Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: Cn1ccnc1-c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: Cn1ccnc1-c1ccc(S(=O)(=O)N[C@H]2CCN(Cc3cccc(C#N)c3)C2=O)cc1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using (1-methyl-1H-imidazol-2-yl)benzene-4-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[CH:28])[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CC.Cl[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1>C(OCC)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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[C:28][C:44]3[CH:49]=[N:48][CH:47]=[CH:46][N:45]=3)[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#Cc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Reactant: Clc1cnccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C#Cc4cnccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-ethynyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (123 mg in 1.5 mL N,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium (13 mg) followed by copper(I) iodide (22 mg), n-propylamine (0.19 mL) and chloropyrazine (0.026 mL) and the mixture heated to 90° C. on an oil bath. After 10 minutes, the mixture was cooled to room temperature, diluted with diethyl ether and washed successively with water and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60; then 50:50) gave the title compound (69 mg).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH2:46]([O:45][C:43]([N:36]1[CH2:37][CH2:38][N:33]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=4)[CH:14]=[C:13]([CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:41])[CH:22]=3)=[O:39])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C(=O)OCC)CC3)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
Triethylamine (0.19 mL, 1.34 mmol) was added slowly at 0° C. to a stirred reaction mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.200 g, 0.33 mmol, prepared as described above) in dichloromethane (7 mL). The reaction mixture was stirred at room temperature for 15 minutes. Ethyl chloroformate (0.07 mL, 0.73 mmol) was added slowly to the reaction mixture and stirring was continued for an additional 3 hours at room temperature. The mixture was diluted with dichloromethane (10 mL), then washed with a saturated solution of sodium bicarbonate (5 mL) and water (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (1:3 ethyl acetate -hexane) to give 0.077 g (41.4%) of 4-[4-(3-ethoxycarbonylmethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester as a viscous yellow solid. MS cald. for C28H29FN2O7S ([M+H]+) 556, obsd. 557.2.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:28])[NH:22][C:23]3[N:24]=[N:25][NH:26][N:27]=3)=[CH:17][CH:16]=2)=[O:12])[CH:5]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:28])[NH:22][C:23]3[N:24]=[N:25][NH:26][N:27]=3)=[CH:17][CH:16]=2)[C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:39])=[O:2])=[CH:34][CH:33]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)c2ccc(C(C)(C)C)cc2)c1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzoic acid methyl ester was added a solution of potassium trimethylsilanolate in THF (1M, 5 mL). The mixture was shaken 4 hours at 25° C., filtered and allowed to react with a solution of acetic acid in THF (20%, 5 mL) at 25° C. overnight. Filtration followed by washing of the resin with dichloromethane (2×10 mL) afforded the resin bound title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][NH2:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1.C(N(CC)CC)C.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[O:16][C:32](=[O:33])[NH:18][N:17]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazide (150 mg, 0.44 mmol) was suspended in tetrahydrofuran (5.0 mL) and triethylamine (0.12 mL, 0.88 mmol) was added. N,N-Carbonyldiimidazole (108 mg, 0.66 mmol) was added and the whole stirred at room temperature for 1 h. No reaction was observed. The whole was sealed and heat at 80° C. for 2 h. More N,N-carbonyldiimidazole (150 mg, 0.92 mmol) was added and the whole heated at 85° C. for 10 min. LCMS indicated clean conversion to the desired product. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulfate. Concentration gave 125 mg colorless solid. A small amount was purified by reverse phase HPLC to give 266 as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br s, 1H), 7.70-7.00 (overlapping m, 4H), 4.23 (t, 2H), 3.21 (t, 2H). MS: (ESI+) 367.0
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][N:15]1[CH2:32][C:33](O)=[O:34].[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][N:44]2[C:33](=[O:34])[CH2:32][N:15]2[CH2:16][CH2:17][CH2:18][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[O:13])=[CH:41][CH:42]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C2CCCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCCC1c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.169 mmol) and 2-(4-fluorophenyl)piperidine (0.030 g, 0.169 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF10-4 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 70% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.46-7.09 (m, 12H), 7.03 (m, 2H), 4.58-4.23 (m, 2H), 3.57 (m, 2H), 2.72-2.55 (m, 2H), 2.45-2.23 (m, 2H), 2.02-1.75 (m, 3H), 1.75-1.47 (m, 6H); MS (DCI+) m/z 471 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([O:23][CH2:24][CH3:25])[CH2:11][CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:24]([O:23][CH:10]([O:9][CH2:7][CH3:8])[CH2:11][CH:12]([CH2:13][OH:14])[CH2:18][OH:19])[CH3:25]
Reactant: CCOC(=O)C(CC(OCC)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CC(CO)CO)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a cooled suspension (0° C.) of lithium aluminum hydride (4.9 g, 0.129 mol) in anhydrous tetrahydrofuran (80 mL), was added a solution of diethyl 2,2-diethoxyethylmalonate (17.6 g, 63.7 mmol) in anhydrous tetrahydrofuran (60 mL), and the mixture was stirred 3 h at room temperature. Then, the reaction mixture was immersed in an ice bath and a mixture of water (4.6 mL) and tetrahydrofuran (9.2 mL) was added dropwise followed by a solution of 15% sodium hydroxide (4.6 mL) and water (12.5 mL). After stirring for 20 minutes, the suspension was filtered off, the solvent was removed at reduced pressure, and 300 mL of chloroform was added. The solution was dried over sodium sulfate and after removal of the solvent, 8.8 g of a white solid was obtained and used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCOC(C)=O.C1COCC1>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-nitrobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (598 mg, 1.36 mmol) in 1:1 EtOAc/THF was added 10 mol % Pd/C (136 mg, 1.36 mmol). The reaction mixture was evacuated and refilled with hydrogen (2×). The black reaction mixture was stirred in a parr shaker under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2Cl2 washes) and concentrated to provide tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate which was confirmed by MS: cal'd 410.1 (MH+), exp 410.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH2:25]([O:27][C:28](OCC)(OCC)OCC)[CH3:26].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:28]([O:27][CH2:25][CH3:26])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 0.19 ml of tetraethylorthocarbonate and 40 μl of acetic acid, and the mixture was heated for 4 hours to 80° C. After cooling, it was mixed with 1N sodium hydroxide solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 124 mg was obtained.
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N+:10]([O-:20])[CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(CC)(OC)c1ccc[n+]([O-])c1C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 0.911 mmol) in CH2Cl2 (10 mL) was added 3-chloroperoxybenzoic acid (0.473 g, 2.75 mmol). The mixture was stirred for 16 h and concentrated by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine 1-oxide as a white solid (0.188 g, 98%). 1H NMR (CDCl3) δ 0.74 (t, 6H, J=7.5 Hz), 1.94 (q, 4H, J=7.5 Hz), 2.80 (s, 3H), 3.01 (s, 3H), 7.07-7.10 (m, 1H), 7.21 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=6.3 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1ncc[nH]1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2ncc[nH]2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 192 %

Procedure:
257 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 260 mg of 2-aminoimidazole were added to 5 ml of bromobenzene, then, the mixture was stirred for 2 hours under heat refluxing condition. Further, to the mixture was added 151 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate, and the resultant mixture was stirred for 2.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 580 mg of 1,6-dimethyl-4-hydroxy-N-(2-imidazolyl)-2-oxo-1,2-dihydropy ridine-3-carboxamide (hereinafter, referred to as present compound 26) represented by the formula:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:18][C:19]([O:21][CH3:22])=[O:20].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:31])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1Br
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(S(=O)c3ccccc3)cn2c1Br
Reaction time: 1 h

Procedure:
Alternatively, one may treat a suspension of 3-bromo-2(methoxycarbonylamino)-6(phenylthio) imidazo [1,2-a] pyridine (1.0 gm. 2.64 mmoles) in 100 ml. of dichloromethane with 85% metachloroperbenzoic acid (464 mg., 2.64 mmoles). After 1 hour at room temperature, the solution is washed with aqueous saturated sodium bicarbonate solution, and with water. After drying the solvent is removed in vacuo and the residue is chromatographed over silica gel to yield 3-bromo-2-(methoxycarbonylamino)-6-phenylsulfinyl imidazo [1,2-a] pyridine m.p. 150°-152° C.
Reaction SMILES: [Na+:1].[CH3:2][CH:3]([C:12]([O-:14])=[O:13])[CH:4]([S:8]([OH:11])(=[O:10])=[O:9])[C:5]([O-:7])=O.[Na+].C(OC(=O)C)(=O)C>>[Na+:1].[O:7]=[C:5]1[CH:4]([S:8]([O-:11])(=[O:10])=[O:9])[CH:3]([CH3:2])[C:12](=[O:13])[O:14]1
Reactant: CC(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1C(=O)OC(=O)C1S(=O)(=O)[O-]
Yield: 47.4 %

