Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([CH3:34])[CH:25]=4)=[CH:18][CH:17]=3)[CH2:12]2)[CH:10]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH2:37][CH:10]1[CH2:9][NH:8][CH2:36][CH2:35][C:11]21[O:15][N:14]=[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=1)[CH2:12]2
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCC12CC(c1ccc(OCc3cc(C)nc4ccccc34)cc1)=NO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1CNCCC12CC(c1ccc(OCc3cc(C)nc4ccccc34)cc1)=NO2
Reaction time: 1 h
Yield: 139.6 %

Procedure:
The intermediate 6-methoxycarbonylmethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-1-oxa-2,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester from Example 33 (0.43 g, 1.87 mmol) was dissolved in methylene chloride (12 mL) and TFA (12 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 1 h and concentrated in vacuo to give {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-1-oxa-2,8-diaza-spiro[4.5]dec-2-en-6-yl}-acetic acid methyl ester (1.2 g, 100%) crude product. MS found: (M+H)+=460.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C)C=O>[CH3:18][C:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylformamide (50 mL) was added tert-butyl 2-bromo-2-methylpropanoate (15 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.0 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.71 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid methyl ester in 2.5 ml THF was added 937 μL of a 1M LiOH solution in water and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 1M hydrochloric acid solution and the formed precipitate was collected by filtration washed with water and dried under high vacuum to yield 232 mg (96.71%) of the title compound as white solid, MS 331.1 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[CH2:21][CH2:20][C:13]2([O:17][C:16](=O)[O:15][C:14]2=[CH2:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:3]([N:10]1[CH2:21][CH2:20][C:13]2([O:17][C:16](=[O:15])[N:2]([CH3:1])[C:14]2=[CH2:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=C1N(C)C(=O)OC12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of 1.6 g of methylamine in 35 ml of xylene prepared at 0° C. is flown to the solution of 13.0 g of 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane in 30 ml of xylene under stirring. The reaction is exothermic, thus the temperature of the reaction mixture increases up to 55° to 60° C. Thereafter, the heterogeneous reaction mixture is heated to a temperature of 100° to 102° C., maintained at the same temperature for 10 minutes, then 0.2 g of p-toluenesulfonic acid monohydrate is added to the solution and the reaction mixture is boiled while the water formed in the reaction is azeotropically distilled out. After termination of the reaction the mixture is cooled down to room temperature, washed with 5% by weight aqueous sodium hydroxide solution and after separation the xylene phase is washed to neutral with water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from a mixture of ethanol and diisopropyl ether under clarifying by activated carbon to obtain the title compound in 96.7% yield, m.p.: 96°-97° C.
Reaction SMILES: [CH2:1]([P:8]([CH2:15][OH:16])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH2:1]([P:8]([CH2:15][O:16][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)(=[O:26])=[O:25])(=[O:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCOP(=O)(CO)Cc1ccccc1
Product: CCCCOP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)Cc1ccccc1

