Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]1[CH:17]=[C:16]([N:18]2[C:26]3[CH:25]=[C:24]([CH2:27][OH:28])[N:23]=[CH:22][C:21]=3[N:20]=[CH:19]2)[S:15][C:14]=1[C:29]([NH2:31])=[O:30])[CH3:11].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]2[N:20]=[CH:19][N:18]([C:16]3[S:15][C:14]([C:29](=[O:30])[NH2:31])=[C:13]([O:12][CH:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[O:3][CH:2]([F:1])[F:32])[CH3:11])[CH:17]=3)[C:26]=2[CH:25]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1OC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 511 mg of 3-{(1-[2-(difluoromethoxy)phenyl]ethoxy}-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 252 mg of methanesulfonyl chloride, and 223 mg of triethylamine in 11 ml dichloromethane give [1-(5-carbamoyl-4-{1-[2-(difluoromethoxy)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:4]1([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccccc1N
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1-n1cccc1

Procedure:
A mixture of 500 g of methyl anthranilate and 438 g of 2,5-dimethoxytetrahydrofuran in 670 ml of glacial acetic acid is heated at reflux temperature for 11/2 hours. The acetic acid is then evaporated under reduced pressure and the residue is distilled to yield methyl 2-(1H-pyrrol-1-yl)-benzoate, b.p. 109°/0.1 mm Hg.
Reaction SMILES: [CH2:1]([N:3]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:4]1)[CH3:2].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:3]1[C:11]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc2c(c1C1CCN(Cc3ccccc3)CC1)CCCC2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCn1nc2c(c1C1CCNCC1)CCCC2
Temperature: 65 °C

Procedure:
A mixture of 0.273 g 4-(2-ethyl-4,5,6,7-tetrahydro-(2H)-indazol-3-yl)-1-benzylpiperidine from Step B above, 0.789 g ammonium formate, and 35 mg 20% Pd(OH)2 in 6 mL methanol was heated at 65° C. for 1 h. Basic aqueous work-up with ether extraction provided the title compound as a colorless solid.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH3:5])C.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[NH2:19].C(N(CC)CC)C.O>ClCCl.CO>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[N:18]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[N:19]=[C:4]([CH3:5])[N:6]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(C)=NC(=O)c1ccccc1OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1-c1nc(C)nn1-c1ccc(S(N)(=O)=O)cc1
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N-(1-ethoxy-ethylidene)-2-methoxy-benzamide 462 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was purified through a flash column chromatography (ethyl acetate:normal hexane=7:3). As a result, 4-[5-(2-methoxy-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (86 mg, yield: 12%) was obtained as a liquid phase.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCCN1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((S)-3-tert-butoxycarbonylaminopiperidin-1-yl)ethyl ester (2.54 g, 7.73 mmol) in DCM (80 mL) was added TFA (20 mL) and the mixture was stirred at RT for 2 h. Toluene was added and volatiles removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 1M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a pale yellow oil (1.567 g, 89%). 1H NMR (CDCl3, 300 MHz): 4.18 (2H, t, J=6.0 Hz), 2.89-2.77 (2H, m), 2.68-2.59 & 2.62 (3H, m & t, J=6.0 Hz), 2.20-2.12 (1H, m), 2.00-1.94 (1H, m), 1.82-1.65 (2H, m), 1.60-1.46 (1H, m), 1.28 (2H, bs), 1.20 (9H, s), 1.15-1.03 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: O=CO
Reactant: CC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)=C1CO
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(n2ccccc2=O)=C1CO

Procedure:
A solution of 1 g of 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)6-amino-3-chromene in 15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. After customary working up, 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formamido-3-chromene is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([OH:16])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:57]=[CH:56][C:55]3[C:54]4[C:49](=[CH:50][C:51]([C:58](=[O:61])[CH2:59]Br)=[CH:52][CH:53]=4)[CH2:48][CH2:47][C:46]=3[CH:45]=2)=[CH:42][N:43]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH2:59][C:58]([C:51]2[CH:52]=[CH:53][C:54]3[C:55]4[C:46](=[CH:45][C:44]([C:41]5[NH:40][C:39]([CH:35]6[CH2:36][CH2:37][CH2:38][N:34]6[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[N:43][CH:42]=5)=[CH:57][CH:56]=4)[CH2:47][CH2:48][C:49]=3[CH:50]=2)=[O:61])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(C(=O)CBr)ccc2-3)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(C(=O)COC(=O)C4C5CCC(C5)N4C(=O)OC(C)(C)C)ccc2-3)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) was added to a solution of 2-{5-[7-(2-bromo-acetyl)-9,10-dihydro-phenanthren-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.37 mmol, crude) in acetonitrile (5 mL). The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2-tert-butyl ester as a brown solid (132 mg, 51% over two steps). m/z 697.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC([C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][NH:12]1)=O.O.[OH-].[Na+].C[CH2:22][O:23]CC>>[OH:23][CH2:22][C:16]1[C:11]([CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOCC
Reactant: COC(=O)C1(C)C=CC=CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1ncccc1CO
Reaction time: 1.5 h

