Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C>[C:22]([O:21][C:19](=[O:20])[CH2:18][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: Ic1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nc(I)c2cccnc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 3-iodo-7-azaindazole (25.50 g) and K2CO3 (41.4 g) in DMF (200 mL) was heated to 85° C. and t-butyl chloroacetate (14.3 mL) was slowly added. The mixture was stirred at this temperature for 1 hour (h), cooled to room temperature followed by the addition of water (300 mL). Filtration of the reaction mixture provided (3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[OH:16]O>C(O)(=O)C>[N+:1]1([O-:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: OO
Agent: c1cncc(-c2ccnc3ccnn23)c1
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1

Procedure:
A mixture of 1.96 g. of 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine, 25 ml. of glacial acetic acid and 2 ml. of 30% hydrogen peroxide is heated on a steam bath for 2 hours. The solvent is removed and the residue crystallized from ethanol to give 0.85 g. of the product of the example, m.p. 223°-226° C.
Reaction SMILES: Br[C:2]1[CH:36]=[C:35]([F:37])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:4]([F:38])[CH:3]=1.C(Cl)Cl.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>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].C1(C)C=CC=CC=1.CCO>[F:38][C:4]1[CH:3]=[C:2]([C:47]2[CH:48]=[CH:49][C:44]([C:43]([F:54])([F:53])[F:42])=[CH:45][CH:46]=2)[CH:36]=[C:35]([F:37])[C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cnc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4c(F)cc(Br)cc4F)c3c2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cnc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4c(F)cc(-c5ccc(C(F)(F)F)cc5)cc4F)c3c2)c(F)c1
Temperature: 110 °C

Procedure:
To a 5 mL microwave vial were added racemic cis-2-{1-(4-bromo-2,6-difluorobenzyl)-6-[(3-fluoro-5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid (40 mg, 0.07 mmol), Pd(dppf)Cl2.DCM (5.0 mg, 0.007 mmol), (4-(trifluoromethyl)phenyl)boronic acid (18 mg, 0.010 mmol), K2CO3 (0.2 mL, 1M in H2O), EtOH (0.67 mL) and toluene (0.3 mL). The mixture was heated at 110° Celsius for 1 h, cooled to RT, concentrated to dryness and purified using FCC to provide the title compound. MS (ESI): mass calcd. for C35H29F6N3O3, 653.21; m/z found, 654.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.19 (s, 1H), 7.78 (dd, J=40.8, 8.3, 4H), 7.56-7.33 (m, 4H), 7.04 (d, J=2.2, 1H), 6.87 (dd, J=8.8, 2.3, 1H), 5.63 (two d, J=16.3, 2H), 5.23-5.11 (m, 2H), 3.90 (d, J=4.6, 1H), 2.78-2.67 (m, 1H), 2.40-2.23 (m, 4H), 2.16-2.06 (m, 1H), 2.05-1.89 (m, 2H), 1.87-1.68 (m, 2H), 1.51-1.37 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:41](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C.CO>CO.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:27]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(OC)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a mixture of (210 mg, 0.37 mmol) of 6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Example 163, Part C) in 2.0 mL of MeOH/CH3CN solution (1:9 ratio) was added (0.091 mL, 0.52 mmol) of diisopropylethylamine and (0.26 mL, 0.52 mmol) 2 M (trimethylsilyl)diazomethane in hexanes at room temperature. The reaction was stirred for 24 h. Another portion (0.20 mL, 0.40 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added along with 0.5 mL of MeOH, and the solution was stirred at room temperature for 24 h. Another portion (0.10 mL, 0.20 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added, and the solution was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness under reduced pressure and then taken up in 30 mL of H2O and washed with 25 mL of H2O and 1:1 satd. NaHCO3-brine solution which were back extracted with CH2Cl2 (3×30 mL) and EtOAc (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 7% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 92 mg (43%) of a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][NH:13]/[N:14]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11]
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: CNN
Solvent: CCO
Product: CN/N=C/c1c(F)cc(F)cc1F

