Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:54][N:55]1[CH2:59][CH2:58][CH2:57][C@@H:56]1[CH:60]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:60]/[C@H:56]4[CH2:57][CH2:58][CH2:59][N:55]4[CH3:54])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCOC)OCC
Reactant: CN1CCC[C@@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)=[CH:21][CH:22]=1>FC(F)(F)C(O)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[N:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[NH:27][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:25][N:24]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)nc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.4 %

Procedure:
In trifluoroacetic acid (3.3 mL) and water (0.33 mL) was dissolved 1-[({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (327 mg), and the solution was stirred at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure, subjected to azeotropic distillation with acetic acid, and isopropyl ether was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-[({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylic acid (217 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[NH2:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.9 %

Procedure:
Next, to a solution of lithium aluminum hydride (1.17 g, 30.9 mmol) in tetrahydrofuran (60 mL) was added a solution of the obtained 4-phenylamino-benzonitrile (2.0 g, 10.3 mmol) in tetrahydrofuran (5 mL), and the solution was stirred at room temperature for 22 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (2.0 g, 98%) as an orange oil. This compound was used in the next reaction without purification.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](Cl)=[O:67])=[CH:64][CH:63]=1>>[Cl:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([CH:51]5[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:67])=[CH:64][CH:63]=1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)C1
Yield: 93 %

Procedure:
The compound of example 548 was prepared analogous to compound of example 97 by reaction of compound of example 543 with 4-chloro benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[NH:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[CH:25]=[N:24]1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cn[nH]c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-pyrazole-4-boronic acid (62 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure and residue and dissolved in EtOAc (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(1H-pyrazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.03 (s, 2H), 7.7 (d, 1H), 7.58 (m, 2H), 7.3 (s, 1H), 7.22 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 1H), 3.17 (s, 3H), 3.0 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][OH:10]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[N:5]=[C:6]([CH2:9][OH:10])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(Br)ccn1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(Br)cc(CO)n1
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methyl-pyridine (735 mg, 4.14 mmol) in methanol (80 mL) and H2SO4 (20 μL) is heated to reflux. A solution of (NH4)2S2O8 (3.78 g, 16.6 mmol) in water (6.5 mL) is added dropwise to the stirred mixture. Upon completion of the addition, refluxing is continued for 2 h. The mixture is cooled and the reaction is quenched by adding 1 M aq. NaS2O3 solution. The mixture is further diluted with sat. aq. NaHCO3 solution and extracted twice with EA (2×300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:2 to give (4-bromo-6-methyl-pyridin-2-yl)-methanol (156 mg) as a white solid; LC-MS: tR=0.32 min, [M+1]+=201.93.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[O:24][CH2:25][CH2:26]Cl)=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17](=[O:20])[NH:18][CH3:19])[C:6]=2[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][O:24][C:23]2=[O:28])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([NH:18][CH3:19])=[O:20])[C:6]=2[CH:21]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)OCCCl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCOC3=O)c(Br)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
2-chloroethyl (5-bromo-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)carbamate (1.00 g, 2.10 mmol) was added to a mixture of KI (0.40 g, 2.10 mmol) and K2CO3 (0.75 g, 6.30 mmol) in DMF (20 mL) and the mixture was stirred under N2 protection at 110° C. for 2 hours. After concentrated in vacuo, the resulting residue was washed with water and EtOAc to provide 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (408 mg, yield: 45%). 1H-NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 7.51 (m, 2H), 7.19 (s, 1H), 7.11˜7.13 (d, J=8.0 Hz, 1H), 6.83˜6.88 (m, 1H), 4.37˜7.41 (m, 2H), 4.12˜4.14 (m, 2H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 433/435.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>BrC1C=CC=CC=1.[Cu]I>[C:2]1([N:12]2[C:13](=[O:19])[CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[N:9]([C:7](=[O:8])[CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]2=3)[CH:3]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)C2CCCC12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: Brc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(c2ccccc2)C(=O)C2CCCC21
Yield: 126 %

