Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:30][CH2:29][CH2:28][S:27][CH3:26])=[N:3][CH:4]=1
Reactant: CSCCN
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: CSCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 13 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.48 mmol) obtained in Example 54 and 2-methylthioethylamine (200 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (29 mg, 13%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 96.7 %

Procedure:
A mixture of ethyl 6-chloro-4-phenyl-3-quinolinecarboxylate (2.5 g), potassium hydroxide (2.24 g) and ethanol (25 ml) was heated for 10 mins. at 80° C. The mixture was diluted with water and acidified with hydrochloric acid to give 6-chloro-4-phenyl-3-quinolinecarboxylic acid as crystals (2.20 g, 96.9%), which was recrystallized from a mixture of methanol and chloroform as pale yellow prisms. m.p. 269°-270° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([C:50](O)=[O:51])[NH:32][C:33]([O:35][CH2:36][CH:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:18]([O:22][C:23](=[O:53])[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([NH:32][C:33]([O:35][CH2:36][CH:37]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]2=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:34])[C:50](=[O:51])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[C:9]2[NH:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 182 mg (0.8 mmol) of 2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 390 mg (0.8 mmol) of 4-[2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acid tert-butyl ester, 216 mg (1.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 192 mg of 1-hydroxybenzotriazole hydrate was added 2.5 mL of dimethylformamide. The mixture was allowed to stir at room temperature overnight. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated to 670 mg of crude product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:38]([CH3:40])[CH3:39])=[C:32]([NH:34][C:35]([NH2:37])=[S:36])[CH:33]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:38]([CH3:40])[CH3:39])=[C:32]([NH:34][C:35]([NH:37][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:36])[CH:33]=1
Reactant: CC(C)c1ccc(Cl)cc1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CC(C)c1ccc(Cl)cc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) and isolated as an off-white solid (0.170 g, 38%).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14][CH2:13][C@H:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of lithium hydroxide (11.2 mg, 0.468 mmol) and ethyl 2-((5S,6S,9S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetate (27.8 mg, 0.060 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred at room temperature for 24 h. The solvent was removed via high vacuum and the crude product (MS(ESI)[M+H+]=433.17) was used as is in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]2[N:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]=1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: c1csc(C2=Nc3cccnc3Nc3ccccc32)c1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2cccs2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(2-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17](OC(OCC)OCC)(=O)C.[OH-].[NH4+]>O>[CH3:16][CH:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:17]1)[CH2:14][OH:15]
Reactant: CC(CO)Nc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(CO)n1cnc2cnc3ccccc3c21

Procedure:
2-[(3-Amino-4-quinolinyl)amino]-1-propanol (0.113 mole) as a crude reaction product obtained by the method of Example 4, was mixed with a 20 percent molar excess of diethoxymethyl acetate (22.3 g, 0.136 mole) and heated for 0.75 hour. To the mixture was added 150 ml of water. The resulting mixture was made basic with concentrated ammonium hydroxide, and extracted first with ethyl acetate, then with chloroform. The extracts were combined, dried over magnesium sulfate, and evaporated, slurried in 1:1 chloroform/diethyl ether and separated by filtration to provide the solid product, beta-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol, m.p. 170°-174° C. after recrystallization from ethanol with treatment with decolorizing carbon. Analysis: Calculated for C13H13N3O: %C, 68.7; %H, 5.8; N, 18.5; Found: %C, 68.5; %H, 5.8; %N, 18.5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([Cl:17])=[O:13])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-quinolinecarboxylic acid (580 mg, 3.35 mmol) in dichloromethane (25 mL) was added oxalyl chloride (2M in CH2Cl2, 3.4 mL, 6.7 mmol) dropwise at room temperature. DMF (1 drop) was added, resulting in immediate gas formation. The reaction mixture was stirred at room temperature for 2 h. Dichloromethane was evaporated. Additional dichloromethane (20 mL) was added to the residue. Concentration of the organic solvent gave the crude product. (640 mg, 99%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C1COCC1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:11])[NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (1.068 g, 5.71 mmol) and 4-amino-1-Boc-piperidine (1.0 g, 5 mmol) was dissolved in THF (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (1.7 g, 4.39 mmol, 88%). 1H NMR (d6-DMSO, 300 Mhz): ∂ 8.77 (s, 1H), 7.55 (s, 4H), 6.26 (d, J=10 Hz, 1H), 3.80 (d, J=Hz, 2H), 3.64 (m, 1H), 2.88 (br, 2H), 1.78 (d, J=5 Hz, 2H), 1.38 (s, 9H), 1.23 (m, 2H).
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:7]#[N:8].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[OH:13][CH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([CH2:3][OH:2])[CH:11]=1)[C:7](=[NH:8])[O:16][CH2:14][CH3:15]
Reactant: CCO
Reactant: N#Cc1cc(CO)cc(CO)c1
Agent: Cl
Product: CCOC(=N)c1cc(CO)cc(CO)c1
Reaction time: 5 h
Yield: 92 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3,5-bis-hydroxymethyl-benzonitrile (50 mg, 0.23 mmol) in anhydrous ethanol (100 mL) at room temperature. After 5 h, hydrogen chloride gas was stopped. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3,5-bis-hydroxymethyl-benzimidate hydrochloride (52 mg, 92%). It was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[ClH:15]>[Pd].CO>[ClH:15].[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CN)c1
Reaction time: 65 h

