Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1C2NC(=O)COC=2C=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OCC)=O.[O:26]=[C:27]1[CH2:32][O:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]=2[NH:28]1.CI>CN(C=O)C>[CH3:2][N:28]1[C:27](=[O:26])[CH2:32][O:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]1=2
Reactant: CCOC(=O)COc1cccc2c1NC(=O)CO2
Reactant: O=C1COc2cccc(O)c2N1
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Reaction time: 16 h
Yield: 56 %

Procedure:
A stirred mixture of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.604 mmol) and K2CO3 (167 mg, 1.21 mmol) in anhydrous DMF (5 mL) was treated with ethyl 2-bromoacetate (121 mg, 0.727 mmol) and stirring continued at room temperature for 16 h. To this solution of crude ethyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yloxy)acetate was added K2CO3 (39.6 mg, 0.287 mmol) followed by MeI (40.7 mg, 0.287 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between water (50 mL) and DCM (100 mL). The organic layer was washed by water followed by and brine, dried over anhydrous Na2SO4, filtered and concentrated and the resulting residue was purified by preparative TLC to give desired product (43 mg, 56% yield). 1H NMR (400 MHz, CDCl3): 6.99 (t, J=8.3 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.55 (d, J=8.3 Hz, 1H), 4.69 (s, 2H), 4.51 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 3.56 (s, 3H), 1.34-1.33 (m, 1H), 1.33 (t, J=7.2 Hz, 3H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[S:18][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)=[CH:20][N:21]=2)=[O:15])[CH2:10][CH2:9]1.CCN=C=NCCCN(C)C.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:42][S:43]([NH:46][C:26]([C:25]1[CH:29]=[CH:30][C:22]([C:19]2[S:18][C:17]([NH:16][C:14]([N:11]3[CH2:12][CH2:13][C:8](=[CH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:15])=[N:21][CH:20]=2)=[CH:23][CH:24]=1)=[O:28])(=[O:45])=[O:44]
Reactant: O=C(O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
The compound (100 mg, 238 μmol) obtained in Example 20 was dissolved in DMF (4 mL), and N,N-dimethyl-4-aminopyridine (hereinafter referred to as DMAP) (6.0 mg, 48 μmol) and WSC (50 mg, 262 μmol) were added thereto, followed by stirring at room temperature for 10 minutes. Methanesulfonamide (34 mg, 357 μmol) was added to the resulting mixture, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and after extraction with methanol:chloroform (1:10), the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:15), thereby giving the title compound (15 mg, 13%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2cc[nH]c2c1

Procedure:
A yellow solution of 5.2 g. 6-nitroindole in 150 ml. ethyl acetate was added to 1.25 g. of pre-induced 10% w/w palladium-on-charcoal in 50 ml. ethyl acetate. The mixture was shaken under 3.45 bar hydrogen overnight and then filtered through diatomaceous earth. The residue was washed with 150 ml. hot chloroform and the combined colourless filtrate and washings were evaporated to give a quantitative yield of 6-aminoindole as a dark oil; NMR: 3.5 (br s, 2H, NH2), 6.4 (m, 1H, H3). 6.5 (m, 2H, H5 +H7), 7.0 (dd, 1H, H2, 7.4 (d, 1H, H4), 7.8 (br, 1H, NH).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].S(=O)(=O)(O)O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22](O)=[O:23].CC([O-])=O.[Na+].Cl>B(F)(F)F.CCOCC>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:22](=[O:23])[CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)CCc1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(CCc1ccccn1)c1ccc(O)cc1O
Reaction time: 5 h
Yield: 24 %

Procedure:
A mixture of resorcinol (2.2 g, 20 mmol), 3-pyridin-2-yl-propionic acid sulphuric acid salt (5 g, 20 mmol) and 50 ml boron trifluoride diethyl etherate (BF3.Et2O) was stirred at 90 C for 5 hours under N2 (monitored by TLC). The reaction mixture was poured into 10% aqueous NaOAc solution and allowed to stand for 30 min and the solution was neutralized to pH=7 by 1M HCl and was extracted with EtOAc (3×50 ml). The combined EtOAc layer was washed with water, brine and dried over Na2SO4. The residue obtained after evaporation of the solvent was chromatographed over silica gel column using hexane-EtOAc mixture (1:1) as eluent to give mixture of products, which was then recrystallized in hot MTBE/Hex to afford final product (24%) with >97% purity.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:28])[CH2:26][CH3:27])=[CH:21][C:20]=3[CH2:29][CH2:30][CH3:31])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH2:33]([Mg]Br)[CH3:34]>>[CH2:26]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:16]([CH3:32])=[CH:15][CH:14]=[C:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:18]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[CH:21]=1)([OH:28])[CH2:33][CH3:34])[CH3:27]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Reactant: CC[Mg]Br
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C

