Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[B-](F)(F)(F)[CH:13]=[CH2:14].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[N:7][C:2]=1[CH:13]=[CH2:14]
Reactant: C=C[B-](F)(F)F
Reactant: COc1ccc(C#N)nc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1nc(C#N)ccc1OC
Temperature: 130 °C

Procedure:
In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (9-2, 200 mg, 0.94 mmol, 1.0 equiv), potassium trifluoro(vinyl)borate (314 mg, 2.35 mmol, 2.5 equiv), tricyclohexylphosphine (52.7 mg, 0.19 mmol, 0.2 equiv), palladium(II) acetate (21.1 mg, 0.09 mmol, 0.1 equiv), and tripotassium phosphate (697 mg, 3.29 mmol, 3.5 equiv) were suspended in toluene (10 mL) and water (0.5 mL). The reaction mixture was heated in a microwave reactor for 20 minutes at 130° C. and then filtered, rinsing with EtOAc. The filtrate was concentrated and the residue purified by normal phase column chromatography (10-35% EtOAc in hexanes) to afford the product (9-3). ESI+MS [M+H]+ C9H9N2O: 161.0 found, 161.1 required.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14]
Reactant: Brc1ccccn1
Reactant: C#CCCCCO
Product: OCCCCC#Cc1ccccn1
Yield: 77.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (6.44 g, 40.8 mmol) and hex-5-yn-1-ol (4.00 g, 40.8 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 1:1) to yield 5.56 g (31.7 mmol, 78%) of 6-pyridin-2-yl-hex-5-yn-1-ol as an orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:17])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(Cl)ccc1Br
Yield: 93 %

Procedure:
To a stirred solution of 3-bromo-6-chloropyridine-2-carboxylic acid (2.00 g, 8.46 mmol) in MeOH (40 ml) was added H2SO4 (189 μl, 3.55 mmol) and the solution was heated to reflux for 16 h. The reaction was cooled and the MeOH removed under reduced pressure, the resulting solid was dissolved in EtOAc (100 ml) and washed with saturated NaHCO3 solution (2×50 ml) followed by brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure to afford the title compound as an off-white solid (1.97 g, 93%) which was used without any further purification. LC-MS 98%, m/z=249.8/251.7/253.7
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CC(C)=O.C(Cl)Cl.O>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[CH:25]=[C:20]3[N:19]([CH:2]=2)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: Cc1ccccn1
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cc3ccccn3c2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (0.44 mmol) and 2-picoline (41 mg, 0.44 mmol) in acetone (2 mL) was heated to reflux for 3 h, diluted with CH2Cl2 (20 mL) and water (10 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL), and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:19 to 1:2) to afford 2-(3-methoxy-4-pyridin-2-ylphenyl)indolizine. 1H NMR (CDCl3, 300 MHz) δ 8.75 (m, 1H), 7.92 (m, 2H), 7.86 (d, 1H), 7.73 (dt, 1H), 7.65 (br s, 1H), 7.41 (dd, 1H), 7.38 (d, 1H), 7.30 (br s, 1H), 7.21 (m, 1H), 6.77 (s, 1H), 6.69 (dd, 1H), 6.49 (dt, 1H), 3.97 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz) δ 157.3, 156.0, 149.4, 137.3, 135.7, 133.7, 131.5, 129.1, 127.2, 125.1, 125.1, 121.6, 119.1, 119.1, 117.6, 110.8, 109.6, 109.2, 96.8, 55.7 ppm. MS (ESI) 301 (M)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([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]([Cl: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])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([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]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCCC(O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.7 %

