Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C(O)(C)(C)C.[N:42]([C:45]1[C:53]([F:54])=[C:52]([F:55])[C:48]([C:49]([OH:51])=[O:50])=[C:47]([F:56])[C:46]=1[F:57])=[N+:43]=[N-:44].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O>[F:55][C:52]1[C:53]([F:54])=[C:45]([N:42]2[CH:36]=[C:35]([CH2:34][NH:33][C:31]([NH:30][C@@:15]([C:4]3[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=3)([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:32])[N:44]=[N:43]2)[C:46]([F:57])=[C:47]([F:56])[C:48]=1[C:49]([OH:51])=[O:50]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: C#CCNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(NCc1cn(-c2c(F)c(F)c(C(=O)O)c(F)c2F)nn1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a suspension of (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(prop-2-ynyl)urea (5.0 mg, 0.01 mmol), prepared as described in Procedure 3, 4, 5, 6 and 12, in a 1:1 mixture of water and tert-butyl alcohol (100 μL) was added 4-azido-2,3,5,6-tetrafluorobenzoic acid (2.3 mg, 0.01 mmol), followed by sodium ascorbate (1 M solution in H2O, 100 μL) and CuSO4.5H2O (1 mg). The reaction mixture was stirred vigorously overnight in a sealed vial. The reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic portions were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Onyx Monolithic 10×100 mm; eluting with 10%-90% MeCN/H2O with 0.1% TFA, monitoring at 220 nm) to provide (R)-2,3,5,6-tetrafluoro-4-(4-((3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Example 319, 5.7 mg, 78% yield). LC/MS: RT=3.610 min [M+H] 742.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, MeOH-d4) δ 8.02 (s, 1H), 7.10-6.79 (m, 11H), 6.53 (d, J=5 Hz, 2H), 6.27-6.04 (m, 1H), 4.38-4.31 (m, 2H), 3.81 (d, J=15 Hz, 1H), 3.73 (d, J=10 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1[O:22][CH2:21][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC2(CO)COC(C)=N2)cc1
Yield: 88.5 %

Procedure:
A solution of 450 mg (1.5 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol, 0.32 mL (1.75 mmol) of triethylorthoacetate and 0.56 mL (3.2 mmol) of DIEA in 6 mL of DMF was stirred at 75° C. for 2 h. The mixture was cooled, partitioned between 40 mL of 3:1 v/v ether/EtOAc and water and the layers were separated. The organic layer was washed with water and dried. Flash chromatography on silica gel using 4:1 v/v CH2Cl2/EtOAc as the eluant afforded 440 mg (91%) of the title compound: Mass spectrum (NH3—CI) 332 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of hydroquinone (Aldrich, 11.01 g, 100 mmol) in DMF (300 mL), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (Aldrich, 12.0 g, 50 mmol), cesium carbonate (40.7 g, 125 mol) were added and the mixture was stirred at 60° C. overnight. The mixture was poured into water (300 mL) and 6N HCl was added to adjust the “pH” to 6. The mixture was extracted with EtOAc (3×60 mL) and the extracts were combined and dried. Removal of solvent gave the crude, which was chromatographied on a ISCO machine eluting with EtOAc/hexane (0-30%) to give a light brown solid. 5.71 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30]>C(Cl)(Cl)Cl.O>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Potassium carbonate (19.87 g, 143.8 mmol) and triethylamine (50.1 mL, 359 mmol) were sequentially added with stirring to a solution of 4-chloro-3-nitroquinoline (30.0 g, 144 mmol) in chloroform (200 mL). After 15 minutes, β-alanine ethyl ester hydrochloride (26.5 g, 173 mmol) was slowly added, and the reaction was stirred overnight at ambient temperature. Water (100 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 27.4 g of ethyl N-(3-nitroquinolin-4-yl)-β-alaninate as a yellow solid, which was used without purification.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: C1CCNC1
Product: Cc1ccccc1N1CN(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and pyrrolidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:17])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:36]([N:44]1[C:48](=[O:49])[CH:47]=[CH:46][S:45]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O.O1CCCC1.Cl>[CH2:36]([NH:44][C:48](=[O:49])/[CH:47]=[CH:46]\[S:45][CH:8]([C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCn1sccc1=O
Reactant: Cn1cccc1C(=O)CC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)/C=C\SC(C(=O)c1ccccc1)C(=O)c1cccn1C
Yield: 18.7 %

