Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl.C[Si](C)(C)N[Si](C)(C)C.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[OH-].[Na+].Cl>O>[CH3:1][N:2]([S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:34])[F:35])=[CH:29][CH:28]=1)(=[O:32])=[O:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
0.194 g (1.00 mmol) of trans-4-methylamino-cyclohexanecarboxylic acid•HCl were mixed with 2.62 mL (12.58 mmol, 12.6 eq) of hexamethyldisilazane and heated under reflux to 140° C. for 1 h (total time 1.5 h). The solution was evaporated, suspended in THF and treated with 0.245 g (1.00 mmol, 1 eq) of 4-(trifluoromethyl)-benzenesulfonyl chloride at 0° C. and stirred at RT overnight. 1 mL of water was added at RT followed by 2 mL of 1M NaOH. Stirring was continued for 1 h at RT after this aqueous 1M HCl was added. The solution was then partitioned between Et2O (×3)/H2O, dried over Na2SO4 and evaporated to yield 0.234 g (64%) of trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid, MS: 364 (M−H−).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:28])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>ClCCl>[CH:1]1([C:6]2[C:7]([O:28][C:37]([O:39][CH3:40])=[O:38])=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CCCC3)c(O)cc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
Tert-butyl 4-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (596 mg, 1.53 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (388 mg, 535 μL, 3.84 mmol) then treated dropwise with methyl chloroformate (178 μL, 2.301 mmol). The reaction was stirred for 5 min at room temperature and then concentrated in vacuo to tert-butyl 4-(5-cyclopentyl-4-(methoxycarbonyloxy)-2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (680 mg, 99% yield). The material was used without purification. LC/MS m/z 447.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1.O>[C:1]1([CH:7]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)C2CCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)C2CCCC2)C1
Yield: 60 %

Procedure:
A solution of N-(2-phenyl-2-cyclopentylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine (159 mg, 0.27 mmol) in MeOH (5 mL), THF (1 mL), H2O (1 mL), and 2.5 N NaOH (2.5 mL) was heated to 50° C. for 1 h. The reaction was cooled, diluted with H2O, acidified to pH=5.5, and extracted with EtOAc. The extracts were washed with H2O, dried, and concentrated to yield the titled compound (93 mg, 70%). MS (ESI) 575 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:25]([NH:29][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(-c2cccc3cncn23)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc3cncn23)cc1
Reaction time: 1.5 h

Procedure:
To a slurry of 0.4 g of 5-(p-carboxyphenyl)imidazo[1,5-a]-pyridine in 40 ml of methylene chloride under nitrogen at room temperature, is added 30 μl of N,N-dimethylformamide followed by 0.16 ml of oxalyl chloride. The reaction mixture is stirred until gas evolution is complete and 0.46 ml of tert-butylamine is added dropwise. Stirring is discontinued after 90 min and 10 ml of saturated sodium bicarbonate solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound, m.p. 128°-131°.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH:8]=[C:7]([CH3:22])[C:3]=1[C:4]([OH:6])=O.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[C:3]([C:4]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:6])=[C:7]([CH3:22])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:19])([F:20])[F:21])[CH:12]=2)[N:10]=1
Reactant: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethoxy-phenyl boronic to give 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow oil. MS: 448.2 (MH+).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Br.O>CS(C)=O.C(OCC)(=O)C>[N:22]1([C@@H:21]([CH3:23])[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: BrCCOCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)OCc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
Under an argon atmosphere, to a solution of L-alanine benzyl ester tosylate (3.4 g, 9.7 mmol) and triethylamine (6.8 ml) in dimethyl sulfoxide (17 ml) was added a solution of 1-bromo-2-(2-bromoethoxy)ethane (1.5 ml, 12 mmol) in dimethyl sulfoxide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. To the reaction solution were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.6 g, yield 64%).
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](OS(C(F)(F)F)(=O)=O)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>O1CCOCC1>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[N:7][C:6]3[C:23]([CH3:27])=[CH:24][CH:25]=[N:26][C:5]2=3)[CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccnc2c1N=C(OS(=O)(=O)C(F)(F)F)c1cccnc1N2C1CC1
Solvent: C1COCCO1
Product: Cc1ccnc2c1N=C(n1ccnc1)c1cccnc1N2C1CC1
Temperature: 100 °C
Yield: 40 %

