Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:37])[N:22]2[C@H:25]2[C:34]3[C:29](=[C:30]([F:36])[CH:31]=[C:32]([F:35])[CH:33]=3)[O:28][CH2:27][CH2:26]2)=[CH:18][N:17]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:37])[N:22]2[C@H:25]2[C:34]3[C:29](=[C:30]([F:36])[CH:31]=[C:32]([F:35])[CH:33]=3)[O:28][CH2:27][CH2:26]2)=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc3[nH]c(=O)n([C@@H]4CCOc5c(F)cc(F)cc54)c3n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N)c(Nc2ncc3[nH]c(=O)n([C@@H]4CCOc5c(F)cc(F)cc54)c3n2)c1

Procedure:
A solution of (R)-4-(2,4-dimethoxybenzylamino)-3-(9-(6,8-difluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (230 mg) in DCM (5 mL) was treated with TFA (5 mL) and triethylsilane (1 mL) for 16 h. The mixture was concentrated in vacuo to provide the intermediate (R)-4-amino-3-(9-(6,8-difluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile. The intermediate was dissolved in 5 mL THF and treated with 3 mL trimethylorthoformate followed by p-toluenesulfonic acid (3 mg). After 1 hour, the mixture was diluted with EtOAc (100 mL) and washed once with saturated aqueous sodium bicarbonate (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (50→100% EtOAc/hexanes) provided 78 mg of the title compound. 1H-NMR (300 MHz, 5% CD3OD in CDCl3) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (dd, 1H), 6.8 (td, 1H), 6.4 (dd, 1H), 5.8 (dd, 1H), 4.6 (m, 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.3 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([O-:3])=[O:2].C(Cl)(=O)C>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7]([CH2:13][C:14](=[O:15])[O:16][C:9]2=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CC(=O)Cl
Product: O=C1Cc2ccc([N+](=O)[O-])cc2C(=O)O1
Temperature: 25 °C

Procedure:
A oven-dried 10 mL round-bottomed flask containing a stirring bar was charged with 5-nitro-2-(carboxymethyl)benzoic acid (500 mg, 2.22 mmol). Freshly distilled acetyl chloride (5.0 ml) was added, the flask was fitted with a condenser and the reaction mixture was refluxed under an argon atmosphere for 16 h. The reaction was then cooled to room temperature and the excess acetyl chloride was removed in vacuo. The solid obtained was triturated with Et2O (5.0 mL), filtered and dried to give 7-nitroisochroman-1,3-dione as an off white solid (372.5 mg, 81%). Spectral data for this compound were consistent with those in the literature. M.p. 154-156° C. (lit. m.p. 154-155° C.); 1H NMR (400 MHz, DMSO-d6): δ=8.67 (s, 1H), 8.54 (d, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 4.41 (s, 2H).
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[NH:10][C:9](=[O:15])[CH:8]=[N:7]2.Br[CH2:17][CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[O:20]1[CH2:21][CH2:22][O:23][CH:19]1[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:3])=[C:13]([F:14])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:15]
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnc2cc(F)c(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
Lithium hydride (52 mg, 6.5 mmol) was added to a solution of 6,7-difluoroquinoxalin-2(1H)one (1 g, 5.4 mmol) in N,N-dimethylformamide (10 ml) under cooling on ice and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again, a solution of 2-(2-bromoethyl)-1,3-dioxolane (0.8 ml, 6.5 mmol) in N,N-dimethylformamide (2 ml) was gradually added thereto and the obtained mixture was stirred for 4 hours. Water was gradually added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 0.6 g (39%) of the title compound.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CC(C)=[O:7].[CH3:9][C@:10]12[CH2:27][CH2:26][C@H:25]3[C@@H:15]([CH2:16][CH2:17][CH:18]4[C@:23]3([CH3:24])[CH2:22]CC[CH2:19]4)[C@@H:14]1[CH2:13][CH2:12][C:11]2=[O:28]>C(Cl)(Cl)Cl.[Pt]=O>[OH:4][C@H:1]1[CH2:2][CH2:24][C@@:23]2([CH3:22])[CH:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:9])[C@:14]3([OH:7])[CH2:13][CH2:12][C:11]2=[O:28])[CH2:19]1
Reactant: CC(C)=O
Reactant: C[C@]12CCCCC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)O
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@]12O

Procedure:
The hydrogenation of 14β-hydroxy-9(11)-androsten-3,17-dione (100 mg.) was carried out over 50 mg. of platinum oxide in 25 ml. of glacial acetic acid. When consumption of hydrogen had ceased, the catalyst was filtered, the solvent was evaporated under vacuum and the product was isolated by chromatography on silica gel using a mixture of 10% acetone in chloroform to afford 70 mg. (~70%) of the androstan-17-one, m.p. 214°-217°.
