Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
Potassium carbonate (1.3 g, 9.6 mmol) was added to a mixture of 4-nitrophenol (1.11 g, 8 mmol) and epibromohydrin (1.37 mL, 16 mmol) The mixture was stirred at 100° C. for 18 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na2SO4. Removal of the solvent in vacuo gave an orange residue, which was purified chromatographically on silica eluting with EtOAc/hexanes (1:10, v/v). The product was obtained as a yellow solid (0.8 g, 51%). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.21 (m, 2H), 6.98 (m, 2H), 4.37 (dd, J=2.8 Hz, 11.1 Hz, 1H), 4.00 (dd, J=5.9 Hz, 11.1 Hz, 1H), 3.90 (m, 1H), 2.93 (t, J=4.8 Hz, 1H), 2.77 (dd, J=2.8 Hz, 4.8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl>O>[CH2:1]([NH:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)OCC)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Temperature: 20 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 850 mg of ethyl 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 10 ml of dioxane, 40 ml of distilled water and 5.8 ml of 1N sodium hydroxide solution is stirred under a stream of argon at a temperature in the region of 20° C. overnight. The reaction mixture is cooled to a temperature in the region of 0° C. and neutralized with 5.8 ml of 1N hydrochloric acid. The precipitate obtained is filtered, washed with distilled water a number of times and dried in an oven. 695 mg of 8-(N-ethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10-H imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid are obtained in the form of a brown solid melting above 300° C. (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm (300 MHz): 1.05 (3H, t, J=6 Hz, CH3), 3.10 (2H, m, NCH2), 3.47 (2H, s, CH2CO), 4.02 (2H, s, CH2), 7.30 (1H, d, J=8 Hz, arom. CH), 7.48 (1H, s, arom. CH), 7.82 (1H, d, J=8 Hz, arom. CH), 8.08 (1H, t, J=5 Hz, NH), 8.52 (1H, s, imidazole H)).
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:7]1)([OH:3])=[O:2].C([SiH](CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:7]1)([OH:3])=[O:2]
Reactant: O=C(O)CCn1cc(CCNS(=O)(=O)c2ccc(F)cc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCN1CC(CCNS(=O)(=O)c2ccc(F)cc2)c2ccccc21
Yield: 77.8 %

Procedure:
0.75 g (1.9 mmol) of N-[2-[1-(2-carboxyethyl)-1H-indol-3-yl]ethyl]-(4-fluorophenyl)sulphonamide are reduced with triethylsilane analogously to Example 1. 0.58 g of a viscous oily product is thus obtained (Rf =0.18, CH2Cl2 :ethyl acetate=100:2). After conversion of the product into its hydrochloride (analogously to Example 1), 0.62 g (76% of theory) of a solid residue is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28]>CC(=O)CC>[CH2:25]([NH:29][C:30]([NH:18][S:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)(=[O:17])=[O:16])=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1ccccc1-c1nnc(SC)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A suspension containing 16 g of the sulfonamide of Example 3, 7.7 g of potassium carbonate and 6.7 g of n-butylisocyanate in 130 of 2-butanone was refluxed for 4 hours, then stirred overnight at room temperature. After concentrating the mixture in vacuo, the residue was diluted with about 150 ml of water and the solution was washed 1×100 ml of ethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid (red to litmus paper) and the resulting suspension was filtered, the suction-dried overnight to give 20 g of the subject compound; m.p. 156°-159° C. IR (nujol): 1680 cm-1 (C=O).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([O-])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([Cl:21])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Yield: 88.5 %