Procedure:
The title compound was prepared from benzylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The resulting white solid (mp 87°-88° C.) was used in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:17]=[CH:18][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:14][CH:15]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1nc(OCCO)c(-c2ccccc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccccc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (63 mg) of 5-bromo-2-chloropyrimidine was used and that 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-phenyl-1H-pyrazol-5-yl}benzenesulfonamide (Example 15) (80 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (52 mg).
Reaction SMILES: [Na].[C:2]1([O:9][CH3:10])[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1([CH:17](Cl)[CH:18]=[CH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:10][O:9][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]=[CH2:19]
Reactant: COc1ccccc1O
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 5 g of guaiacol sodium salt in 60 ml of dimethylformamide, 1-phenylallyl-chloride (5.22 g) (J.C.S. 1959, p. 2720) was added under a nitrogen atmosphere. The whole was stirred for 4 hours at room temperature and for two hours at 50° C., poured into water and extracted with ethyl ether. After standard working up, followed by chromatographic separation, 3-(2-methoxy-phenoxy)-3-phenyl-propylene (8.1 g; 98%) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH2:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cccc(NC(N)=O)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1cccc(CCCCO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[3-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)phenyl]urea (5.67 g) in THF (50 ml) was treated with TFA (13.56 ml) and stirred at room temperature for 1 h. Further TFA (5 ml) was added and the reaction mixture stirred for a further 16 hours. The reaction mixture was concentrated in vacuo. The residue was co-evaporated with methanol and then suspended in methanol and heated at reflux for 20 h prior to concentration in vacuo. The residue was purified by chromatography (SPE, DCM-MeOH 9:1) to give the title compound. LCMS RT=2.14 min.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH2:20][NH3+:21])[CH:11]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>ClCCl>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[S:42]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([NH:16][C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[N:15]=[CH:14][N:13]=2)[CH:18]=1)(=[O:44])=[O:43]
Reactant: COc1ccccc1-c1cc(Nc2cccc(C[NH3+])c2)ncn1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cc(Nc2cccc(CNS(=O)(=O)c3c(Cl)cccc3Cl)c2)ncn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
171 mg 3-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylamino]-benzyl-ammonium chloride (prepared in Example 69) (0.5 mmol) was dissolved in 50 cm3 dry dichloromethane, 0.350 cm3 N,N-diisopropyl-ethylamine (259 mg, 2 mmol) was added and the mixture was cooled to 0° C. in an ice bath. After stirring it for 15 minutes 196 mg 2,6-dichlorobenzenesulfonyl-chloride (0.8 mmol) was added and the mixture was stirred for 2 hours at 0° C. and overnight at room temperature. Then 50 cm3 5% NaHCO3 solution was added and it was extracted three times with 50-50 cm3 of chloroform. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated under reduced pressure. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product as an yellow solid. Yield: 34 mg (13%). For analitical results and compound identification see Table 1.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 170 °C

Procedure:
(S)-tert-Butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.670 g, 13.76 mmol), ethyl hydrazinecarboxylate (7.160 g, 68.80 mmol), DBU (1.037 mL, 6.88 mmol) and NMP (34.6 mL) were mixed in a 200 mL high pressure reaction vessel. The resulting suspension was heated at 170° C. overnight and was then cooled to room temperature. Crushed ice was added and the mixture was stirred. A yellow precipitate was collected by vacuum filtration, washed with additional water, and dried in a vacuum oven at 45° C. overnight to give the title compound, which was used in the next step without further purification (5.47 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33-1.51 (m, 9H), 2.09-2.38 (m, 2H), 3.39-3.60 (m, 3H), 3.75 (dd, J=12.20, 4.88 Hz, 1H), 6.03-6.22 (m, 1H), 7.62-7.71 (m, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.95-8.05 (m, 1H), 8.11-8.29 (m, 2H), 11.78 (s, 1H), 12.03 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(F)c(Br)c1
Yield: 81.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 24 for the preparation of I-24a above, 3-bromo-4-fluoro-benzenethiol (2.0 g, 9.756 mmol) was reacted with 1-chloro-propan-2-one (0.86 mL, 10.73 mmol), DMF (6.0 mL), and potassium carbonate (2.69 g, 19.51 mmol) to afford crude product which was purified by column on silica gel (5% ethyl acetate in hexane) to afford 2.1 g of the product (82% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[Na+]>CN(C)C=O>[C:13]1([C:10]2[C:9]3[C:19](=[O:20])[CH:5]([CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:6][CH2:7][C:8]=3[O:12][N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (4.00 g) and dimethylformamide (69 ml) was added diisopropylethyl amine (4.81 ml), piperidine (1.50 ml) and sodium iodide (0.62 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed at 83°-85° C. for 7-8 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted twice with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatogaphy (silica gel, 2% triethylamine/0-4% methanol/ethyl acetate) afforded 2.30 g of the product. Recrystallization from ether/pentane yielded 6,7-dihydro-3-phenyl-5-[3-(1-piperidinyl)-propyll-1,2-benzisoxazol-4(5H)-one, m.p. 91.5°-93.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:44][C:45]1[N:46]([CH2:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[CH:48][N:49]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28](=[O:43])[NH:29][C@H:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32][C:33](O)=[O:34])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][CH:63]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:53]([O:52][C:51](=[O:57])[CH2:50][N:46]1[CH:47]=[CH:48][N:49]=[C:45]1[CH2:44][N:14]([CH2:13][C:9]1[N:8]([CH2:7][C:6](=[O:58])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28]([NH:29][C@@H:30]([CH2:31][CH2:32][C:33](=[O:34])[NH:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]([S:68](=[O:69])(=[O:70])[NH2:71])=[CH:66][CH:67]=1)[C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:43])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
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
Product: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)NCCc1ccc(S(N)(=O)=O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Yield: 101.8 %

