Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 36.3 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.75 g) synthesized in Example 35(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.57 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.44 g, 36%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(C)(=O)=O)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A27 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (50 μl), methanesulfonyl chloride (10 mg, 0.087 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 2.13 (m,4H), 2.85 (s, 3H), 3.08 (s, 3H), 3.31 (m, 2H), 3.57 (m, 2H), 4.13 (m, 1H), 5.69 (m, 1H), 7.87 (d,2H), 7.98 (d,2H), 8.42 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C14H21N5O7S2 471.09, found 472.3 (MH+).
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[C:25]([CH3:33])([CH2:31]C)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:1]([S:21][C:25]([CH3:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CCOC(=O)C(C)(Br)CC
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) in dry DMF (10 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). After fifteen minutes ethyl 2-bromo-2-methylbutyrate (154 μL, 1.05 mmol) was added and the mixture was stirred for 1.5 hour at 0° C. The reaction mixture was quenched by addition of sat. aq. NH4Cl (20 mL). Water (20 mL) and heptane (50 mL) were added and the phases were separated. The water phase was extracted with heptane (2×25 mL). The combined organics were washed with water (25 mL) and brine (2×25 mL), dried (MgSO4), filtered and evaporated to give 377 mg of the title compound as a crude oil. Purification by flash chromatography on silica gel using isocratic elution (heptane:EtOAc 98:2) afforded 307 mg (77% yield) of the title compound as oil.
Reaction SMILES: CN(C=O)C.[Na].[CH2:7]([SH:9])[CH3:8].[CH3:10][NH:11][C:12]1[C:17]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=2Cl)=[O:20])=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[CH:14][N:13]=1.C1COCC1>O>[CH3:10][NH:11][C:12]1[C:17]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=2[S:9][CH2:7][CH3:8])=[O:20])=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[CH:14][N:13]=1
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cc(Cl)nnc1Cl
Reactant: CCS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nnc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
6 ml of a DMF solution of 342 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 1.19 g of 3,6-dichloropyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 2 ml of DMF and 2 ml of THF under ice cooling, then the mixture was heated to room temperature, and stirred for 1 hour. The mixture was allowed to stand overnight, then water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.04 g of 6-chloro-3-ethylsulfanylpyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 6-chloro-3-ethylsulfanylpyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12]O)=[CH:9][CH:8]=1)#[N:6]>C(Cl)(Cl)(Cl)Cl>[C:5]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][Br:2])=[CH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
A solution of phosphorus tribromide (5 g) in carbon tetrachloride (10 ml) was added, dropwise, to a solution of 4-cyanophenethyl alcohol (8.06 g) in carbon tetrachloride (60 ml). The mixture was heated under reflux for 4 hours. On cooling to room temperature, the mixture was poured onto ice (200 g). the layers were separated and the organic layer was washed with 10% aqueous sodium carbonate (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to give a colourless oil which solidified on standing. The solid was chromatographed on silica eluting with ethyl acetate containing hexane (20%). The fractions containing the less polar (higher Rf) produce were combined and concentrated in vacuo to give 4-cyanophenethyl bromide as a yellow oil which solidified on standing, yield 8.9 g. The fractions containing the more polar (lower Rf) product were combined and concentrated in vacuo to give the title compound as a colourless solid, yield 0.47 g, m.p. 152-153°.
