Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.C=C[C@@H:16](C)[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2(C)[C:24](=CC(=O)C[CH2:28]2)CC3)[CH2:19][CH2:18]1.[CH3:38][C:39]([CH3:41])=[O:40]>>[CH3:16][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:34]12[CH3:35])[C@:29]1([CH3:28])[C:41](=[CH:1][C:2](=[O:3])[CH2:4][CH2:24]1)[C:39](=[O:40])[CH2:38]3
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
Refer to FIG. 189. Jones reagent (2.67 M, 0.88 ml, 2.3 mmol) was added to a solution of 17β-methylandrost-5-en-3β-ol (5, 135.5 mg, 0.4697 mmol) (J. B. Jones and K. D. Gordon, Can. J. Chem. 1972, 50, 2712-2718) in acetone (15 ml) and the mixture was 10 stirred 45 min. The reaction was quenched with the addition of 2-propanol (0.44 ml). After stirring a further 10 min. the reaction mixture was poured into 30 ml of water and extracted with three 15 ml portions of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated sodium bicarbonate+15 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (silica gel GF, 1000μ, 25% ethyl acetate/hexanes as eluent), and recrystallization from aqueous ethanol gave lustrous off-white crystals (37.5 mg, 0.125 mmol, 27%), m.p. 94-95° C., homogeneous to TLC (25% ethyl acetate/hexanes on silica gel, Rf 0.39).
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)COc1ccccc1
Product: COC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
Methyl phenoxyacetate (99.9 g, 0.6 mol) was added dropwise to chlorosulfonic acid (279.6 g, 159.5 mL, 2.4 mol) at −5° C. at such a rate to maintain internal temperature between 0 to −5° C. (addition took about 60 min). Some solid formed during this addition. The cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 1.5 hr. The reaction mixture was poured into a vigorously stirring mixture of dichloromethane (900 mL) and methanol (100 mL) at 0° C. After 15 min the cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hr. The resulting mixture was washed with ice cold water (2×250 mL). The combined aqueous layers were back extracted with dichloromethane (1×250 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous magnesium sulfate (15 g) and concentrated under reduced pressure to give 132 g (83%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[BrH:12]>C(O)(=O)C>[Br:12][C:5]1[N:4]=[C:3]([C:9]([OH:11])=[O:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)c1nc(Br)ccc1Cl
Temperature: 110 °C

Procedure:
20.0 g (104.2 mmol) of 3,6-dichloropyridine-2-carboxylic acid are admixed with 50 ml of acetic acid. Then 5 ml (33% by weight; 28.96 mmol) of a solution of hydrogen bromide in acetic acid are added. The mixture is heated to 110° C., and a further 22 ml (33% by weight; 127.4 mmol) of a solution of hydrogen bromide in acetic acid are added dropwise at this temperature. The reaction mixture is stirred at 110° C. until monitoring of the reaction by HPLC indicates virtually complete conversion. To accelerate the conversion, a further 40 ml in total (33% by weight; 231.7 mmol) of a solution of hydrogen bromide in acetic acid are added dropwise on three occasions during the reaction. For workup, the reaction mixture is poured onto ice-water. The contents are filtered and the residue is washed with water. The residue obtained is 20.5 g of the product with a purity of approx. 95% by weight. The filtrate is freed of the solvents on a rotary evaporator and the residue is stirred with water. The mixture is filtered; the residue obtained is 2.78 g of the product with a purity of approx. 89% by weight.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31]([Cl:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.CN(C)C=O>[ClH:38].