Procedure:
A solution of (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (80 mg, 0.098 mmol), 4-(2-aminoethyl)benzenesulfonamide (30 mg, 0.15 mmol), HATU (50 mg, 0.17 mmol), and DIPEA (0.50 mL) in DMF (5 mL) was stirred at 40° C. overnight. The solvents were evaporated under reduced pressure to give a residue, which was purified by Biotage SP4 using a gradient of 0-20% MeOH in DCM to give (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1,5-dioxo-5-(4-sulfamoylphenethylamino)pentan-2-yl)ureido)hexanoate (100 mg, 100%). ESMS m/z: 501.9 (M/2+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].CC[N:28]=C=NCCCN(C)C.O>CC(N(C)C)=O>[C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:28])=[O:25])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(=O)O)c1
Reactant: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(N)=O)c1
Yield: 45.8 %

Procedure:
A solution of 4-(4-cyano-3-cyclopentyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylic acid (14 mg) obtained in Example 65, EDCI (7.36 mg) and HOBt ammonium salt (18 mg) in DMA (3 mL) was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (6.4 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(C)ccc1C=O
Yield: 91.8 %

Procedure:
By the method of Example 1, Step F, 8,27 g (0.060 mole) of 4-methylsalicylaldehyde and 11.15 g (0.073 mole) of methyl bromoacetate were reacted in the presence of 10.1 g (0.073 mole) of anhydrous potassium carbonate in 150 mL of acetone, yielding 11.47 g of methyl (2-formyl-5-methylphenoxy)acetate as a white solid, m.p. 63°-64° C. The NMR was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:31])[CH2:27][CH2:28][CH2:29][CH3:30]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: CCCCCN
Product: CCCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and pentylamine (2 ml) the subtitle compound was obtained (289 mg, 100%). MS 402 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[SH:12][CH2:13][C:14]([OH:16])=[O:15]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[S:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CS
Reactant: Clc1ccc2ccccc2n1
Product: O=C(O)CSc1ccc2ccccc2n1

Procedure:
The present invention provides a single stage method for the production of 2-(quinolylthio)acetic acid by reacting 2-chloroquinoline with mercaptoacetic acid; the desired 2-(quinolylthio)acetic acid is obtained with high purity and yield.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>CCCCO>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in n-BuOH (5 mL), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (153 mg, 1.00 mmol, 1.00 equiv) and N-ethyl-N-isopropylpropan-2-amine (0.5 mL). The resulting solution was stirred overnight at 130° C. and concentrated under vacuum. The crude product was purified by applying onto a C18 Column (water/acetonitrile) to afford 150 mg (41%) of 148 as a white solid. LC-MS (ES, m/z): 355 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.97 (s, 1H), 7.69 (d, 1H), 7.48 (m, 5H), 7.25 (m, 2H), 7.11 (m, 2H), 6.58 (d, 1H), 5.65 (q, 1H), 1.71 (d, 3H)