Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([Cl:21])=[O:17])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 2 h

Procedure:
To a suspension of 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylic acid 3bp (1.50 g, 4.82 mmol, 1 equiv) in dichloromethane (45 mL) at 24° C. was sequentially added oxalyl chloride (3.1 mL, 6.3 mmol, 1.3 equiv, 2.0 M in dichloromethane) and N,N-dimethylformamide (56 μL, 0.72 mmol, 0.15 equiv), as in General Procedure B. After 2 hr, the clear yellow solution was concentrated in vacuo (˜20 mm Hg) to afford crude 4bp.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[P:10]([O-:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[OH:7])=[CH:4][CH:3]=1
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99.1 %

Procedure:
Under a nitrogen atmosphere a solution of 20.0 grams (0.143 mole) of 4-chlorobenzaldehyde and 19.7 grams (0.142 mole) of diethyl phosphite was stirred at ambient temperature for 4 days. Gas chromatographic analysis of the reaction mixture indicated the reaction had not gone to completion. Ten ml of triethylamine was added, and the reaction mixture was stirred at ambient temperature for an additional 4 days. Gas chromatographic analysis of the reaction mixture indicated the reaction mixture still had not gone to completion. The reaction mixture was warmed to 40°-50° C. where it was stirred for 24 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding 39.2 grams of diethyl (4-chlorophenyl)hydroxymethylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=23)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(OCC)(=O)C>[F:22][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:2]=1[NH:1][C:32]([NH:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[F:23])=[O:33])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(N)c(F)c3)c2s1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.62 g, 5.1 mmol) was taken up in 55 mL of ethyl acetate followed by the dropwise addition of 2-fluoro-5-methylphenyl isocyanate (0.85 g, 5.6 mmol) in 5 mL ethyl acetate. The solution afforded a lavender solid after stirring at room temperature for overnight. The solid was collected by filtration and washed with diethyl ether to give methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate as an off white solid. Yield: 1.75 g (73%); MS [M+H]+ 470.1; 1HNMR (DMSO-d6) δ: 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H, 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 3.9 (s, 3H), 2.1 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:62][CH:59]2[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methylpiperidin-4-amine (41 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)]. Then the residue was partitioned with ethyl acetate and water, the organic extract was washed with aqueous sodium hydrogen carbonate (saturated) dried over sodium sulfate and concentrated to afford the title compound (94 mg, 72%) which was obtained as a white solid. MS: m/e=407.5 [M+H]+.
Reaction SMILES: CO.[NH3:3].[Br:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11](OCC)=[O:12])=[CH:7][CH:6]=1>>[Br:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([NH2:3])=[O:12])=[CH:7][CH:6]=1
Reactant: N
Reactant: CCOC(=O)COc1ccc(Br)cc1
Solvent: CO
Product: NC(=O)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
7M-Ammonia methanol solution (10 ml, 70 mmol) was added to ethyl 2-(4-bromophenoxy)acetate (1.0 g, 3.86 mmol), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure to give 2-(4-bromophenoxy)acetamide (870 mg, yield 98%) as a white solid.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1>CO.C(Cl)Cl.[Pd]>[S:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(C2=CCSCC2)cn1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(C2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A suspension of 5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-2-amine (260 mg, 1.35 mmol), Pd/C (36 mg, 0.33 mmol) in methanol (16 mL) was stirred under hydrogen at ambient temperature for 16 h. The reaction mixture was diluted with DCM (80 mL), and was filtered through Celite. The filtrate was concentrated to give 5-(tetrahydro-2H-thiopyran-4-yl)pyridin-2-amine (240 mg, 91% yield) as yellow color solid. LCMS (m/z): 195 (MH+), 0.46 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]O.C([S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[CH:43][S:42][C:41]=12)(=O)C.C[O-].[Na+].CO.BrCC1C=CC=CN=1.[Cl-].[NH4+]>ClCCl.CO>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:36][C:37]1[N:38]=[CH:39][N:40]2[CH:44]=[CH:43][S:42][C:41]=12
Reactant: OCc1ccccn1
Reactant: CC(=O)Sc1ncn2ccsc12
Agent: BrC(Br)(Br)Br
Agent: BrCc1ccccn1
Agent: C[O-]
Solvent: CO
Solvent: ClCCl
Product: c1ccc(CSc2ncn3ccsc23)nc1
Reaction time: 1.5 h

Procedure:
Triphenylphosphine (2.95 g) and 3.73 g of carbon tetrabromide were added to a solution of 0.724 ml of (pyridin-2-yl)methanol in 40 ml of dichloromethane under ice cooling, and the mixture was stirred at that temperature for 1.5 hr. The reaction solution was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to prepare 2-bromomethylpyridine. A solution of 990 mg of 7-acetylthioimidazo[5,1-b]thiazole in 5 ml of methanol was cooled in ice. A 1.018 M sodium methoxide/methanol solution (5.4 ml) was added to the cooled solution, and the mixture was stirred for 30 min. The above solution of 2-bromomethylpyridine in 5 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature for 20 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with saturated brine, and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 776 mg of 7-(pyridin-2-yl)methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[OH-].[K+]>[Cu].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccccc1S
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccccc1C(=O)O

