Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=O)=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:50][C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:16]([NH:56][CH2:55][C:54]2[CH:57]=[CH:58][C:51]([F:50])=[CH:52][CH:53]=2)=[O:18])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromopicolinic acid (1.90 g, 6.2 mmol), HATU (4.69 g, 12.4 mmol) and Et3N (0.5 mL) in DMF (20 mL) was added 4-fluorobenzylamine (2.30 g, 18.5 mmol) dropwise. The mixture was stirred at room temperature overnight. Then it was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (PE:EtOAc=2:1) to afford the product of 3-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)picolinamide (2 g, yield: 77.8%). 1H-NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.42˜7.45 (m, 3H), 7.23˜7.37 (m, 6H), 6.97 (t, J=8.8 Hz, 2H), 5.21 (s, 2H), 4.57 (d, J=6.0 Hz, 2H). MS (M+H)+: 415/417.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:16][CH3:17])[CH3:15]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH2:16][CH3:17])[CH3:15]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.2 g) and 4-amino-1-benzyl-3-ethyl-3-methylpiperidine (0.6 g, 2.58 mmol) in methanol (210 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3-ethyl-3-methylpiperidine. Yield 0.27 g (74%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI.[CH3:22][N:23]([CH3:26])C=O>>[CH3:14][O:13][C:11]([C:5]1[C:26]2[N:23]([CH3:22])[N:8]=[N:9][C:10]=2[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:12].[CH3:14][O:13][C:11]([C:5]1[C:6]2=[N:7][N:23]([CH3:26])[N:9]=[C:10]2[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)c2[nH]nnc12
Agent: [Cs+]
Solvent: CI
Product: COC(=O)c1ccc(C)c2nn(C)nc12
Product: COC(=O)c1ccc(C)c2nnn(C)c12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of 4-methylbenzotriazole-7-carboxylic acid (0.1 g) in dimethyl formamide (20 ml) was treated with cesium carbonate (0.37 g) and methyl iodide (0.1 ml) stirred at 50° C. for 5 h. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated. Chromatographic purification (hexane/ethyl acetate 85:15) gave 1,4-dimethylbenzotriazole-7-carboxylic acid methyl ester (30 mg) and 2,4-dimethylbenzotriazole-7-carboxylic acid methyl ester (26 mg).
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[BH4-].[Li+].C1COCC1.Cl>O>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[C:18]([C:2]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCOC(=O)c1cc2ccc3ccccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccc3ccccc3c2o1
Yield: 85 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added ethyl naphtho[1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 6.85 g, 28.5 mmol), lithium borohydride (Aldrich, 0.62 g, 28.5 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (500 mL) then dissolved in CH2CL2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL), and placed in a vacuum oven overnight (80°) to give a total of 4.8 g (69.7%) of naphtho[1,2-b]furan-2-methanol, mp 105.5°-107°, (C,H).
Reaction SMILES: C(OCC)(=O)C.CCCCCC.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=[CH:16][CH:15]=1.[Br:35]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])=[O:27])=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1

Procedure:
The starting material can be obtained, for example, as follows: 14.2 g of 4-methyl-2'-carboxybiphenyl (EP 253,310) are dissolved in 60 ml of acetonitrile and 10.7 ml of pyridine and 11.4 ml of trimethylsilylethanol are added. The mixture is treated at 0° with 15.1 g of dicyclohexylcarbodiimide and stirred at this temperature for 3 hours. After this, the reaction mixture is evaporated in a high vacuum, the residue is treated with ether, and dicyclohexylurea is filtered off. After flash chromatography (ethyl acetate/hexane 95:5), 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl is obtained as a slightly yellowish oil. (TLC: ethyl acetate/hexane 95:5) Rf : 0.42. 312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9H), 0.7 ppm (t, 2H), 4.5 ppm (s, 2H), 7.1-8 ppm aromatics.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([S:8][C:9]([CH3:35])([CH:33]=[N:37][OH:38])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=NO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), hydroxylamine hydrochloride (0.26 g), potassium carbonate (0.52 g) and methanol (8 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (0.25 g, yield 55%) as colorless amorphous crystals. MS: 543(MH+).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:24]([O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:14]2[O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9](=[O:46])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:49]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.O.ClCCl.[Hg](OC(C)=O)OC(C)=O>[CH2:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:24]([O:25][C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:14]2[O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9](=[O:46])[N:8]=1)[C:2](=[O:49])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)=O
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 14a (0.77 g, 1.2 mmol) in 50 mL acetone is treated with a 0.1 M solution of Hg(OAc)2 (15 mL) in aqueous acetic-H2O (1:1) and the mixture stirred at room temperature for 18 hr. The reaction is further diluted with dichloromethane (100 mL), washed with cold saturated NaHCO3 solution, dried over magnesium sulfate and evaporated in vacuo. The resulting residue is flash-chromatographed using chloroform/acetone 19:1 to afford a yellowish solid. This solid is triturated with cold methanol to afford 15a, 0.47 g, 59%. 1H-NMR (DMSO-d6): 12.5 (s, 1H, enol); 8.0-7.4 (m, 16H, H-6 plus aromatic 6.15 (d, 1H, H-1′, J=2 Hz); 5.90 (m, 3H, H-5,2′,3′; 5.39 (s, 1H, vinylic, Jvinyl, allyl=<1 Hz)); 2.30, 1.47, 1.24 and 0.86 (4 m, 9H, n-butyl). Anal. Calcd for C36H34N2O8: C, 67.70; H, 5.37; N, 4.39. Found: C, 67.51; H, 5.28; N, 4.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>C1COCC1.O.C(#N)C>[Cl-:1].[C:28]([CH:26]1[CH2:27][NH+:24]([CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]3[S:16][C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][N:14]=3)[C:18]=2[CH2:31][CH3:32])[CH2:25]1)([OH:30])=[O:29]
Reactant: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(C[NH+]2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.9 %