Procedure:
To a stirred solution of 0.78 g (0.0034 mol) of 1-(1-methylpyrrol-2-yl)-3-phenyl-1,3-propanedione in 5 mL of N,N-dimethylformamide under nitrogen was added 3.4 mL (0.0034 mol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 10 min a solution of 0.73 g (0.0034 mol) of 2-n-octyl-4-isothiazolin-3-one in 5 mL of N,N-dimethylformamide was added. After 12 h another 3.4 mL of the 1M tetrabutylammonium fluoride solution was added. After 12 h the reaction mixture was diluted with 10% aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed several times with water, once with brine, and dried over magnesium sulfate. Removal of solvents and recrystallization of the crude product from ethyl acetate/hexane gave 0.28 g (19% yield) of N-n-Octyl-cis-3-{[1-phenyl-3-(1-methylpyrrol-2-yl)-1,3-propanedionyl]thio}acrylamide as a white solid, m.p. 131°-132° C. See Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:27]([CH3:28])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)=[C:16]([NH:25][CH3:26])[CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:29])[C:5]=1[CH3:30])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:27]([CH3:28])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[NH:24][N:23]=[CH:22][CH:21]=4)=[C:16]([NH:25][CH3:26])[CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:29])[C:5]=1[CH3:30]
Reactant: CNc1cc(CC2(C)CC3C(=C(C)C(C)=C([N+](=O)[O-])C3C)O2)ccc1-c1ccn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1cc(CC2(C)CC3C(=C(C)C(C)=C(N)C3C)O2)ccc1-c1ccn[nH]1
Yield: 91.3 %

Procedure:
To 0.26 g of 5-(4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)methylaminophenyl) pyrazole, 10 ml of ethanol was added and 0.43 g of stannous chloride dihydrate and 3 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 2 hours. The reaction solution was poured into water, neutralized with a sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 0.22 g of the objective product (melting point: 113-117° C.)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[CH2:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (10 g., 0.099 mole) and N,N-diisopropylethylamine (87 ml., 0.495 mole) were dissolved in methylene dichloride (200 ml.). The solution was cooled (ice bath) and protected from atmospheric moisture (drying tube), and benzyl chloroformate (14.1 ml., 16.9 g., 0.099 mole) was added over 2 hrs. Water (20 ml.) was added and the solvents were evaporated in vacuo (approx. 1 mm. pressure, solid CO2 cold finger condenser). The residue was shaken together with water (200 ml.) and ethyl acetate (200 ml.), and the mixture was separated. The organic phase was washed with water (4×50 ml.), dried (Na2SO4), and the solvent evaporated to give 1-benzyloxycarbonyl-4-hydroxypiperidine as a colourless oil, I.R.λmax 3800 cm.-1 and 1685 cm.-1.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:9]([OH:11])=[O:10])[N:3]=[CH:2]1.[CH2:12](N(CC)CC)[CH3:13].[CH2:19](O)[CH3:20]>ClCCl>[NH:1]1[C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[C:4]([C:9]([O:11][CH2:19][CH3:20])=[O:10])[N:3]=[CH:2]1
Reactant: CCN(CC)CC
Reactant: CCO
Reactant: O=C(O)c1nc[nH]c1C(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1nc[nH]c1C(=O)OCC
Temperature: 0 °C
Yield: 52 %

Procedure:
Imidazole-4,5-dicarboxylic acid (7.55 g, 50.0 mmol) is dissolved in absolute ethyl alcohol (120 mL). The solution was cooled in an ice bath to 0° C. and bubbled dry HCl gas for 1 h. Later, the reaction mixture was refluxed at 80° C. for 7 h during which time all the starting material was consumed. The solvent was removed and the residue that obtained was dissolved in dichloromethane (200 mL) and the organic layer was neutralized with triethylamine. The organic layer was washed with cold water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.50 g (52%) of white solid: mp 175-177° C.; 1H NMR (CDCl3) δ 1.40 (t, 3H), 4.41 (m, 2H), 7.84 (1H, C2H) and 11.55 (br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:11]([F:13])([F:12])[F:14])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(F)(F)F)cnc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.87 g) in ethyl acetate (40 mL) was added tin(II) chloride dihydrate (8.22 g), and the mixture was stirred at 80° C. for 2 hours. After cooling, to the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution, and the mixture was vigorously stirred at room temperature and filtered through a celite pad. The residue was washed with ethyl acetate. The filtrate was combined with the washings, washed successively with an aqueous saturated sodium hydrogencarbonate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was triturated with n-hexane to give 3-amino-2-chloro-5-(trifluoromethyl)pyridine (0.99 g) as a pale yellow powder.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl.O1CCOCC1>ClCCl>[NH2:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:43])([CH3:44])[CH3:42])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:31])[F:32])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(CC(F)(F)F)c(=O)c3ccccc31)n2CCCCOC(=O)C(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CN)ccc21
Yield: 92.4 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 4-{5-(tert-butoxycarbonylamino-methyl)-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl}-butyl ester (59 mg, 0.089 mmol) and TFA (138 μL, 1.79 mmol) in dichloromethane (2 mL) was stirred for 4 hrs at room temperature. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. A solution of 4N HCl in dioxane (233 μL, 10 equiv.) was added, followed by concentration. The residue was triturated from diethyl ether and filtered to give the title compound (46 mg, 87%) as a tan solid:
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:26]2[CH:27]=[CH:28][N:23]=[N:24][CH:25]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Reactant: Nc1ccnnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 mL, 6.84 mmol) and 4-pyridazinamine (0.49 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (DMF; 25 ml) and the mixture was stirred at room temperature. The DMF was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and the organic layer washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a dark yellow solid. 0.98 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:26][CH:27]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C1NCCCCC1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-n2cncn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 62.7 %

