Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C[Al](C)C.C([O:19][C:20]([C:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[CH:30][C:25]=2[O:24][N:23]=1)=O)C>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([C:22]2[C:26]3[CH:27]=[CH:28][C:29]([O:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:30][C:25]=3[O:24][N:23]=2)=[O:19])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1noc2cc(Oc3ccncn3)ccc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1noc2cc(Oc3ccncn3)ccc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 46 μl (0.35 mMol) 4-fluoro-3-trifluoromethyl-aniline are dissolved in 6 ml toluene and cooled to 10° C. Then 550 μl Me3Al (2 M in toluene; 1.1 mMol) are added via syringe. After 1 h at rt, a solution of 101 mg (0.35 mMol) 6-(pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 1.25 ml THF is added and the reaction mixture stirred for 25 min in an oil bath at 110° C. Work up as described in step 1.2 gives the title compound: MS: [M−1]=419; Anal.: C,H,N,F.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[C:18]([CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:19]>>[CH2:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][C:18]1[NH:19][C:13](=[O:15])[C:3]2[C:4]([CH3:12])=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=2[N:1]=1)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#CCCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Product: Cc1c(C(=O)O)sc2nc(CCNC(=O)OCc3ccccc3)[nH]c(=O)c12

Procedure:
Using diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate and benzyl N-(2-cyanoethyl)carbamate, the ring-closing reaction was carried out similarly to Production Example 1. Successively the hydrolysis was carried out similarly to Example 1, to provide 2-(2-benzyloxycarbonylaminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]([CH3:31])[CH3:30])[NH:9]1)=[O:7])(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]([CH3:31])[CH3:30])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 49b (0.64 g, 1.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.7 g, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([F:15])[CH:7]=1.[NH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:16])=[O:11])=[C:8]([F:15])[CH:7]=1
Reactant: N
Reactant: O=C(Cl)c1ccc(OCCCCl)cc1F
Product: NC(=O)c1ccc(OCCCCl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
4-(3-chloropropoxy)-2-fluorobenzoyl chloride i80 (0.73 g, 2.91 mmol, 1 eq) is treated with aqueous ammonia (35 ml) and the resulting mixture is vigorously stirred at room temperature overnight. The mixture is then filtered to give 0.41 g of 4-(3-chloropropoxy)-2-fluorobenzamide i82 as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OC)(OC)OC.C=O.[C:14]1([OH:24])C2[C:18](=CC=CC=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:24]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: Oc1cccc2ccccc12
Reactant: CO[Si](CCCN)(OC)OC
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 80 %