Procedure:
To a solution of 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (18.95 g) in THF (700 mL), water (190 mL) and acetonitrile (50 mL) was added methanolic hydrogen chloride (44.2 mL, 1.0 M). A clear solution was obtained and stirred for 30 min at rt. The solution was concentrated under the reduced pressure then dried in vacuum at 50° C. to give 3-carboxy-1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidin-1-ium chloride (Example 4C, 20.3 g) as white solid. δH (DMSO-d6, 400 MHz): 1.09 (3H, t), 1.35 (6H, d), 2.92 (2H, q), 3.68 (1H, m), 4.26 (4H, m), 4.59 (2H, br. s.), 4.84 (1H, dt), 7.38 (1H, d), 7.47 (1H, m), 7.65 (1H, d), 7.73 (1H, br. s.), 7.96 (1H, dd), 8.10 (1H, d), 11.33 (1H, br. s.), 13.13 (1H, br. s.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])=[N:2]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])=[N:2]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccon1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccon1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-isoxazol-3-yl-ethyl)-amide (113 mg, 0.211 mmol) was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.65 ml, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.86 ml, 12.7 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 46 mg (54%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-isoxazol-3-yl-ethyl)-amide as a light yellow powder. MS: (M+H)+=406; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.89 (br. s., 1H), 9.12 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.50 (s, 1H), 8.44 (dd, J=8.9, 5.5 Hz, 1H), 7.68 (dd, J=9.6, 2.1 Hz, 1H), 7.02 (td, J=9.1, 1.9 Hz, 1H), 6.68 (d, J=1.5 Hz, 1H), 5.53 (quin, J=7.2 Hz, 1H), 4.15 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([OH:10])=[O:9].[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:14]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:11][C:2]1([CH3:1])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([O:10][CH2:22][C:14]1[C:15]([F:21])=[C:16]([F:20])[CH:17]=[C:18]([F:19])[C:13]=1[F:12])=[O:9]
Reactant: OCc1c(F)c(F)cc(F)c1F
Reactant: C/C=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C=C\[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)cc(F)c2F)C1(C)C
Reaction time: 24 h
Yield: 93 %

Procedure:
To a mixture solution of 0.42 g of (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylic acid, 0.49 g of (2,3,5,6-tetrafluorophenyl)methanol, 0.93 g of triphenylphosphine and 20 ml of tetrahydrofuran, 2.0 ml of 40% toluene solution containing diisopropyl azodicarboxylate was added. After one day, the reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.80 g of (2,3,5,6-tetrafluorophenyl)methyl (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1.ClC(Cl)(Cl)C(=N)O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:12]([O:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC(O)CO1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=C1CC(OCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 75.5 %

Procedure:
To a stirred solution of 4-hydroxydihydrofuran-2(3H)-one (25 g, 245 mmol) and benzyl 2,2,2-trichloroacetimidate (68.6 mL, 367 mmol) in CH2Cl2 (500 mL) and cyclohexane (500 mL) at 0° C. was added, dropwise, trifluoromethanesulfonic acid (2.175 mL, 24.49 mmol) over 10 min. The reaction mixture was stirred for 2 h at 0° C. and 48 h at room temperature. After this, it was diluted with hexanes (0.75 L), filtered and the filtrate washed with sat. aq. NaHCO3 (150 mL), dried (Na2SO4), filtered and concentrated. The resulting yellow oil was purified by flash column chromatography on silica gel column using 5-40% ethyl acetate/hexane (5% increment for every liter) to afford 4-(benzyloxy)dihydrofuran-2(3H)-one (35.52 g, 185 mmol, 75% yield) as a clear yellow oil. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.39 (2 H, m), 7.29-7.34 (3 H, m), 4.53 (1 H, d, JAB=11.9 Hz), 4.52 (1 H, d, JAB=11.90 Hz), 4.34-4.41 (3 H, m), 2.64-2.68 (2 H, m).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[NH:10][C:11](=O)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:18])=[N:6]1)([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]2[C:7]([CH3:18])=[N:6][N:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:9]=2[N:10]=1
Reactant: Cc1nn(C(C)(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C(C)(C)C)c2nc(Cl)cc(C(=O)O)c12
Reaction time: 0.25 h

