Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH3:35])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CNCCOC
Product: COCCN(C)CCOc1n[nH]c2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c12
Yield: 52 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and (2-methoxyethyl)methylamine to give the title compound in 52% yield; NMR Spectrum: 2.30 (s, 3H), 2.45 (s, 3H), 2.62 (t, 2H), 2.86 (t, 2H), 3.17 (s, 3H), 3.41 (t, 2H), 4.41 (t, 2H), 7.19 (d, 1H), 7.26 (br s, 2H), 7.72 (d, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 484 (MH+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>CCCCCC>[CH2:11]([CH2:10][C:9](=[O:8])[CH3:1])[CH3:12].[CH3:4][CH2:3][CH2:2][CH2:1][CH2:9][CH3:10]
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Combine 1-((2-trimethylsilyl)ethoxymethyl)-1 H-benzimidazole (91.2 g, 367 mmol) and tetrahydrofuran (500 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of n-butyl]ithium (146 mL, 2.5 M in hexane, 367 mmol) at such a rate that the temperature of the reaction mixture remains at about −70° C. After the addition of n-butyllithium is complete allow to stir for 30 minutes at −78° C. Add a solution of 1-(t-butoxycarbonyl)-piperidine-4-(N-methyl-O-methyl)-hydroxamic acid (99.9 g, 367 mmol) in tetrahydrofuran (100 mL). Warm to ambient temperature. After 18 hours, add dropwise a saturated aqueous ammonium chloride solution (100 mL). Add water (300 mL) and extract with diethyl ether. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetone/hexane to give a residue. Recrystallize the residue from methanol/water to give (1-(t-butoxycarbonyl)-4-(1-((2-trimethylsilyl)ethoxymethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine.
Reaction SMILES: [H-].[Na+].CO[C:5](=O)[CH:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].IC[CH2:24][CH2:25][CH:26]([O:32]C(=O)C)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:20][S:17]([CH:6]([CH2:5][CH2:24][CH2:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:18])=[O:19]
Reactant: CCCCCC(CCCI)OC(C)=O
Reactant: COC(=O)CCCCCCC(C(=O)OC)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.3 %

Procedure:
A suspension of 57% sodium hydride/mineral oil (3.84 g., 0.091 mole) is washed by decantation with petroleum ether to remove the mineral oil. The residual solid is suspended in dry dimethylformamide (100 ml.) and treated with a solution of dimethyl-2-methylsulfonylazelate (23.5 g., 0.08 mole) in dry dimethylformamide (60 ml.) added dropwise at ambient temperature under a nitrogen atmosphere. The resulting solution is stirred for 1 hour at room temperature, cooled to ~10° C., and treated with 1-iodo-4-acetoxynonane (30 g., 0.096 mole) added at such a rate as to maintain an internal temperature less than 35° C. After 19 hours at ambient temperature, the reaction mixture is filtered. Collected sodium iodide (17.1 g.) is washed with ether. The combined filtrate and washings are concentrated in vacuo at ~100° C. yielding a residual oil which is partitioned between ether and dilute hydrochloric acid. The organic extract is washed with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo leaving the title compound as a viscous oil (37.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.0 (s, 3H), 3.65 (s, 3H), 3.81 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH:17]=[O:18])=[CH:9][CH:10]=[CH:11][C:4]1=2>CO>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH2:17][OH:18])=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: O=CC1=C(c2cccc3sccc23)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1=C(c2cccc3sccc23)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
Sodium borohydride (0.05 g) was added in portions over 2 minutes to a stirred suspension of 3-(benzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.36 g) in methanol (10 ml), then the mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then water (20 ml) and ethyl acetate (30 ml) were added and the mixture was stirred at ambient temperature for 2 hours. The aqueous phase was separated and washed with ethyl acetate (30 ml), then the combined ethyl acetate solutions were dried (MgSO4) and the solvent was removed in vacuo at 60° C. to give [3-(benzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazol-2-yl]methanol (0.315 g) as a cream solid, m.p. 145-149° C.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH2:22][OH:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:23][CH2:22][C:19]1[N:11]2[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH2:9][C:10]2=[N:21][N:20]=1)(=[O:26])[CH3:25]
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 17 h