Procedure:
Sixty grams of potassium 4-chloro-3,5-dinitro-o-toluenesulfonate, 70 grams of phosphorus pentachloride and 120 ml. of phosphorus oxychloride are mixed and refluxed for 3 hours. The mixture is filtered to remove some insoluble solid. The filtrate is carefully poured into water at 20° C. to 30° C. The precipitated solid is collected and dissolved in 500 ml. of benzene. The benzene solution is washed with water and then dried over MgSO4. After removing the magnesium sulfate, the benzene is concentrated to 100 ml. and 400 ml. of hexane added. The precipitated solid is collected and recrystallized from 300 ml. hexane and 100 ml. of benzene to yield 50 grams of solid with melting point 105° C. to 107° C.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:19])=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:11]=2)[C:5]1=[O:23])(=O)C.[OH-].[Na+].Cl>CO.C1COCC1>[CH:16]([C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:13]=1[OH:19])[CH:9]=[C:6]1[CH2:7][CH2:8][NH:4][C:5]1=[O:23])([CH3:18])[CH3:17]
Reactant: CC(=O)N1CCC(=Cc2cc(C(C)C)c(O)c(C(C)C)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C=C2CCNC2=O)cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 810 mg (2.57 mmol) of the thus obtained 1-acetyl-3-(3,5-di-isopropyl-4-hydroxybenzylidene)pyrrolidin-2-one in 5 ml of methanol and 10 ml of THF was added 2 ml of 1N aq. sodium hydroxide at room temperature and the mixture was stirred for 3 hours. the reaction mixture was poured into ice-water containing ethyl acecate and 3 ml of 1N hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated under reduced pressure to give a residue, which was crystallized from a ether/n-hexane mixture to give 800 mg of the objective compound as yellowish white crystal in 100% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11]([Cl:36])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.9 Reaction of 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoic acid with thionyl chloride gives the compound 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoyl chloride.
Reaction SMILES: C([C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(C3C=NC(N)=CC=3)=CC=2)C)[CH2:6][CH2:5]1)C=C>O1CCCC1>[C:26]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Solvent: C1CCOC1
Product: O=C1NCCC(c2ccccc2)O1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 0.23 mmol) in tetrahydrofuran (10 mL) was added BH3 THF (3.0 mL, 1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then NaOH (2 mL, 3 mol/L) and H2O2 (1 mL) was added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:13]/[N:14]=[C:15](/[C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)\[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]CO>CS(C)=O>[C:1]([O:5][C:6]([C:8]1([O:13]/[N:14]=[C:15](/[C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)\[C:16]([O:18][CH3:24])=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2ccco2)CCCC1
Solvent: CS(C)=O
Product: COC(=O)/C(=N\OC1(C(=O)OC(C)(C)C)CCCC1)c1ccco1
Yield: 96 %

Procedure:
This compound was prepared from Z-2-(1-tert-butoxycarbonylcyclopent-1-yloxyimino)-2-(fur-2-yl)acetic acid by the method described in Preparation 7(a) above, λmax (EtOH), 280.5 nm (ε17,300), νmax (Nujol) 1740, 1725 (sh) cm-1 (CO2R), τ(DMSO d6) 2.10, 3.18, 3.34 (α-furyl); 6.11 (CO2Me), 7.6-8.8 (cyclopentyl), 8.60 (CMe3). Yield 96%.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1ccccn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6 g, 28.8 mmol) in toluene (150 ml) at 0° C., trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 2-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over 10 minutes and the reaction mixture was heated to 85-90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1500 ml) and filtered. The pale yellow solid (5.2 g, 66%) was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2C#N)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(Cl)(=O)C([Cl:28])=O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=2)=[CH:9][C:5]([C:6]([Cl:28])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2ccc(C(F)(F)F)nc2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring dichloromethane solution (5 mL) containing 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (Step 38C or 38C.1, 436 mg, 1.2 mmol), was added 2 drops of DMF and then oxalyl chloride (128 μL, 1.5 mmol) under N2. The mixture was stirred at rt for 2 hrs and concentrated to yield 4-chloro-2-methoxy-5-(6-trifluoromethyl-pyridin-3-yl)-benzoyl chloride as a solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][N:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(C(N)=O)cn1
Solvent: ClCCCl
Product: N#Cc1ccc(C(=O)N=C=O)cn1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 6-cyanonicotinamide (Synthesis (1983), 316) (1.2 g) in 1,2-dichloroethane (28 ml) was added oxalyl chloride (1.3 ml) and the mixture was heated at reflux with stirring for 2.5 hours. The reaction mixture was cooled and the solvents were removed in vacuo to yield 6-cyanonicotinoyl isocyanate as a yellow solid residue. Then in a similar manner to Example 1, starting material step (a), this residue, t-butyl 4-aminophenoxyacetate, acetate salt (1.59 g), triethylamine (3.8 ml) and acetonitrile (140 ml total) gave, after stirring at ambient temperature for 3 hours followed by evaporation of the solvents, a yellow solid, which was collected, washed with cold acetonitrile and with hexane and dried to give t-butyl 4-[3-(6-cyanopyrid-3-ylcarbonyl)ureido]phenoxyacetate (2.37 g): m.p. 220°-222° C. (decomposes); NMR Spectrum (DMSO-d6) 1.48 (9H, s), 4.67 (2H, s), 6.94 (2H, d), 7.52 (2H, d), 8.27 (1H, d), 8.58 (1H, dd), 9.25 (1H, d), 10.41 (1H, s), 11.40 (1H, s); Mass Spectrum m/Z 396 (M+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C.O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a suspension of NaH (50.5 mg, 2.00 mmol) in DMF (1.00 mL) was added 1-(3-hydroxyphenyl)ethanone (136 mg, 1.00 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. To this mixture was added a solution of 1-bromo-3-chloropropane (188 mg, 1.20 mmol) in DMF (0.500 mL). The reaction mixture was stirred at room temperature for 5 h. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (4:1) to afford the desired product 1-[3-(3-chloropropoxy)phenyl]ethanone (235 mg, 55.2%): 1H NMR (400 MHz, CDCl3) δ 7.7 (d, 1H, J=6.6 Hz), 7.52 (s, 1H), 7.25 (t, 1H, J=6.6 Hz), 7.01 (m, 1H), 4.11 (t, 2H, J=7.9 Hz), 3.69 (t, 2H, J=7.9 Hz), 2.61 (s, 3H), 1.95–1.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
was added to a solution of 3-bromo-5-nitroaniline (3.4 g, 15.7 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine) (2.27 mL, 18.80 mmol) in dioxane (78 ml) at room temperature, under nitrogen. The mixture became heterogeneous instantly and upon heating, a solution was obtained. The mixture was stirred at 100° C. for 18 hours then cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate and dichloromethane were added, the organic phase was recovered using a phase separator and then concentrated under reduced pressure. The residue was washed in hexanes/ether and filtered to afford N-(3-bromo-5-nitrophenyl)-4-(trifluoromethyl)pyrimidin-2-amine.
Reaction SMILES: [F:1][C:2]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([O:16]CC)=[O:15])[N:7]([CH3:19])[N:6]=1)([CH3:4])[CH3:3].[OH-].[K+].O>CO>[F:1][C:2]([C:5]1[C:9]([C:10]([F:11])([F:12])[F:13])=[C:8]([C:14]([OH:16])=[O:15])[N:7]([CH3:19])[N:6]=1)([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)F)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(C)(C)F)c(C(F)(F)F)c1C(=O)O
Temperature: 50 °C