Procedure:
Stir under reflux for 3 hours a mixture of 70 g (0.5 mole) of o-methoxythiophenol, 120.5 g (0.486 mole) of o-iodobenzoic acid 81.7 g (1.46 mole) of potassium hydroxide, 85 g (1.34 mole) of copper powder and 800 ml of water. Filter the reaction mixture hot and again filter the filtrate through celite. Acidify the filtrate with concentrated hydrochloric acid. Separate the precipitate, wash well with water and dry in vacuo at 70° C. to obtain the title product. (m.p. 198°-200° C.)
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:48](=O)([O:56]C1C=CC([N+]([O-])=O)=CC=1)[O:49][CH:50]([O:52][C:53](=[O:55])[CH3:54])[CH3:51].O>CN(C)C=O>[C:53]([O:52][CH:50]([O:49][C:48]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:56])[CH3:51])(=[O:55])[CH3:54]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)OC(C)=O)CC3)CC2=O)cc1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
To a suspension of 107 mg of ethyl 4-[[2-oxo-4-(piperidin-4-yl)piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 2 ml of N,N-dimethylformamide were added 110 mg of proton sponge and 85.7 mg of 1-acetoxyethyl 4-nitrophenyl carbonate with stirring at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 ml of water and extracted three times with 4 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation. The residue thus obtained was purified by chromatography on an LH-20 column (chloroform:methanol=1:1) to give 119 mg of the title compound (100%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][Mg]Cl>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([OH:36])([CH3:37])[CH3:35])=[CH:32][CH:33]=2)=[CH:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Cl
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)=O)cc1)n2S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(C(C)(C)O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a stirred solution of 1-{4-[1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (300 mg, 0.6 mmol) in dry tetrahydrofuran (5 mL) was added a methylmagnesium chloride solution in tetrahydrofuran (3 M, 2 mL, 6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h, quenched with an ammonium chloride solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 2-{4-[1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (160 mg, 51.8%) as a light yellow solid: LC/MS m/e calcd for C30H32N2O4S [M+H]+ 517.66, observed 517.1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27](O)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27]([O:1][C@H:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]3)[CH:28]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: COC(=O)[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Product: COC(=O)[C@H]1C[C@@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C

Procedure:
1-tert-butyl 2-methyl (2R,4R)-4-hydroxypiperidine-1,2-dicarboxylate (16) was coupled to 4-chloro-7-methoxyquinazolin-6-ol analogously as for the equivalent step in Example 7 to give 1-tert-butyl 2-methyl (2R,4S)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (17): 1H NMR Spectrum: (DMSO-d6) δ1.39-1.46 (10H, m), 1.73-1.84 (1H, m), 1.92-2.03 (1H, m), 2.10-2.18 (1H, m), 2.60-2.69 (1H, m), 3.15-3.40 (3H, m), 3.74-3.85 (1H, m), 4.01 (3H, s), 4.61-4.73 (1H, m), 5.06 (1H, s), 7.43 (1H, s), 7.47 (1H, s), 8.89 (1H, s), 8.97 (1H, s); Mass Spectrum: (M+H)+ 452.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:7]([CH3:25])[N:6]([CH2:26][C:27]([O:29]CC)=[O:28])[C:5]=1[CH3:32])(=[O:3])[CH3:2].[Li+].[OH-].CCOC(C)=O.Cl>CO.C1COCC1.O>[C:1]([C:4]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])=[C:7]([CH3:25])[N:6]([CH2:26][C:27]([OH:29])=[O:28])[C:5]=1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(C(C)=O)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(C)n(CC(=O)O)c1C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
To the crude mixture of ethyl 2-(3-acetyl-2,5-dimethyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (25 mg, 0.055 mmol) in MeOH:THF:water 3:3:1 (5 ml total) was added LiOH (3.96 mg, 0.165 mmol) and the resulting mixture was stirred for 30 min. To this mixture were added EtOAc (3 mL) and HCl (1N aq., 3 mL). The ethyl acetate layer was separated and dried over Na2SO4, filtered and subjected to column chromatography on silica gel (0 to 100% ethyl acetate in hexanes, followed by 0 to 20% MeOH in ethyl acetate). Collection and concentration of pertinent fractions resulted in the isolation of 2-(3-acetyl-2,5-dimethyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (10.5 mg, 45%) as a tan solid. 1H NMR (CDCl3/400 MHz) 8.23-8.20 (m, 1H), 7.84 (d, 2H), 7.51 (t, (t, 1H), 7.48-7.40 (m, 2H), 7.36-7.30 (m, 2H), 6.84-6.21 (m, 1H), 4.51 (s, 2H), 4.09 (s, 2H), 2.37 (s, 3H), 1.79 (s, 3H), 1.62 (s, 3H). MS m/z=426.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 5-bromonicotinaldehyde (4.36 g, 23.4 mmol) in EtOH (90 mL) at 0° C. was added sodium borohydride (4.4 g, 120 mmol). The reaction mixture was allowed to stir and warm to rt overnight and then quenched by the addition of saturated aq. NH4Cl. The mixture was concentrated to small volume and the residue was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give (4.21 g, 86%) as a light yellow oil which was used without purification. LCMS: (FA) ES+ 186.0.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([CH2:6][NH:7][C:8]2[C:9]3[N:10]([C:15](C(O)=O)=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[C:4]([CH3:25])[CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C>[CH3:18][C:16]1[N:17]=[C:9]2[C:8]([NH:7][CH2:6][C:5]3[C:4]([CH3:25])=[CH:3][C:2]([F:1])=[CH:23][C:22]=3[CH3:24])=[CH:13][C:12]([CH3:14])=[CH:11][N:10]2[CH:15]=1
Reactant: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)c(C(=O)O)n2c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)cn2c1
Yield: 55.5 %