Procedure:
In a manner similar to that of Example 1(q), by reacting 300 mg (0.7 mmol) of 1-{5′-[2-(3,4-bis(hydroxymethyl)phenyl)ethyl]-2′-methyl-2-propylbiphenyl-4-yl}propan-1-one with 1.9 ml (5.6 mmol) of ethylmagnesium bromide (3M/ether), and after purification on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60), 180 mg (56%) of (4-{2-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxy-methylphenyl)methanol are obtained in the form of white crystals with a melting point of 76° C.
Reaction SMILES: [F:1][C@@H:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:29][N:28]=2)=[CH:23][CH:22]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:10][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][C:5]([O:4][CH2:3][C@@H:2]([F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:7]=3)=[CH:22][CH:23]=2)=[N:32][CH:31]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCC[C@H](F)COc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(OC[C@@H](F)CCCCCC)cc3)cc2)nc1

Procedure:
(S)-4-(2-Fluorooctyloxy)benzoic acid and 2-(4-hydroxyphenyl)-5-n-nonylpyrimidine are reacted analogously to give (S)-[4-(5-n-nonylpyrimidin-2-yl)phenyl]4-(2-fluorooctyloxy)benzoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nccs2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (200 mg, 0.82 mmol), 2-tributylstannylthiazole (Frontier Scientific) (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (Aldrich Chemical Company) (19 mg, 0.021 mmol) and triphenylphosphine (Aldrich Chemical Company.) (43 mg, 0.16 mmol) in anhydrous toluene (2 mL) was refluxed under N2 for 4 d. TLC showed that the reaction was not complete. Therfore, additional portions of 2-tributylstannylthiazole (338 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.021 mmol) and triphenylphosphine (43 mg, 0.16 mmol) were added to the reaction mixture, and the mixture was stirred at 120° C. for 3 d. Upon cooling to the room temperature, the reaction was quenched with 5% HCl (50 mL) and the solution was extracted with CHCl3 (3×100 mL). The organic extracts were washed with H2O (2×150 mL), filtered through a pad of Celite, washed with saturated NaCl (150 ml), dried over Na2SO4 and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (1-3%):CH2Cl2 (99-97%) afforded 119 mg (50%) of the title compound as a yellow solid. Mp: 248-250° C. 1H NMR (acetone-d6; 400 MHz): δ 2.69 (s, 3), 7.01(s, 1), 7.57-7.47 (m, 3), 8.06 (di 2, J=7.17), 8.97 (s, 1), 9.18 (s, 1), 10.76 (s, 1). MS m/z: 293 (M+1), 291 (M−1). HRMS: Calcd for M+H: 293.0861. Found: 293.0866.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5(NS(C(C)(C)C)=O)CC[CH2:28]5)=NC=4)=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44].BrC1C=C[C:51]([C:54](C)([CH3:57])[C:55]#[N:56])=CC=1>>[O:1]=[C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:10](=[O:38])[C:11]([C:21]4[CH:28]=[CH:27][C:24]([C:54]([CH3:57])([CH3:51])[C:55]#[N:56])=[CH:23][CH:22]=4)=[C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[O:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cn2)CCC1
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Product: CC(C)(C#N)c1ccc(-c2c(-c3ccccc3)oc3c(ccn4c(=O)n(COCC[Si](C)(C)C)nc34)c2=O)cc1
Yield: 99 %