Reaction SMILES: [CH3:1][C:2]1([CH2:5]Cl)[CH2:4][O:3]1.[C-:7]#[N:8].[Na+].[C-:10]#[N:11].[K+]>Cl.O>[C:7]([CH2:4][C:2]([CH3:1])([OH:3])[CH2:5][C:10]#[N:11])#[N:8]
Reactant: CC1(CCl)CO1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(O)(CC#N)CC#N
Temperature: 40 °C
Reaction time: 10 h
Yield: 96.8 %

Procedure:
To a solution of 50 g 2-methyl-2-chloromethyloxirane in 23 ml concentrated hydrochloric acid at ice-bath temperature a solution of 27.4 g sodium cyanide in 23 ml hydrochloric acid was added. After stirring for 10 hours at that temperature the reaction mixture was warmed to 40° C. and a solution of 33.8 g potassium cyanide in 50 ml water was added. The resulting mixture was warmed to 50° C. and stirred for 4 hours. After cooling the solution was neutralized and extracted three times with 150 ml ethyl acetate each. The combined organic layers were dried with anhydrous magnesium sulphate. Removal of the solvent afforded 56.4 g (96%) of 1,3-dicyano-2-methyl-2-hydroxypropane. This crude material was sufficiently pure to be submitted directly to the following ring closure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:35]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
Combine 4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (100 g, 231 mmol), ammonium acetate (178.3 g; 2.31 mol, 10 eq), and methanol (1000 mL). The reactor used for this transformation is a coiled 1/16″ I.D. stainless steel tube (total internal volume of tubing in oven is 541 mol). Heat the reactor in an oven to 140° C. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point. Pump the solution prepared above continuously through the heated tube under pressure at 6.01 mL/min (affording a total residence time in the heated tube of 90 minutes). As the solution exits the oven, cool it back to 20° C. in a tube-in-tube heat exchanger. Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL. Add ACN (200 mL) and heat the solution to 50° C. Add water (700 mL) drop wise with seeding over 2 hours to crystallize the product. Cool the resulting slurry to 20° C. and filter the solid, then wash with 20% MeOH in water (2×200 mL). Dry the resulting solid under vacuum at 50° C. Re-slurry the solid in ACN (200 mL) at 50° C. Cool the slurry to ambient temperature, filter the solid and wash with ACN (100 mL) to afford 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (54.43 g, 132 mmol, 57%) as an off white solid. 1H NMR (300 MHz, DMSO): 12.01 (s, 1H), 8.08-8.04 (m, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.43 (m, 1H), 3.99 (d, J=12.6 Hz, 2H), 2.92-2.85 (m, 3H), 1.91-1.87 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-]>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc2oc(C(O)[C@H](C)NC(=O)OCc3ccccc3)nc2c1
Yield: 53 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 53% yield from the above cyanohydrin (1.10 g, 4.70 mmol) and 2-amino-p-cresol (636 mg, 5.17 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (7 : 1 mixture of isomers). mp: 134-135° C.; IR (KBr) υ 1718, 1691 cm−1; 1H-NMR (400 MHz, CDC13) δ 7.47-7.09 (m, 8H), 5.47 (d, J=8.6 Hz, 1H), 5.12-4.87 (m, 4H), 4.54-4.30 (m, 1H), 2.44 (s, 3H), 1.32 and 1.13 (2×d, J=6.7 and 6.7 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 165.90, 165.19, 156.09, 149.04, 140.24, 136.28, 134.38, 128.34, 128.09, 127.91, 126.32, 119.87, 119.69, 110.23, 70.84, 70.57, 66.92, 66.67, 50.48, 50.29, 21.34, 17.24, 15.32; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H20N2O4) C, H, N.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#N)=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:35].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:40]>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]([OH:40])=[O:35])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCCCc1nc(-n2cccc2)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Product: CCCCc1nc(-n2cccc2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 2-butyl-5-cyano-4-(1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole (Example 15, 1.4 g) and 2N NaOH (75 mL) was heated at reflux for 24 hours. The cooled solution was acidified to pH 3.5 by portionwise addition of citric acid. The resulting precipitate was collected by filtration and rinsed well with water. The solid was then purified by C18 -reversed phase chromatography eluting with acetonitrile water (40:60). The majority of the acetonitrile was evaporated from the pure fractions at reduced pressure, keeping the temperature below 30° C. The remaining aqueous portion was washed with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in ether and evaporated once again to give the title compound as a colorless powder. MS (FAB, thioglycerol) 468 (m+1), 424 (m-CO2 +1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+]>O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: Clc1ccnc2cccnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(CCNc2ccnc3cccnc23)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 500 mg of 4-chloro-1,5-naphthyridine and 1.0 g of N-[2-[4-(t-butyl)phenyl]ethyl]amine