Procedure:
1-(1,1-Dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5.07 g, 20.34 mmol) and phosphorus oxychloride (28.4 ml, 305 mmol) were heated at 100° C. for 16 hours. The contents were concentrated in vacuo. The residue was added to ice water followed by 1N NaOH until basic (pH>10). After stirring for 15 minutes, the mixture was adjusted to pH 3-4 by addition of 1N HCl. The contents were extracted with EtOAc, then washed with water, brine and concentrated in vacuo. The crude product was purified by reverse phase HPLC (40-70% ACN/H2O, 0.1% TFA). The product was collected as a solid, 0.50 g (9%). LCMS E-S (M+H)=268.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 (s, 9 H), 2.56 (s, 3 H), 7.48 (s, 1 H), 14.17 (br. s., 1 H).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([O:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([O:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(OC)c(=O)[nH]2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.9 %

Procedure:
Anisole (1 mL) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one (65 mg) in trifluoroacetic acid (2 mL), and the mixture was stirred at 80° C. for nine hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a colorless powder (29 mg).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[S:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C:15](=[O:23])[N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(-c2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(-c3ccccc3)n2)sc2ccccc12
Yield: 57.7 %

Procedure:
6-Phenyl-2-pyridinecarbonitrile (0.72 g, 4.0 mmol) and methyl thiosalicylate (1.20 g, 7.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.73 g, 57%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Ic1ccc(-c2cn3ccccc3n2)cc1
Yield: 79 %

Procedure:
Dissolving 27 g (83 mmol) of crude 2-bromo-4′-iodo acetophenone thus obtained and 8.0 g (85 mmol) of 2-aminopyridine into 200 milliliter of ethanol, adding 10 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 21 g of 2-(4-iodophenyl)-imidazo [1,2-a] pyridine (yield: 82%).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[N:4]=[CH:3]1.[C:14]1([CH:24]([NH2:26])C)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][NH:26][C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[NH:2][CH:3]=[N:4][C:5]=3[CH2:10]2)=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Reactant: CC(N)c1cccc2ccccc12
Agent: Cl
Product: O=C(NCc1cccc2ccccc12)C1CCc2[nH]cnc2C1
Yield: 65.5 %

Procedure:
By a similar procedure as described in Example 1 using 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid, hydrochloride (2.2 g, 10 mmol) and 1-(naphth-1-yl)ethylamine (1.6 g, 10 mmol), 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid (naphth-1-ylmethyl)amide (2.0 g, 67%) was obtained. The free base was dissolved in 1 N hydrochloric acid (5 ml) and the mixture was diluted with H2O (10 ml). On standing a precipitate was formed which was isolated and dried to give the title compound (0.95 g).
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][C:12]3[N:13]([CH:16]=[C:17]([C:19](OC)=[O:20])[N:18]=3)[C:14]=2[N:15]=1.ClC1C=CC2OCCC3[N:34](C=C(C(OC)=O)N=3)C=2N=1.CC(C#C)CO.N.O>O1CCOCC1.O>[OH:1][C:2]([CH3:23])([CH3:24])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][C:12]3[N:13]([CH:16]=[C:17]([C:19]([NH2:34])=[O:20])[N:18]=3)[C:14]=2[N:15]=1
Reactant: COC(=O)c1cn2c(n1)CCOc1ccc(C#CC(C)(C)O)nc1-2
Reactant: COC(=O)c1cn2c(n1)CCOc1ccc(Cl)nc1-2
Agent: C#CC(C)CO
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)C#Cc1ccc2c(n1)-n1cc(C(N)=O)nc1CCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Into a 20-mL sealed tube was placed a solution of methyl 2-(3-hydroxy-3-methylbut-1-yn-1-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate (100 mg, 0.31 mmol, 1.00 equiv, prepared by reaction of methyl 2-chloro-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate with 2-methylbut-3-yn-ol similar to as described in General Procedure G. The crude mixture was reacted with NH3.H2O (2 mL, 37%) in 1,4-dioxane (4 mL) similar to as described in General Procedure M. The resulting solution was stirred overnight at 100° C., diluted with 10 mL of H2O, extracted with 3×50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): Column, silica gel; mobile phase, DCM/MeOH (100:1-10:1); Detector, UV 254 um. This resulted in 423 mg (44%) of the titled compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[C:4]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])=[CH:5][C:6]([C:12]([F:15])([F:13])[F:14])=[C:7]([CH:11]=1)[C:8]([NH:51][CH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[O:9]
Reactant: COc1cc(C(=O)O)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reactant: NCCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)NCCc2ccccn2)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a stirred solution of 5-methoxy-4-[3-(5-methyl-pyrazin-2yl)-ureido]-2-trifluoromethyl-benzoic acid (37 mg, 0.1 mmol) in 1 mL NMP at room temperature in a capped reaction vial was added HBTU (42 mg, 0.11 mmol) and the suspension stirred for 15 minutes. 2-aminoethylpyridine (13 μL, 0.11 mmol) was added followed by DIEA (35 μL, 0.2 mmol) and the reaction was stirred overnight. NMP was then removed by bulb to bulb transfer under high vacuum at 70° C. and the residue triturated and filtered with EtOAc to give the desired amide as a tan solid (32 mg, 68%).