Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:7]1([CH2:12][CH2:11][N:10]([CH:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[CH2:9][CH2:8]1)[CH2:6]2.Cl[CH2:25][C:26]1[NH:27][C:28](=[O:36])[C:29]2[CH2:35][O:34][CH2:33][CH2:32][C:30]=2[N:31]=1.[H-].[Na+]>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:7]1([CH2:8][CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][N:15]([CH2:25][C:26]4[NH:27][C:28](=[O:36])[C:29]5[CH2:35][O:34][CH2:33][CH2:32][C:30]=5[N:31]=4)[C:14]3=[O:18])[CH2:11][CH2:12]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CC1(CCN(C3CCNC3=O)CC1)C2=O
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)CC1(CCN(C3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC1)C2=O
Temperature: 70 °C
Yield: 41.4 %

Procedure:
To a solution of 5-methoxy-1′-(2-oxopyrrolidin-3-yl)spiro[indene-2,4′-piperidin]-1(3H)-one (3.34 mmol, 1.05 g) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (3.67 mmol, 0.737 g) in THF (40 mL) and DMF (5 mL) was added sodium hydride (60%, 11.69 mmol, 0.468 g) and the suspension was heated at 70° C. for 45 min. The reaction was allowed to cool to ambient temperature, diluted with 100 mL of ether, an off-white solid was collected by filtration and was dried in vacuo. Recrystallization from isopropyl alcohol/methyl alcohol provided the title compound as an off-white solid (661 mg, 41.4% yield). Calculated MS=478.6, MS (ESI) m/e 479.0 (M+H+); 1H NMR (400 MHz, MeOD) 8 ppm 1.33-1.46 (m, 2H) 1.92-2.07 (m, 2H) 2.07-2.27 (m, 2H) 2.49-2.65 (m, 3H) 2.89 (dd, J=8.53, 2.51 Hz, 2H) 3.02-3.15 (m, 3H) 3.35-3.50 (m, 2H) 3.70 (t, J=8.78 Hz, 1H) 3.85-3.98 (m, 6H) 4.16 (d, J=15.06 Hz, 1H) 4.44-4.53 (m, 3H) 6.96 (dd, J=8.53, 2.51 Hz, 1H) 7.05 (s, 1H) 7.62 (d, J=9.03 Hz, 1H). HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.391 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][NH:24][CH3:25])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][N:24]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH3:25])=[CH:21][CH:20]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 72.4 %

Procedure:
3.0 g (13.6 mmol) of 1-(4-nitrophenyl)-4-piperidone and 2.0 g (13.6 mmol) of N-(4-methoxybenzyl)-N-methylamine were reacted in a similar manner to Example 1. 3.5 g of 4-(N-(4-methoxybenzyl)-N-methylamino)-1-(4-nitrophenyl)piperidine were obtained. Melting point 144°-145° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[C:31]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)(=[O:34])[CH2:32][CH3:33]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25]Cl)=[O:12])=[CH:5]2.[I-:28].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25][I:28])=[O:12])=[CH:5]2
Reactant: O=C(CCl)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CI)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 93.2 %