[CH2:31]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:11][CH2:12]3)=[O:17])=[CH:27][CH:26]=2)[CH2:21][CH2:22][C:23]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCOc4ccccc4)CC3)ccc2N1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)CCC(=O)N2Cc1ccccc1)N1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 Milligrams of 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 70 ml of 50%-sodium hydride in oil were mixed into 5 ml of dimethylformamide and stirred at a room temperature for 1 hour. Then to this mixture was added a solution of 0.17 ml of benzyl chloride with 3 ml of dimethylformamide was added dropwise slowly and stirred at a room temperature for 4 hours. The reaction mixture was poured in a voluminous amount of water and the organic matters were extracted with chloroform, and the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue obtained was converted into hydrochloride by adding a concentrated hydrochloric acid and recrystallized from methanol-water to obtain 150 mg of 1-benzyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless powdery crystals. Melting point: 261°-264° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O>CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: COC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Yield: 203.5 %

Procedure:
10 g (36 mmol) of 3-methyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 1) were dissolved in 500 ml of CH3CN; 13 g (72 mmol) of N-bromosuccinimide were added and the reaction mixture was heated to reflux. After adding 1 g (4.1 mmol) of dibenzoylperoxide; the reaction was refluxed for 24 h; then additional 4 g (22.5 mmol) of N-bromosuccinimide and 0.5 g (2.0 mmol) of dibenzoylperoxide were added and the reaction was refluxed for 4 h. The solvent was evaporated in vacuo to dryness to yield 26.1 g of crude title compound which has been used in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:16]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)cc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1

Procedure:
A mixture of 2.0 g (7.02 mmol) of 3-bromo-5-(trifluoromethoxy)benzoic acid, 906 mg (7.72 mmol) of zinc cyanide and 486 mg (0.42 mmol) of tetrakis(triphenylphosphine)palladium(0) in 23 ml of DMF was initially degassed and then, under an atmosphere of argon, heated under reflux for 4 h. A further 243 mg (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) and 453 mg (3.86 mmol) of zinc cyanide were then added, and the mixture was stirred under reflux for another 16 h. The reaction was then concentrated to a volume of about 5 ml under reduced pressure and stirred into 100 ml of 0.1 M aqueous sodium hydroxide solution. The solid formed was filtered off, the filtrate was adjusted to pH 1 with concentrated hydrochloric acid and the precipitate formed was filtered off again. The filtrate was extracted twice with in each case 50 ml of tert-butyl methyl ether, and the combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was isolated by preparative HPLC (Method 20). Evaporation of the product fractions and drying of the residue under high vacuum gave 75 mg (92% pure, 4% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:17][CH:16]=1
Reactant: O=C(O)CNc1ccc(-c2ccccc2F)nc1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccccc2F)nc1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 79 mg (0.21 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 35.7 mg (0.42 mmol) piperidine. Yield: 4.3 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:24])([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:24])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CC(C)(N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)CC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2,4-dimethyl-1-pentanol (CAN 13893-55-5) as starting materials and isolated (193 mg, quant.) as colorless oil; LC-MS (UV peak area, m/z) 100%, 341.1623 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([OH:21])[C:13]=2[CH2:22][CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][CH:6]=2)=[C:13]([CH2:22][CH2:23][CH3:24])[C:14]=1[OH:21])(=[O:20])[CH3:19]
Reactant: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Yield: 83 %

Procedure:
A solution of 3.30 g 4-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester and 48 mL of 1.0 N sodium hydroxide dissolved in 100 mL of methanol was stirred at reflux for 1.25 hour. The solvent was removed in vacuo and the reaction mixture was acidified with 6 N hydrochloric acid. The product was extracted with ethyl acetate and the dried (over magnesium sulfate) extract was concentrated in vacuo to give a solid. Recrystallization from acetonehexane gave 2.613 g, mg 187°-189°, (83% yield) of 4-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid, the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[C:7]=1[C:16]#[N:17])=[O:4].S(=O)(=O)(O)[OH:19]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[C:7]=1[C:16](=[O:19])[NH2:17])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCS(=O)(=O)c1nsc(NC(=O)NC)c1C#N
