Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:35][C:36](=[O:38])[CH3:37])[C:24]2[NH:25][CH:26]=[C:27]([CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[N:28]=2)=[CH:18][CH:17]=1>C(Cl)Cl.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:35][C:36](=[O:38])[CH3:37])[C:24]2[N:25]([S:10]([N:9]([CH3:14])[CH3:8])(=[O:12])=[O:11])[CH:26]=[C:27]([CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[N:28]=2)=[CH:18][CH:17]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.48 mL, 34.5 mmol) followed by dimethylsulfamoyl chloride (0.24 mL, 46 mmol) were added to an ambient temperature solution of N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide (450 mg, 11.5 mmol) in methylene chloride (10 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2ccccc2)cc1
Yield: 91.9 %

Procedure:
According to the general procedure A, 4-chloroanisole (73 mg, 0.51 mmol) reacted with benzylamine (68 mg, 0.63 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (60 mg, 0.63 mmol) in toluene at 100° C. for 4 h to give the title compound (100 mg, 93%) as a solid: 1H-NMR (500 MHz, CDCl3): δ 6.63 (d, 2H, J=8.84 Hz), 6.81 (d, 2H, J=8.83 Hz), 7.41-7.35 (m, 4H), 7.30 (t, 1H, J=7.08 and 7.03 Hz), 4.31 (s, 2H), 3.77 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 152.18, 142.42, 139.66, 128.56, 127.52, 127.14, 114.89, 114.09, 55.78, 49.23. GC/MS(EI): m/z 213 (M+).
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]=[CH2:13])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:12]=[CH2:13]
Reactant: C=C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C=C=C(CCO)COC(=O)c1ccccc1

Procedure:
Combine 5-(p-methoxybenzyloxy)-3-benzoyloxymethylpent-1,2-diene (12.0 mmol), methylene chloride (25 mL) and water (1.25 mL). Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.5 mmol) with rapid stirring. After 1.5 hours filter the reaction mixture and extract the filtrate three times with water, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1>O1CCOCC1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:22]2[C:21]([CH2:20][O:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([NH:9][CH2:8][CH2:7][O:6][CH3:5])=[O:11])=[CH:14][N:15]=3)=[C:25]([CH2:26][OH:27])[O:24][N:23]=2)=[CH:29][CH:30]=1
Reactant: COCCN
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reaction time: 8 h
Yield: 16 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.51 mL, 1.00 mmol) was added to a solution of 2-methoxyethylamine (88.0 μL, 1.00 mmol) in dioxane (4 mL). After stirring for 45 min at 50° C. a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (90.0 mg, 0.25 mmol) in dioxane (4 mL) was added and stirring was continued overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate) to yield the title compound (16.1 mg, 16%) as a white solid. MS: m/e=400.0 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)OCO3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)OCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a solution of 4-(benzo[1,3]dioxole-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in 10 mL of DCM, was added 2 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours, then solvent was removed by reduced pressure to yield the title product (0.35 g, 1.35 mmol). MS (ESI) m/z 234.9 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.11 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1>>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: Nc1ccncc1
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Yield: 92.7 %