Procedure:
5-Chloro-N-{1-[(chloroacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Method 7; 2.0 g, 5.0 mmol) and potassium iodide (2.0 g, 12.0 mmol) in acetone (50 mL) was heated at reflux for 6 hours and then cooled and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (50 mL) washed with IM aqueous sodium thiosulphate (2×25 mL), water (25 mL), brine (25 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (2.3 g, 92%) as a pale yellow powder.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([F:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@H:11]([O:12][C:6](=[O:7])[CH3:5])[C@H:10]([F:13])[C@@H:9]([CH2:14][O:15][C:20](=[O:22])[CH3:21])[O:8][CH:6]1[O:7][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](F)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1C(OC(C)=O)O[C@H](COC(C)=O)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-4-fluoro-2,4-dideoxy-D-glucopyranose (1.35 g, 6.048 mmol) in a mixture of pyridine (50 ml) and acetic anhydride (25 ml, 27 g, 264 mmol) was stirred at room temperature for 24 hours at which time no starting material but two close spots appeared by TLC. Stirring continued for another 15 hours. Solvent was then removed by evaporation in vacuo; the residue was now co-evaporated with toluene (4×50 ml) then dried in vacuo. This material was now adsorbed on 5 g of silica gel then placed on a silica gel column (45 g, 20×360 mm) poured in CH2Cl2/acetone (8:1). The column was eluted with 500 ml of CH2Cl2/acetone (8:1) followed by 500 ml of CH2Cl2/CH3OH (7:3). The product and trailing spots eluted immediately, with virtually no separation. The CH2Cl2/CH3OH flush produced a trailing spot. All were evaporated and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][C:14](=O)CC(=O)C>CCO.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[N:9]=[C:13]([CH3:14])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 5-bromo-3-nitrobenzene-1,2-diamine (464 mg) and pentane-2,4-dione (400 mg) in EtOH (27 mL) and 5 N HCl (7.4 mL) was refluxed for 3 h. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution and brine. The organic layer was concentrated to afford the desired product as a solid (460 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 2.73 (s, 3H), 8.11 (d, 1H, J=1.8 Hz), 8.24 (d, 1H, J=1.8 Hz), 10.20 (s, 1H, s); LC-MS: m/e=256 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(C)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-(bromoacetyl)-4-methylpyridine hydrobromide (F. H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842). 1H-NMR (CDCl3) δ: 8.46 (1H, d, J=4.8 Hz), 8.22 (1H, d, J=1.8 Hz), 7.89 (1H, s), 7.51 (1H, d, J=8.4 Hz), 7.24 (1H, dd, J=1.8, 8.4 Hz), 7.20 (1H, br d, J=4.8 Hz), 5.97 (2H, br s), 3.80 (2H, q, J=7.0 Hz), 2.46 (3H, s), 0.90 (3H, t, J=7.0 Hz)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:5]=[O:6])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: O=Cc1cc(-c2ccc(Cl)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 130.5 %

Procedure:
To a mixture of 3-chloro-6-trifluoromethylbenzaldehyde (1.0 g, 4.79 mmol), 4-chlorophenyl boronic acid (1.12 g, 7.19 mmol), potassium phosphate (2.03 g, 9.59 mmol), dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (0.079 g, 0.19 mmol) and palladium acetate (0.022 g, 0.096 mmol) is added degassed toluene (9 ml), then the mixture is further purged with nitrogen. The suspension is next sealed then stirred at ambient temperature for 5 minutes, than heated at 160° C. for 1 hour under microwave irradiation. After cooling the reaction mixture is partitioned between 2M hydrochloric acid and dichloromethane, and the aqueous phase further extracted with dichloromethane (×2). The organic fractions are combined then evaporated under reduced pressure to yield a crude product which is purified by flash column chromatography (100% hexane to 10% ethyl acetate in hexanes as eluant) to afford 4′-chloro-4-trifluoromethyl-biphenyl-3-carbaldehyde (1.78 g) as an orange gum. This material is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([OH:21])(=[O:20])[CH3:19].C(OC(=O)C)(=O)C>[Pd]>[C:18]([OH:21])(=[O:20])[CH3:19].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Reaction time: 7 h
Yield: 126.2 %

Procedure:
Add 10% Pd/C (0.079 g; 37.12 μmoles) to 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (805 mg; 1.00 equiv; 3.31 mmoles) in acetic acid (15 mL; 261.77 mmoles) and acetic acid anhydride (0.5 mL; 5.29 mmoles). Hydrogenate at room temperature for 7 hr at 20 PSI. Purge flask with nitrogen to provide 1.2 g of a foam. Triturate with acetonitrile and filter to provide 270 mg (28%) of the product as a white solid.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: O
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -1 °C
Reaction time: 0.5 h

Procedure:
solution of 110.6 g (0.475 mol, 95% assay) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 25.2 g (0.6 mol) of cyanamide in 600 mL of acetonitrile was cooled to −5° C. To this solution was added 750 g (0.575 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 45 min with the temperature kept below 0° C. The reaction mixture was allowed to stir at −1° C. for 30 min To the mixture was added 9.5 g (0.05 mol) of sodium metabisulfite in 25 mL of water and the two phase mixture was allowed to settle. The aqueous phase was re-extracted 2×'s with 50 mL of acetonitrile. The organics were combined and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 40:54 (area) ratio of two isomers.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[C:3]1=[O:13].[BH4-].[Na+].CC(C)=O.O>CCO>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][C:8]=2[CH3:11])[CH:3]1[OH:13]
Reactant: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1cc(C)c2c(c1)C(O)C(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
37.48 g of 2,4,6-trimethyl-indan-1-one (0.215 mol) were dissolved in 200 mL of EtOH in a 500 mL, 3-neck rounded bottom flask equipped with a magnetic stirring bar, a thermometer and a reflux condenser. NaBH4 (15.01 g, 0.397 mol) was then slowly added keeping the temperature below 20° C. during the addition. The light yellow suspension was stirred at r.t. for 18 h. Then 100 mL of acetone were cautiously added (careful: exothermic reaction!) and subsequently the solvents removed giving a white solid. The latter was treated with 100 mL of water and extracted with toluene (2×150 mL). The water phase was further extracted with toluene, the organic phases were combined and washed with a 10% aqueous solution of NH4Cl. After washing, the organic phase was dried over Na2SO4, filtered and evaporated to give 35.57 g of a yellow sticky solid: its 1H-NMR analysis showed the target product as 1.4/1 mixture of two diastereoisomers, contaminated by 5% wt. of starting indanone (yield 89.2%). The product was used as such in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][C@@H:23]3[CH2:22][O:21][C:20]=2[C:19]=1[C:30]([O:32]C(C)(C)C)=[O:31])(=[O:16])=[O:15])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][C@@H:23]3[CH2:22][O:21][C:20]=2[C:19]=1[C:30]([OH:32])=[O:31])(=[O:15])=[O:16])[CH3:38]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC(C)(C)C)OC[C@H]1CCN21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OC[C@H]1CCN21
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
A solution of tert-butyl (R)-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 42, 0.017 g) in TFA (2 mL) and DCM (2 mL) was left to stand at room temperature for 30 minutes then concentrated in vacuo. The residue was dissolved in methanol (15 mL) and potassium carbonate (0.2 g) was added and the mixture stirred for 5 minutes then filtered. The filtrate was acidified with formic acid and concentrated in vacuo. The residue was triturated with 20% methanol in DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant solid was triturated with diethyl ether and filtered to give (R)-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,2a,3-tetrahydro-4-oxa-8b-aza-cyclobuta[a]naphthalene-5-carboxylic acid (0.008 g) as a light brown solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C:13]1[C:21]([CH2:22]/[CH:23]=[C:24](\[CH3:31])/[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:20]([O:32][CH3:33])[C:19]([CH3:34])=[C:18]2[C:14]=1[C:15](=[O:35])[O:16][CH2:17]2.Cl>N1C=CC=CC=1>[CH3:33][O:32][C:20]1[C:19]([CH3:34])=[C:18]2[C:14]([C:15](=[O:35])[O:16][CH2:17]2)=[C:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[CH2:22]/[CH:23]=[C:24](\[CH3:31])/[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
p-Toluenesulfonyl chloride (30 g) was added to a solution of methyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (40 g) in pyridine (200 ml) at 0° C. After 6 hours the solution was poured on to ice and acidified to pH 3 with dilute hydrochloric acid. The solution was extracted with ethyl acetate and the extract was dried and evaporated to afford methyl (E) 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [OH:1][CH:2]([C:7](=[O:25])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)S(O)(=O)=O.[Na].Cl.S(=O)=O>O>[OH2:1].[O:25]=[C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: O=C(c1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(O)S(=O)(=O)O
Agent: Cl
Agent: O=S=O
Agent: [Na]
Solvent: O
Product: O=CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
A 374 g. portion of hydroxy[p-(α,α,α-trifluoro-m-tolyloxy)benzoyl]methanesulfonic acid, sodium salt was suspended in 3485 ml. of water and the mixture was stirred at 50° C. while 316 ml. of 6N hydrochloric acid were added during 30 minutes. The cloudy solution was warmed slowly until sulfur dioxide evolution ceased and an oil began to separate at about 75° C., then was stirred and heated at reflux for 1.5 hours. The mixture was cooled and extracted with three 1000 ml. portions of ether. The extracts were combined, washed with water, saturated sodium bicarbonate and brine, dried and concentrated to a yellow solid. This solid was recrystallized from ether:hexane (1:1) at 5° C., to yield the desired product as a white solid, m.p. 73°-80° C.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[C:26]([O-:30])(=[O:29])[CH2:27][CH3:28]>>[F:25][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[C:21]([F:22])[C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:16]2[C:21]([F:22])=[CH:20][C:19]([CH2:28][CH2:27][C:26]([OH:30])=[O:29])=[CH:18][C:17]=2[F:25])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: CCC(=O)[O-]
Reactant: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Product: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2,6-difluoro-4-methoxyphenyl)-5-(trifluoromethyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluoro)phenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 6.55-6.69 (m, 4H), 5.01 (s, 2H), 3.78 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H14F7NO4S, 508.1 (M−H). found 507.9.
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[N:13]=1)(=O)OC.[Li+].[Cl-].C([O:27][C:28](=[O:43])[CH2:29][CH:30]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=O)C.C1CCN2C(=NCCC2)CC1.[Li+].[OH-].Cl>C(#N)C.CCO.[Pd].O>[O:22]=[C:8]([CH2:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[N:13]=1)[CH2:7][CH2:31][CH:30]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][C:28]([OH:43])=[O:27]
Reactant: COP(=O)(CC(=O)CCCc1ccc2c(n1)NCCC2)OC
Reactant: CCOC(=O)CC(C=O)c1cnc2ccccc2c1
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: O=C(O)CC(CCC(=O)CCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ketophosphonate 22-5 (1.0 g, 3.1 mmol), anhydrous LiCl (170 mg, 4.0 mmol), and 22-4 (0.797 g, 3.1 mmol) in anhydrous acetonitrile (60 mL), was treated with DBU (0.52 mL, 3.3 mmol) and the resulting suspension stirred at room temperature for 1 h. The solvent was removed at reduced pressure and the resulting residue partitioned between brine and methylene chloride. The organic layer was removed, dried, and concentrated to afford 22-6 as mixture of E and Z olefins. The crude mixture was dissolved in EtOH (50 mL), treated with 10% Pd/C (200 mg) and stirred under a hydrogen filled balloon for 4 h, then filtered. The filtrate was treated with LiOH (2.0 eq) and water (20 mL) and stirred at room temperature for 12 h, then neutralized with 1N HCl and evaporated Chromatography on silica gel (10% MeOH/methylene chloride) afforded 22-7 as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:23]([C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:32])([CH3:33])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=[C:14]2[C:30]#[N:31])=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 64.4 %