Procedure:
This compound was prepared according to the method described in previous examples using 3-aminopropyltrimethoxysilane (17.9 g, 100 mmole), paraformaldehyde (6.3 g, 210 mmole), 1-naphthol (14.4 g, 100 mmole), and toluene (200 ml). The final product was obtained as a viscous liquid. The yield was 80% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:25]=[O:26])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5 g of the compound [1-1] was dissolved in 100 mL of tetrahydrofuran and cooled to −78° C. Thereafter, 31.2 mL of n-butyllithium (1.6 M hexane solution) was added thereto, and the mixture was stirred for 1 hour at the same temperature. 774 μL of N, N-dimethylformamide was added to the produced white suspension, which was stirred for 5 hours while gradually heating back to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-50/50), to obtain 514 mg of tert-butyl[(1S)-1-(4-formylphenyl) ethyl]carbamate [15-1] (hereinafter, referred to as the compound [15-1]) as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][CH2:16][CH3:17])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(=CC(=O)OCC)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC(=O)OCC)c1ccc(F)cc1
Yield: 99.6 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)hexenoate (58.12 g, 0.246 mol) and 10% palladium on carbon (1.1 g, Aldrich) in 95% ethanol was shaken in a Parr hydrogenator under a pressure of 2-4 atm of hydrogen for 0.75 hr. The mixture was filtered and concentrated by spin evaporation in vacuo to give 58.4 g (99.6%) of ethyl 3-(4-fluorophenyl)hexanoate as a clear liquid, NMR (DMSO-d6): d 7.27-7.20 (m, 2H), 7.12-7.04 (m, 2H), 3.91 (q, 2H, J=7.2 Hz), 2.99 (m, 1H), 2.66-2.59 (m, 1H), 2.52-2.44 (m, 1H, partially obscured by DMSO), 1.59-1.46 (m, 2H), 1.13-1.07 (m, 2H), 1.02 (t, 3H, J=7.2Hz), 0.78 (t, 3H, J=7.5 Hz).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccc(C(C)C)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(c(C)c1O)Cc1c-2[nH]c2ccc(C(C)C)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
5,10-Dihydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole (0.50 g, 1.64 mmol) was dissolved in dry dichloromethane (DCM, 2 cm3) under anhydrous conditions and cooled to -78° C. Boron tribromide (2 cm3 1.2 eq of 1 M solution in DCM) was added, and warmed to room temperature, whereupon a suspension formed. After 20 minutes, this had re-dissolved. Water (2 cm3) was cautiously added, and the mixture extracted between more DCM, and saturated sodium bicarbonate solution (some solid around during extraction finally dissolved). The DCM layer was dried (Na2SO4) and filtered through a pad of "flash" silica, eluting with DCM to yield a white solid (0.43 g, 90%) M.p. 173° C.(dec.). 1H NMR (CDCl3)δ: 8.04 (1H, br), 7.43 (1H, br), 7.29 (1H, d, J=8.2), 7.04 (1H, br), 4.58 (1H, br), 3.55 (2H, br), 30.2 (1H, septet, J=7.0Hz, 2.30 (3H, s), 2.29 (3H,s), 1.33 (6H, d, J=7.0Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][Cl:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:7]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS. (PS-A2) Rt 3.07 [M+H]+ No Ionization.
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[CH:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])[OH:4].[Cl:16][C:17]([Cl:22])([Cl:21])[CH:18](O)O.S(=O)(=O)(O)O>>[Cl:1][CH:2]([Cl:15])[CH:3]1[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:6]=2[O:14][CH:18]([C:17]([Cl:22])([Cl:21])[Cl:16])[O:4]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(O)c(C(O)C(Cl)Cl)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)C(C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2,2-dichloro-1-(2-hydroxy-5-carboxyphenyl)ethanol (1.25 g.), chloral hydrate (1.0 g.) and concentrated sulphuric acid (12.5 ml.) was stirred at room temperature for 3 days. The reaction mixture was poured onto ice, and the product was filtered off, washed with water, dried and crystallised from aqueous acetic acid to give 4-dichloromethyl-2-trichloromethylbenzo[1,3]dioxin-6-carboxylic acid, m.p. 209° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(O)CN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CC(O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 57.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 2.5 °C

Procedure:
6.0 g of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone (trans-isomer of Formula IV) as obtained in Example 3 was suspended in 120 ml methanol. 6.0 g sodium hydroxide dissolved in 60 ml water was added drop-wise to the suspension under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5° C. and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 g (70% yield) atovaquone.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](OB(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:32][N:31]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Reactant: COc1ncc(OB(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc3ncc4c(=O)[nH]c(=O)n(-c5cccc(C(F)(F)F)c5)c4c3n2)cn1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (300 mg, 0.77 mmol), (2-methoxypyrimidin-5-yl)boric acid (119 mg, 0.77 mmol), potassium carbonate (317 mg, 2.3 mmol) and tetrakis(triphenylphosphine)palladium(45 mg, 0.04 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, filtered with Celite, and concentrated. 40 mL water was added. The resulting mixture was filtered to obtain a crude product, which was successively washed with ethyl acetate (30 mL) and methanol (10 mL) to produce 9-(2-methoxypyrimidin-5-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (150 mg).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]([NH2:17])=O)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]#[N:17])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Reflux 2.1 g. 5-bromo-3-phenylbenzo[ b]thiophene-2-carboxamide (0.0063 mole) together with 10 ml. of phosphorus oxychloride for 11/2 hours and then carefully pour onto ice water. Filter off the white precipitate. Dry. Recrystallize the title compound from methanol; m.p. 145°-146°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:14][C:15]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[S:17][N:16]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[S:17](=[O:6])[N:16]=1)[CH3:13]
Reactant: CCOc1nsc(OC)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC1=NS(=O)C(OC)=C1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.4 %

Procedure:
A solution of m-chloroperoxybenzoic acid (100 mg, 0.49 mmol) in methylene chloride (1.5 ml) wad added dropwise with stirring to an ice-cooled solution of 3-ethoxy-4-chloro-5-methoxyisothiazole (87 mg, 0.45 mmol) in methylene chloride (1.0 ml). The solution was then stirred for 12 hours at room temperature. The m-chlorobenzoic acid, which precipitated out of solution, was filtered off. The filtrate was concentrated in vacuo, and the residue was chromatographed on a silica gel column, eluting with toluene followed by chloroform, to give 40 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(F)cc4F)cc23)CC1
Yield: 100.5 %