Procedure:
A solution of 2,4,6-Trifluoro-benzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 ml, 18.74 mmol) in 20 ml anhydrous ethanol was stirred at room temperature for 1 hour. Solvent was evaporated to give the title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+=189, tR=2.16 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: Clc1ccc2[nH]ccc2c1
Product: Clc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 96 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-chloroindole (5 g, 33 mmol) ) to afford 9.14 g (96%) of the title compound as a white solid: mp 178-181° C.; MS EI m/e 273 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH3:29])[C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CCc1c(C2=NCC(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
To a solution of 26 (100 mg, 0.23 mmol) in acetonitrile (8 mL) at room temperature was sequentially added potassium carbonate (150 mg, 1.09 mole) and methyl iodide (2 g, 14.08 mmol) slowly. The mixture was stirred at 60° C. for 6 h. Water was added and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography on silica gel eluting with hexanes/ethyl acetate (1:1) gave the compound 29 (70 mg, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.30 (d, 2H), 7.25 (dd, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 4.88 (s, 0.82H), 4.51 (s, 1.18H), 3.42 (s, 1.77H), 3.24 (s, 1.23H), 2.65 (q, 2H), 1.15 (t, 3H); ESMS m/: 447.0 (M+1).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=O.C(N(CC)C(C)C)(C)C>C(#N)C.CC1CCCO1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:3]=[C:1]([CH3:2])[N:4]([NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:14]=1
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Solvent: CC#N
Product: Cc1nc(-c2ccccc2F)cn1NC(=O)OC(C)(C)C

Procedure:
Compound C1 (11.4 g, 65.8 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (13.0 g, 59.9 mmol) and N,N-diisopropylethylamine (23.0 mL, 132 mmol) were combined in a mixture of acetonitrile (100 mL) and 2-methyltetrahydrofuran (300 mL) and heated at reflux for 18 hours. After cooling, the reaction mixture was concentrated in vacuo; the residue was mixed with ethyl acetate, then washed sequentially with saturated aqueous ammonium chloride solution and with saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale brown foam. Yield: 18.1 g, assumed quantitative. LCMS m/z 292.4 [M+H]+. 1H NMR (500 MHz, CDCl3), presumed to be a mixture of rotamers: δ 8.15 (v br s, 1H), 8.03-8.07 (m, 1H), 7.30 and 7.31 (2 s, 1H), 7.13-7.20 (m, 2H), 7.02-7.08 (m, 1H), 2.31 (s, 3H), 1.49 (br s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17](O)=[O:18])[C:5]=3[C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:18])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C1CCNC1
Reactant: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c2ccc(Cl)cc2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21
Reaction time: 15 h

Procedure:
A solution of 1.5 g (4 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 1.2 g (7.4 mmol) of 1,1′-carbonylbis-1H-imidazole in tetrahydrofuran is stirred for 1 h at 50° C. The mixture is cooled and an excess of pyrrolidine is added. After stirring for 15 h, the precipitate is collected by filtration, washed with water and with ether and recrystallized from propan-2-ol. 0.65 g (1.5 mmol) of solid is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2].[I-].[Na+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCN1CCCCC1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one (0.72 g, 2.26 mmol), sodium iodide (0.15 g, 0.1 mmol), and piperidine (1.72 g, 20 mmol) were combined in DMF (8.0 mL) and the mixture was heated to 80° C. for 4.5 hours. Water was then added to form a precipitate. Filtration gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)pentan-1-one (0.8 g, 2.18 mmol), m.p. 74°-75° C.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[N:13]2[CH3:18]
Reactant: C1CCNC1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)N2CCCC2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and pyrrolidine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=245.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:32](=[CH:33][CH:34]=2)[O:31][C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:17][C:16]3=[O:35])[CH:10]=[N:9][CH:8]=1)(C)(C)C.[ClH:37]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[O:35]=[C:16]1[C:15]2[C:32](=[CH:33][CH:34]=[C:13]([C:11]3[CH:10]=[N:9][CH:8]=[C:7]([CH:12]=3)[C:6]([OH:36])=[O:5])[CH:14]=2)[O:31][C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-{1′-tert-butoxycarbonyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid tert-butyl ester (14.0 g, 28.3 mmol) was dissolved in CHCl3 (70 mL) and 4N HCl in dioxane (210 mL) was added thereto, and stirred at room temperature for 20 h. The resulted precipitate was filtered and washed with CHCl3 and Et2O to afford 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11]>O1CCCC1.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:10]=[S:11])=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C=Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 4-bromo-2-chloroaniline (30.0 g, 0.145 mol) in tetrahydrofuran (150 mL) and aqueous saturated sodium hydrogen carbonate (150 mL) was added thiophosgene (13.3 mL, 0.174 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with cold-n-hexane to give the title compound as a colorless solid (25.51 g, 0.103 mol, 71%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[C-:18]#[N:19].[K+].CCOCC>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reaction time: 6 h
Yield: 68.4 %

