Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O)=[O:19].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2C=O)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate (1.0 g, 3.3 mmol), (2-formyl-5-methoxyphenyl)boronic acid (777 mg, 4.3 mmol), Pd(dppf)Cl2 (364 mg, 0.5 mmol), and K2CO3 (918 mg, 6.6 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 2 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[C:24]1([C:30]2[S:31][CH:32]=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH:19][C:35]([C:33]4[N:34]=[C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[S:31][CH:32]=4)=[O:36])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1)c1csc(-c2ccccc2)n1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenylthiazole-4-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol, dissolved in CH2Cl2, washed with dilute NaHCO3, concentrated and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5O2S2: 513.13. Found (M+H)+ m/z=514.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C(N(CC)CC)C>C(OCC)C>[O:15]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1
Reactant: Oc1ccccc1Cl
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C=COc1ccccc1

Procedure:
A solution of 5.77 mmol of ethyl propiolate in 20 ml ethyl ether is treated with 5.77 mmol 2-chlorophenol and 0.4 ml triethylamine (added slowly and with stirring). The reaction mixture is stirred overnight at RT, after which the solvent is removed under vacuum to yield ethyl 3-phenoxy-2-propenoate.
Reaction SMILES: [CH:1]([C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7](C(OC)=O)[S:6][C:5]=2[CH:4]=1)=[O:2].[OH-].[K+].Cl.N1C2C(=CC=CC=2)C=CC=1>C(Cl)(Cl)Cl.CCCCCC.O.CO>[CH:8]1[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]([CH:1]=[O:2])=[CH:4][C:5]=2[S:6][CH:7]=1
Reactant: COC(=O)c1cc2c(cc(C=O)c3ccccc32)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: O=Cc1cc2sccc2c2ccccc12
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added methyl 5-formylnaphtho-[2,1-b]thiophene-2-carboxylate (7A, 9.75 g, 36 mmol), KOH (85%, Mallinckrodt Co., St. Louis, Mo. 63147, 18.0 g, 320 mmol), CH3OH (40 mL) and H2O (80 mL). The mixture was refluxed for 1.5 h, cooled and neutralized with 3N HCl (500 mL). A yellow solid formed which was filtered and washed with H2O (3×300 mL) and dried in a vacuum oven overnight to give crude 5-formylnaphtho-[2,1-b]thiophene-2-carboxylic in quantitative yield. This material was then slurried with quinoline (Mallinckrodt, 60 mL) and cuprous oxide (MCB, 6.2 g, 43.3 mmol) and heated to 185° in an oil bath for 1 h. The reaction mixture was allowed to cool to RT then partitioned between Et2O (500 mL) and concentrated HCl (200 mL) containing saturated NH4Cl (100 mL). The layers were separated and the aqueous layer extracted with additional Et2O (500 mL). The Et2O layers were combined and washed in succession with 1N HCl (300 mL), H2O (2×300 mL) and saturated NaCl solution (2×300 mL), dried (MgSO4), filtered and concentrated to give a light brown crude solid. After chromatography on SiO2 using CHCl3 /hexane as the eluting solvent and crystallization (CHCl3 /cyclohexane) there was obtained 4.98 g (65.2% yield) of naphtho[2,1-b]thiophene-5-carbaldehyde, mp 101°-102°, (C,H,S).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:10][CH:8]1[CH2:7][NH:6][CH2:5][C:4]2[CH:3]=[CH:2][O:1][C:9]1=2
Reactant: OC1CNCc2ccoc21
Reactant: Fc1ccccc1Br
Product: Brc1ccccc1OC1CNCc2ccoc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:31])[CH2:13][CH2:14][C:15]3[C@@:16]4([CH3:30])[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][C@@H:17]4[C:18](=[O:21])[O:19][C:20]=3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7])[CH:2]=[CH2:3]>C(OCC)(=O)C.[C].[Pd]>[CH3:29][O:28][CH2:27][O:26][C@@H:23]1[CH2:22][C@@H:17]2[C:18](=[O:21])[O:19][C:20]3[C@@H:11]4[CH2:10][CH2:9][C@H:8]([C@H:6]([CH3:7])[CH2:5][O:4][CH2:1][CH2:2][CH3:3])[C@@:12]4([CH3:31])[CH2:13][CH2:14][C:15]=3[C@@:16]2([CH3:30])[CH2:25][CH2:24]1
Reactant: C=CCOC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OCOC)C[C@@H]1C(=O)O3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OCOC)C[C@@H]1C(=O)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Compound 66 (3.7 mg, 0.0086 mmol) obtained in Example 68 was dissolved in ethyl acetate (2 mL), and 10% palladium-carbon (2.0 mg) was added thereto, followed by stirring at room temperature for 2 hours under a hydrgen atmosphere. The catalyst was sparated by filtration, followed by concentrating the filtrate to obtain the title compound (2.8 mg, 76%).
Reaction SMILES: C(O)/C=C\CCCCCCC.[CH2:12]([OH:26])[C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C2C(=CC=CC=2)C=CC=1>>[CH2:12]([OH:26])/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC#CCO
Agent: CCCCCCC/C=C\CO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCC/C=C\CO