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxycyclohexyl)amide (106 mg, 0.19 mmol) was dissolved dichloromethane (3 mL). Trifluoroacetic acid (0.2 mL, 2.6 mmol) was added and the orange reaction mixture was stirred at room temperature for 15 h. Additional trifluoroacetic acid (0.7 mL) was added and the reaction stirred for an additional 5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.20 mL, 2.96 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 74 mg (91%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl)-amide as a white solid and a 2:1 mixture of cis and trans isomers (unassigned). MS: [M+Na] 447.
Reaction SMILES: [C:1]1([CH3:42])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][N:16]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:43][C:44]1([CH3:52])[O:51][CH2:50][CH:49]2[CH:47]([O:48]2)[CH2:46][O:45]1>CN(C)C=O>[OH:48][CH:49]1[CH2:50][O:51][C:44]([CH3:52])([CH3:43])[O:45][CH2:46][CH:47]1[N:13]1[CH2:14][CH2:15][N:16]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:17][CH2:18][N:19]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH2:20][CH2:21][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:42])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:11][CH2:12]1
Reactant: CC1(C)OCC2OC2CO1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C3COC(C)(C)OCC3O)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
50 g (78.76 mmol) of 4,7,10-tris(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane and 13.63 g (94.51 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo-[5.1.0]-octane are dissolved in 300 ml of dimethylformamide and heated in an autoclave for 24 hours to 170° C. It is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1). The main fractions are concentrated by evaporation and recrystallized from methyl tert-butyl ether/methanol. Yield: 52.76 g (86% of theory) of a cream-colored powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([CH3:13])[N:12]=1)(=[O:22])[CH3:21]
Reactant: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1-c1nc(C)c(-c2cccnc2)[nH]1

Procedure:
A solution of 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.5 g) and acetic anhydride (0.38 ml) in acetic acid (5 ml) was stirred at ambient temperature for 1.5 hours. The resulting precipitate was collected by filtration, and recrystallized from ethanol to give 2-(2-acetamidophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.55 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 92 %