Reaction SMILES: [CH3:1][OH:2].[OH-:3].[K+].Cl[C:6](Cl)(Cl)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.S(=O)(=O)(O)O>ClCCl.O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:2][CH3:1])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc(CC(Cl)(Cl)Cl)c1
Reactant: [OH-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Seventy ml. of methanol was combined with 10.7 g. of 86% pure potassium hydroxide and the mixture was stirred for 0.5 hour. To it was added 8.0 g. of 1,1,1-trichloro-2-(3-trifluoromethylphenyl)ethane over 3-4 minutes. The mixture was heated and stirred under reflux at 68° for 4.75 hours, cooled to 10° and made acid with 8 ml. of concentrated sulfuric acid. The mixture was then stirred under reflux for 45 minutes more, and cooled to ambient temperature overnight. To it was then added 100 ml. of water and 50 ml. of dichloromethane. The aqueous layer was extracted with two 40 ml. portions of dichloromethane, and the organics were combined, dried over sodium sulfate and concentrated under vacuum to obtain 5.7 g. of brown oil, found to be 96.6% pure product by vapor phase chromatography. The product was further purified by distillation at 70°-73° under 1.3 torr to obtain 4.89 g. of more highly purified product.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH3:21])[C:15]=2[Cl:22])=[O:13])=[CH:8][N:9]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH3:21])[C:15]=2[Cl:22])=[O:13])=[CH:8][N:9]=1)=[O:31])([CH3:3])[CH3:2]
Reactant: CCc1nn(C)c(C(=O)NCc2cnc(SC(C)C)s2)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nn(C)c(C(=O)NCc2cnc(S(=O)C(C)C)s2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
0.65 g of N[2-(isopropylthio)thiazol-5-ylmethyl]-4-chloro-3-ethyl-1-methylpyrazole-5-carboxamide was dissolved in 20 ml of chloroform, to which was added little by little 0.40 g of metachloroperbenzoic acid, and the mixture was stirred at room temperature overnight. The resultant solution was washed with saturated aqueous sodium hydrogencarbonate, then with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica-gel chromatography (developing solvent: ethyl acetate/hexane=2/1) to obtain 0.46 g of the titled compound.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:52]=C=O)[CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49]>>[CH3:51][O:50][C:46]1[CH:45]=[C:44]([NH:52][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[CH:43]=[C:42]([O:41][CH3:40])[C:47]=1[O:48][CH3:49]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1cc(OC)c(OC)c(OC)c1
Yield: 7.2 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 3,4,5-trimethoxyphenyl isocyanate as described in Example 16 in a 7.2% yield; ESMS, (M+1)+536.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]2[CH2:24][CH2:23][C@:22]3([CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25]3)[C:21]2=[O:40])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[C:65](O)(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>>[C:65]([O:13][C@@H:14]1[CH2:15][CH2:16][C@H:17]([N:20]2[CH2:24][CH2:23][C@:22]3([CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:25]3)[C:21]2=[O:40])[CH2:18][CH2:19]1)(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (163.0 μL, 0.001035 mol) was added to a mixture of benzyl (5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (200.0 mg, 0.0005175 mol, this compound was prepared by using the procedures of example 472-a, step 1), and triphenylphosphine (271.4 mg, 0.001035 mol) in tetrahydrofuran (3.0 mL, 0.037 mol) at rt. The mixture was stirred at rt for 5 minutes, then benzoic acid (66.36 mg, 0.0005434 mol) was added. After stirring for an additional 2 h, the volatiles in the mixture were removed in-vacuo and the residue was purified by flash chromatography to afford the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH:7]1[C:12](O)=[CH:11][CH:10]=[C:9]([Br:14])[CH:8]=1.Cl.C(OC=C)C>CCOCC>[CH2:5]([O:4][CH:1]([O:3][C:12]1[CH:11]=[CH:10][C:9]([Br:14])=[CH:8][CH:7]=1)[CH3:2])[CH3:6]
Reactant: CCOC(C)=O
Reactant: Oc1ccc(Br)cc1