Procedure:
cis-2-Tetradecen-1-ol was prepared as described above for cis-2-decen-1-ol except that 1.0 g of 2-tetradecyn-1-ol, 50 mg of catalyst, and 0.10 ml of quinoline was used. A clear oil, 0.72 g, was obtained after kugelrohr distillation. 1H NMR δ5.57 (m, 2) 4.19 9d, 2, J=6 Hz), 2.07 (dd, 2, J=6, 13 Hz), 1.5-1.2 (m, 18), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[Cl:25]C1C=CC(C2N=C3C=CC=CN3C=2C=O)=CC=1.CN1C=CN=C1>>[Cl:25][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]3[C:8]=2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Agent: Cn1ccnc1
Product: Cn1ccnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Yield: 19 %

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-methyl-1H-imidazole. (21.6 mg, 19% yield). M/e+ 323.1 for C18H15ClN4 (M+H)+; 1H-NMR (300 MHz, DMSO, δ) 8.25 (d, J=6.9 Hz, 1H), 7.75 (dd, J=8.7, 2.1 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.51 (dd, J=8.4, 1.8 Hz, 2H), 7.28 (t, J=2.1 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 6.91 (t, J=6.9 Hz, 1H), 6.68 (d, J=0.9 Hz, 1H), 4.53 (s, 2H), 3.58 (s, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C.CCCCCC>[C:1]1([S:7][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
Benzenethiol (500 mg, 4.54 mmol) was dissolved in 6 mL of DMF. K2CO3 (940 mg, 6.81 mmol) was added and the resulting mixture was stirred at room temperature for 10 mins. 4-Fluoro-benzaldehyde (675 mg, 5.44 mmol) was then added and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was then stirred at 80° C. for 3 hours. Water was added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 5/95 EtOAc:hexane as the eluent) afforded 940 mg (96% yield) of 4-phenylsulfanyl-benzaldehyde. LC-MS purity: 91.3%
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)C=C.[CH3:25][C:26]1C=CC=C[C:31]=1C>>[CH2:31]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:9][CH:10]=[N:11]2)[CH:26]=[CH2:25]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OC
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.54 g, 1.39 mmol) (from Example 17, Step C, supra) in o-xylene (75 mL) was heated at 150° C. for 4.5 hours, during which time TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.33 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)n1nnc(N)n1
Product: CC(C)n1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 175-177° and MS: (neg. ions): m/e=320.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:13][C@@H:12]1[CH3:41])(=[O:10])[CH3:9]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=3)=[CH:18][CH:19]=2)[C@H:14]([NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:13][C@@H:12]1[CH3:41])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(-c3cn(CC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cn(CC(=O)O)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 84 %