Procedure:
The example 14 was prepared form the reaction of piperazino derivative 2 and 4-nitrobenzoyl chloride by following the similar procedure described for the example 12. After column purification the product was obtained as brown prisms in 92% yield.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C([NH:23][C:24]1[S:25][CH:26]=[C:27](/[C:29](=[N:53]/[O:54][CH3:55])/[C:30]([NH:32][C@@H:33]2[C:51](=[O:52])[N:35]3[C:36]([C:48]([OH:50])=[O:49])=[C:37]([CH2:40][S:41][C:42]4[N:46]([NH2:47])[N:45]=[N:44][N:43]=4)[CH2:38][S:39][C@H:34]23)=[O:31])[N:28]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH:1]([OH:3])=[O:2].[NH2:23][C:24]1[S:25][CH:26]=[C:27](/[C:29](=[N:53]/[O:54][CH3:55])/[C:30]([NH:32][C@@H:33]2[C:51](=[O:52])[N:35]3[C:36]([C:48]([OH:50])=[O:49])=[C:37]([CH2:40][S:41][C:42]4[N:46]([NH2:47])[N:45]=[N:44][N:43]=4)[CH2:38][S:39][C@H:34]23)=[O:31])[N:28]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To 80% formic acid (17 ml) was added 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (4.3 g, 5.7 mmol) with stirring at room temperature and the mixture was stirred for an hour and a quarter. After adding water (85 ml), the mixture was filtered to remove insoluble material and the filtrate was concentrated below 45° C. The residue was treated with tetrahydrofuran (10 ml)-ether (5 ml) and concentrated again under reduced pressure. The residue was treated with ether to give pale yellow substances of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid formate (2.98 g, 93.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2.[H-].[Na+].Br[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH:21][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:19][C:18]([CH:22]([NH:24][CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH3:23])=[N:17][C:16]=13)=[CH:5]2
Reactant: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC1CCOCC1)c1cc(NCCC(=O)OC(C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
A stirred solution of 3-(6-fluoroquinolin-3-yl)-5-[1-(tetrahydro-2H-pyran-4-ylamino)ethyl]pyrazolo[1,5-a]pyrimidin-7-amine (240 mg, 0.50 mmol) in anhydrous DMF (6 mL) was treated with sodium hydride (60% suspension in mineral oil, 59 mg, 1.5 mmol) in a single portion under an atmosphere of nitrogen. The resulting yellow-orange slurry was stirred at room temperature for 15 min, and tert-butyl 3-bromopropanoate (128 uL, 0.77 mmol) was added dropwise, gas evolution occurring during the addition. The mixture was stirred at room temperature overnight and was then quenched with water (15 mL) and extracted with EtOAc (2×25 mL). The combined organics were washed with water (3×20 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo and the residue was purified by flash chromatography (40 g silica gel, 3-9% MeOH/DCM) to give tert-butyl 3-(3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoate (185 mg, 69%) as a glassy solid. MS (ESI+) for C29H35FN6O3 m/z 535 (M+H)+; HPLC, 3.27 min (Method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:39]([F:49])[CH:38]=2)[CH2:33][CH2:32]1)=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37]6[CH:42]=[CH:41][C:40]([C:43]7[N:44]=[CH:45][CH:46]=[CH:47][N:48]=7)=[C:39]([F:49])[CH:38]=6)[CH2:33][CH2:32]5)=[O:30])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Reactant: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (12AB) (40 mg, 0.09 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (37 mg, 0.11 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (23 mg, 32 uL, 0.18 mmol, 2 equiv). The reaction content was stirred at room temperature overnight.
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:52])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18]([CH3:51])[CH:17]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:58]>CC#N.O>[Na+:58].[CH3:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([CH3:51])[C:19]=1[S:23]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[S:35]([CH2:37][C:38]1[C:43]([CH3:44])=[C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=[CH:40][N:39]=1)=[O:36])(=[O:24])=[O:25])[O:15][CH2:14][C:13]([O-:52])=[O:12]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2c(C)cc(OCC(=O)[O-])cc2C)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 58, 1.6 g, 1.90 mmol) in 10 mL of CH3CN was added a solution of NaHCO3 (208 mg, 2.47 mmol, 1.3 eq) in 5 mL of H2O. The mixture was heated to 65° C. for 3 h. Thereafter all the volatile materials were removed under vacuum, the mixture was washed with EtOAc (2×), and then the aqueous layer was lyophilized overnight. The solid was dissolved in 80 mL of CH2Cl2, and then the mixture was filtered to remove insoluble material. The filtrate was concentrated and the residual oil was dissolved in 5 mL of CH2Cl2. EtOAc was added to the mixture to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc, and dried under vacuum to yield 800 mg (62%) of 3,5-dimethyl-4-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}phenoxyacetic acid sodium salt (Compound 33) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH:6]([C:29]1[CH:38]=[N:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:14]=1)[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Yield: 92.1 %

Procedure:
A solution of the 22-4 (0.141 g, 0.268 mmol) in 25 mL absolute EtOH was treated with 10% Pd—C (0.015 g, 10% by wt) at room temperature under an argon atmosphere. Then ammonium formate (0.101 g, 1.61 mmol) was added and the heterogeneous mixture was refluxed for 30 minutes. The reaction was >50% complete (by ms). At this point, more Pd—C (0.008 g, 5% by wt) and NH4CO2 (0.050 g, 0.80 mmol) were added and the mixture refluxed for an additional 30 minutes (reaction complete by ms). The solution was then filtered through a Celite plug, washed with EtOH (75 mL), and concentrated in vacuo to afford 0.130 g 22-5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH:20]1([C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([C:32]4[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=4)=[N:3][N:4]=3)[C@H:13]([CH3:26])[CH2:14]2)=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(C(=O)C2CCCCC2)CCN1c1nnc(Cl)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)C2CCCCC2)CCN1c1nnc(-c2ccc(CO)cc2)c2ccccc12
Temperature: 100 °C

