Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]([OH:15])=[CH:5][CH:4]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:6]1[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(O)c(-c2cccnc2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(SC)nc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-Methylsulfanyl-[2,3′]bipyridin-3-ol (13 mg), 4-chloro-6,7-dimethoxyquinoline (46 mg), and 4-dimethylaminopyridine (29 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (25 mg, yield 91%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:18]([C:22]([O:24]CC)=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(N3CCOCC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(N3CCOCC3)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
400 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (Example 34A; 0.927 mmol, 1 equivalent) were dissolved in 24 ml of THF/methanol 5:1, 4.6 ml of 1N aqueous lithium hydroxide solution (4.6 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 4 h. The mixture was cooled, acidified to pH 4 with 6 N hydrochloric acid and concentrated. Water was added to the residue and the mixture was extracted repeatedly with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried, filtered and concentrated. This gave 145 mg of the title compound (35% of theory) which was reacted further without further work-up.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:8]
Reactant: COc1cc(C(=O)O)cc2c1OCO2
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-methoxy-4,5-methylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26].C(OCC)C>CN(C)C=O>[C:1]1([S:7]([CH2:10][C:11]2([C:14]([O:17][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])([CH3:15])[CH3:16])[CH2:13][CH2:12]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(O)C1(CS(=O)(=O)c2ccccc2)CC1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)C1(CS(=O)(=O)c2ccccc2)CC1
Yield: 126.3 %

Procedure:
To a stirred and ice-cooled solution of 8 (4.05 g, 15.9 mmol) and imidazole (2.16 g, 31.7 mmol) in N,N-dimethylformamide was added chlorotriethylsilane (4 mL, 23.8 mmol), and the mixtrue was stirred at ambient temperature overnight. To the mixture was added ice and diethyl ether and the mixture was stirred at ambient temperature for 20 min. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 7.40 g of an oily material, which was purified by column chromatography (silica gel 70 g, 4-12% ethyl acetate in n-hexane) to give 5.89 g (quantitative) of 9, as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ: 0.55 (6H, q, J=7.9 Hz), 0.80(2H, dd, J=6.8 and 4.2 Hz), 0.91(9H, t, J=7.9 Hz), 0.92(2 H), 1.20 (6H, s), 3.39(2H, s), 7.55(2H, t, J=7.4 Hz), 7.64(1H, t, J=7.4 Hz), 7.89(2H, d, J=7.4 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]([CH3:24])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].C(O)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COc1cc2c(-c3cc4cc(Cl)cnc4[nH]3)cn(C)c2cc1OC
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A suspension of 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine and 0.58 g of potassium tert-butoxide in 25 ml of 1-methylpyrrolidin-2-one is heated at a temperature in the region of 70° C. for approximately 4 hours 30 minutes. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 40 ml of water and the pH of the suspension obtained is brought to approximately 4-5 by adding glacial acetic acid. After agitation for approximately 10 minutes, the solid is filter-dried, washed with three times 5 ml of water and then air-dried. After recrystallization from 160 ml of propan-1-ol, 0.28 g of 5-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a beige solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=4)[CH2:22]3)[C@@H:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].O.[CH3:44]N(C=O)C>IC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=4)[CH2:22]3)[C@@H:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:14][O:15][CH3:44])[CH:4]=[C:3]([C:2]([F:39])([F:1])[F:40])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccccc1C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The compound from EXAMPLE 3 (0.02 g, 0.035 mmol) was dissolved in DMF (15 mL) and cooled to 0° C. NaH solid (12.8 mg, 0.07 mmol) was added, and the reaction mixture was stirred at 0° C. for 5 min. A few drops of iodomethane (excess) were added to the mixture. After stirring for another 10 min at 0° C., water (1 mL) was added and the water/DMF were removed in vacuo. The residue was taken into ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by preparative TLC (10% methanol in ethyl acetate) to afford the title compound. M++1: 582.47.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[C:24]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2c(CNc3ccc(-c4ccc(Cl)cc4)cc3)cccc2C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2c(CNc3ccc(-c4ccc(Cl)cc4)cc3)cccc2C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of NaOH (0.30 mL, 0.30 mmol) was added to a THF (0.6 mL) and MeOH (0.3 mL) solution of ethyl 3-(5-(2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)-6-(trifluoromethyl)phenyl)picolinamido)propanoate (57.5 mg, 0.10 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 45 min the resulting mixture was acidified with 1M HCl (0.31 mL, 0.31 mmol) and then extracted with DCM. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:10]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[O:13][C:9]=2[C:8](=[O:18])[N:7]([OH:19])[C:6]1=[O:20].[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=2[O:26]1>>[O:26]1[C:27]2[CH:28]=[CH:29][C:30]([C:24]3[CH:2]=[C:3]([CH:21]=[CH:22][CH:23]=3)[CH2:4][N:5]3[C:10]4[C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[O:13][C:9]=4[C:8](=[O:18])[N:7]([OH:19])[C:6]3=[O:20])=[CH:31][C:32]=2[O:33][CH2:25]1
Reactant: O=c1c2oc3ccccc3c2n(Cc2ccccc2Br)c(=O)n1O
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=c1c2oc3ccccc3c2n(Cc2cccc(-c3ccc4c(c3)OCO4)c2)c(=O)n1O