Product: CCS(=O)(=O)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 8.8 g of 1-methyl-3-(4-cyano-3-(ethylsulfonyl) -5-isothiazolyl)urea and 10 ml of concentrated sulfuric acid was heated at 100° for 2.25 hours, then poured into 150 ml of ice-water. The solid was isolated and recrystallized from acetic acid-water to give 2.8 g of 1-methyl-3-(4-carbamoyl-3-(ethylsulfonyl)-5-isothiazolyl)urea, m.p. 219°-220°. An additional 2.2 g was obtained by concentrating the mother liquor from the recrystallization. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH:10]1[O:12][CH2:11]1.C(N(CC)CC)C>CO>[Br:8][CH2:9][CH:10]([OH:12])[CH2:11][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCC1CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CBr)CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophenol, 11.0 g (0.10 mole), was added dropwise over a period of one hour, to a cold (0° C.) mixture of 13.69 g [8.5 ml (0.1 mole)] 1-bromo-2,3-epoxypropane (epibromohydrin), 1.5 ml [1.09 g (0.02 moles)] triethylamine and 1.5 ml methanol. The reaction mixture was then allowed to come to room temperature and was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ether, washed several times with water and once with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 22.7 g of the above-identified product as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH2:27](Br)[CH3:28].[H-].[Na+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[NH4+].[Cl-]>[CH2:27]([O:15][CH2:14][CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[CH3:28]
Reactant: CCBr
Reactant: CCOc1cc(C(CCO)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOCCC(c1ccc(OC)c(OCC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a stirred solution of 3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimido-1-propanol (1 gram, 2.82 mmol), ethyl bromide (0.42 mL, 5.63 mmol), and tetrabutyl ammonium iodide (200 mg, 0.54 mmol) in THF (10 mL) at room temperature, was added NaH (270 mg, 60%, 6.75 mmol). The mixture was stirred at room temperature for 45 minutes, and then was heated to reflux for 4 h. To the mixture was added a few drops of NH4Cl, then HCl (1N, 25 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel 100 grams, 1:5 EtOAc:hexane) gave 1-ethoxy-3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimidopropane as an oil, (800 mg, 74% yield): 1H NMR (CDCl3)δ1.06 (t, J=7Hz, 3H, CH3), 1.46 (t, J=7 Hz, 3H, CH3), 2.46-2.58 (m, 1H, CHH), 2.75-2.95 (m, 1H, CHH), 3.37 (q, J=7 Hz, 2H, CH2), 3.44 (q, J=7 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 4.12 (q, J=7 Hz, 2H, CH2), 5.49 (dd, J=6.4, 9.5 Hz, 1H, NCH), 6.81 (d, J=8.2 Hz, 1H, Ar), 7.10-7.48 (m, 2H, Ar), 7.68-7.72 (m, 2H, Ar), 7.77-7.83 (m, 2H, Ar); 13C NMR (CDCl3)δ14.73, 14.98, 31.31, 52.24, 55.89, 64.30, 66.33, 67.73, 111.11, 112.99, 120.61, 123.11, 132.00, 132.09, 133.80, 148.11, 148.84, 168.44; Anal Calcd for C22H25NO5 : C, 68.91; H, 6.57; N, 3.65. Found: C, 68.77; H, 6.47; N, 3.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH:9]=O)[CH:7]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=3)=[N:16][N:17]=2)[C:5]([O:11][CH3:12])=[C:6]([CH2:8][CH2:9][N:32]2[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]2)[CH:7]=1
Reactant: O=C(O)C1CNC1
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
To a solution of [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (90 mg) and 3-azetidinecarboxylic acid (80 mg) in dichloromethane (DCM) (20 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (84 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was purified by Mass Directed AutoPrep to give 1-{2-[5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E14) (45 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.34 (6H, d), 2.69 (4H, m), 3.17 (3H, m), 3.41 (2H, m), 3.79 (3H, s), 4.94 (1H, m), 7.43 (1H, dd), 7.52 (1H, d), 7.88 (1H, dd), 8.27 (2H, m). δF (DMSO-d6, 376 MHz): −117.2, −61.3. MS (ES): C25H25F4N3O4S requires 539. found 540.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CS(C)=O>[I:1][C:2]1[C:7]2[C:8](=[O:10])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(I)c2C(=O)N2CC[C@@H]12