Procedure:
A solution of 700 mg (2.48 mmol) of ethyl 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 10 ml of methanol is admixed with 208 mg (3.72 mmol) of potassium hydroxide and 1 ml of water and heated at 50° C. for one hour. The reaction mixture is concentrated by evaporation, admixed with water and extracted with diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid and extracted twice with ethyl acetate, and the organic phase is dried over sodium sulphate and, after filtration, is concentrated by evaporation. This gives 498 mg of 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>>[CH:30]1([C:34]([N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]3[S:11][C:7]4[C:6]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[N:9]=3)=[O:23])=[CH:19][CH:18]=2)[CH3:22])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: O=C(Cl)C1CCC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)C4CCC4)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and cyclobutanecarbonyl chloride, the title compound was prepared as light yellow crystals (59% yield). MS: m/e=495(M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>C(OCC)C>[C:17]([O:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])(=[O:19])[CH3:18]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 519.3 %

Procedure:
A stirred mixture of (3-hydroxy-4-nitro-phenyl)acetic acid (1 2.0 g), aqueous sodium hydroxide (152.3 mL, 1M) and diethyl ether (150 mL), cooled to 0° C. in an ice salt bath, was treated dropwise with acetic anhydride (8.1 g) at a rate to maintain the temperature at 0° C. When the addition was complete the mixture was stirred at 0° C. for a further 2 hours then acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extracts were dried over magnesium sulphate and then evaporated to give the title compound (12.6 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:21]=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Thiophen-3-yl-carbamic acid tert-butyl ester described in Preparation Example U-1 (1.00 g, 5.02 mmol) was dissolved in tetrahydrofuran (20 mL), to which n-butyl lithium (2.47M hexane solution, 4.47 mL, 11.0 mmol) was added at −78° C., and the mixture was stirred at −78° C. for 1 hour. N,N-dimethylformamide (466 μl, 6.02 mmol) was added to the reaction mixture at −78° C., and the solution was stirred for 1 hour at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (1.14 g, quantitatively) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:22])[C@H:16]1[OH:23].C(N(CC)CC)C>CCO>[OH:21][CH2:20][C@H:18]1[CH2:19][C@@H:15]([NH:14][C:2]2[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[C@H:16]([OH:23])[C@@H:17]1[OH:22]
Reactant: COc1nc(SC)nc(Cl)c1I
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Temperature: 130 °C

Procedure:
Compound 3 (5.00 g, 15.7 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (Compound 4) (5.80 g, 31.6 mmol) were dissolved in EtOH (50 mL). Triethylamine (6.60 mL, 47.4 mmol) was added, the reaction was sealed, and heated to 130° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a colorless oil. LCMS 1.23 min, 428 (M+H).
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][C@@H:2]1[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:5]([CH2:3][C@H:2]1[CH2:12][CH2:13][CH2:14][NH:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(NC[C@H]2CCCN2)cc1
Temperature: 0 °C
Reaction time: 11 h

Procedure:
To a solution of D-Proline anilide (1.15 g, 6.0 mmol) in 20 mL of THF at 0° C. was added a 1 M solution of lithium aluminum hydride (14 mL, 14 mmol) in THF. The resulting solution was stirred at 0° C. for 11 hours. The reaction was carefully quenched with a saturated solution of Na2SO4 and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil. The oil was purified by silica gel chromatography with 3% CH3OH/CH2Cl2 and 1% triethyl amine to give the title compound as a yellow oil (0.029 g, 63%). ES (+) MS m/e=177 (M+H)