28](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>[NH2:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:6])=[C:3]([CH3:26])[C:2]([C:27]#[N:28])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
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: Cc1c(C#N)ccc(N)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 108A (2 g, 4.8 mmol), zinc cyanide (335 mg, 2.9 mmol), and DMF (48 mL) was degassed with argon for 30 minutes, treated with Pd(PPh3)4 (330 mg, 0.28 mmol), heated to reflux for 1.5 hours, cooled, and filtered. The filtrate was concentrated and purified using a Biotage 40 gram silica gel cartridge to provide the desired product. MS (ESI(−)) m/e 265 (M−H)−; (DCI) m/e 267 (M+H)+, 284 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 7.45 (m, 6H), 6.66 (d, 1H), 6.57 (s, 2H), 5.34 (s, 2H), 3.27 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:35])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO>[C:31]([O:30][C:28]([NH:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:35])=[CH:21][CH:22]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CCNCC2)cc1
Reaction time: 3 h
Yield: 97.1 %

Procedure:
3.64 g of 1-benzyloxycarbonyl-4-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]piperazine (starting material B3), dissolved in 100 ml methanol are hydrogenated over palladiumicarbon (10%) for 3 h. The catalyst is filtered off and the solvent is removed in vacuo, giving 2.55 g of the title compound. The mass spectrum shows the molecular peak MH+ at 348 Da.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: NCCCO
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol using methods similar to Example 563 to provide a grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 8 H), 2.21 (t, J=6.31 Hz, 2 H), 2.82-2.87 (m, 1 H), 3.20-3.24 (m, 2 H), 3.37 (t, J=7.23 Hz, 2 H), 3.45-3.56 (m, 4 H), 4.17-4.25 (m, 3 H), 4.26-4.32 (m, 1 H), 7.09-7.15 (m, 2 H), 7.35-7.40 (m, 2 H), 7.86 (s, 1 H), 8.53 (s, 1 H), 10.29 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16](=[O:27])[C:17]([C:20]2[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH2:12]1.CC(C)([O-])C.[Na+].C(OC)(C)(C)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([N:15]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:17]([CH3:19])([CH3:18])[C:16]2=[O:27])[CH2:12]1
Reactant: CC(C)(C(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncccc21
Temperature: 80 °C

Procedure:
N-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-2-(2-chloropyridin-3-yl)-2-methylpropanamide (0.086 g, 0.216 mmol), sodium t-butoxide (0.040 g, 0.416 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl-phenyl)]palladium(ii), methyl t-butyl ether adduct (0.010 g, 0.012 mmol) were sealed in a microwave vessel under argon. Dry, sparged dioxane (0.5 mL) was added and the reaction heated at 80° C. After 35 minutes the mixture was cooled and partitioned between ethyl acetate (100 mL), water (100 mL) and saturated sodium bicarbonate (10 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) followed by reverse phase HPLC gave 1-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.0481 g, 0.126 mmol, 58.6% yield) as an off white solid. M+1: 365.1. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 2.45 (m, J=3.36 Hz, 2 H) 3.38-3.63 (m, 2 H) 4.51-4.72 (m, 1 H) 5.30 (quin, J=8.66 Hz, 1 H) 5.59-5.80 (m, 1 H) 6.97 (dd, J=7.16, 5.26 Hz, 1 H) 7.04-7.16 (m, 1 H) 7.21-7.35 (m, 1 H) 7.43 (dd, J=7.31, 1.61 Hz, 1 H) 7.59 (dd, J=10.52, 8.33 Hz, 2 H) 8.19 (dd, J=5.19, 1.53 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Bi].[OH-].[Na+].OO>[Pt].CO>[CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Agent: [Pt]
Agent: OO
Agent: [Bi]
Solvent: CO
Product: CCCCc1ncc(C=O)[nH]1
Yield: 94.5 %

Procedure:
4.4 g of 2-n-butyl-5-hydroxymethylimidazole (crude starting material, 90.4 percent), 0.6 g of 5 percent platinum and 5 percent bismuth on activated carbon (comprising 61.3 percent water), 25.6 ml of 1N NaOH solution and 5 ml of methanol were heated to about 60° C. with stirring. At 60° to 64° C., 6.8 g of 15 percent strength aqueous H2O2 solution was added dropwise over the course of 45 min. The reaction mixture was then allowed to react for 15 min and then filtered. The pH of the filtrate was adjusted from 13.0 to 9.0 using 20 percent H2SO4, as a result of which a yellow suspension formed. This was cooled, and the crude product was able to be filtered off and/or extracted with methylene chloride. The reaction was monitored by GC analysis. The reaction yield was 94.5 percent (3.5 percent of starting material).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH:28][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(Oc2ccccc2)c1
Product: FC(F)(F)c1cc(Nc2cccc(Oc3ccccc3)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-phenoxyaniline (71 mg, 0.386 mmol) similar to Example 58 and isolated as a pale white solid (33 mg, 42%). 1H NMR (CDCl3): 9.74 (d, J=2.1 Hz, 1H), 8.72-8.66 (m, 2H), 8.52 (bs, 1H), 7.45-7.37 (m, 4H), 7.21-7.10 (m, 5H), 6.97 (s, 1H), 6.93 (dd, J=2.1, 8.1 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9](COCCOC)[C:10]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl>C(O)(=O)C>[C:17]([C:15]1[CH:14]=[N:13][N:12]([C:10]2[NH:9][C:8]3[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)[CH:16]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(=O)OC)ccc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c(-n3cc(C(=O)O)cn3)nc2c1
Temperature: 100 °C
Yield: 0.3 %

Procedure:
To a stirred solution of 2-(4-ethoxycarbonyl-pyrazol-1-yl)-1-(2-methoxy ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (0.150 g, 0.373 mmol) and acetic acid (4.5 mL) was added aqueous hydrochloric acid (6M, 4.5 mL). The reaction mixture was heated to 100° C. for 18 h and then cooled to 23° C. The resulting precipitate was collected to yield the titled compound (0.30 mg, 30% yield). MS (ESI/CI): mass calcd. for C12H8N4O4, 272.1; m/z found, 273.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.94 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.87 (dd, J=8.4, 1.5 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H).