Procedure:
70 g (242 mmol) of 6-iodoisatoic acid anhydride and 24.46 g (242 mmol) of L-azetidine-2-carboxylic acid in 140 ml of dimethyl sulphoxide are stirred at 105° for 2 hours, the dimethyl sulphoxide is removed in vacuo and the residue is heated to 140° in a high vacuum for 2.5 hours. By chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained (S)-1,10a-dihydro-5-iodo-azeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 186°-187°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:25](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]2[N:9]=[CH:25][NH:8][C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(Cl)c(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cc2nc[nH]c2cc1Cl
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine (2.00 g, 7.80 mmol), sodium dithionite (7.06 g, 40.5 mmol), trimethyl orthoformate (23.1 mL, 210 mmol), DMF (23 mL), and acetic acid (4.0 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc (100 mL) and saturated aq. NaHCO3 (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound (1.46 g, 78%). MS (ESI/CI): mass calcd. for C8H4ClF3N2O, 236.0; m/z found, 237.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.11 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then purified by trituration with diethyl ether to obtain 2-[2-(2,4-dichlorophenyl)-2-oxoethyl]isoindoline-1,3-dione.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[N:15]=[CH:14][S:13][C:8]3=2)[N:3]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[Cl:16][S:17]([C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2)=[C:8]2[S:13][CH:14]=[N:15][C:7]=12)(=[O:19])=[O:18]
Reactant: Oc1nc2ccc3ncsc3c2nc1O
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc2nc(O)c(O)nc2c2scnc12
Temperature: 25 °C
Yield: 47 %

Procedure:
7,8-Dihydroxythiazolo[5,4-f]quinoxaline (0.44 g, 2 mmol) was added portionwise to 2 ml of chlorosulfonic acid with stirring at room temperature. Then the mixture was stirred at 150° C. for 5 h, and left over night at room temperature. The solution was added dropwise to 50 g of crushed ice with stirring. The resulting solid was collected by filtration after 1 h and washed with ice-water and a small amount of ethanol and ether, affording 0.30 g (47%) of crude 4-chlorosulfonyl-7,8-dihydroxythiazolo[5,4-f]quinoxaline. The crude product was stirred with 25 ml of aqueous ammonium hydroxide (25%) for 20 min at room temperature and at 100° C. for 10 min. Nitrogen was bubbled through the hot solution for 5-10 min and after cooling to 0° C. the solution was acidified to pH 1 with 4M hydrochloric acid. The resulting precipitate was isolated by filtration and dissolved in 150 ml of hot N,N-dimethylformamide. A solid impurity was removed from the hot solution by filtration, and after treatment with charcoal the solution was cooled and evaporated to dryness. The residue was taken up with 15 ml of hot 2N sodium hydroxide, the resulting solution was treated with charcoal, cooled to 0° C. and acidified with 4M hydrochloric acid. The precipitated solid was isolated by centrifugation and washed with water and ethanol to give 60 mg (21%) of the title compound, m.p.>400° C.; IR (KBr): 1710, 1690 cm-1 ; 1H-NMR (DMSO-d6) 7.28 (broad s, 2H, NH2), 7.90 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.17 (broad s, 1H, OH), I2.60 (broad s, 1H, OH).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1.CO>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([S:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccc1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To solution of 3-Phenylsulfamoyl-benzoic acid (380 mg, 1.36 mmol) in THF (10 ml) was added BH3.THF (1M, 5.4 ml, 5.4 mmol) dropwise. After the addition, the reaction mixture was allowed to stir for 3 d at room temperature. Methanol was added to the reaction and the mixture concentrated in vacuo (5×). This compound was used in the next step without further purification.