Procedure:
By a method similar to Example 31, using 2,4-difluorobenzenesulfonyl chloride (463 mg, 2.2 mmol) was added to a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (418 mg, 1.8 mmol) in 0.2 N sodium hydroxide (10 mL, 2.0 mmol) and THF (5 mL) gave 735 mg of product. The crude product was recrystallized from ethyl acetate/hexanes to give 680 mg (92%) of white crystals: mp=163-164° C.; MS(m/e): 406 (M+); Calculated for C20H20F2N2O3S: C, 59.10; H, 4.96; N, 6.89. Found: C, 58.86; H, 4.94; N, 6.95.
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[O:30]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:21])[CH2:16][CH2:15][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC(C)=C(C)C
Solvent: ClCCl
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC1(C)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution containing 10.4 g. of 3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2,6-octadiene in 100 ml. of methylenechloride, 7 g. of m-chloroperbenzoic acid were added portionwise. After this addition, the reaction mixture was allowed to stand for 2 hours at 0° to 3°C. under constant stirring. After this period, the reaction mixture was diluted with 250 ml. of diethylether, and washed with ice cold 1N sodium hydroxide and saturated aqueous sodium chloride solution. After washing, the reaction mixture was dried over sodium sulfate and evaporated. By chromatography on Kieselgel with hexane-diethylether (4:1 parts by volume) and distillation under vcuum, there was obtained pure 6,7-epoxy-3,6,7-trimethyl-1-[3,4-(methylenedioxy)-phenoxy]-2-octene; b.p. 120°-122°C./0.004 mmHg; nD20 = 1.5277.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]([CH:16]([F:18])[F:17])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]([CH:16]([F:17])[F:18])=[N:10]2)=[CH:6][C:7]=1[O:8][CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
A mixture of 0.7 g (0.0023 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one, 0.9 g (0.0067 mole) of potassium carbonate, and 0.6 g (0.0027 mole) of tert-butyl 2-bromopropionate in 40 mL of acetone was stirred at room temperature for approximately 72 hours. The reaction mixture was partitioned between water and methylene chloride and the organic phase was washed with water. After drying over anhydrous magnesium sulfate the organic phase was filtered. Evaporation of the filtrate under reduced pressure yielded 0.9 g of tert-butyl 2-[2-chloro-4-fluoro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 40.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[CH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>O1CCCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[CH:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2ncnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To the mixture of 4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one (19 mg, 0.077 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (20 mg, 0.12 mol) at rt. The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (3.10 mg, 12.4%). LCMS calculated for C11H14BrN6O(M+H): 325.0; found: 325.0, 327.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:12]([S:17]([CH3:20])(=[O:19])=[O:18])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)#[N:2]>CO.CCOC(C)=O.[Pd]>[NH2:9][C:7]1[CH:6]=[C:5]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[S:17]([CH3:20])(=[O:18])=[O:19])[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=1
Reactant: CS(=O)(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(c1cc(N)cc(C#N)c1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
A suspension of Intermediate 76A (240 mg, 0.752 mmol) and 10% Pd/C (105 mg, 0.099 mmol) in MeOH (30 mL) and EtOAc (15 mL) was degassed and then stirred under a hydrogen atmosphere (balloon) for 1.5 hours. The catalyst was filtered off, and the filtrate was concentrated to give Intermediate 76 (215 mg, 99%). HPLC: Rt=0.847 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (1H, s), 8.82 (1H, d, J=1.76 Hz), 7.43 (1H, t, J=1.63 Hz), 7.23 (1H, s), 7.14 (1H, t, J=2.01 Hz), 3.55 (6H, s). Intermediate 76 was used in the synthesis of Example 179.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccc(C(=O)O)cc2)cc1OC
Yield: 53.7 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.66 g, 4.0 mmol) and 4-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-4-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 53%) as a yellow crystalline solid; mp 258-259° C., lit. [24] 267-269° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.72 (d, J=15.6 Hz, 1H, CH═CHCO), 7.01 (d, J5′,6′=8.2 Hz, 1H, H5′), 7.20 (d, J5′,6′=8.2 Hz, 1H, H6′), 7.22 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.80 (d, J2,3=J5,6=8.4 Hz, 2H, H3, H5), 7.90 (d, J2,3=J5,6=8.4 Hz, 1H, H2, H6), 10.43 (s, 1H, NH), 12.68 (br s, 1H, CO2H).