Procedure:
To a suspension of 4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (584 mg, 1.5 mmol) and potassium carbonate (228 mg, 1.6 mmol) in bromobenzene (3 mL) was added copper (I) iodide (57 mg, 0.3 mmol), and the mixture was heated for 90 minutes under reflux. To the reaction mixture was added chloroform, which was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-ethanol-hexane to give 440 mg (yield 63%) of a mixture of cis-compound and trans-compound (3:2), m.p. 272°-273° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)=[N:7][C:8]=2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH3:2].O.NN>CO.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[N:5]=[C:4]3[C:9]=2[N:10]=[CH:11][N:3]3[CH2:1][CH3:2])[CH:18]=[CH:17][CH:16]=1
Reactant: CCn1cnc2c(Nc3cccc([N+](=O)[O-])c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCn1cnc2c(Nc3cccc(N)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
A flask is charged with 795 mg (2 mmol) of trans-4-[9-ethyl-6-(3-nitro-phenylamino)-9H-purin-2-yl-amino]-cyclohexanol in 75 ml of methanol and kept under argon. At 40° C. 40 mg of Raney-Nickel is added slowly, followed by addition of 1 ml (31 mmol) of hydrazine monohydrate. After completion the reaction mixture is filtered, the filtrate concentrated and the crude product is taken up into EtOAc (300 ml), extracted with water, dried and evaporated to obtain trans-4-[6-(3-amino-phenylamino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (94% yield); m.p. 149-151° C.; ESI-MS: 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][CH2:6][CH2:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5]1
Reactant: BrCc1ccccc1
Reactant: CON=C1CCNc2cc(C(F)(F)F)ccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CON=C1CCN(Cc2ccccc2)c2cc(C(F)(F)F)ccc21

Procedure:
A mixture of Example 16D (1.71 g, 7.0 mmol), benzyl bromide (0.88 mL, 7.35 mmol), diisopropylethylamine (2.44 mL, 14.0 mmol) in acetonitrile (12 mL) were heated in a microwave Personal Chemistry at 150° C. for 40 minutes. Ethyl acetate (200 mL) was added and the organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, concentrate under reduced pressure, and chromatographed on silica gel eluting with 0-10% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.84 (t, J=6.61 Hz, 2H), 3.39 (t, J=6.61 Hz, 2H), 3.93 (s, 3H), 4.60 (s, 2H), 6.90 (m, 2H), 7.31 (m, 5H), 7.90 (d, J=8.81 Hz, 1H). MS (DCI) m/z 335.10 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[C:5]2[CH:11]=[C:12]([CH:14]=[O:15])[S:13][C:4]=2[NH:3]1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:3]2[C:4]3[S:13][C:12]([CH:14]=[O:15])=[CH:11][C:5]=3[C:6]3=[CH:10][CH:9]=[N:8][N:7]3[C:2]2=[O:1])=[CH:19][CH:20]=1
Reactant: O=Cc1cc2c([nH]c(=O)n3nccc23)s1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n3nccc3c3cc(C=O)sc32)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
5-Oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde (30 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3.0 mL), 1-(chloromethyl)-4-methoxybenzene (0.04 ml, 0.27 mmol) and potassium carbonate (57 mg, 0.41 mmol) were added and the reaction stirred at 60° C. for 5 h. Reaction poured into saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (3×10 mL), organics washed with saturated ammonium chloride solution (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with ethyl acetate in hexanes, to yield 4-(4-methoxybenzyl)-5-oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde as a powder (16 mg, 89%). 1H NMR (400 MHz, acetone-d6) δ 3.80 (s, 3H), 5.46 (s, 2H), 6.92-7.00 (m, 3H), 7.51 (d, J=8.66 Hz, 2H), 8.08 (d, J=1.76 Hz, 1H), 8.37, (s, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(-c3ccncc3)cc2)c(C#N)c(CC)n1C
Reaction time: 2.5 h