Procedure:
A mixture of 3-(3-cyano-phenyl)-acrylic acid methyl ester of Step B (1.37 g, 7.32 mmol), 10% palladium on carbon (1.0 g), and HCl (4N in dioxane, 3 mL) in MeOH (50 mL) was hydrogenated on a Parr shaker at 50 psi for 65 h. The catalyst was removed by filtration through Celite and the solution was concentrated to provide the title compound (1.97 g). 1H NMR (400 MHz, CD3OD) δ 7.35-7.24 (m, 4H), 4.06 (s, 2H), 3.60 (s, 3H), 2.92 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.CON(C)[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13]>C1COCC1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(Br)cn1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (1.25 g, 7.2 mmol) in anhydrous THF (15 mL) at −40° C. under an argon atmosphere, lithium dibutyl(isopropyl)magnesate (5.2 mL, 0.7 M, 3.6 mmol) was added. The stirring was continued at the same temperature for 1 h. The resulting mixture was cannulated into a solution of 8 (1.5 g, 5.5 mmol) in THF (20 mL) at −78° C. The solution was maintained at −78° C. for 1 h, and then quenched with sat. aqueous NH4Cl and allowed to warm to room temperature. The organic layer was separated and then the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by chromatography on silica gel to obtain the desired compound 9a (0.7 g, 42%). 1H NMR (CDCl3): δ 1.49 (s, 9H), 1.68-1.87 (m, 4H), 2.63 (s, 3H), 3.35 (m, 1H), 4.18 (br, 2H), 7.28 (d, J=8.4 Hz, 1H), 8.11 (dd, J=8.4, 2.1 Hz, 1H), 9.04 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[CH:15]=[CH:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn(C3CCCCO3)n2)cc1
Yield: 92.6 %

Procedure:
A solution of the 5-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (322 mg, 1.33 mmol) prepared in Example 148c, 3,4-dihydro-2H-pyran (0.728 mL, 7.98 mmol) and p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) in dichloromethane (5.0 mL) was stirred for 3 hours under reflux. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (402 mg, 93%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)=[CH:13][CH:12]=1>>[N:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:5]5[C:4]/4=[CH:9][CH:8]=[CH:7][N:6]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2c(C=Cc3ccncc3)n[nH]c2c1
Product: O=C1Nc2ncccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 87.6 %