Procedure:
To a suspension of lithium aluminum hydride (2.0 g, 53 mmol) in anhydrous ether (300 ml) was added a solution of methyl-2-methylpyridine carboxylate (8.14 g, 53.8 mmol) in 100 ml anhydrous ether over 20 min. The reaction mixture was stirred 1.5 h at room temp. and the treated carefully in succession with 2 ml of water, 2 ml of 15% aqueous sodium hydroxide, and 6 ml of water. The white slurry was stirred 1 h at room temp. and then filtered through Celite. After several washings with ether, the combined filtrates were washed with brine, dried (MgSO4), and concentrated in vacuo to a pale yellow oil. This material was purified by column chromatography on silica with 5% methanol/chloroform as eluent to afford the product as a colorless oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][N:8]=1.CN([CH:26]=[O:27])C.[BH4-].[Na+]>C1COCC1.CO>[Si:16]([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:26][OH:27])=[N:8][CH:9]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BuLi (14.6 ml of a 1.6 M solution in hexanes, 23 mmol) was added to a stirred solution of 2-bromo-5-[2-(tert-butyldimethylsilyloxy)ethyl]pyridine (4.92 g, 15.6 mmol) in THF (100 ml) at −78° C. The resulting pale yellow solution was stirred for 1 h and then DMF (3.6 ml, 46.6 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred for 90 min. MeOH (70 ml) was added, followed by NaBH4 (589 mg, 15.6 mmol) and stirring was continued for a further 1 h. The reaction was quenched by cautious addition of NH4Cl (sat. 100 ml) and the organics extracted with EtOAc (3×100 ml). The combined extracts were then washed with H2O (70 ml) and brine (70 ml), dried (MgSO4) and concentrated under reduced pressure. The material was used crude without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:29])[NH:16][C:17]2[S:18][C:19]3[CH2:25][C@@H:24]([N:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:10]=1)(C)(C)C.[ClH:31].O1CCOCC1>C(Cl)Cl.CO.CCOCC>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:25][C@@H:24]([N:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:29].[ClH:31].[ClH:31].[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:25][C@@H:24]([N:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:29]
Reactant: CN(C)[C@H]1CCc2nc(NC(=O)c3cccc(CNC(=O)OC(C)(C)C)c3)sc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)[C@H]1CCc2nc(NC(=O)c3cccc(CN)c3)sc2C1

Procedure:
To a solution of [3-((S)-6-Dimethylamino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (1.60 g, 3.72 mmol) in DCM (40 mL) and MeOH (0.5 mL) at rt add 4M HCl in dioxane (4.65 mL, 18.6 mmol) and stir the reaction at rt overnight. Dilute the solid suspension with Et2O (300 mL) then filter and wash with Et2O to afford the desired product 3-aminomethyl-N—((S)-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide dihydrochloride as a solid (1.32 g, 3.27 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[N:12]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=3)[C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(OC)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(OC)nn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Ethyl 7-(4-cyanophenyl)-2-methoxy-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (185 mg, 0.55 mmol), 3-(trifluoromethyl)phenylboronic acid (207 mg, 1.09 mmol, 2 eq.), anhydrous copper(II) acetate (198 mg, 1.09 mmol, 2 eq.) and molecular sieve (80 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (12 ml), pyridine (176 μl, 2.18 mmol, 4 eq.) and triethylamine (152 μl, 1.09 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (103 mg, 39% of theory).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]4[CH2:34][CH2:33][O:32][C:31]4=[O:35])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3[N:25]=[CH:26][N:27]=[C:28]([O:29][C@@H:30]([CH2:34][CH2:33][OH:32])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:35])[C:23]=3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1OCC[C@@H]1Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)[C@H](CCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
Trimethylaluminium (0.347 mL, 0.69 mmol) was added to 5-methylpyridin-2-amine (71.7 mg, 0.66 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one (Intermediate T1) (200 mg, 0.60 mmol) in toluene (2 mL) and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated at 50° C. for 2 hours. The reaction mixture was allowed to cool and was neutralised with citric acid (1M, aq.) and then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in DCM to afford the product (185 mg, 69.8%). 1H NMR (400 MHz, CDCl3) 2.30 (3H, s) 2.33-2.40 (1H, m), 2.44-2.52 (1H, m), 2.55 (1h, s), 3.83-3.92 (2H, m), 6.07-6.10 (1H, m), 7.46-7.49 (1H, m), 7.52-7.55 (1H, m), 8.00-8.02 (1H, m), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.47 (1H, s), 8.61-8.62 (1H, m), 8.64 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=440; HPLC tR=1.68 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13]([N:16](C(C)C)CC)(C)[CH3:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][CH:14]=[CH:13][N:16]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1-c1ncco1
Temperature: 135 °C

