Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:19][C:20]1[O:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1>CN(C)C=O>[F:26][C:25]([F:28])([F:27])[C:22]1[O:21][C:20]([CH2:19][N:11]2[C:12]3[CH:13]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[C:9](=[O:15])[C:10]2=[O:14])=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc21)OCCO3
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey and Sternbach, Synthesis 1993:993-997) (3.08 g, 15.0 mmol) in dry N,N-dimethylformamide (150 mL) was added sodium hydride (0.9 g, 60% in mineral oil, 22.5 mmol) at ambient temperature. The deep purple mixture was stirred for 20 min followed by the addition of 2-(bromomethyl)-5-(trifluoromethyl)furan (3.80 g, 16.5 mmol) in one portion. The dark solution was stirred at ambient temperature for 1 h and concentrated in vacuo to dryness. The residue was mixed with water (150 mL) and stirred. The fine orange precipitation was filtered off and dried to afford 6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (4.13 g, 78%): 1H NMR (300 MHz, CDCl3) δ7.18 (s, 1H), 6.76-6.73 (m, 1H), 6.48 (s, 1H), 6.45-6.40 (m, 1H), 4.85 (s, 2H), 4.42-4.32 (m, 2H), 4.28-4.20 (m, 2H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>O.C(#N)C>[I:39][CH2:2][CH2:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A stirred solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (254 mg, 1.26 mmol), Ph3P (381 mg, 1.45 mmol.15), imidazole (129 mg, 1.89 mmol0) and acetonitrile (6.5 mL) at 0° C.; was treated with iodine (368 mg, 1.45 mmol.15). Mixture was allowed to reach 25° C. and stirring continued for 18 h. The reaction mixture was then diluted with water and extracted with hexanes (6×25 mL). The combined organics were dried (MgSO4) and concentrated, then purified by chromatography (40 g column, 50 μm from Analogix, 0-30% EtOAc in hexanes over 15 min to give tert-butyl 3-(2-iodoethyl)azetidine-1-carboxylate (271 mg, 871 μmol, 69.0%) as a colorless oil. 1H NMR (CDCl3) δ: 4.03 (t, J=8.3 Hz, 2H), 3.56 (dd, J=8.7, 5.7 Hz, 2H), 3.10 (t, J=7.0 Hz, 2H), 2.63 (quint, J=7.8, 5.4 Hz, 1H), 2.13 (q, J=7.1 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([CH3:67])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:61]1[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][C:60]=1[CH3:67])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)c(C)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(NC(C)=O)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (130 mg) was reacted with 2-acetylamino-5-methyl-thiazole-4-sulfonyl chloride (54 mg) to furnish (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z: 965) according to General Procedure E. The title compound (16 mg) was prepared by the hydrolysis of (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (20 mg) using General Procedure B. LCMS (m/z): 952.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1>ClCCl>[Cl:26][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[CH2:9][O:8][C:7]=2[CH:23]=1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 1-b (6.58 g) was dissolved in 200 ml of dichloromethane, and 6.2 ml of thionyl chloride and 6.9 ml of pyridine were added to the solution. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The obtained product was unstable and immediately subjected to the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][C@H:15](C)[NH:14][C:13]2=[O:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:19][C:20]1N=C(N2CCNC2=O)S[C:24]=1[C:25](OCC)=O.BrCCC=C>>[CH2:25]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:18])[CH2:24][CH:20]=[CH2:19]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: CCOC(=O)c1sc(N2C[C@H](C)NC2=O)nc1C
Agent: C=CCCBr
Product: C=CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O

Procedure:
Following the procedure as described in Preparation 5, making variations as required to replace (S)-ethyl 4-methyl-2-(4-methyl-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate and with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate to react with 4-bromobut-1-ene, the title compound was obtained as an off-white solid (2.05 g, 85%): mp 97-98° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d5) δ 5.86-5.72 (m, 1H), 5.16-5.02 (m, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.02-3.79 (m, 2H), 3.60-3.55 (m, 2H), 3.34-3.29 (m, 2H), 2.51 (s, 3H), 2.33-2.26 (m, 2H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 309.8 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)cc1
Reactant: CS(N)(=O)=O
Product: Cc1ccc(C2CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)cc1
Yield: 28.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-methylphenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.03 g, 28%) was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26](C)=[CH2:27])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.C1C[O:36]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.O.[Ru](Cl)Cl>[C:26]([C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[C:12]4[CH:32]=[CH:31][CH:30]=[CH:29][C:13]=24)[N:10]=[CH:9][N:8]([C@H:7]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[OH:1])[C:17]3=[O:18])=[CH:25][CH:24]=1)(=[O:36])[CH3:27]
Reactant: C1CCOC1
Reactant: C=C(C)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: Cl[Ru]Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-isopropenylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.042 g, 0.098 mmol) in a mixture of 1 mL of acetone, 1 mL of THF, and 1 mL of water was added ruthenium(II) chloride hydrate (5.5 mg, 0.025 mmol) and sodium periodate (0.084 g, 0.39 mmol). After 1.5 h, the mixture was diluted with water and extracted 3× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 460.1763 for [M+H]+ [Calc'd for C25H24N3O4, [M+H]+=430.1761]: 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J=8.1 Hz, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.65-7.56 (m, 2H), 7.47-7.45 (m, 1H), 4.84-4.78 (m, 1H), 4.33 (s, 2H), 4.26-4.09 (m, 2H), 4.07-4.05 (m, 1H), 3.70 (br s, 1H), 3.57 (t, J=11.0 Hz, 1H), 3.34 (t, J=10.0 Hz, 1H), 2.64 (s, 3H), 2.25-2.20 (m, 1H), 2.01-1.97 (m, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=O)C.[CH3:19][NH:20][CH3:21].O>C(O)(=O)C>[NH2:4][C:5]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:20]([CH3:21])[CH3:19]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC1CO1
Reactant: CNC
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.085 mol (21.5 g) of 1-(2'-acetylamino-4'-nitrophenoxy)-2,3-epoxypropane (compound described in Example (4) is introduced into 100 ml of a 40% strength aqueous solution of dimethylamine, and the reaction mixture is stirred for 30 minutes at ambient temperature. After dilution by the addition of 225 ml of iced water, followed by neutralisation with acetic acid, the mixture is evaporated to dryness in vacuo. The dried residue is taken up in 150 ml of ethyl acetate. After washing with acetone, the material which is insoluble in ethyl acetate consists of 28.5 g of 1-(2'-acetylamino-4'-nitrophenoxy)-3-dimethylaminopropan-2-ol. This acetylated derivative is heated under reflux for two hours in 220 ml of ethanol saturated with hydrogen chloride. After the reaction medium has cooled, the expected product in the form of the hydrochloride is filtered off. After this hydrochloride has been dissolved in water and the aqueous solution has been rendered alkaline with sodium hydroxide solution, the 1-(2'-amino-4' -nitrophenoxy)-3-dimethylaminopropan-2-ol is precipitated in the form of crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][Br:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CO)COC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25.8 g. (0.176 mole) of (R)-(+)-3-tert. butoxy-2-methyl-1-propanol and 50.5 g. (0.193 mole) of triphenylphosphine in 105 ml. of CH2Cl2 was stirred while 32.8 g. (0.184 mole) of N-bromosuccinimide was added in portions, keeping the temperature below 30° C. with occasional ice bath cooling. The resulting solution was stirred at room temperature for one hour then most of the solvent was distilled under a water aspirator pressure using a Vigreaux column. The product was distilled from the residue using a short distilling head giving 0.7 g. of forerun b.p. 58°-62° C. (23 mm Hg) and then the main fraction (31.1 g.) b.p. 62°-69° C. (14-18 mm Hg). The total distillate (31.8 g.) was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume and 9:1 parts by volume hexane-ether yielded the pure (S)-(+)-3-tert. butoxy-2 -methyl-1-bromopropane which was distilled giving 26 g. (70.6%) of colorless liquid, b.p. 71° C. (16 mm Hg); [α]25D + 23.32° (c 4.23, C6H6).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25].C([O-])(=O)C.[Na+]>C(O)C>[CH3:21][O:22][C:23]([CH2:24][N:25]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:26]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
11.4 g (0.044 mol) of 6-phthalimido-2,5-hexanedione, 27.6 g ((0.22 mol) of glycine methyl ester hydrochloride and 9.1 g (0.11 mol) of sodium acetate are heated under reflux in ethanol for 16 hours and the mixture is worked up as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(Br)ccc1F
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 15 g (73.9 mmol) 5-bromo-2-fluorobenzaldehyde in diethyl ether (100 ml) at 0° C. were slowly added 27.1 ml (81.3 mmol) of ethyl magnesium bromide solution (3 M in diethyl ether). After stirring at 0° C. for 3 h, water (20 ml) was carefully added upon which a white precipitate formed. The solid was filtered off and washed with tert-butyl methyl ether. The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (16.1 g, 93% of th.) was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1sccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccsc3Cc3ccccc32)cc1
Yield: 62.3 %

Procedure:
A mixture of 400 mg of 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine and 700 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between chloroform and water. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 543 mg of the desired product. M+1=439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[C:32]3[CH:41]=[C:40]([CH2:42][CH3:43])[O:39][C:33]=3[C:34]([O:37][CH3:38])=[N:35][CH:36]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[C:32]2[CH:41]=[C:40]([CH2:42][CH3:43])[O:39][C:33]=2[C:34]([O:37][CH3:38])=[N:35][CH:36]=1)=[O:28]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Cc1cnccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)Nc3ccncc3C)cnc(OC)c2o1
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
A solution of 4-amino-3-methylpyridine (76 mg) in dry N,N-dimethylformamide (20 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Sodium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 0.77 ml) was added and stirring continued at 0° C. for 10 minutes. 2-Ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) was added and stirring continued at room temperature for 90 minutes. The solvent was then removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with water (100 ml) then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with ethyl acetate followed by trituration with diethyl ether gave the title compound (66 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2sccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([C:11]([NH:13][C:14]4[O:15][C:16]([C:19]5[O:20][CH:21]=[CH:22][CH:23]=5)=[N:17][N:18]=4)=[O:12])[CH:3]=3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:25]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(C(=O)Nc4nnc(-c5ccco5)o4)cc([N+](=O)[O-])c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-5-nitrobenzenecarboxamide prepared in Reference Example 37 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:30]([Si:36]([CH3:39])([CH3:38])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.CCOC(C)=O>[CH3:38][Si:36]([CH3:39])([C:30]([CH3:32])([CH3:31])[CH:33]([CH3:35])[CH3:34])[O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C(C)C)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (540 mg, 1.67 mmol) in 8 ml N,N-dimethylformamide cooled to 0° C., were added 398 mg (5.85 mol) imidazole and 1.1 ml (5.85 mmol) thexyl-dimethylchlorosilane. The reaction mixture was stirred 50 minutes at 0° C., diluted with AcOEt, washed with water/ice, HCl (1M)/ice and brine and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na2SO4 and evaporated. Chromatography (SiO2; AcOEt/heptane) delivered 346 mg (45%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.C([Mg]Br)#C.O.O1C[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([C:11](=[O:12])[C:26]#[C:27][CH3:28])=[C:4]2[CH:3]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Reactant: C1CCOC1
Agent: C#C[Mg]Br
Solvent: O
Product: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.93 g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added ethynyl magnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was dissolved in dichloromethane (50 mL) and manganese dioxide (5 g) was added. This slurry was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to a solid. This solid was purified by flash chromatography (dichloromethane) to give 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.63 g, 62% for two steps) as a white solid. 1H NMR (CDCl3): δ 8.52 (d, 1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s, 1H). 19F NMR (CDCl3): δ−111.69; MS m/z 299 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:27]4[CH:28]=[CH:29][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][N:22]=5)=[CH:25][CH:26]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)nc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc4nc(C5CC5)c(C)n4c3)cc2)nc1

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-methyl-2-pyridyl)benzenecarboxylic acid, to provide the title compound as white solid.