was stirred at 130° C. for 30 minutes. Then a 50/50 mixture of ammonium hydroxide and water was added. The product was extracted into methylene chloride, which was then concentrated. The product was purified by HPLC (silica gel, 20% ethyl acetate/80% pentane). The fractions containing the major product were collected and concentrated giving 0.277 mg of the title product as an oil. Yield 30%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]([C:28](=[O:31])[NH:29][OH:30])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:30][NH:29][C:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.147 g (0.325 mmol) of the product of Example 58, 4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester, in 3.0 mL of dichloromethane was added 0.3 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 1 h. The reaction was then concentrated in vacuo and the residue was diluted with dichloromethane. The organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.053 g of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([CH3:41])[CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([F:33])=[CH:35][C:36]=3[CH3:41])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Yield: 17.2 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.171 g, 0.372 mmol) obtained in step 2 and 4-fluoro-2-methylaniline (0.050 mL, 0.446 mmol), the title compound (0.035 g, 17%) was obtained.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.C(O)C.O1CCCC1.[OH-].[Na+]>[Cl-].[Na+].O>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
The 17β-ethyl carboxylate prepared in Example 1B (0.9259 g, 2.793 mmol) is dissolved in 60 mL warm ethanol/tetrahydrofuran (1:1), 6M sodium hydroxide is added (NaOH, 10.0 mL, 60 mmol) and the reaction is stirred at room temperature for 2 ½ hours. The reaction mixture is diluted with brine (100 mL) and extracted with EtOAc (3×50 mL). The combined organic phases are washed with brine (50 mL) and ammonium chloride (NH4Cl), dried over magnesium sulfate, filtered and evaporated to give a crude reaction product. The crude product is recrystallized from ethanol to give colorless crystals (0.3132 g, 1.0822 mmol) of 17β-hydroxy-4-aza-androst-5(6)-en-3-one. The mother liquor is concentrated and the recrystallization procedure above repeated in order to give a second crop of crystals. (0.3945 g, 1.363 mmole).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=O)[CH2:13]C.[O-]CC.[Na+]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:12][CH3:13])=[O:9])[CH:3]=1
Reactant: CCOC(=O)CC
Reactant: CCOC(=O)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl propionate (15.3 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirred and heated under nitrogen at 100° C. for five hours. After cooling, the mixture was diluted with water (150 ml) extracted with diethyl ether (50 ml) and the aqueous layer made acidic to pH 1 with concentrated hydrochloric acid (50 ml). The aqueous layer was heated at 90° C. for two hours, cooled, made alkaline with solid potassium carbonate and extracted with diethyl ether (3×75 ml). The dried (magnesium sulphate) organic layer was concentrated and distilled to give ethyl 3-pyridyl ketone (b.pt 97°-99°/14 mm Hg).
Reaction SMILES: C[C:2]1([CH3:23])S[C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)[C:112](=[O:113])[N:108]2[C@H]1C([O-])=O.[K+]>>[CH3:5][C@H:7]([NH2:10])[C:8]([NH:4][C@H:3]([C:20]([OH:22])=[O:21])[CH2:2][CH2:23][C:112]([NH2:108])=[O:113])=[O:9]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
Penicillin/Streptomycin are aseptically added to 500 mL RPMI in a biosafety cabinet. The Penicllin/Streptomycin 100× stock is supplied by, for example, Gibco (10,000 Units/mL Penicillin, 10,000 ug/mL Streptomycin). Stock L-glutamine 100× (as supplied, for example, by Invitrogen) Note: To be kept in a fridge (4° C.) for 4 weeks. Warm up in a water bath set at 37° C. prior to use. Anti-Human IL-17 Detection Antibody Components:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(Cl)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogen carbonate (1.23 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.42 g, 55%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.P(=O)(O)(O)O>CCO.C1COCC1.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CNc1ccc(OC)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(NCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
2M NaOH (aq.) (149 mL, 0.30 mol) was added dropwise to a stirred solution of ethyl 2-((4-methoxyphenyl)amino)acetate (17) (59.2 g, 0.28 mol) in EtOH/THF (300 mL/80 mL). The reaction was stirred at 40° C. for 3 h. The mixture was diluted with water (100 mL) and phosphoric acid (85% wt in water) (35.9 g, 0.31 mol) was added to pH 3. The resulting brown precipitate was collected by filtration and washed with water (100 mL) and dried under vacuum to give 2-((4-methoxyphenyl)amino)acetic acid (18) (45.5 g, 84%) as a brown solid: m/z 182 (M+H)+ (ES+); 180 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 6.78-6.64 (m, 2H), 6.55-6.44 (m, 2H), 3.74 (s, 2H), 3.64 (s, 3H).