Procedure:
To a solution of 11-cyclopropyl-4-methyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.12 g, 0.3 mmol) in dioxan (1 mL) was added imidazole (0.06 g, 0.88 mmol). The mixture was heated at 100° C. for 10 min. After cooling to room temperature, the reaction mixture was diluted with ethyl adetate, washed with water, dried over sodium sulfate, filtered and concentrated. The residue was fractionated by preparative layer chromatography (silica gel, eluted with 67% ethyl acetate/hexane) to give the title compound (0.04 g, 0.12 mmol, 42%) which crystallized from di-isopropyl ether, m.p. 198°-200° C.
Reaction SMILES: C(#N)C.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].C(O)=O.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[O:23][C@@H:22]1[CH2:28][OH:29].CN(C)C(=O)C>>[S:5](=[O:6])(=[O:7])([O:29][CH2:28][C@@H:22]1[C@@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])[O:25][C:24]([CH3:27])([CH3:26])[O:23]1)[NH2:8]
Reactant: CC1(C)O[C@H](c2ccccc2Cl)[C@@H](CO)O1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O=CO
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC1(C)O[C@H](c2ccccc2Cl)[C@@H](COS(N)(=O)=O)O1
Temperature: 0 °C
Reaction time: 6 h
Yield: 72.3 %

Procedure:
To a 100 ml flask, Acetonitrile (2.26 ml, 43.2 mmol) was added and cooled to 0° C. Chlorosulfonyl isocyanate (1.5 ml, 17.3 mmol), and formic acid (0.65 ml, 17.3 mmol) was added dropwise and stirred at room temperature for 6 hours. ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation example 6, 1.05 g, 4.3 mmol) in N,N-dimethyl acetamide (13.2 ml, 142.7 mmol) was slowly added at 0° C. and stirred at room temperature for 1 hours. The reaction mixture was quenched with H2O, extracted with EtOAc, and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (1.00 g, 50˜80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C)C=O>[CH3:15][S:16]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: Nc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
9.9 g of 4-aminopyridine (104.8 mmol) and 14.5 ml of triethylamine (10.6 g, 104.8 mmol) were dissolved at room temperature in 72 ml of dimethylformamide. Likewise at room temperature, 8.1 ml of methanesulphonyl chloride (12.0 g, 104.8 mmol) were added dropwise to this solution over the course of one hour. The exothermic reaction meant that the temperature had to be maintained by ice bath cooling. After 20 h of stirring at room temperature the solvent was distilled off in vacuo. The residue which remained was taken up in 100 ml of methylene chloride and in 150 ml of 1 N NaOH. The organic phase was separated off. The aqueous phase was adjusted cautiously to a pH of 4admixed with 100 ml of EtOH and 100 ml of methylene chloride. After the organic phase had been separated off, the aqueous phase was further admixed three times with 100 ml of EtOH and 100 ml of methylene chloride. The collected organic phases were freed from the solvent, and the crude product which remained was recrystallized from acetonitrile. This gave 3.2 g of product. The constitution of the compound was verified by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[F:9][C:10]1[CH:11]=[C:12]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cnc(-c2cccc(F)c2)s1
Temperature: 120 °C
Yield: 54 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (0.6 g, 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One chromatography (using 6% ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02. found 208.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][CH2:24][CH3:25])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1
Reactant: O=CNc1ccc(Cl)cc1
Reactant: CCOCCn1cnc2c(Cl)nc(Cl)nc21
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-(2-ethoxy-ethyl)-9H-purine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[C:25]([CH:28]=1)[CH:26]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:26]1[C:25]1[CH:28]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=1[N:29]1[CH:33]=[CH:32][CH:31]=[N:30]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: O=Cc1cc(Cl)ccc1-n1cccn1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2cc(Cl)ccc2-n2cccn2)nc2cc(-c3cnc(N)nc3)ccc21
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (50 mg, 0.19 mmol) in DMF (5 mL) is added 5-chloro-2-pyrazol-1-yl-benzaldehyde (60 mg, 0.29 mmol) at room temperature. Oxone (119 mg, 0.19 mmol) in H2O (1 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (20 mg, 23%) as a pale brown solid. LCMS (ESMS): m/z 444.69 (M++1)
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C@H:21]3[CH2:22][O:23][C:30]([CH3:32])([CH3:31])[O:24]3)=[CH:25][CH:26]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(OC[C@H](O)CCl)cc3)cc2)O1
Reaction time: 14 h