Agent: C=COCC
Agent: Cl
Solvent: CCOCC
Product: CCOC(C)Oc1ccc(Br)cc1

Procedure:
Into 100 ml of dehydrated ethyl acetate, were fed 11.0 g (50 mmol) of p-bromophenol, and 4.8 ml of a solution composed of hydrochloric acid (1.0 mol/L) and ether, and the mixture was set at 40° C. Into the mixture, 10.8 g (150 mmol) of ethylvinylether was added dropwise, and the mixture was kept with stirring for one night. After completion of the reaction, the reaction solution was rinsed with sodium hydrogen carbonate solution and then rinsed with water to remove solvent. By purifying with silica gel column chromatography (eluate: hexane), 10.7 g (36.5 mmol) of 1-(1-ethoxy)ethoxy-4-bromobenzene was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:20]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19].[BrH:22].[C:23]([OH:26])(=O)[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[C:23]([O:1][CH:2]([CH2:20][Br:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[CH:13][N:12]([CH3:18])[C:11]1=[O:19])(=[O:26])[CH3:24]
Reactant: Br
Reactant: CC(=O)O
Reactant: Cc1cn(C)c(=O)n(CCCCCCCC(O)CO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCn1c(=O)c(C)cn(C)c1=O
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 3-(8,9-dihydroxynonyl)-1-methylthymine (2.16 g, 7.6 mmol) and a 30% solution of hydrogen bromide in acetic acid (4.5 mL, 23 mmol) was stirred for 1 hour. The reaction was added slowly to a beaker containing sodium bicarbonate (8.4 g, 0.1 mol), ice water (30 mL), and dichloromethane (30 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×60 mL). The combined organic layers were washed with water (30 mL), saturated aqueous salt solution (30 mL), and dried over sodium sulfate. The solvent was removed to yield 2.59 g (85% yield) 3-(8-acetoxy-9-bromononyl)-1-methylthymine (inventive compound no. 1908) as a thick, slightly orange oil.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+].FC(F)(F)C(O)=O.N>ClCCl.O>[N:21]([C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Agent: N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(N=[N+]=[N-])c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (135 mg, 0.50 mmol) and sodium azide (71.5 mg, 1.1 mmol) in dichloromethane (1 ml) is added a solution of trifluoroacetic acid (316 μl, 4.1 mmol) in dichloromethane (0.6 ml) dropwise under external cooling with ice. The reaction mixture is stirred for 3 days at room temperature. Water (5 ml) and 25% aqueous ammonia (0.5 ml) are added. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to afford 2-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white solid; HPLC/MS 1.98 min (C), [M+H] 295.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
In a round-bottomed flask, 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (81 mg, 0.13 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.41 ml, 5.32 mmol) was added. The yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.54 ml, 8.00 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and washed with hot water and ethyl acetate and dried under high vacuum to provide 38 mg (60%) of 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder. MS: (M+Na)+=502; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.81 (br. s., 1H), 9.04 (s, 1H), 8.49 (dd, J=8.8, 5.3 Hz, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.62 (dd, J=10.0, 2.1 Hz, 1H), 7.16 (td, J=9.1, 2.3 Hz, 1H), 5.60 (s, 2H), 3.69-3.77 (m, 2H), 3.57-3.67 (m, 4H), 3.42-3.50 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>C(OCC)C.C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: FC(F)(F)c1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A solution of crude 2,4-dichloro-6-(trifluoromethyl)pyrimidine (62, 6.7 mmol) in diethyl ether (10 mL) was diluted with ethanol (25 mL) and cooled in an ice-water bath. 