Procedure:
Following the general procedure of Examples 2 and 3, 791.0 mg (8.404 mM) of 4-aminopyridine was reacted with 212.5 mg (26.73 mM) of lithium hydride and 3002.4 mg (8.4 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one to give 92.7% yield (95.9% purity) of 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:6][N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CC(C)CCNCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a stirred mixture of (3,4-dichloro-benzyl)-(3-methyl-butyl)-amine hydrochloride (283 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give viscous yellow oil. Purification on a Silica gel column using hexanes/ethyl acetate (20–40% EtOAc) as the eluent gave the title compound as a viscous yellow oil (400 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.42–7.26 (2H, m), 7.11 (0.67H, d, J=8.2 Hz), 7.01 (0.33H, d, J=8.2 Hz), 6.14 (0.67H, s), 6.00 (0.33H, s), 4.56 (1.34H, s), 4.52 (0.66H, s), 3.39–3.36 (0.67H, m), 3.29–3.26 (1.33H, m), 1.74 (4H, s), 1.70 (2H, s), 1.59–1.50 (1H, m), 1.47–1.42 (2H, m), 0.90–0.88 (6H, m). MS calcd for C19H24Cl2NO4 (M+H): 400.1. found: 400.07.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][C@@H:9]([CH3:11])[O:10][C:6]=2[C:5]([NH2:12])=[CH:4][C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>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>[CH3:11][C@@H:9]1[CH2:8][C:7]2[C:2]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)=[C:3]([CH3:13])[CH:4]=[C:5]([NH2:12])[C:6]=2[O:10]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(N)c2c(c1Br)C[C@@H](C)O2
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)c2c(c1-c1ccncc1)C[C@@H](C)O2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
The mixture of (R)-4-bromo-2,5-dimethyl-2,3-dihydrobenzofuran-7-amine (3g) (1.0 g, 4.3 mmol), pyridin-4-ylboronic acid (1.08 g, 8.77 mmol), Cs2CO3 (3.56 g, 10.9 mmol), Pd(PPh3)4 (0.506 g, 0.438 mmol) and water (9 mL) in DMF (44 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (150 mL, washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (3h) as a solid. MS-ESI (m/z): 241 (M+1)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[C@H:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1>C(O)C.[Pd]>[CH3:21][O:20][C:18]([CH:4]1[CH2:3][CH:2]([OH:1])[CH2:7][CH2:6][NH:5]1)=[O:19]
Reactant: COC(=O)[C@@H]1C[C@H](O)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CC(O)CCN1

Procedure:
A solution of compound 12 (7 g, 1 eq.) and Pd/C (1.4 g, 20 w %) in dry ethanol (110 mL) was stirred overnight at room temperature under hydrogen. The mixture was filtered, and the filtrate was evaporated to give compound 31 as a yellow oil in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.34-1.48 (m, 2H), 1.84 (s, 2H), 1.90-1.96 (m, 1H), 2.27-2.33 (m, 1H), 2.60-2.67 (m, 1H), 3.21 (dt, J=3.86 and 12.79 Hz, 1H), 3.38 (dd, J=3.08 and 10.91 Hz, 1H), 3.70-3.78 (m, 1H), 3.75 (s, 3H).
Reaction SMILES: [CH:1]([CH2:3][N:4]([CH3:22])[C:5]([C:7]1[C:12]([C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6])=[O:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH3:22][N:4]1[C:3]([CH:1]=[O:2])=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6]
Reactant: Cc1ccc(C(=O)c2cccnc2C(=O)N(C)CC=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2c(C=O)n(C)c(=O)c3ncccc23)cc1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A mixture of the compound obtained in Step 4 (3.0 g), toluene (60 ml) and 1,8-diazabicyclo [5.4.0]undec-7-ene (0.3 ml) was stirred for 30 minutes under reflux. The mixture was cooled, and the crystals separated were collected by filtration, washed with ethyl ether to give 7,8-dihydro-7-methyl-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxaldehyde as pale yellow crystals (1.98 g).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[C:21]1=[O:39].Cl.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>C1COCC1.ClCCl>[Cl:38][C:35]1[S:34][C:33]([C:31]([NH:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[C:28](=[O:29])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[C:21]3=[O:39])=[O:32])=[CH:37][CH:36]=1
Reactant: NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 mg (0.24 mmol) of triethylamine and a catalytic amount of 4-dimethyl-aminopyridine are added to 40 mg (0.08 mmol) of N-[2-(4-aminobutyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-5-chloro-2-thiophenecarboxamide trifluoroacetate in 2 ml of THF. At 0° C., 17.4 mg (0.10 mmol) of isonicotinoyl chloride hydrochloride are then added. The reaction mixture is warmed to RT, stirred at RT for 3 h and then heated at reflux for 20 h. After cooling to RT, the reaction mixture is diluted with dichloromethane and washed with aqu. sat. NaHCO3 solution. The organic phase is dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica gel (CH2Cl2/EtOH=50/1). This gives 18.5 mg (47% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18](O)([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[CH:25][C:26]=3[CH3:27])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[CH:25][C:26]=3[CH3:27])=[CH:17][CH2:16]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C2CCC(O)(c3c(C)ccnc3C)CC2)CC1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C2CC=C(c3c(C)ccnc3C)CC2)CC1
Yield: 74.2 %