Procedure:
Trifluoracetic acid (1 mL) was added at room temperature to a solution of 1,1-dimethylethyl {(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetate (for a preparation see Example 91) (1.26 g, 2.68 mmol) in DCM (5 mL). The reaction mixture was allowed to stand at room temperature for 16 h then concentrated in vacuo. The residue was co-evaporated twice with toluene then triturated with Et2O to give {4-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}acetic acid trifluoroacetate (1.19 g, 2.252 mmol, 84%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:15]([C:14]([F:13])([F:23])[F:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][C:8]=2[CH:11]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc([N+](=O)[O-])ccc2OC1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 5-nitrosalicylaldehyde (4.80 g, 28.7 mmol) and ethyl 4,4,4-trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was warmed to 60° C. and treated with anhydrous K2CO3 (3.90 g, 28.9 mol). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacua to afford an oil. The oil was dissolved in diethyl ether (5 mL). Hexanes was added until the solution became cloudy. Upon standing at room temperature overnight the ester was obtained as yellow crystals (0.856 g, 7% yield). This material was of sufficient purity to be used in subsequent steps without further purification. 1H NMR (CDCl3/300 MHz) 8.15–8.19 (m, 2H), 7.74 (s, 1H), 7.09 (d, 1H, J=8.9 Hz), 5.81 (q, 1H, J=5.8 Hz), 4.29–4.39 (m, 2H), 1.35 (t, 3H, J=6.0 Hz),
Reaction SMILES: [CH2:1]([N:8]1[C:15](=O)[CH2:14][O:13][CH2:12][C:9]21[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F-].[Na+].O>O1CCCC1>[CH2:1]([N:8]1[CH2:15][CH2:14][O:13][CH2:12][C:9]21[CH2:10][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC2(CC2)N1Cc1ccccc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCOCC23CC3)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A solution of 4-benzyl-5-oxo-7-oxa-4-azaspiro[2.5]octane (695.3 mg) in tetrahydrofuran (8 ml) was added dropwise to an ice-cooled suspension of lithium aluminum hydride (112 mg) in tetrahydrofuran (5 ml) over 20 minutes and then the mixture was stirred at 50° C. for 2 hours under nitrogen atmosphere. After being cooled to room temperature, sodium fluoride (495 mg) was added to the mixture. The mixture was stirred vigorously and cooled with ice-bath. Water (0.16 ml) was added thereto and the mixture was filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent to give 4-benzyl-7-oxa-4-azaspiro[2.5]octane (334.8 mg). 4-Benzyl-7-oxa-4-azaspiro[2.5]octane in ethanol (8 ml) was hydrogenated over palladium hydroxide on carbon for 2 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate was treated with 4N hydrogen chloride in ethyl acetate (2 ml) and concentrated under reduced pressure to give 7-oxa-4-azaspiro[2.5]octane hydrochloride (81 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]=2[N:7]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[N:13][C:14]6[C:19]([CH:20]=5)=[CH:18][CH:17]=[CH:16][CH:15]=6)[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)[CH3:22]
Reactant: Clc1ncc2scc(-c3cnc4ccccc4c3)c2n1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cnc6ccccc6c5)c4n3)cn2)CC1
Yield: 68.4 %

Procedure:
N-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)-7-(quinolin-3-yl)thieno[3,2-d]pyrimidin-2-amine (32 mg, 67% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidine (30 mg, 0.10 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (31 mg, 0.15 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>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>[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23]([C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2cnn([C@H](CC#N)C3CCCC3)c2)OC1(C)C
Reactant: Clc1ncnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC[C@H](C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 95 °C
Reaction time: 17 h
Yield: 64.3 %

Procedure:
Method C. To a 25 mL round bottom flask equipped with a stir bar, condenser, and three-way valve connected to nitrogen and vacuum was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 154 mg, 1.00 mmol), (3R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-24, 445 mg, 1.41 mmol, 1.41 equiv), 1,4-dioxane (2.78 mL, 35.6 mmol), water (1.39 mL, 77.2 mmol), and potassium carbonate (K2CO3, 693 mg, 5.02 mmol, 5.0 equiv) at room temperature. The resulting mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.180 mmol, 0.18 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 17 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (20 mL) and 20% aqueous brine (11 mL). The mixture was stirred vigorously at room temperature until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-100% ethyl acetate/hexanes gradient elution) to afford (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-12, 197 mg, 306.4 mg theoretical, 64.3% yield) as colorless oil, which was solidified upon standing at room temperature. For (R)-12: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.1 (bs, 1H), 8.80 (d, 1H, J=0.42 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.59 (dd, 1H, J=2.34, 3.51 Hz), 6.98 (dd, 1H, J=1.40, 3.44 Hz), 4.53 (td, 1H, J=19.5, 4.63 Hz), 3.26 (dd, 1H, J=9.77, 17.2 Hz), 3.18 (dd, 1H, J=4.32, 17.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65 to 1.13 (m, 7H); C17H18N6(MW, 306.37) LCMS (EI) m/e 307 [M++H].
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[C:5]([CH2:16][CH3:17])[C:4]=1[CH:18]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[C:5]([CH2:16][CH3:17])[C:4]=1[CH2:18][C:20]1[NH:24][CH:23]=[CH:22][N:21]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccccc2)c(CC)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Oc2ccccc2)c(CC)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diethyl-3-phenoxy-benzyl)-1H-imidazole was prepared from rac-(2,6-diethyl-3-phenoxy-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 307.3 ([M+H]+, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]1[C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=[N:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:40][CH2:39][C:38]5[N:34]([CH3:33])[N:35]=[CH:36][CH:37]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: Cn1nccc1CN
Product: Cn1nccc1CNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 84.5 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with (1-methyl-1H-pyrazol-5-yl)methylamine (available from Aldrich Chemical Company, Inc.; 69 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(2-methyl-2H-pyrazol-3-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (100 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.07 (t, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.4, 1.9 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.32 (d, J=1.8 Hz, 1H), 6.19 (d, J=1.5 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Yield: 79 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 4′-methoxy[1,1′-biphenyl]-4-sulfonyl chloride (15.6 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 79% yield (16 mg). MS (ESI+) calcd mass for C20H17N5O3S 407.105210, found 407.105280.