Procedure:
4-Bromo-2-ethyl-benzoic acid (6.8 g, 30 mmol), diisopropylethylamine (7.8 mL, 44.7 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 14 g, 37 mmol), and aminoacetaldehyde dimethyl ether (4 mL, 37 mmol) in 2:1 dichlormethane/dimethylformamide (120 mL) 5 h at room temperature. The solution was washed with several portions of water, then 1N HCl(aq) and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude light yellow oil. The residue was redissolved in Eaton's reagent (P2O5 in methanesulfonic acid, 100 mL), and the solution was heated at 135° C. under argon for 6 h. The solution was cooled to room temperature and carefully poured onto ice. The mixture was extracted with dichloromethane, and the organic layer was backwashed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude oil. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to pure brown liquid (3.16 g, 44%) 1H NMR (300 MHz, CDCl3): δ ppm 1.24 (t, J=7.54 Hz, 3 H) 3.09 (q, J=7.54 Hz, 2 H) 7.27 (s, 1 H) 7.42 (dd, J=8.38, 1.98 Hz, 1 H) 7.48 (d, J=2.07 Hz, 1 H) 7.74 (s, 1 H) 7.81 (d, J=8.48 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([S:12][CH3:13])=[N:7][C:6]=2[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[N:7]=[C:8]([S:12][CH3:13])[N:9]=[CH:10][C:11]=2[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2c(C)c[nH]c(=O)c2n1
Product: CSc1ncc2c(C)cnc(Cl)c2n1
Yield: 52 %

Procedure:
A solution of 5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 186, 48 mg, 0.232 mmol) in POCl3 (1.5 mL) was heated to 70° C. for 2 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried and adsorbed on silica. The residue was purified by silica gel column chromatography eluting with 0 to 15% EtOAc in cyclohexanes to give the title compound (27 mg, 52%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]([C:20]1[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=1)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9].[CH2:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CCOCC.C(O)C>[CH2:29]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8]([N:11]([C:20]2[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=2)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9])=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1Cl
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: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cnccc1-c1ccc(CC(C)C)cc1
Yield: 77.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.018 g) was added to a deoxygenated mixture of 4-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2(trimethylsilyl) ethoxymethyl]pyridine-3-sulphonamide (0.225 g), 4-isobutylphenylboronic acid (0.109 g), toluene (4 ml), ethanol (2 ml) and 2M sodium carbonate solution (6 ml) and the mixture was stirred and heated under reflux for 18 hours. Ether (25 ml) was added and the mixture was washed with water (2×25 ml) and saturated sodium chloride solution. Aqueous layers were back-extracted with ether (25 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 25-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 4-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]-pyridine-3-sulphonamide (0.213 g) as an oil; 1H NMR (d6 -DMSO): -0.1 (s, 9 H), 0.7 (t, 2 H), 0.9 (d, 6 H), 1.9 (m, 1 H), 2.45 (s, 3 H), 2.5 (d, 2 H), 3.5 (t, 2 H), 3.8 (s, 3 H), 4.7 (s, 2 H), 7.2 (d, 2 H), 7.3 (d, 2 H), 7.4 (d, 1 H), 8.0 (s, 1 H), 8.8 (d, 1 H), 9.2 (s, 1 H); mass spectrum (+ve ESP): 543 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:10]
Reactant: OCc1ccc(F)c(I)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(F)c(I)c1
Reaction time: 8 h
Yield: 29.2 %

Procedure:
The product from Example 30B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with an additional portion of manganese dioxide (2.25 g), stirred overnight, filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Cl[C:26]1[C:27]([C:44]#[N:45])=[N:28][CH:29]=[C:30]([C:32]#[C:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][C:35]=2[CH3:43])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:41][N:40]([CH3:42])[C:37]1[CH:38]=[CH:39][C:34]([C:33]#[C:32][C:30]2[CH:29]=[N:28][C:27]3[C:26]([CH:31]=2)=[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]2=[N:8][C:44]=3[NH2:45])=[C:35]([CH3:43])[CH:36]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: Cc1cc(N(C)C)ccc1C#Cc1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: Cc1ccc2c(c1)nc(N)c1ncc(C#Cc3ccc(N(C)C)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.3 eq.) and 3-chloro-5-((4-(dimethylamino)-2-methylphenyl)ethynyl)picolinonitrile (from the previous step) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (10 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.17 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-((4-(dimethylamino)-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid.