Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>CO.C(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 62.8 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(4-methylphenyl)thiophene (100 mg, 0.37 mmol) with 5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, after column chromatography using 10% MeOH/CHCl3, 96 mg final product as a pale yellow solid, (63% yield, m.p. 175° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]([CH3:21])[N:13]=1.C[Li].[CH3:26]COCC.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:26])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CCOCC
Reactant: CCN(c1nc(C)cc(C(=O)O)n1)c1ccc(C(C)C)cc1Br
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(C)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 78 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine (3.7 g, 9.8 mmol) in anhydrous THF (25 mL) was cooled with stirring to 31 78° C. under a nitrogen atmosphere. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was stirred at -78° C. for 1 h. The CeCl3 suspension was transferred via cannula into the reaction mixture and stirring at -78° C. was continued for 5 h. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was then warmed gradually to room temperature over 16 h. After cooling the reaction mixture to -78° C., the reaction was quenched with a 1N HCl solution and warmed to room temperature. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an orange yellow oil. Column chromatography (ethyl acetate:hexanes::1:4) afforded the title product as an oil (2.5 g, 68% yield, Rf 0.5): NMR (CDCl3, 300 MHz): 7.55 (d, 1H, J=1), 7.25-7.15 (m, 2H), 6.95 (s, 1H), 4.30-4.10 (m, 1H), 3.90-3.70 (m, 1H), 3.00-2.85 (m, 1H), 2.80-2.05 (m, 6H), 1.35-1.20 (m, 9H); CI-HRMS: Calcd (C18H22BrN3O): 376.1024 (M+H), Found: 376.1042.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2].[C:33]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]([CH3:33])[C:21]3=[N:29][C:30]#[N:31])[C:8]=2[CH:32]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=NC#N)n(C)c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
400 mg (0.91 mmol) of the compound obtained in example 1 was dissolved in 5 ml of DMF, then 250 mg (1.82 mmol) of K2CO3 and 170 mg (1.18 mmol) of CH3I were added thereto. The reaction was stirred at room temperature for 12 hours, 30 ml of saturated NaHCO3 solution was added, and aqueous layer was extracted with 50 ml of ethyl acetate. Organic layer was washed with brine and dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 390 mg (yield: 95%) of the target compound.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[S:25]([N:20]1[C:21]2([CH2:23][CH2:22]2)[CH2:24][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:29]
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 45 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (0.85 mmol). Stirred at 45° C. for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol: 2,2,2-trifluoroethanol (3:1, 4 mL) at 150° C. for 2 h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol:EtOAc affording the title compound as solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[N+:4]([C:7]1[CH:8]=[C:9]([C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]>O.N1C=CC=CC=1>[N+:4]([C:7]1[CH:8]=[C:9](/[C:13](=[N:2]\[OH:3])/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCOC(=O)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)/C(=N/O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 16.9 %

Procedure:
Ethyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate can be obtained in the following manner: a solution of 62 g of hydroxylamine hydrochloride in 200 cm3 of water is added to a solution of 10 g of ethyl 3-nitrophenyl-glyoxylate in 250 cm3 of pyridine and the mixture is brought for 2 hours to a temperature near to 100° C. The reaction mixture is concentrated under reduced pressure (1.2 kPa). The residue is diluted with 250 cm3 of water and extracted with 250 cm3 of ethyl acetate. The organic phase is washed with a 1N aqeuous solution of hydrochloric acid, dried over magnesium sulphate, filtered and evaporated to dryness to give a white solid. This solid is purified by chromatography on a column of diameter 4 cm containing 500 cm3 of silica, eluting with a cyclohexane/ethyl acetate mixture and collecting fractions of 100 cm3. The fractions between 1 and 1.2 liters are combined and concentrated to dryness to give 1.8 g of ethyl (E)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a colorless oil; the fractions between 1.4 and 1.6 liters are combined and concentrated to dryness to give 2.5 g of ethyl (Z)-3-nitro-alpha-hydroxyiminophenylacetate in the form of a solid which is used as such in the subsequent syntheses.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>>[CH:14]1([CH:10]([C:9]2[CH:8]=[N:7][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:13][CH:12]=2)[OH:11])[CH2:16][CH2:15]1
Reactant: O=Cc1ccc(-c2ccsc2)nc1
Reactant: Br[Mg]C1CC1
Product: OC(c1ccc(-c2ccsc2)nc1)C1CC1

Procedure:
Synthesized using compound 56b (270 mg, 1.43 mmol) and cyclopropylmagnesium bromide (5.72 mL, 2.86 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Yellow solid. Yield: 138 mg, 42%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.37-0.45 (m, 1H), 0.50 (dq, J=9.7, 4.8 Hz, 1H), 0.57-0.71 (m, 2H), 1.18-1.29 (m, 1H), 2.48 (br. s., 1H), 4.06 (d, J=8.2 Hz, 1H), 7.39 (dd, J=5.0, 3.2 Hz, 1H), 7.60 (dd, J=8.2, 0.6 Hz, 1H), 7.64-7.68 (m, 1H), 7.78-7.85 (m, 1H), 7.89 (dd, J=3.0, 1.4 Hz, 1H), 8.60-8.64 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=2.8, 3.6, 19.1, 76.1, 120.0, 123.4, 126.2, 126.3, 134.5, 137.2, 141.9, 147.6, 152.8; (ESI): m/z=232.26 [M+H]+.
Reaction SMILES: [OH:1][NH:2][CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([N:41]([CH2:45]C)C(C)C)(C)C.ClC(Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl.N>C1COCC1>[NH2:41][C:45]([N:2]([OH:1])[CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])=[O:50]
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: C1CCOC1
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.050 g, 0.096 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.096 mmol) in THF (10 mL) was added dropwise to a suspension of triphosgene (0.0094 g, 0.032 mmol) in THF (2 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. 28% Aqueous ammonia (0.065 mL, 0.960 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from EtOH-water to give the title compound as a white powder (0.045 g, 83%).
Reaction SMILES: [CH:1]1([CH:4](O)[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1CC(O)C1CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1CC(Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 4 g (18.5 mmol; purity 96%) of 1-cyclopropyl-2-(2-nitrophenyl)ethanol in 50 ml of toluene are added, at room temperature, 2.3 g (19.5 mmol) of thionyl chloride, and then the mixture is stirred at 80° C. for 0.5 h. Then another 460 mg of thionyl chloride are added and the mixture is stirred at room temperature for a further 45 minutes.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:19]=[C:18]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:52][C:53]([F:62])([F:61])[CH:54]1[CH2:59][CH2:58][CH:57](O)[CH2:56][CH2:55]1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:15]=1[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH:57]2[CH2:58][CH2:59][CH:54]([C:53]([F:62])([F:61])[F:52])[CH2:55][CH2:56]2)=[CH:30][CH:31]=1
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: O=C(O)C1(c2ccc(-c3ccc(O)cc3)c(F)c2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(-c3ccc(OC4CCC(C(F)(F)F)CC4)cc3)c(F)c2)CC1
Reaction time: 8 h
Yield: 26 %

Procedure:
Diethyl azodicarboxylate (370 μL, 2.4 mmoles) is added to a solution of 200 mg of 1-(2-fluoro-4′-hydroxy-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.8 mmoles), triphenyl phosphine (623 mg, 2.4 mmoles) and 4-trifluoromethyl cyclohexanol (400 mg, 2.4 mmoles) in dry THF (3 mL) at 0° C. under nitrogen atmosphere. The resulting clear orange solution is left under stirring overnight, then quenched with water and extracted with ethyl acetate. The organic phase is washed with 10% w/v HCl solution, dried on Na2SO4 and evaporated. Purification by chromatography on silica gel by eluting with methylene chloride:methanol 98:2 v/v furnishes 1-[2-fluoro-4′-(4-trifluoromethyl-cyclohexyloxy)-biphenyl-4-yl]-cyclopropanecarboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Yield: 83.2 %

Procedure:
A solution of methyl 2-hydroxy-4-[2-(phenethyl)phenethyl]benzoate (0.25 g) in THF (5 ml) and methanol (5 ml) containing aqueous 2N sodium hydroxide (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to small volume and acidified with aqueous 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate (25 ml each time) and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. The solid obtained on removal of the solvent was crystallised from a mixture of diethyl ether and hexane to give 2-hydroxy-4-[(2-phenethyl)phenethyl]benzoic acid (0.2 g), m.p. 134-7° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccnc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), N′-isopropylnicotino hydrazide (187.14 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried, so that ivory (E)-tert-butyl 3-(3-(1-isopropyl-2-nicotinoyl hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (83 mg, 26.6%).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](SC)[C:7]1=[O:15])[CH2:4][CH3:5])[CH3:2].O[O:17][S:18]([O-:20])=O.[K+].[CH2:22]1COCC1>O.C(OCC)(=O)C>[CH2:1]([CH:3]([N:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([S:18]([CH3:22])(=[O:20])=[O:17])[C:7]1=[O:15])[CH2:4][CH3:5])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCC(CC)n1cc(C)nc(SC)c1=O
Reactant: C1CCOC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)n1cc(C)nc(S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A solution of XXXII (200 mg, 0.9 mmol) in THF (25 mL) was treated with Oxone™ (1.1 g, 1.8 mmol) portionwise as a solid at 25° C. The reaction mixture was stirred at 25° C. for 16 h and diluted with water (20 mL) and ethyl acetate (25 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give the product XXXIII (153 mg, 67%) as a yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][N:3]=[CH:2]1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[ClH:18].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:18])=[O:15])=[CH:8][CH:7]=2)[CH2:5][CH2:4][N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc(N2C=NCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cl
Product: O=C(Cl)Cc1ccc(N2C=NCC2)cc1

Procedure:
10 g of 4-(2-Imidazolinyl)-phenylacetic acid were stirred for 5 hours at 55° C with a mixture of 150 ml of benzene and 90 ml of thionyl chloride. The reaction mixture was then cooled, filtered with suction, washed with benzene and diethyl ether and dried under reduced pressure. 11 g of 4-(2-Imidazolinyl)-phenylacetic acid chloride-hydrochloride were obtained.
Reaction SMILES: ClC1C=CC(N2N=CC=N2)=C(C=1)C(N[C@H]1CCC[C@@H]1NC1C=CC(C(F)(F)F)=CN=1)=O.Cl.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[CH:37][C:38]([NH:41][C@H:42]2[CH2:46][CH2:45][CH2:44][C@@H:43]2[NH2:47])=[N:39][CH:40]=1.[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54](O)=[O:55]>>[F:50][C:51]1[C:52]([N:61]2[N:65]=[CH:64][CH:63]=[N:62]2)=[C:53]([CH:57]=[C:58]([F:60])[CH:59]=1)[C:54]([NH:47][C@H:43]1[CH2:44][CH2:45][CH2:46][C@@H:42]1[NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:48])[F:49])=[CH:40][N:39]=1)=[O:55]
Reactant: O=C(O)c1cc(F)cc(F)c1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(F)cc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 97) from (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 50 mg, 0.20 mmol) and 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 40a; 46 mg, 0.20 mmol) except this was purified by column chromatography (silica, 0-30% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CN1CCN(C)C1=O.[OH:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[N:24][C:23]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:28][C:26]1[N:25]=[N:24][C:23]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:22]([OH:21])[CH:27]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a mixture of 27.4 g (purity: 92.9%; 149 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 1,3-dimethyl-2-imidazolidinone was added 2.5 g (purity: 98.5%; 14.9 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 120 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.58 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 86.9%) and 17 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:4][N:3]=1.Cl.CN.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:29])=[O:21])=[CH:4][N:3]=1
Reactant: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccccc3)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1cnc(N)c2c(-c3ccccc3)csc12
Yield: 84.6 %

Procedure:
A mixture of Example 13 (0.1 g, 0.34 mmol), methylamine hydrochloride (0.115 g, 1.69 mmol), HOBT (0.137 g, 1.01 mmol), N-methylmorpholine (0.25 mL, 2.36 mmol), and EDCI (0.199 g, 1.01 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 89 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (d, J=4.8 Hz, 3H), 5.75–5.85 (br s, 2H), 6.58 (d, J=15.9 Hz, 1H), 7.53 (m, 5H), 7.58 (d, J=15.9 Hz, 1H), 7.67 (s, 1H), 8.14 (m, 2H); MS (ESI(+)) m/e 310 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:18][C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)ccc1I
Reactant: COc1ccc(C=O)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccc(I)c(C)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
5-Iodo-6-methyl-pyridin-2-ylamine (28, 1.7 g, 7.3 mmol) and 6-methoxy-pyridine-3-carbaldehyde (29, 1.1 g, 8.0 mmol) were combined in a round bottom flask with trifluoroacetic acid (2.80 mL, 36.3 mmol), triethylsilane (5.80 mL, 36.3 mmol) and 50 mL of acetonitrile. The reaction was stirred at room temperature overnight, then heated to reflux for 6 hours. The reaction was concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography, eluting with 10-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (30, 1.80 g). MS (ESI)[M+H+]+=356.80.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][N:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][CH2:3]2)=[CH:10][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O[C@H]1CCNC1
Product: Clc1ccc(O[C@@H]2CCNC2)cn1

Procedure:
By the procedure of Example 2, employing the appropriate 3-(S)-hydroxypyrrolidine in place of 3-hydroxypyrrolidine and 2-chloro-5-hydroxypyridine in place of 3-hydroxypyridine, 2-chloro-5-(3-(R)-pyrrolidinyloxy)-pyridine was produced as a clear oil: 1H NMR (300 MHz, CD3OD) δ8.10 (1H, s), 7.50 (1H, dd, J=2.3, 8.8 Hz), 7.40 (1H, d, J=8.8 Hz), 5.28 (1H, s), 3.63-3.31 (4H, m), 2.34 (2H, m).