Procedure:
4-Chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (0.16 g, 0.52 mmol), 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazol (0.25 g, 1.03 mmol), potassium carbonate (0.72 g, 5.17 mmol) and potassium iodide (0.02 g, 0.10 mmol) in 5 ml dimethylformamide were stirred at 65° C. for 5 hours. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate yielded 0.15 g (64%) 4-chloro-N-(2-oxo-azepan-3-yl)-N-(4-[1,2,4]triazol-1-yl-benzyl)-benzenesulfonamide as white solid, MS: m/e (%)=460.1 (MH+, 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].Cl>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][C:9]([C:13]([O:15][CH3:16])=[O:14])([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[CH:17]=1
Reactant: COC(=O)CCCBr
Reactant: COC(=O)C1CCOc2ccc(F)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCC1(C(=O)OC)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.81 g (0.183 mol) 50% NaH in 300 ml of DMF was added, dropwise, a solution of 27.5 g (0.131 mol) of methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 100 ml of DMF. After stirring at room temperature for 1 hour, a solution of 33 g (0.183 mol) of methyl 4-bromobutyrate in 25 ml of DMF was added. The resultant homogeneous solution was stirred at room temperature for 16 hours and then poured onto ice/H2O and acidified to pH 3.0 with concentrated HCl. The aqueous was extracted twice with CH2Cl2 and the combined extracts were dried (NaSO4) and filtered. The filtrate was evaporated in vacuo to an oil (44 g) which was purified by column chromatography on 2 Kg of silica gel, eluting with CH2Cl2 /Et2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[O:15]C=CC=3)=[C:12]([C:19]#[N:20])[C:11]([C:21]([F:24])([F:23])[F:22])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C.O.I([O-])(=O)(=O)=[O:35].[Na+]>O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]([OH:15])=[O:35])=[C:12]([C:19]#[N:20])[C:11]([C:21]([F:24])([F:22])[F:23])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c(C#N)c2-c2ccco2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)c(C#N)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-cyano-5-(2-furyl)pyrazole (0.68 g, 2.04 mmol) in 4:4:6 carbon tetrachloride/acetonitrile/water was added sodium periodate (1.96 g, 9.2 mmol) and ruthenium (III) chloride monohydrate (42 mg, 0.20 mmol). The resulting biphasic reaction was stirred vigorously at ambient temperature for 24 h. The reaction was quenched with 10% aq HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4), filtered through a pad of Celite and concentrated. The residue was dissolved in 1:1 hexanes/ethyl acetate and extracted with sat'd aq Na2CO3 (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to afford 0.42 g (67%) of the title compound as a solid. LRMS (ES−): 310.0 (M−H)−.
Reaction SMILES: [CH3:1][N+:2]([O-:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](C)[CH:11]=1)[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.C[C:19]1[CH:20]=[C:21]([O:25][CH2:26][CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=1>>[C:10]1([C:3]2([CH2:4][N:5]3[CH:9]=[N:8][CH:7]=[N:6]3)[CH2:28][CH:27]([CH2:26][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=3)[O:17][N:2]2[CH3:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C(Cn2cncn2)=[N+](C)[O-])c1
Reactant: C=CCOc1cccc(C)c1
Product: CN1OC(COc2ccccc2)CC1(Cn1cncn1)c1ccccc1

Procedure:
Compound 3 (R1 =R2 =H) was prepared by a procedure similar to that described in Example 1 by reacting N-methyl-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1, R1 =H) with allyl phenyl ether (2, R2 =H). The resulting cis- and trans-diastereomeric mixture of the title compound was flash-chromatographed on neutral silica gel using chloroform-methanol (99:1 by volume) as eluent. Isomer A has a melting point 68°-75° C. (ethyl acetate-hexane, 1:1 by volume).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 6.0 kg. of 1-amino-2-nitro-4-chlorobenzene and 7.2 kg. of potassium carbonate in 25 l. of DMF under nitrogen is treated with 4.0 kg. of thiophenol. The mixture is stirred for 2 hours, cooled, and diluted with 140 l. of ice water. The mixture is stirred for 1 hour, and 1-amino-2-nitro-5-phenylthiobenzene is isolated by filtration.
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ncccc12
Product: Clc1ncnc2ncccc12
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of pyrido[2,3-d]pyrimidin-4(3H)-one (1.471 g, 10 mM) and POCl3 (16 ml) is stirred for 1 h at reflux. The excess of POCl3 is removed under vacuum. Then dichloromethane and iced water is added and the mixture stirred until the black solid dissolves. The organic layer is separated, washed with bicarbonate solution, dried over Na2SO4 and then evaporated to dryness. The yellow residue is recrystallized from toluene/hexane to give almost pure title compound in 70% yield. mp 137° C.