Procedure:
Following the procedure used to prepare 2-methyl-propane-2-sulfinic acid (1-{5-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-pyridin-2-yl}-cyclobutyl)-amide, 2-(4-bromo-phenyl)-2-methyl-propionitrile was reacted to give the title compound (55 mg, 99%). LCMS (Method A): RT=4.83 min, [M+H]+=553.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-3-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 12a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:17]([CH2:19][C:20]([N-:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=1)=[O:21])#[N:18]>>[OH:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][NH:22][C:20](/[C:19](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]([OH:13])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:17]#[N:18])=[O:21]
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Reactant: COc1cc(C=CC=O)cc([N+](=O)[O-])c1O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccc(O)c(O)c2)cc([N+](=O)[O-])c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3-methoxy-4-hydroxy-5-nitrocinnamaldehyde (22 mg, 0.1 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (21 mg, 0.1 mmol). After refluxing for 4 h and recrystallization from ethanol-water an orange solid was obtained (19 mg, 46%). The product gave the following analytical data:
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[Cl:35]>CO.O1CCCC1>[Cl:35][C:7]1[CH:8]=[C:9]([NH:12][C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH:10]=[CH:11][C:6]=1[C:5]([OH:36])=[O:4]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CCC2
Reaction time: 16 h

Procedure:
3 M Potassium hydroxide solution (2 ml) was added to a solution of crude 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester (0.097 g, 0.13 mmol) in MeOH (2 ml) and tetrahydrofuran (1 ml) and the mixture stirred for 16 hours. The organic solvent was evaporated and the solution neutralized with 3 M HCl solution (3 ml) forming a white precipitate. The precipitate was filtered and washed with heptane. The solid was then dried under vacuum to give 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, 0.037 g, as a red solid. LC @215 nm; Rt 2.06: 98%, m/z (ES+): 489.23 (M+H+.); δH (400 MHz; d6-DMSO) 13.18 (1H, br.s), 10.63 (1H, s), 8.22 (1H, d), 8.08 (1H, d), 7.83-7.91 (2H, m), 7.76 (1H, dd), 7.55-7.67 (2H, m), 7.43-7.48 (2H, m), 7.30 (1H, d), 3.84 (2H, m), 2.52 (2H, m), 1.62 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH3:19])[C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH2:24])(=[O:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH3:19])[C:13]=2[CH:12]=[C:11]([NH:24][C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(OCc3ccccc3)cc(Br)cc2n1C
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of 10 g (30.2 mmol) 4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzimidazole, 2.1 g (36.2 mmol) acetamide, 524 mg (0.9 mmol) xantphos, 13.7 g (42.3 mmol) cesium carbonate and 276 mg (0.3 mmol) Pd2(dba)3 in 60 ml dioxane was stirred at 100° C. for 20 h. The reaction mixture was cooled to room temperature and poured into dichloromethane. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=2:1) to afford 5.8 g (62%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(N)c1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)Nc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 3-methoxy-aniline to afford the title compound. MS: m/e=364 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)[CH3:2].[Br:10]N1C(=O)CCC1=O>ClCCCl>[Br:10][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CC(Br)c1ccc(Br)cn1
Yield: 80 %

Procedure:
A solution of 2-ethyl-5-bromopyridine (1.86 g, 10 mmol), N-bromosuccinimide (1.78 g, 10 mmol) in 1,2-dichloroethane (20 ml) was brought to reflux before the addition of azoisobutyronitrile (AIBN) (20 mg). The solution was then refluxed for a further two hours. The cooled suspension was filtered and evaporated in vacuo. Purification by column chromatography (silica gel, eluting with 1:1 dichloromethane/hexane) gave the desired product as a pale yellow oil (2.12 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[CH2:10][C:11]#[CH:12].[OH-].C[N+](C)(C)CC1C=CC=CC=1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]2=[N:14][CH2:15][CH2:16][N:17]2[C:11]([CH3:12])=[CH:10]1
Reactant: C#CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: CC1=CN(c2c(Cl)cccc2Cl)C2=NCCN12
Yield: 18.5 %