Procedure:
1-(2-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was treated with 3,4-methylenedioxyphenylboronic acid according to general procedure C to provide the title compound as a yellow solid. 1H NMR (d6-DMSO, 300 MHz) 5.61 (s, 2H); 6.05 (s, 2H); 6.98 (d, J=8 Hz, 1H); 7.10 (dd, J1=8 Hz, J2=2 Hz, 1H); 7.18-7.21 (m, 2H); 7.35 (dd, J=8 Hz, 2H); 7.49 (br d, J=8 Hz, 1H); 7.57-7.62 (m, 2H); 7.80 (d, J=8 Hz, 1H); 7.87 (d, J=8 Hz, 1H); Ret. time=2.95 min., m/z=429.0.
Reaction SMILES: [OH-:1].[Na+].[C:3]1(=[O:16])[C:15]2[C:7]([C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=[CH:4]1>C1(C)C(C)=CC=CC=1>[C:7]12([C:11]3[C:12]([C:13]4[C:9]([CH:10]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:13][CH:14]=[CH:15]1)[C:8]1[C:14]([C:15]3[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:4]([C:3]([OH:1])=[O:16])[CH:5]=[CH:6]2
Reactant: [OH-]
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(O)C1=C2C(=Cc3ccccc32)C2(C=CC=C3C2=Cc2ccccc23)C=C1

Procedure:
 In a 2 l flask, 100 g of fluorenone were dissolved in 1000 ml of dry xylene and admixed while stirring with 200 g of dry NaOH. The mixture was subsequently refluxed for 70 hours. After cooling, the mixture was filtered with suction and the residue was admixed with about 2 l of water. The aqueous suspension was filtered with suction and the precipitate was again slurried with toluene, filtered off with suction and dried. This intermediate was dissolved using about 5 ml of glacial acetic acid per 1 g by refluxing in a 500 ml two-necked flask fitted with reflux condenser and drying tube, 20 ml of concentrated HCl were added and the mixture was refluxed for 5 hours. The reaction mixture was evaporated to about half its volume and was subsequently poured into four times its volume of H2O. The precipitate formed was filtered off with suction, washed well with H2O and dried. To purify it further, it was dissolved at room temperature in an alkaline MeOH/water (10:1) mixture and shaken with toluene. The MeOH/water phase was separated off and, after acidification with hydrochloric acid, poured into water. The spirobifluorene-4-carboxylic acid which was precipitated was filtered off with suction, washed with water and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(OC(C)C)(=O)C>C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC=CN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 144 h