Procedure:
(R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(cyclohexyl)methanone (JK-21) (150 mg, 0.402 mmol), 4-(hydroxymethyl)phenylboronic acid (85.6 mg, 0.563 mmol), and tetrakis(triphenylphosphine)palladium (0) (23.6 mg, 0.0201 mmol) were dissolved in toluene (5 mL) and aqueous sodium carbonate (2.0M, 0.500 mL) under an atmosphere of argon. The reaction was heated at 100° C. for 23 hours, then cooled and taken up in ethyl acetate (80 mL). After washing with aqueous K2CO3 (10%), water, and saturated sodium chloride, the organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a pale yellow solid, JK-29. MS (M+H)+=445.4.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[C:6]1([S:12][CH:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[C:6]1([S:12][C:13]2[C:17]([C:18]#[N:19])=[CH:16][S:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1=CSCC1Sc1ccccc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1cscc1Sc1ccccc1
Yield: 90 %

Procedure:
3.6 Parts by volume of sulfuryl chloride in 25 parts by volume of methylene chloride are added, at 0° C., to a solution of 8.76 parts of 3-phenylthio-4-dihydrothiophene-nitrile in 100 parts by volume of methylene chloride. During the reaction, nitrogen is passed into the mixture. The end product is isolated from the reaction mixture by the method described in Example 5c. 7.8 parts (90% of theory) of 3-phenylthio-4-thiophene-nitrile of melting point 32°-34° C. are obtained.
Reaction SMILES: C(N(C=O)CC(C1C=CC=CC=1C#N)=O)=O.[CH:17]([N-:19][CH:20]=[O:21])=[O:18].[Na+].Br[CH2:24][C:25]([C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:26]>C(#N)C>[CH:17]([N:19]([CH:20]=[O:21])[CH2:24][C:25]([C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:26])=[O:18]
Reactant: CCOC(=O)c1ccccc1C(=O)CBr
Reactant: O=C[N-]C=O
Agent: N#Cc1ccccc1C(=O)CN(C=O)C=O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccccc1C(=O)CN(C=O)C=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
The 2-(N,N-diformylglycyl)benzonitrile can be prepared in the following manner: 5.54 g of sodium diformylamide are added to a solution of 14.45 g of ethyl 2-bromoacetylbenzoate in 150 ml of acetonitrile and the mixture is stirred for 16 hours at boiling temperature and then, after cooling to 20° C., the insoluble matter produced is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue is chromatographed on a neutral silica gel, eluting with a methylene chloride-ethyl acetate (80-20 by volume) mixture. 8.4 g of ethyl 2-(N,N-diformylglycyl)benzoate are thus obtained in the form of an orange-coloured oil [1H spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.22 (3H, t, J=6 Hz, CH3), 4.23 (2H, q, J=6 Hz, OCH2), 4.90 (2H, s, NCH2CO), between 7.60 and 7.90 (4H, m, 4 arom. CH), 9.20 (2H, B, 2 CHO)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:21])[CH3:20])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:21])[CH3:20])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1

Procedure:
N-{3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (28.9 g, 98.5 mmol) was dissolved in 1.0 L of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at room temperature. The solution was filtered through celite and the solvent was evaporated. Yield: 25.9 g (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.4 (m, 2 H), 1.7 (m, 2 H), 1.82-1.91 (m, 1 H), 2.13 (s, 3 H), 2.99 (d, J=6.64, 2 H), 3.42 (dt, J=11.86, 2.05 Hz, 2 H), 4.02 (dd, J=10.94, 3.71 Hz, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10-8.12 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:17][CH:18]=3)[N:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)=O>[CH:19]([OH:21])=[O:20].[F:1][C:2]1[C:7]([N:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[N:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3cccnc3F)nn2)CC1
Solvent: O=CO
Product: Fc1ncccc1-n1cc(C2=CCNCC2)nn1
Temperature: 25 °C

Procedure:
tert-Butyl 4-[1-(2-fluoropyridin-3-yl)-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (24 mg) prepared in Example 4 was dissolved in 2 ml of formic acid, followed by stirring for one night at room temperature and the solvent was evaporated in vacuo to give the title compound as a mixture.