Procedure:
The title compound (64 mg, 64%) was synthesized as orange red solid according to the method described for Example A11B from 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (26.8 mg, 0.2 mmol) and E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H, NH), 11.28 (s, 1H, NH), 8.57 (d, J=5.6 Hz, 2H), 8.39 (d, J=8.4 Hz, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.95 (s, 2H), 7.90 (d, J=6.4 Hz, 1H, partially overlapping with the peak at 7.87 ppm), 7.87 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.90 ppm), 7.71 (d, J=5.6 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H, partially overlapping with the peak at 7.56 ppm), 7.56 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.57 ppm), 6.91 (dd, J=7.6 Hz, 5.2 Hz, 1H); MS ESI 366.1 [M+H]+, calcd for [C22H15N5O+H]+ 366.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([SiH:24]2[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:27]2[CH2:28][CH2:29][Si@H:24]([CH:21]3[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COCCCCCC1CCC([SiH]2CCC(O)CC2)CC1
Product: COCCCCCC1CCC([Si@H]2CC[C@H](OC(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-fluorobenzoic acid and 4-(4-(5-methoxypentyl)cyclohexyl)-4-silacyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClC1C=C(C=CC=1)C(OO)=O.C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (9.3 g, 23.0 mmol). 3-Chloroperoxybenzoic acid (7.9 g of 50% pure material, 23 mmol) was added in five portions during the oxidation step, which was stirred overnight. Additional 3-chloroperoxybenzoic acid (200 mg) was added, and the reaction was stirred for 20 mintues before ammonium hydroxide (60 mL) and p-toluenesulfonyl chloride (6.58 g, 34.5 mmol) were added. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration and purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 6.0 g of 7-bromo-2-ethoxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 186-188° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[N:2]=1.[ClH:18]>C1COCC1.O1CCOCC1>[ClH:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([NH2:10])[CH2:9][CH2:8]2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2cccnn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-(pyridazin-3-yl)cyclopropylcarbamate (0.3 g) in THF (3 ml) at 0° C. was added HCl in dioxane (5 ml) and the mixture stirred at r.t. for 3 hr. The reaction mixture was concentrated, and the crude product was taken for the next coupling reaction. Yield: 0.21 g
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=O.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:1][C:3]3[O:7][C:6]([C:8]4[CH:12]=[CH:11][S:10][C:9]=4[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=3)[CH2:32][CH2:33]2)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH:18]([CH3:34])[CH3:17]
Reactant: COC(=O)c1sccc1-c1ccc(C=O)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COC(=O)c1sccc1-c1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)o1

Procedure:
Prepared by Procedure F and Scheme R using methyl 3-(5-formyl-2-furyl)-2-thiophenecarboxylate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]=O)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[O:34]1[CH2:35][CH2:36][N:31]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:26]4[CH2:30][CH2:29][O:28][CH2:27]4)[CH:9]=3)=[CH:25][CH:24]=2)[CH2:32][CH2:33]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3C=O)cc1)cn2C1CCOC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3CN3CCOCC3)cc1)cn2C1CCOC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]benzaldehyde (0.15 g), morpholine (64 mg), sodium triacetoxyborohydride (117 mg) and 1,2 dichloroethane (5 ml) was stirred at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was filtered through an EMPORE® cartridge. The filtrate was evaporated and the residue was dissolved in dichloromethane (5 ml) and then tris(2-aminoethyl)amine-polymer bound (0.3 g) and 2 drops of glacial acetic acid were added and the mixture was stirred at ambient temperature overnight. The polymer was removed by filtration and washed with dichloromethane and then with methanol. The combined organic filtrate and washings were evaporated under reduced pressure to give an oil which was triturated with diethyl ether/ethyl acetate with warming to dissolve the solid and then the solution was cooled in ice and filtered to give 5-[4-(2-morpholinomethylphenoxy)phenyl] -7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 169-171° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[NH2:6])[CH3:2].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCc1cc(N)cc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2cccnc2)c1

Procedure:
The title compound (0.276 g, 0.87 mmol) was prepared by the methodology of description 67, using 3-ethyl-5-(pyrid-3-yl)aniline, phenyl chloroformate (0.13 ml, 0.96 mmol) and triethylamine (0.13 ml, 0.96 mmol) in dichloromethane (10 ml)