Procedure:
An amount of 7.0 g of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol is dissolved in 50 ml of absolute pyridine; to the solution are added 2.4 ml of acetic anhydride, and the whole is then allowed to stand for 17 hours at 25°. The reaction mixture is afterwards concentrated in vacuo. The residue is dissolved in methylene chloride, and the solution washed with water and saturated sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. After crystallisation of the residue from ethyl/acetate is obtained 1-(acetoxymethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 210°-212°.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:41]=[CH:40][CH:39]=[CH:38][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])=[CH:24][CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][CH:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:38]=[CH:39][CH:40]=[CH:41][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]3)[C:16]([C:17]([F:19])([F:20])[F:18])=[CH:15][N:14]=2)=[CH:27][CH:26]=1)[CH3:29]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 1-(4-(4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate 70 (0.11 g, 0.19 mmol) in DCM (4 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 16 hours before the volatiles were removed in vacuo. The crude residue was purified using an SCX conditioned with MeOH, product was eluted off with 2 M ammonia in EtOH) to give the title compound 70A as a cream solid (0.073 g, 81%). LCMS-C: rt 4.48 min; m/z 470 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:6]#[N:7].C(N(CC)CC)C.C[Si]([N:42]=[N+:43]=[N-:44])(C)C.[OH-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:3]=1[CH2:4][N:5]([CH2:8][C:9]1[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6]1[N:42]=[N:43][NH:44][N:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2Br)c2nn[nH]n2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To the product of step C (909 g, 1.80 mol) in methyl tert-butyl ether (9 L) was added triethylamine (2.5 L, 18 mol) followed by trimethylsilylazide (415 g, 3.60 mol). The resulting mixture was heated to 50° C. for 8 hours. An aliquot was checked by HPLC and starting material was still present. The mixture was cooled and trimethylsilylazide (50 g) was added. The mixture was again heated to 50° C. and stirred 3 hours. After cooling, 1N sodium hydroxide (9 L) was added. The layers were separated (added 150 ml ethanol to facilitate separation). The organics were washed with aqueous 10% citric acid solution (8 L, then 2 L) until washings were acidic. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid turned white upon standing (976 g, 99% yield). 1H-NMR (CD3OD) δ 7.47 (m, 3H), 7.64 (d, 8.3 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.38 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.88 (s, 2H), 4.86 (s, 2H). Mass Spec (ESI): M+1=548.0
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12]CC)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2(C#N)CCC(=CC(=O)O)CC2)c2c1OCCO2
Temperature: 70 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a suspension of Compound 10 (0.31 g, 0.87 mmol) obtained in Example 10 in ethanol (3.1 mL) and THF (3.1 mL) was added a 2 mol/L aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol), the mixture was stirred at 70° C. for 1 hour, and then a 2 mol/L aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol) was further added, followed by stirring at 70° C. for 1 hour. 1 mol/L hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, the solvent was evaporated in vacuo, and the residue was triturated with ethanol to give Compound 11 (0.23 g, 82%) as a white solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[I:19])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[I:19][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[N:14]([CH3:18])[N:13]=1
Reactant: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(I)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.7 %

Procedure:
To a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-methyl-1H-indazole (1 g, 2.57 mmol) in THF (5 mL) was added TBAF (6.42 mL, 12.85 mmol) at 0° C., after the addition, the reaction mixture was warmed to room temperature and stirred for 0.5 hour, then H2O (25 mL) was added to the mixture and product extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was triturated with petroleum ether (5 mL), filtered and dried to give 3-iodo-1-methyl-1H-indazol-5-ol (0.85 g, 93.3%) as a white solid. Crude material used into the next step without further purification. LCMS: (M+H)+=275.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1074549 A2) was treated with the 4-phenylpiperidine in N,N-dimethylformamide in the presence of N-ethyldiisopropyl-amine at room temperature to yield the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3H-pyrimidin-4-one as yellowish solid; m.p. 210-213° C.; MS: [M+H]+=315.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])[CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:21]=[O:22])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([N:15]=[C:21]=[O:22])(=[O:13])=[O:14])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1C1=CCCC1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)c1ccccc1C1=CCCC1

Procedure:
A solution of 2.5 g of 2-(1-cyclopentenyl)benzenesulfonamide in 20 ml of xylenes was contacted with 1.4 g of n-butylisocyanate and a trace amount (ca. 20 mg) of DABCO then heated to reflux of 139°. Liquified phosgene (1.2 ml) was then added thereby reducing the temperature and reflux continued until the boiling point of the mixture stopped rising towards the original 139° (ca. 15 min. required), which indicated a complete reaction. The solution was then evaporated under reduced pressure to yield an oil. The infrared spectrum exhibited the characteristic 2220 cm-1 band indicating the presence of the title compound which was used directly.
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2].[CH2:16](N(CC)C1C=C(C=C(C)N=1)C(O)=O)C>>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CCN(C)c1cc(C(=N)NO)cc(C)n1
Product: CCN(CC)c1cc(C(=N)NO)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-(ethyl-methyl-amino)-N-hydroxy-6-methyl-isonicotinamidine from 2-(diethylamino)-6-methyl-isonicotinic acid; LC-MS: tR=0.50 min, [M+1]+=223.12.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][CH:8]([C:16]3[N:17]=[C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[S:19][CH:20]=3)[C:9](=[O:15])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:16]3[N:17]=[C:18]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[S:19][CH:20]=3)[C:9](=[O:15])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1CC(c1csc(-c3ccncc3)n1)C(=O)N2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]c(=O)c(-c3csc(-c4ccncc4)n3)cc12
Temperature: 85 °C