Procedure:
To a solution of 1-(2-methoxyphenyl)-4-[1-hydroxy-1-(2,4-dimethylpyridin-3-yl)-cyclohex-4-yl]piperazine (0.8 g, 2.0 mmol) in dry THF (70 ml) under argon was added imidazole (0.3 g, 4.4 mmol) followed by methyl oxalyl chloride (0.6 ml, 6.5 mmol). The non-homogeneous reaction mixture was refluxed for 24 hours. The reaction solvent was removed and replaced with anhydrous toluene (50 ml). The reaction mixture was refluxed for a further 48 hours. The solvent was removed and the residue partioned between water and chloroform. The organic layer was removed and washed with saturated NaCI solution. The resulting organic phase was dried (MgSO4) filtered and reduced to an oil. Purification of the oil by silica gel column chromatography eluting with chloroform/methanol (20/1) gave the title product (560 mg) which was dissolved in chloroform to which ethereal HCl was added. The solvent was removed and the residue recrystallised from methanol/ether to give the title compound as the trihydrochloride, 1.75 hydrate, m.p. 215°-216° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13])(C)C.[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:17]=1[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(N(CC)CC)C.O1CCCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:15][C:16]1[CH:21]=[C:20]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:19]=[CH:18][C:17]=1[F:23]
Reactant: Fc1ccc(I)cc1Cl
Reactant: C[Si](C)(C)C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2ccc(F)c(Cl)c2)c1
Temperature: -78 °C
Yield: 31.2 %