Procedure:
Add 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxy-phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.204 g, 0.474 mmol, prepared in example E-97a or E-97b), 4-pyridyl boronic acid (0.116 g, 0.948 mmol), Pd2(dba)3 (13.02 mg, 0.01422 mmol), triphenyl phosphine (14.92 mg, 0.0569 mmol), 2M aqueous potassium carbonate (2 mL, 4.0 mmol) in 3 ml of dioxane, and heat to reflux with stirring. After 2.5 hours, cool the reaction mixture and pour into water. Extract the quenched reaction with ethyl acetate. Combine the organic extracts, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with 1:1 ethyl acetate:hexanes to ethyl acetate to provide the title compound. Mass spectrum (m/e) 360.1 (M+1).
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:47][CH2:48][N:49]([CH:5]([CH3:6])[CH3:4])[CH2:50][CH2:51]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.CCOC(C)=O.[Cu]I>[N:11]1[N:12]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccccc1I
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1-n1nccn1
Temperature: 120 °C

Procedure:
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 114 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N′-dimethylcyclohexane-1,2-diamine. The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-1,2,3-triazol-2-yl)benzoyl acid, B-1. Data for B-1: 1HNMR (500 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired 2-(1H-1,2,3-triazol-2-yl)benzoic acid (B-2) eluted second.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:28][C:27]2[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:29])[CH:26]=2)[C@@H:21]2[C@@H:5]1[C@H:6]1[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)[CH:2]=[CH2:3]>[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[CH2:1]([CH:4]1[CH2:28][C:27]2[C@:22]([CH3:30])([CH2:23][CH2:24][C:25](=[O:29])[CH:26]=2)[C@@H:21]2[C@@H:5]1[C@H:6]1[C@:18]([CH3:31])([CH2:19][CH2:20]2)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1)[CH2:2][CH3:3]
Reactant: C=CCC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12
Reaction time: 2 h

Procedure:
1.0 g of the 7-allyl-enone 14, 5 ml. EtOAc and 50 mg triphenylphosphine rhodium chloride (Wilkinson's catalyst) were allowed to stir two hours (under H2 atmosphere). The reaction products were filtered through 25 ml silica gel, and evaporated to dryness to yield fairly pure title product, 18, as confirmed by proton NMR.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 75.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (395 mg, yield: 75.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:24][CH2:23][CH2:22][C@@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1.C(N(CC)C(C1CCCN(C2CCN(C(C3C4C(=CC=C(C)C=4)N=C(C4C=CN=CC=4)C=3)=O)CC2)C1)=O)C>>[CH2:20]([O:19][C:17]([C@@H:16]1[CH2:22][CH2:23][CH2:24][N:14]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH2:15]1)=[O:18])[CH3:21]
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN(CC)C(=O)C1CCCN(C2CCN(C(=O)c3cc(-c4ccncc4)nc4ccc(C)cc34)CC2)C1
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(Cc3ccccc3)C2)C1

Procedure:
Reductive amination of 1-benzyl-pyrrolidin-3-one with (3R)-ethyl nipecotate was carried out according to the procedure described above for Intermediate 1 to give (3R)-1-(1-benzyl-pyrrolidin-3-yl)-piperidine-3-carboxylic acid ethyl ester (containing a small amount of the isopropyl ester) as a yellow oil (1.23 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27].C[O-].[Na+]>CO.O>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([S:26]([NH:27][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=3)[CH:18]=2)=[O:24])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: CC(=O)Oc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(O)cc4)oc3C)cc2)cc1
Yield: 20.6 %

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with acetic acid 4-sulphamoyl-phenyl ester (64 mg) in an analogous manner to that described in Example 2A. The acetic ester intermediate was hydrolysed with sodium methoxide (80 mg) in a mixture of methanol (10 mL) and water (1 mL) for 1 hour. The solution was concentrated in vacuo then partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (starting at 30% acetonitrile and increasing at a rate of 1% per minute up to 98% acetonitrile) to give compound 13 as a white solid (15 mg). LC/MS System C: Rt=3.50 mins, m/z (ES−)=492 (M− for C26H23N2O7S).