Procedure:
In an oven-dried, 100-mL, round-bottomed flask was placed 1,2,3,4-tetrahydro-2-oxo-3-[2-(4-pyridyl)-4-thiazolyl]-5-quinolinecarboxylic acid methyl ester (Step a, 60 mg, 0.16 mmol), NBS (Aldrich, 32 mg, 0.18 mmol), and AIBN (Aldrich, 5 mg, 0.03 mmol) in CCl4 (10 mL). The mixture was heated to 85° C. for 2 h, cooled to RT, and quenched with 2N NH3 in MeOH (5 mL). The crude product was concentrated in vacuo, and the resulting solid was filtered, washed with H2O (3×5 mL), and MeOH (1×2 mL) to afford 1,2-dihydro-2-oxo-3-[2-(4-pyridyl)-4-thiazolyl]-5-quinoline carboxylic acid methyl ester as a yellow solid: Mp: >250° C. MS m/z: 364 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([OH:16])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc2cc(O)ccc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2cc1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 3,7-dihydroxynaphthalene-2-carboxylic acid methyl ester (3.32 g, 15.5 mmol), bromoacetic acid tert-butyl ester (2.29 mL, 15.5 mmol) and potassium carbonate (4.28 g, 31.0 mmol) in DMF (20 mL) is stirred at 60° C. for 18 h. The reaction mixture is poured to EtOAc, wash with water and brine. It is then dried with MgSO4 and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(C(F)(F)F)c1
Yield: 88.8 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 18.4 g (0.114 mole) of α,α,α-trifluoro-m-cresol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 22.5 g (82%) of a white solid, mp 100°-102° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1.CC1C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1>C(OCC)C.CS(C)=O>[C:12]([C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[CH:30][NH:31][CH:32]=1)(=[O:13])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1c[nH]cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
A suspension of NaH (80% in paraffin) (3.97 g; 0.165 moles) in anhydrous ethyl ether (100 ml), maintained under nitrogen stream, is dropwise added with a solution of 3-(4-chlorophenyl)-1-phenyl-2-propen-1-one (18.11 g; 0075 moles) and tosylmethylisocianide (TOSMIC) (14.60 g; 0.075 moles) in anhydrous dimethylsulfoxide (170 ml) diluted with anhydrous ethyl ether (300 ml). Upon the additions are completed, the mixture is maintained under stirring at room temperature for 3 hours. After dilution with water (800 ml) the precipitate is filtered, washed with absolute ethanol and lastly with petroleum ether. There are obtained 10.40 g (yield 49.4%) of 4-benzoyl-3-(4-chlorophenyl)-1H-pyrrole, which is crystallized from N,N-dimethylformamide and water (m.p.: 232°-235° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Product: COC(=O)c1ccc(CN(c2ccc(C#N)cc2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-[N-(4-cyanophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromomethylbenzoate
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: NC(N)=S
Product: Cc1sc(N)nc1-c1ccccc1

Procedure:
Reaction of a α-substituted-α-bromoacetophenone with thiourea or substituted thiourea, at elevated temperatures may give gave an intermediate G1. Suitably, this reaction may be performed under refluxing conditions in the presence of DMF (dimethylformamide). This intermediate (G1) may be reacted with chlorosulfonic acid to yield the sulfonyl chloride B-1. For example 2-bromopropiophenone may be reacted with thiourea to yield 2-amino-5-methyl-4-phenylthiazole, which can be further transformed to 4-(2-amino-5-methylthiazol-4-yl)phenyl sulfonyl chloride.
Reaction SMILES: CC(O)=[O:3].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:19][O:18]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([C@H:17]([OH:3])[CH2:19][OH:18])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1
Reactant: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R,R)-(−)-N,N′-Bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) (32.6 mg, 53.9 mmol) was dissolved in toluene (2.0 mL). AcOH was added (6.1 μL), and the resulting mixture was stirred at room temperature for 1 hour under air. The mixture was then concentrated and dried under high vacuum. (S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (2.3 g, 10.8 mmol) was added, followed by water (97.1 μL), and the resulting mixture was stirred vigorously for 6 hours. Hexanes (15 mL) was added. The resulting solid was manually crushed and additional hexanes was added and stirred until the red solid became a yellowish precipitate. The precipitate was filtered and washed with 2 portions of hexanes. The precipitate was dried under vacuum to yield (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester as an off-white solid (1.3 g). The filtrate was concentrated and purified by SiO2 flash chromatography (0-100% EtOAc in hexanes) to yield (S)—(R)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (970 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([NH:23][CH3:24])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[F:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1COCC1>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:20]=[C:19]([CH:21]([N:23]([CH3:24])[S:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)(=[O:45])=[O:44])[CH3:22])[CH:18]=[CH:17][C:10]=2[O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(C)c1ccc(OCC(=O)OC)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(C(C)N(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(methylamino)ethyl)phenoxy)acetate (18) (100 mg) in 2 mL of THF, was added DIEA (105 mg), and 4-fluorobenzene-1-sulfonyl chloride (87 mg). The reaction mixture was stirred at room temperature for 1 hr and then purified via silica gel chromatography (25% EtOAc/hexane) to give methyl 2-(2-(3-trifluoromethylphenyl)-4-(1-(4-fluoro-N-methylphenylsulfonamido)ethyl)phenoxy)acetate (19) which was carried directly to the next step.