Procedure:
A mixture of 3-[(7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.05 mmole) in a mixture of trifluoroacetic acid (3 ml) and dichloromethane (1 ml) was stirred room temperature for 80 minutes before it was concentrated to give the title compound as a white solid (13 mg). LC-MS ESI−: 402 (M−1)−.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:16]2[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=[CH:12][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(=O)c1ccc(Oc2ccncc2[N+](=O)[O-])cc1

Procedure:
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4,4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method C1a to afford the urea.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.[NH2:22][OH:23].Cl.NO.[Na]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][OH:23])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1
Reactant: NO
Reactant: COc1cc(Cc2cnc(N)nc2Cl)cc(OC)c1OC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2NO)cc(OC)c1OC
Reaction time: 48 h

Procedure:
3 g of 2-amino-4-chloro-5-(3,4,5-trimethoxybenzyl)-pyrimidine is added to a methanolic hydroxylamine solution prepared from 1.4 g of hydroxylamine-hydrochloride, 0.46 g of sodium and 50 ml of absolute methanol. The mixture is stirred for 48 hours at 40°; it is subsequently concentrated in vacuo and the residue is recrystallised from butanol to obtain 2-amino-4-(hydroxyamino)-5-(3,4,5-trimethoxybenzyl)-pyrimidine, M.P. 208°-210°, which is identical to the product described in Example 2.