Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[O:9][C:10]([CH3:14])=[CH:11][C:12]=1[SH:13].[Cl-].C([NH+](CC)CC)C.Cl>C(C(C)=O)C.C(N(CC)CC)C.O>[C:2](=[O:3])([S:13][C:12]1[CH:11]=[C:10]([CH3:14])[O:9][C:8]=1[CH3:7])[O:4][CH2:5][CH3:6]
Reactant: Cc1cc(S)c(C)o1
Reactant: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)Sc1cc(C)oc1C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a mixture of ethyl chloroformate (0.86 g, 7.9 mmol) and 2,5-dimethyl-furan-3-thiol (1 g, 7.8 mmol) in methyl ethyl ketone (10 ml) was added triethylamine (0.8 g, 7.9 mmol). The mixture was cooled in ice and stirred for 3 hours. After reaching room temperature water (10 g) was added to the mixture to dissolve the triethylammonium chloride which was formed during the reaction. Concentrated hydrochloric acid (2 g) was added to neutralise the excess triethylamine. The organic layer was separated and washed with a saturated sodium hydrogen carbonate solution (10 g), water (10 g) and finally a sodium sulphate solution (10 g). After evaporation of the solvent the residue was analysed and confined by NMR spectroscopy as O-ethyl S-(2,5-dimethyl-3-furyl) thiocarbonate yield 89% (1.4 g, 7 mmol) purity 91%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH:17]([O:23][CH3:24])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:44]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60]O)[CH:55]=2)[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:46][CH2:45]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:44]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:11][C:12]=3[CH:17]([O:23][CH3:24])[CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:55]=2)[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:46][CH2:45]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)c(C(CC(C)(C)C)OC)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2C(CC(C)(C)C)OC)c1)C1CC1
Yield: 78.4 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-3-(1-methoxy-3,3-dimethylbutyl)-[1,1′-biphenyl]-4-ol (290 mg) in THF (5.0 mL) were added triphenylphosphine (343 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (325 mg) and a 40% solution of diethyl azodicarboxylate in toluene (600 μL), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (385 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:30][CH2:31][C:32]([NH2:34])=[O:33].ClC(OCC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[O:21])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(N)=O
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=O)CNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Na -t-butyloxycarbonyl-Nim -benzyloxycarbonyl-L-histidine was dissolved in tetrahydrofuran (THF) and neutralized with one equivalent of N-methylmorpholine. It was then coupled with glycinamide hydrochloride using isobutyl chloroformate and N-methylmorpholine. After two hours at -20° C. and an additional hour at ambient temperature, the reaction was quenched with 2N aqueous potassium bicarbonate. This product was extracted into ethyl acetate, washed with 1M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave Na -t-butyloxycarbonyl-Nim -benzyloxycarbonyl-L-histidyl-glycine amide.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[N:38]=[CH:37][CH:36]=[N:35]1)=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[CH2:20]3)[N:10]=1
Reactant: O=C(c1ccccc1-n1nccn1)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 25 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C20H21N7O, 375.44; m/z found, 376.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](C2OCCN(C(=S)C)C2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)COCCO[CH2:29][CH2:30][OH:31].[OH-:33].[K+].Cl>O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:29][C:30]([OH:31])=[O:33])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OCCOCCOCCO
Reactant: CCCCCCCc1ccc(C2CN(C(C)=S)CCO2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 18 %

Procedure:
To 56.1 g of the 4-[2-(4-heptylphenyl)-1-thioxoethylmorpholine thus obtained, were added 300 ml of triethylene glycol, 50 ml of water and 37.3 g of potassium hydroxide. The resulting mixture was heated under reflux for six hours and then allowed to cool to room temperature. Then 10% hydrochloric acid was added thereto by portions until the pH value of the solution became slightly acidic. The reaction product was extracted with 300 ml of ethyl acetate and the organic layer was washed with water until the aqueous layer became neutral. Then the organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was recrystallized from hexane. Thus 28.0 g of p-heptylphenylacetic acid was obtained. Yield: 18%.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:18]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1C(=O)c3ccccc3C1=O)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a solution of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.98 g) in DMF (10 ml) was dropwise added potassium phthalimide (924 mg). After being stirred at room temperature for 12 hr, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) and then recrystallized from hexane gave the entitled compound (1.74 g) as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: COc1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: COc1ccnc(N2CCNCC2)c1
Temperature: 115 °C