Procedure:
A mixture consisting of 5.4 gm of 2-[N-(2,6-dichloro-phenyl)-N-propargyl-amino]-2-imidazoline and 40 ml of ethanol containing 5 drops of trimethylbenzyl ammonium hydroxide was refluxed for five hours, while stirring. Thereafter, the ethanol was evaporated in vacuo, and the residue was dissolved in dilute hydrochloric acid. The resulting solution was fractionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). The thin-layer chromatographically uniform ethereal fractions having a pH of 9 or more were combined, dried over magnesium sulfate, and the ether was evaporated in vacuo, leaving 1 gm (18.7% of theory) of 7-(2,6-dichloro-phenyl)-2,3-dihydro-5-methyl-imidazo[1,2-α]imidazole, m.p. 113°-117° C.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)O.[OH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9]#[CH:10]>CO>[OH:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9](=[O:1])[CH3:10]
Reactant: O
Reactant: C#CC(C)(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=O)C(C)(O)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The title compound is prepared by using a modified method of G. F. Hennion and B. R. Fleck, J. Amer. Chem. Soc., 77,3258(1955). To a mixture of methanol (5 ml), water (0.2 ml), sulfuric acid (100 mg), and mercuric sulfate (100 mg) is added at 55° C. a solution of 3-hydroxy-3-phenyl-1-butyne (2 g) in 90% aqueous methanol (5 ml) over a period of 90 min. The reaction is slightly exothermic, and the inside temperature is maintained at 55°-57° C. During the reaction time, 50 mg of mercuric sulfate is added. When addition of the acetylenic component is complete, another portion (50 mg) of mercuric sulfate is added, and the mixture is stirred at 55° C. for 1 hour. During this time 1 ml of water is added. After cooling, the reaction mixture is poured into ice-water and extracted with diethyl ether. The combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The resultant oil is chromatographed on silica gel using benzene. The appropriate eluates are evaporated to give 0.5g of the title compound, ir(CHCl3)3450 and 1741 cm-1 and nmr(CDCl3) δ 1.75(s), 2.08(s), 4.50(s) and 7.40(m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[N:7]=[C:6]2[C:12]([CH3:16])=[N:13][N:14]([CH3:15])[C:5]=12)([CH3:3])[CH3:2].C1COCC1.Cl>CCO.[Pd]>[CH:1]([C:4]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]=[C:6]2[C:12]([CH3:16])=[N:13][N:14]([CH3:15])[C:5]=12)([CH3:3])[CH3:2]
Reactant: Cc1nn(C)c2c(C(C)C)cc(C#N)nc12
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nn(C)c2c(C(C)C)cc(CN)nc12
Reaction time: 8 h

Procedure:
7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile (from the previous step, 91.05 g, 5.15 mmol) was dissolved in EtOH:THF:conc.HCl (25 mL:10 mL:1.5 mL). 400 mg of 10% Pd/C was added and the reaction mixture was stirred under hydrogen balloon overnight. The catalyst was filtered out and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid. Spectroscopic data: 1H-NMR (300 MHz, CD3OD): δ ppm 1.41 (d, J=6.74 Hz, 6 H), 2.56 (s, 3 H), 3.77 (hept, J=6.74 Hz, 1 H), 4.02 (s, 2 H), 4.21 (s, 3 H), 7.36 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[CH:13][N:12]2[CH:35]=1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH:26][CH3:27])[CH2:20][CH2:19]3)=[CH:13][N:12]2[CH:35]=1
Reactant: COc1ccccc1-c1cn2cc(C3CCN(CCN(C)C(=O)OC(C)(C)C)CC3)cc(C)c2n1
Agent: Cl
Solvent: ClCCl
Product: CNCCN1CCC(c2cc(C)c3nc(-c4ccccc4OC)cn3c2)CC1
Yield: 127.9 %

Procedure:
Compound 223 (45 mg, 0.094 mmol) was stirred in a saturated solution of HCl in DCM (1 mL) for 1.5 hours. The reaction was taken to dryness under high vacuum to give 224 (45.5 mg, tris-HCl salt) as a white solid. 1H NMR: (DMSO-d6) δ(ppm): 11.23 (br s, 1H), 9.51 (br s, 2H), 8.74 (s, 1H), 8.69 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.52 (dt, J=1.6, 8.8 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 3.98 (s, 3H), 3.75-3.72 (m, 2H), 3.54 (m, 4H), 3.24-3.16 (m, 2H), 3.05-2.99 (m, 1H), 2.69 (s, 3H), 2.60 (t, J=5.2 Hz, 3H), 2.19-2.05 (m, 4H). LRMS (ESI): (calc.) 378.2 (found) 379.4 (MH)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1)=[O:1]
Reactant: N#Cc1ccc(C2OCCO2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cn1
Reaction time: 16 h
Yield: 101.7 %

Procedure:
In THF (5.0 mL) was dissolved 5-(1,3-dioxolan-2-yl)picolinonitrile (478 mg, 2.71 mmol) obtained in Step 2, and 1 mol/L hydrochloric acid (5.0 mL) was added under a nitrogen atmosphere at room temperature. The mixture was stirred at the same temperature for 16 hours and further stirred at 50° C. for 13 hours. The reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure to give 5-formylpicolinonitrile (364 mg, 100% yield).