Procedure:
A further batch of N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt was prepared substantially according to the previous method except that the following quantities and reaction conditions were used: N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one (racemate) (4.96 g); (-)-3BCS in acetonitrile (1.85M; 9.4 ml); trifluoroacetic acid (2.1 ml); and isopropyl acetate (55 ml). The mixture was stirred at 90° C. for 6 days and then cooled to 0°-5° C. and aged for 1 hour. The solid N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3BCS salt was collected and washed with isopropyl acetate (20 ml). Yield 9.40 g (90%); ee 99.6% (S) isomer. The chiral composition of the remaining liquors was determined as 88% (R), 12% (S).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:20][NH2:21].O>C(O)C>[N+:16]([C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:21][N:20]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol (300 mL) was added hydrazine monohydrate (50 mL, 1 mol). The resultant solution was stirred overnight (16 hrs.) at ambient temperature, then poured into water (2L) and stirred for an additional 2 hours. The precipitate that formed was collected by filtration, washed with water (2×100 mL) and air dried to give 5-Nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow solid: 1H NMR (DMSO-d6) δ 7.48 (tt, 1H, J=1.3, 7.4 Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01 (dd, 2H, J=1.3, 7.1 Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz), 13.88 (s, 1H). Anal. (C13H9N3O2) C, H, N.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:7]([C:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]=1)=[O:9]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (317 mg, 1.471 mmol) and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3)(508 mg, 1.471 mmol) in DMF (10 ml) was added DIPEA (0.257 ml, 1.471 mmol) and HATU (559 mg, 1.471 mmol). The orange suspension formed was stirred at RT for 16 hrs. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 ml). The mixture was filtered and the filtrate was dry loaded in MeOH onto silica (˜5 g). Purification was carried out by chromatography on silica (12 g silica cartridge) eluting with 0-100% EtOAc/iso-hexane. The product fractions were combined and concentrated to give a gum. This was dissolved in minimum volume of EtOAc and applied to a combined 10 g Isolute® PEAX/SCX-2 cartridge. The column was washed with MeOH and the fractions combined and concentrated under reduced pressure. The resultant solid was dissolved in DMSO (500 μl), MeCN (2 ml) and water and applied to a 13 g C18 cartridge which was eluted with 0-100% MeCN/water. The product fractions were combined and concentrated to give an aqueous suspension which was extracted with EtOAc (50 ml). The extracts were dried (MgSO4) and concentrated to give 3,5-dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5]C)=O.[CH3:20][C:21]([Mg]Cl)([CH3:24])[CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1>[CH3:20][C:21]([CH3:24])([CH2:22][CH3:23])[C:3](=[O:5])[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:1]
Reactant: COC(=O)C(=O)C1CCCNN1Cc1ccccc1
Reactant: CCC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1Cc1ccccc1
Reaction time: 5 h
Yield: 69 %

Procedure:
A solution of methyl 2-oxo-2-[2-benzylperhydropyridazinyl]acetate (9.0 g, 29.4 mmol) in 30 ml dry THF was cooled to −78° C. and treated with 35 ml of 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at for 5 hours, the mixture was poured into saturated ammonium chloride (150 ml) and extracted into ethyl acetate. The organic layer was washed with water, dried and concentrated. The crude material was purified by silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 7.0 g product (69% yield) as clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.76 (t, 3H, J=7.0); 1.06 (s, 6H) 1.69 (m, 6H); 2.80 (m, 1H); 3.15 (m, 1H), 4.03 (m, 1H); 4.13 (m, 1H), 5.18 (m, 2H), 7.36 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: CNc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 11.5 h
Yield: 76.4 %

Procedure:
A mixture of 4-chloro-2-cyano-pyridine (6.9 g, 0.05 moles), 4-methylamino-3-nitrophenol (8.4 g, 0.05 moles), and K2CO3 (10.4 g, 0.075 moles) in DMSO (80 mL) was heated to 60° C. After 11.5 h, HPLC analysis indicated complete conversion of both starting materials. After cooling to 20° C., water (240 mL) was added to the reaction mixture. The temperature rose to 40° C. before decreasing to ambient temperature. The solid was collected by filtration and washed with water (2×40 mL). The solid was then slurried in heptane (40 mL). The solid was collected and washed with heptane (40 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 10.33 g (76%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 1H), 8.2 (m, 1H), 7.9 (m, 1 H), 7.7 (m, 1H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 3.0 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 165.1, 152.9, 144.4, 140.6, 134.1, 130.4, 130.1, 117.9, 117.1, 117.0, 116.5, 114.9, 29.8; APCI MS [M+H]+=271; HPLC >99% (LCAP).
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])(=[O:53])=[O:52])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56]([NH:27][OH:28])=[O:57])(=[O:53])=[O:52])[CH2:49][CH2:50]3)=[N:43][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)NO
Yield: 76 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.068 g), to provide the title compound as a cream solid (0.053 g, 76%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[Li+].[OH-].Cl>C1COCC1>[N:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:6][CH:7]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: COC(=O)Cc1ccc(-n2cnc3ccccc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of 0.535 g of (4-benzoimidazol-1-yl-phenyl)-acetic acid methyl ester and 2 ml of an 1N aqueous solution of LiOH in 2 ml of THF is stirred for 3 hours at 45° C. The mixture obtained is allowed to cool to rt and acidified to pH 5 by addition of 0.5 N aqueous HCl. A solid precipitates and is collected by vacuum filtration. (4-Benzoimidazol-1-yl-phenyl)-acetic acid is obtained. ES-MS: 253.1 [M+H]+; single peak at tR=2.36 min (System 1).