Procedure:
To 756 mg (5.29 mmol) of 2-Chloro-4-methoxypyridine and 2.27 g (26 mmol) of piperazine in a pressure flask was added 2.7 mL dimethylformamide, and the mixture was heated at 115° C. for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over Na2SO4, filtered, and the filtrate was acidified with 2M HCl in ether. The product crystallized over night, and the solids were isolated by filtration to yield product as a white solid: 1H NMR (D2O, 400 MHz) 7.72 (d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 3.79 (m, 4H), 3.36 (m, 4H) ppm.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][CH2:11][O:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: Fc1ncccc1C1CCCOC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2C2CCCOC2)cc1)c1nc2ccccc2[nH]1
Temperature: 140 °C
Reaction time: 72 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.33 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 72 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 400.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21].C(NC(C)C)(C)C.O>C1COCC1.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.[Cu]I>[CH3:23][Si:22]([C:20]#[C:21][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:25])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a mixture of methyl 4-(4-bromobenzoyl)benzoate (1.20 g, 3.76 mmol), ethynyltrimethylsilane (554 mg, 5.66 mmol), (PPh3)2PdCl2(106 mg, 0.151 mmol), CuI (14.3 mg, 0.075 mmol) in THF (30 ml), diisopropyl amine (799 mg, 7.92 mmol) was added dropwise under argon atmosphere. The mixture was stirred at 50° C. for 4 h. Water was added to the mixture after cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give methyl 4-(4-trimethylsilylethynylbenzoyl)benzoate (83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[N+:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)#[C-:18]>CO.O=[Pt]=O>[C:9]1([CH3:8])[CH:16]=[CH:15][CH:14]=[C:11]([C:12]2[N:7]=[C:2]3[CH2:3][NH:4][CH2:5][CH2:6][N:1]3[C:18]=2[NH:17][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:10]=1
Reactant: Cc1cccc(C=O)c1
Reactant: [C-]#[N+]c1ccc(C)cc1
Reactant: Nc1cnccn1
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1ccc(Nc2c(-c3cccc(C)c3)nc3n2CCNC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Example 266 was synthesized by the following way: to a 100-mL round-bottom flask, was placed a solution of pyrazin-2-amine (1.2 g, 12.6 mmol), 3-methylbenzaldehyde (1.44 g, 12.0 mmol) and HClO4 (200 mg, 2.0 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 30 minutes, then to the mixture was added 1-isocyano-4-methylbenzene (1.2 g, 10.3 mmol). The resulting solution was allowed to stir for 12 hr at room temperature. After removing the solvent, the residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to result 1.1 g the Ugi adduct. To a solution of the obtained Ugi adduct (1.0 g, 3.18 mmol) in methanol (50 mL) was added PtO2 (72 mg, 0.32 mmol). Then the reaction mixture was evacuated and back filled with H2. The reaction mixture was stirred at RT overnight. The solid was filtered out and the filtrate was concentrated under vacuum to result in the title compound as a white solid.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C:7]([NH:31][C:32](=[O:34])[CH3:33])([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[CH2:14]1)[C:8](OCC)=[O:9])C>C1COCC1.C(OCC)(=O)C>[OH:9][CH2:8][C:7]([NH:31][C:32](=[O:34])[CH3:33])([CH2:6][OH:5])[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=2)[CH2:14]1
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CCC(C(CO)(CO)NC(C)=O)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
Lithium borohydride (2M solution in THF, 0.88 ml, 1.76 mmol) was added to compound 6 (200 mg, 0.44 mmol) in 5 ml THF at 0° C. The reaction mixture was stirred at room temperature for 48 hours and diluted with 40 ml ethyl acetate. The solution was washed with brine (2×20 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 4% MeOH in CH2Cl2) to provide 55 of mg compound 7 (33%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.I[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.O>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:23][CH3:24]
Reactant: CCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Combine 3-hydroxybenzaldehyde (790 g), K2CO3, (1627 g) and DMF (8 L). Add 1-iodopropane (1000 g) and heat to 105° C. and stir for 4 h. Cool to about 50° C. and add water (15 L), continue cooling to about room temperature and add toluene (10 L). Separate the organic layer and extract the aqueous phase with toluene (2×10 L), combine organic phases and wash with NaOH 1N (2×5.8 L), concentrate the combined organic layers in vacuo to afford the title compound.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][C:39]#[N:40].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[C:38]([C:34]4[S:33][CH:37]=[CH:36][N:35]=4)[C:39]#[N:40])=[CH:23][CH:24]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: N#CCc1nccs1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Yield: 72.9 %