Procedure:
A mixture of 8-(4-fluoro-2,6-dimethylbenzylamino)-2-methyl-6-methylimidazo[1,2-a]pyridine 3-carboxylic acid (0.35 g, 1.03 mmol) and diphenyl ether and refluxed for 10 min. Petroleum ether 40-60 was added at room temperature followed by hydrogen chloride in diethyl ether. The petroleum ether diphenlether layer was removed from the formed precipitate. The precipitate was washed with petroleum ether thereafter dissolved in methylene chloride and basified with sodium hydroxide (2M). The layers were separated and the organic layer was washed with water. The solvent was evaporated and the residue was chromatographed (hexane:ethyl acetate, 2:1) giving 0.17 g (50%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([CH2:36][O:37][C:38]2[CH:43]=[C:42]([Sn](C)(C)C)[N:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[N:39]=2)=[CH:34][CH:33]=1>CN(C=O)C.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.[Cu]I>[CH:17]([NH:16][C:14]1[O:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH:3]=[C:2]3[C:42]2[CH:43]=[C:38]([O:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[N:39]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[N:41]=2)=[N:12][N:13]=1)([CH3:18])[CH3:19]
Reactant: COc1ccc(COc2cc([Sn](C)(C)C)nc(S(C)(=O)=O)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (800 mg, 1.532 mmol) and 4-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)-6-(trimethylstannyl)pyrimidine (875 mg, 1.914 mmol) in DMF (5 mL) followed by Pd(PPh3)4 (88 mg, 0.077 mmol) and CuI (72.9 mg, 0.383 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was filtered through a plug of celite and washed with DCM. The filtrate was washed with water (25 mL×3) and the organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-20% EtOAc in DCM with 1% MeOH) to give N-isopropyl-5-(3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (660 mg, 0.958 mmol, 62.6% yield) as a brown solid. MS (ESI, pos. ion) m/z: 688.8 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[Cl:56]CCl>CO.Cl>[ClH:56].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([NH2:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: Cl
Solvent: CO
Product: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 0.5 h

Procedure:
5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide (A) (500 mg) was dissolved in a mixture of methanol (5 ml), dichloromethane (3 ml) and concentrated hydrochloric acid (0.7 ml) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was dissolved in a minimum of methanol. Ether was added to precipitate a solid which was collected by filtration. The solid was recrystallised from acetonitrile/methanol to give 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxamide hydrochloride (220 mg), m.p. 264° C. (dec); NMR (d6 -DMSO+d4 -acetic acid): 1.29(t, 3H), 1.39(t, 3H), 3.02(q, 2H), 3.42(q, 2H), 5.66(s, 2H), 7.1(d, 2H), 7.25(d, 2H), 7.45-7.75(complex m, 5H), 9.03(s, 1H), mass spectrum (+ve FAB, methanol/DMSO/NBA): 480 (M+H)+ ; microanalysis, found: C, 61.7; H, 4.9; N, 18.7%; C27H25N7O2HCl.0.5H2O requires: C, 61.7; H, 4.9; N, 18.6%.
Reaction SMILES: [Li].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][CH2:21]I>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:8]2([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Cc2cccnc2)cc1
Reactant: ClCCCCI
Agent: [Li]
Product: N#Cc1ccc(C2(c3cccnc3)CCCC2)cc1

Procedure:
Using procedure described in Example 36, the lithium salt of 4-(3-pyridylmethyl)-benzonitrile is treated with 1-chloro-4-iodobutane and the intermediate cyclized to obtain 1-(4-cyanophenyl)-1-(3-pyridyl)-cyclopentane.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)P(N(C)C)N(C)C.I[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1.[CH3:28][NH:29][CH:30]=[O:31].CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:26][C:24]1[CH:25]=[C:20]([N:29]([CH3:28])[CH:30]=[O:31])[CH:21]=[C:22]([CH3:27])[CH:23]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: CNC=O
Agent: [Cu]I
Agent: CN(C)P(N(C)C)N(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), K3PO4 (430 mg, 2.03 mmol), evacuated, backfilled with Ar. Hexamethylphosphorous triamide (18.5 μL, 0.102 mmol, 10 mol %) 5-iodo-m-xylene (145 μL, 1.00 mmol), N-methylformamide (72 μL, 1.23 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL) and ethyl acetate (2 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 76% yield of N-(3,5-dimethylphenyl)-N-methylformamide.