Procedure:
A solution of 17 g of 3-bromomethyl-4'-chlorobenzophenone in 75 cc of dioxane at 70° C. was added to the solution of 26.5 g of potassium cyanide in 75 cc of water and the mixture was refluxed with stirring for 6 hours. After cooling, 500 cc of ether were added to the mixture and the aqueous phase was decanted off. The organic phase was washed with water until the wash waters were neutral, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was crystallized from methanol to obtain 9.61 g of 3-p-chlorobenzoyl phenyl acetonitrile melting at 86° to 90° C.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: Nc1nnco1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1nnco1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 239-240° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from [1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride. The [1,3,4]oxadiazol-2-ylamine, white solid, MS: m/e=85 (M+) used in the above reaction was prepared in accordance with the general method of example 44b from formic acid hydrazide and cyanogen bromide.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3].C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=2)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccc(Cl)cc1Cl
Temperature: 115 °C
Yield: 43.2 %

Procedure:
To a solution of 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (0.133 g, 0.320 mmol) in 1,4-dioxane (8 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (0.115 g, 0.384 mmol), lithium chloride (0.0407 g, 0.961 mmol), copper (I) iodide (0.0183 g, 0.0961 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0185 g, 0.0160 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 3 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.0650 g, 43%). LCMS: (FA) ES+, 472, 474. 1H NMR (400 MHz, d4-Methanol) δ: 8.75-8.72 (m, 1H), 8.45-8.41 (m, 1H), 7.71-7.68 (m, 1H), 7.58-7.55 (m, 1H), 7.43-7.35 (m, 2H), 7.20 (d, J=1.51 Hz, 1H), 7.14 (d, J=1.51 Hz, 1H), 5.69-5.58 (m, 1H), 5.13-5.08 (m, 1H), 4.94-4.88 (m, 1H), 4.38-4.33 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:46][C:47]1[CH:52]=[C:51](B(O)O)[CH:50]=[CH:49][N:48]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:51]4[CH:50]=[CH:49][N:48]=[C:47]([Cl:46])[CH:52]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc2nc(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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
Product: Cc1cc2nc(-c3cccc(-c4ccnc(Cl)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3- (trifluoromethylsulfonyloxy)phenyl)benzo[d]thiazol-6-yl)ethyl pivalate (30 mg, 0.0438 mmol), 2-chloropyridine-4-boronic acid (10 mg, 0.0657 mmol), 2N K2CO3 (100 μL), Pd(PPh3)4 (5.0 mg, 0.0044 mmol) in dioxane (2 mL) was heated at 120° C. in sealed tube for 2hs. The reaction was washed by sat. NaHCO3, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C36H36Cl2N2O3S: 647.2 (M+H+); Found: 647.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O.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>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[C:4]([F:17])[CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cn1
Temperature: 80 °C
Yield: 91 %

Procedure:
According to Scheme 3 Method A: To a mixture of 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 1.00 mmol, 0.40 g) in dioxane/K3PO4 (2M, 10 mL), were added Pd(PPh3)4 (0.3 eq, 0.4 mmol, 0.4 g) and 6-methoxypyridin-3-ylboronic acid (1.5 eq, 2.00 mmol, 0.30 g) then the reaction mixture was heated at 80° C. for 17 hours. The mixture was diluted with AcOEt. The organic fraction washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 70/30) and by crystallization in pentane/Et2O to afford 1-(4-chloro-2-fluorobenzyl)-5-(6-methoxypyridin-3-yl)pyridin-2(1H)-one (0.91 mmol, 0.40 g, 91%) as a white solid.