Procedure:
To a 25 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.1 g, 0.000221 mol) and 2-(thiazol-2-yl)acetonitrile (0.082 g, 0.000663 mol) were taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed overnight and ethanol was distilled out and water was added to residue. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.090 g of 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N)=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.N(OCCCC)=O.[H+].[F:24][P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:24])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Nc1ccc(Cl)nc1Oc1ccccc1
Agent: CCCCON=O
Agent: [H+]
Product: Fc1ccc(Cl)nc1Oc1ccccc1

Procedure:
A diazonium salt is formed by reacting 2-chloro-5-amino- 6-phenoxypyridine with butyl nitrite in the presence of HPF6 and is decomposed by heating (Baltz-Schiemann reaction) to obtain 2-chloro-5-fluoro-6-phenoxypyridine. The obtained product is reacted with magnesium and then with a formylating agent such as dimethylformamide to obtain 5-fluoro-6-phenoxy picolinic aldehyde. In the case where cyano(5-fluoro-6-phenoxy-2-pyridyl) methyl alcohol is required, it is prepared by reacting the aldehyde with sodiumbisulfite and then with a cyanide compound such as sodium cyanide.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[CH:10]([CH3:13])[CH2:11][NH2:12])[CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CCN(CC)CC.CCOC(C)=O>CC(O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]3[CH2:3][CH2:2][O:1][C:9]=23)[CH3:13])[CH:20]=1
Reactant: CC(CN)c1ccnc2c1OCC2
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(CNc1cc(Cl)ncn1)c1ccnc2c1OCC2
Temperature: 80 °C
Yield: 81 %

Procedure:
As shown in step 6-iv of Scheme 6, to a suspension of 2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propan-1-amine.2HCl and 4,6-dichloropyrimidine (456.0 mg, 3.061 mmol) in i-PrOH (17.01 mL) was added Et3N (1.291 g, 1.778 mL, 12.76 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature, and partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined organics were washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, then isocratic EtOAc) to afford 6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (600.3 mg, 81% yield over two steps). Chiral SFC purification (20% MeOH at 5 mL/min on a ChiralPak® AD-H (4.6 mm×100 mm) column, 100 bar, 35° C., 220 nm) provided (S)-6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine (Compound 2021, 300 mg, SFC retention time 1.05 minutes): LCMS=291.04 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.00 (d, J=4.5 Hz, 1H), 6.92 (d, J=4.4 Hz, 1H), 6.36 (s, 1H), 5.24 (s, 1H), 4.71 (t, J=8.9 Hz, 2H), 3.61-3.35 (m, 4H), 3.23 (dd, J=14.0, 6.9 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H). The corresponding (R)-enantiomer had a retention time of 1.25 minutes).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH3:37])[N:24]=1>>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH3:37])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: COc1cc2nc(C)nc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2nc(C)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 10 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-dimethoxy-2-methylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 53.1 mg (yield: 10%) of Compound 80 was obtained as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][O:31][CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH2:37][C@@H:33]4[CH2:32][O:31][CH3:30])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1CCOc1n[nH]c2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c12
Yield: 58 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (2R)-2-(methoxymethyl)pyrrolidine to give the title compound in 58% yield; NMR Spectrum: 1.43-1.49 (m, 1H), 1.61-1.70 (m, 2H), 1.81-1.87 (m, 1H), 2.32 (dd, 1H), 2.45 (s, 3H), 2.68 (m, 1H), 2.74-2.80 (m, 1H), 3.13-3.16 (m, 2H), 3.17 (s, 3H), 3.28-3.31 (m, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.27 (br s, 2H), 7.73 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].Cl[C:24]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2C)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccccc2C)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 5-(2′-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 5-(2′-methylbenzoyl)-1,4, α-trimethylpyrrole-2-acetate.