Procedure:
40 g 3-methyl-2-sulfosuccinic acid sodium salt (cis and trans diastereomers) was stirred with 50 g acetic anhydride and then heated to 86 degrees Centigrade while distilling over acetic acid for 1.5 hours. 100 mL ethyl acetate was added and the mixture was filtered. The precipitate was washed with 100 mL ethyl acetate. The precipitate was dried to produce 16.0 g yellowish-white solid. 1H-NMR (d6-DMSO) 3.40 ppm d J=10.52 Hz, 2.92-2.98 ppm m, 1.28-1.31 ppm m J=7.12 Hz.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:11]([NH:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ncc2sccn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 150 mg (0.98 mmol) of 5-aminomethylimidazo[5,1-b]thiazole in 1 ml of methylene chloride were added 1 ml of acetic anhydride and 0.5 ml of pyridine, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated. The residue was dissolved in methylene chloride, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel, eluting with ethyl acetate to give 159 mg (yield 83%) of the title compound as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1cccc(C(=O)CBr)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(OC)c2)[nH]c1N

Procedure:
Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethan-1-one (2-bromo-3'-methoxy-acetophenone; Janssen) to form the title compound; m.p. 96-97oC; TLC-Rf =0.2 (hexane/ethyl acetate [2:1]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](B(O)O)=[CH:7][C:6]=2[CH:13]=1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH2:33]C)=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:15]3[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=4)[N:16]=3)=[CH:7][C:6]=2[CH:13]=1
Reactant: OB(O)c1cc2cc(F)ccc2o1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 5-fluorobenzofuran-2-ylboronic acid (614.3 mg, 3.41 mmol) in dioxane (15 ml) was added ethyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (500 mg, 1.70 mmol), K3PO4 (725 mg, 3.42 mmol), Pd(PPh3)4 (40.5 mg, 0.035 mmol) and water (1.0 ml), and the resulting mixture was stirred for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (536 mg, 80%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.246 g, 1.26 mmol) according to the general procedure VI. Obtained as a white solid (0.140 g, 40%). MS (ISP) 407.2 [(M+H)+]; mp 172-190° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]2[N:11](CC3C=C(C)C=C(C)C=3)[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]>C(O)=O.[Pd]>[C:1]([CH:5]1[CH2:10][CH:9]2[NH:11][CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CC2CCC1N2Cc1cc(C)cc(C)c1
Agent: [Pd]
Solvent: O=CO
Product: COC(=O)C1CC2CCC1N2
Yield: 48 %

Procedure:
The product formed in Example 72 was treated with an equal weight of 10% Pd-on-C and refluxed in 96% formic acid for 12 hours. The mixture was filtered, the filtrate was partitioned between 10% aqueous Na2 CO3 and methylene chloride, and the extract dried and evaporated, affording a 48% yield of the title compound. Major (endo) isomer: 1H NMR (CDCl3) δ 4.12 (t, 1H), 3.92 (t, 3H), 3.8 (s, 3H), 3.2 (m, 1H), 2.3 (br s, 1H), 2.2-1.55 (m, 6H).
Reaction SMILES: [Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>C(N(CC)CC)C.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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:23][CH:24]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 86 %

Procedure:
1 g of bis(triphenylphosphine)palladium(II chloride, 3.8 g of copper(I) iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. This mixture was heated to the reflux temperature, after which 43.4 g of 3-butynol were added dropwise in the course of 20 minutes at this temperature (about 100° C.). Stirring was carried out for a further 5 hours at this temperature. After cooling, the triethylamine was distilled off. The residue was taken up in methyl tertbutyl ether and water. The aqueous phase was extracted twice more with methyl tert-butyl ether, and the combined organic extracts were washed in succession with 1N hydrochloric acid and with 10% sodium bicarbonate solution and dried over sodium sulfate. After the solvent had been removed, the crude product was distilled at greatly reduced pressure. Yield: 86%.