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (1000 mg, 2.53 mmol) in acetone (8.0 mL) was added 2,2-dimethoxypropane (630 μL, 5.06 mmol) and catalytic amounts of p-toluenesulfonic acid. After 14 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:52]1[CH2:55][CH:54]([OH:56])[CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([N:52]4[CH2:55][CH:54]([OH:56])[CH2:53]4)=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N3CC(O)C3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 30 mg, 0.084 mmol) was added HATU (38 mg, 0.10 mmol) and azetidin-3-ol hydrochloride (11 mg, 0.10 mmol) at ambient temperature, followed by dropwise addition of DIEA (0.044 ml, 0.25 mmol) at 0° C. After stirring for 20 minutes at ambient temperature, the reaction was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (26 mg, 75%). LCMS (apci) m/z=413.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([Cl:14])[C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: N#Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Yield: 67.7 %

Procedure:
A suspension of methyl 2,6-dichloro-4-cyanobenzoate (620 mg, 2.6 mmol) in pyridine (5 mL) was treated with anhydrous lithium iodide (1000 mg, 8 mmol). The resulting reaction mixture was stirred at reflux for 1 hour and concentrated under vacuum to remove pyridine. The residue was acidified with hydrochloric acid (2N) under ice-cold condition to adjust the pH between 2 to 3. The precipitated solid was filtered, washed with water and dried to yield 2,6-dichloro-4-cyanobenzoic acid (380 mg, 86%) as a pale brown solid.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:35]([CH3:38])([O-:37])=[O:36].Cl>CCCCCCC>[N+:35]([CH2:38][C@:6]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:1]2[C@H:5]1[CH2:4][CH2:3][CH2:2]2)([O-:37])=[O:36]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1C[C@H]2CCC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Reaction time: 17 h
Yield: 87.6 %

Procedure:
The n-heptane solution (12.5 L) of the acrylic ester of Example 6 (0.921 Kg; 5.11 mol) was concentrated by distillation at atmospheric pressure to 36% of its original volume. The n-heptane was then replaced with tetrahydrofuran by atmospheric azeotropic distillation at constant volume. The reaction mixture was cooled to 20–25° C., then tetrabutylammonium fluoride trihydrate (2.10 Kg; 6.64 mol) and nitromethane (0.499 Kg, 8.18 mol) were added. The resulting brown solution was stirred at 20–25° C. for 17 hours. To the reaction mixture a 2M aqueous solution of hydrochloric acid (4.5 L) was added, causing the reaction temperature to rise by 8° C. n-Heptane (4.5 L) was added and the phases were separated. The organic layer was then washed with demineralised water (4.5 L) to give the title product (1.08 Kg) in 88% yield as an organic solution which is used directly in the next step.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)(=[O:20])=[O:19])[CH:11]=1)=O)(C)(C)C.Cl>CO>[CH:26]1[C:27]2[C:22](=[C:21]([S:18]([NH:17][CH2:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH2:8])[CH:11]=3)(=[O:19])=[O:20])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNS(=O)(=O)c2cccc3cnccc23)c1
Agent: Cl
Solvent: CO
Product: NCc1cccc(CNS(=O)(=O)c2cccc3cnccc23)c1
Yield: 81 %

Procedure:
According to Reference Example 5, Step C, a reaction was performed by using Intermediate 63 (5 g) and 10% hydrogen chloride in methanol (20 ml) to obtain the title compound (3.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Bromo-3-nitroquinolin-4-ol (42 g, 156 nmmol) was suspended in POCl3 (130 mL) and brought to 102° C. under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature. The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH2Cl2 (3 L) and 2M Na2CO3 (500 mL). The organic layer was separated, washed with H2O (1×), dried over Na2SO4, filtered, and concentrated to afford 33.7 g of 7-bromo-4-chloro-3-nitroquinoline as a beige solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[CH2:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][CH3:11].Cl>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:9][CH2:10][CH3:11])=[CH:13][C:14]=1[C:5](=[O:6])[CH3:7]
Reactant: CCCc1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1ccc(OC)c(C(C)=O)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A suspension of 10.6 g of AlCl3 in 150 mL of dichloromethane is cooled to −10° C. 5.7 mL of AcCl and 6 g of 4-propylanisole are added. The medium is stirred for 30 minutes at −10° C. and then poured into a beaker containing ice mixed with 35% HCl. After separation of the phases by settling, the aqueous phase is extracted 3 times with DCM and the combined organic phases are washed with water, with saturated NaCl solution, dried over MgSO4 and then evaporated to give 7.86 g of a brown oil.