Procedure:
Stir 5-trimethylsilanylethynyl-nicotinonitrile (300 mg, 1.5 mmol), (prepared essentially as described in PREPARATION 3), 2-chloro-1-fluoro-4-iodobenzene (390 mg, 1.5 mmol), bis(triphenylphosphine)palladium (II) dichloride (50 mg, 0.08 mmol) and copper (I) iodide (20 mg, 0.15 mmol) in triethylamine (15 mL) under nitrogen and cool to −78° C. Add a 1 M solution of tetrabutylammonium fluoride (1.5 mL) in tetrahydrofuran and warm to room temperature and then heat at 70° C. until complete by thin layer chromatography. Concentrate and purify the residue by silica gel chromatography, eluting with hexanes:ethyl acetate, and then recrystallize from hexanes:ethyl acetate to give the title compound (120 mg, 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23](OC)=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34]>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([C:23]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:24])[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[O:16])[CH:7]=[C:8]([C:10]([NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(NC(=O)c2cc(C(=O)OC)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Reactant: NCC(O)CO
Product: O=C(NCC(O)CO)c1cc(NC(=O)c2cc(C(=O)NCC(O)CO)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
3-Nitro-5-methoxycarbonylphenylaminocarbonyl-(3'-nitro-5'-methoxycarbonylbenzene) (1.21 g, 3.0 mmol) was suspended in aminopropan-2,3-diol (0.55 g, 6.0 mmol) and the mixture was heated to 90° C. After 30 min, the pressure was reduced to 200 mm Hg and heating was continued for 90 min. The product was purified by preparative HPLC. Yield: 0.73 g (47%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Cl)Cl.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[OH:1][C:2]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: ClCCl
Reactant: CSCc1ccc(C(=O)O)c(O)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(CSC)cc1O
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a mixture of 2-hydroxy-4-(methylthiomethyl)benzoic acid (3.96 g, 20 mmol), CH2Cl2 (75 mL), and MeOH (15 mL) was added a solution of 2 M trimethylsilyldiazomethane (TMSCHN2) in hexane (10.5 mL, 21 mmol) over 30 min. After stirring for 10 min, the reaction was concentrated and vacuum dried. The residue was chromatographed (250 g SiO2, hexanes to 5% EtOAc/hexanes) to give the title compound as a colorless oil (3.96 g, 93%).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([OH:15])=[O:14])[CH2:5][CH2:6][CH2:7]1.S(OCC)(O[CH2:20][CH3:21])(=O)=O>>[CH:3]12[CH2:12][CH:9]([CH2:10][CH2:11]1)[CH:8]1[C:4]2([C:13]([O:15][CH2:20][CH3:21])=[O:14])[CH2:5][CH2:6][CH2:7]1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)C12CCCC1C1CCC2C1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C12CCCC1C1CCC2C1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
55.0 g (0.275 mole) of 20% aqueous sodium hydroxide solution was added dropwise to a mixture of 90.0 g (0.5 mole) of tricyclo[5.2.1.02,6 ]decane-2-carboxylic acid (mixture of endo and exo compounds) and 84.8 g (0.55 mole) of diethyl sulfate over one hour under stirring at 50 C.°. After completion of the addition, the stirring was continued at that temperature for 30 minutes. After completion of the stirring, the mixture was allowed to stand at room temperature for a while to form layers. The lower aqueous layer was taken out. The temperature was elevated again to 50 C.°. 55.0 g (0.275 mole) of a 20% aqueous sodium hydroxide solution was added dropwise to the remainder over one hour under stirring at that temperature for 30 minutes. Then, 16.5 g (0.0825 mole) of 20% aqueous sodium hydroxide solution was added thereto and the whole reaction mixture was stirred at 100 C.° for 45 minutes in order to decompose unreacted diethyl sulfate. The mixture was allowed to cool and divided into layers. After the distillation, 93.6 g (yield 90.0%) of pure ethyl tricyclo[5.2.1.02,6 ]decane-2-carboxylate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=C1NCCN1c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCNC3=O)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)imidazolidin-2-one. MS (ESI): mass calcd. for C19H16FN5O, 349.13; m/z found, 350.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.10 (s, 1H), 7.94 (m, 1H), 7.81-7.77 (m, 1H), 7.51-7.46 (m, 5H), 3.51 (t, J=6.2, 2H), 3.37 (t, J=6.2, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5][C:4]=2[C:3]=1[C:17]([OH:19])=O.[CH3:20][N:21](C)C=O.C(Cl)(=O)C(Cl)=O.CN>ClCCl>[Cl:1][C:2]1[C:3]([C:17](=[O:19])[NH:21][CH3:20])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(C(=O)O)c2nc1OC
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 0.5 h
Yield: 281.7 %

Procedure:
To a solution of 6,7-dichloro-2,3-dimethoxyquinoxaline-5-carboxylic acid (Preparation 6, 0.890 g, 2.93 mmol) in dichloromethane (25 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (50 μL, 47.2 mg, 0.64 mmol) followed by oxalyl chloride (0.338 mL, 3.8 mmol). After 0.5 hours, the mixture was concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue at room temperature under nitrogen, followed by methylamine (33% w/w solution in ethanol, 10 mL, 80.3 mol). After 10 minutes, the mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and 1M aqueous hydrochloric acid solution. The organic extract was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99:1, by volume) as the eluent to give a solid which was recrystallised from toluene to afford the title compound (0.570 g, 61%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccncc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccncc1
Yield: 8.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with pyridine-4-boronic acid (available from Combi-Blocks Inc.; 49 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyridin-4-yl-benzoic acid (7 mg, 8%). 1H NMR (300 MHz, DMSO-d6), δ 13.35 (br s, 1H), 8.69 (d, J=6.0 Hz, 2H), 8.50 (s, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.30 (dd, J=7.9, 1.9 Hz, 1H), 8.10 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (d, J=5.8 Hz, 2H).