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (2, 3.4 mmol) was added, followed by triethylamine (2 mL). Two additional portions of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (2, 100 mg each) were added, the mixture was slowly warmed to room temperature and stirred overnight. Additional triethylamine (4 mL) was added to the mixture, which was then concentrated to dryness under reduced pressure. The residue was purified via flash silica gel chromatography (40% ethyl acetate/hexanes) to provide the title compound as a light colored solid (1.2 g, 61%). MS (ES+): 294.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:27])[C:24](C)=[CH2:25])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:18]([O:22][C:23](=[O:27])/[CH:24]=[CH:25]/[C:10]1[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]=1[O:14][CH3:15])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 104 °C

Procedure:
The title compound was prepared in the manner described in Example 44 using the 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (2.18 g) and tert-butylmethacrylate (17.1 g) in toluene (70 mL) with tris (dibenzylideneacetone)dipalladium (O) (0.10 g) and tri-orthotolylphosphine (0.13 g). The mixture was treated with triethylamine (0.84 mL, 0.61 g) and heated at 104° C. for 3.7 hours. The mixture was concentrated to a dark solid which was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×18 cm long) using 25% ethyl acetate in hexane. Concentration of the main fraction gave a white solid (0.77 g). A portion (0.21 g) of the solid was dissolved in hot ethyl acetate (7 mL). The solution was diluted with hexane (5 mL) and the crystals formed at room temperature. The solid was filtered off, washed with ethyl acetate, washed with hexane, and air-dried to give white crystals (0.11 g); mp=189.1°-199.8° C.; 1H NMR(CDCl3) 7.27 (s,1) for olefin proton; MS: m/z=322 (base peak), 378 (M+1). Analysis for C19H20ClNO5 : Calculated: C, 60.40; H, 5.34; N, 3.71; Found: C, 60.18; H, 5.43; N, 3.72.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9](I)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cu][C:19]#[N:20]>CS(C)=O.CO>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:19]#[N:20])=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#C[Cu]
Reactant: Fc1cnc2c(c1)c(I)nn2CC1CCCC1
Solvent: CO
Solvent: CS(C)=O
Product: N#Cc1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 150 °C

Procedure:
Under an atmosphere of argon, 6.370 g (purity 83%, 15.447 mmol) of 1-(cyclopentylmethyl)-5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 1.522 g (16.992 mmol) of copper(I) cyanide were initially charged in 45 ml of absolute DMSO, and the mixture was heated at 150° C. for 1.5 h. After cooling, the reaction was diluted with methanol and filtered through Celite. The organic phase was washed twice with a mixture of 25% strength aqueous ammonia solution and saturated aqueous ammonium chloride solution (v/v=1:3), then washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. This gave 3.670 g (purity 86%, 97% of theory) of the target compound.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].CO>C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][C:11]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:10][CH:9]=2)[NH:3][N:2]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(C#N)c(F)c2)C1=O
Reactant: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccncc1N1CCN(c2ccc3c(N)n[nH]c3c2)C1=O
Temperature: 170 °C
Yield: 17.6 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (I-123a: 163 mg) in 2-methoxymethanol (10 mL). The resulting mixture was heated to 170° C. and maintained for 22 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by preparative HPLC afforded 30 mg of the product (17.6% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 57.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide (38 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (58 mg), 2-methoxyethylamine (12 mg), HBTU (65 mg), and DIEA (37 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.49 (t, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.78 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H), 7.37 (d, 1H), 3.67 (s, 3H), 3.54-3.40 (m, 4H), 3.29 (s, 3H).