Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2].[O:44]1[CH:48]=[CH:47][C:46]([NH2:49])=[N:45]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:49][C:46]4[CH:47]=[CH:48][O:44][N:45]=4)(=[O:29])=[O:30])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: Nc1ccon1
Reactant: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A solution of perfluorophenyl 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (398 mg, 0.638 mmol), isoxazol-3-amine (66.0 pdr, 0.894 mmol) and THF (6383 μl) was cooled in an ice-bath for 15 min, then lithium bis (trimethylsilyl)amide (1M in THF) (1596 μl, 1.596 mmol) was added dropwise. After 1.5 h, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (270 mg, 81% yield) as light-yellow solid. m/z [M+H]+=524.0. NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=6.99 Hz, 2 H) 4.01-4.13 (m, 2 H) 6.42 (s, 1 H) 6.82 (d, J=9.68 Hz, 1 H) 6.88 (d, J=9.10 Hz, 1 H) 7.27-7.37 (m, 1 H) 7.43 (d, J=6.94 Hz, 1 H) 7.50-7.67 (m, 4 H) 7.86 (dd, J=8.95, 2.20 Hz, 1 H) 8.24 (d, J=9.59 Hz, 1 H) 8.37 (d, J=2.05 Hz, 1 H) 8.69 (s, 1 H) 11.66 (br. s., 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=1)[CH3:2].CO[CH:13](OC)[CH2:14][NH2:15].C(S(O)(=O)=O)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][O:10][CH:13]([CH2:14][NH2:15])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COC(CN)OC
Reactant: CCc1ccc(CCO)s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(s1)CCOC2CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-ethylthiophen-2-yl)ethanol (1 g, 6.4 mmol, 1.1 eq) and aminoacetaldehyde dimethylacetal (612 mg, 5.83 mmol, 1 eq) was added CF3SO3H (2.7 g, 17.5 mmol, 3 eq) dropwise at 0° C. After stirring at room temperature overnight, the reaction mixture was diluted with water, adjusted pH to ˜8 with Na2CO3, and extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The crude product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:6]=[CH:7]2)[CH:13]=1
Reactant: COc1cccc(I)c1
Reactant: Clc1ccc2cc[nH]c2c1
Product: COc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-methoxybenzene: ESMS m/e: 257.9 (M+H)+.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([O-:54])=[O:53])=[CH:48][CH:47]=1.[Na+]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:46]1([CH3:55])[CH:51]=[CH:50][C:49]([S:52]([S:11][C@H:12]2[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:14](=[O:33])[C@H:13]2[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitrobenzyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIc, 3.25 g, 0.005 mole) in acetone (90 mL) and water (10 mL) was treated at room temperature with silver nitrate (1.06 g, 0.00625 mole), followed by treatment with a solution of sodium p-toluenesulfinate hydrate (0.90 g, 0.050 mole) in acetone (70 mL) - water (10 mL). The slurry was stirred for 1 h at room temperature under darkness. It was then filtered through Celite, which was washed with acetone. The volume of the filterate was reduced in vacuo, and the product was extracted into ether (3×250 mL). The ether phase was dried over magnesium sulfate and concentrated. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the pure title product, XIIId, as a solid (2.053 g, 62%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[O:24][CH3:25].CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH3:25]
Reactant: BrBr
Reactant: COc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(F)(F)F)nc2ccc(-c3oc4ccccc4c3Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-methoxy-2-(trifluoromethyl)quinoline (0.930 g, 2.71 mmol) in HOAc (30 mL) at 0° C. was added KOAc (0.319 g, 3.25 mmol). The reaction was stirred at this temperature for 10 minutes, and then a solution of Br2 (0.154 mL, 2.98 mmol) in HOAc (5 mL) was added dropwise to it over a period of ˜10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was then diluted with H2O (10 mL). The solid that formed was filtered off and washed with excess H2O and hexane. This solid was then recrystallized from EtOAc:hexane to afford the product (0.750 g, 66%) as a solid. Mass spectrum (+ESI, [M+H]+) m/z 422/424. 1H NMR (500 MHz, DMSO-d6): δ 8.95 (s, 1H), 8.65 (d, 1H, J=8.9 Hz), 8.29 (d, 1H, J=8.9 Hz), 7.80 (d, 1H, J=8.1 Hz), 7.66 (d, 1H, J=8.1 Hz), 7.36-7.58 (m, 3H), and 4.26 ppm (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([OH:15])=[CH:13][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.BrCC(OCC)=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(N)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
A solution of ethyl bromoacetate (7.19 ml, 63 mmol) and 4-amino-o-cresol (7.39 g, 60 mmol) in dry acetonitrile (420 ml) was treated at 15° C. with Cs2CO3 (42.03 g, 129 mmol) and stirred at RT for 2 h. Additional ethyl bromoacetate (0.33 ml, 3 mmol) was added and after 4 h, the mixture was filtered, washed with acetonitrile and evaporated. The residue was suspended in CH2Cl2, filtered and evaporated to give 13.34 g (quantitative) of (4-amino-2-methyl-phenoxy)-acetic acid ethyl ester as a green oil, MS: 210 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:35]=[CH:34][C:23]2[O:24][CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[C:28](=[O:29])[C:22]=2[CH:21]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CO>[O:29]=[C:28]1[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[CH2:25][O:24][C:23]2[CH:34]=[CH:35][C:20]([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[CH:21][C:22]1=2
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2COc2ccc(CCN3CCN(c4ccccc4)CC3)cc21
Yield: 31.5 %

Procedure:
A mixture of 6.3 g (0.039 m) of N-phenylpiperazine, 4.32 g (0.013 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1 and 1.79 g (0.013 m) of K2CO3 in 50 ml of MeOH was refluxed overnight. The reaction mixture was poured into water, extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated to give the crude product (6.5 g). Two recrystallizations from absolute ethanol gave 1.63 g (32%) of crystals of 1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-4-phenylpiperazine, m.p. 107°-108° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:15])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH:21]=1.O>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([O:15][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH:21]=2)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCOC[C@@H](O)CC1CCCCC1
Reactant: COC(=O)c1ccc(CI)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCC(CC1CCCCC1)OCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of (S)-3-cyclohexyl-1-butoxy-2-propanol (example 1308D, 1.0 g) in DMF (15 mL) was added NaH (0.184 g of a 60% oil dispersion). After 15 min, the reaction was chilled to 0° C., and 4-iodomethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1308E, 1.54 g) was added. After 45 min, the reaction was poured into water (150 mL), and extracted with EtOAc (2×75 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane to give a colorless oil (1.18 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH3:20])[CH2:8][CH2:9][O:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[Cl:17])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][CH2:9][O:10][C:11]1[C:16]([Cl:17])=[N:15][C:14]([Cl:18])=[N:13][C:12]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CN(CCOc1c(Cl)nc(Cl)nc1Cl)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(CCOc1c(Cl)nc(Cl)nc1N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl-[2-(2,4,6-trichloro-pyrimidin-5-yloxy)-ethyl]-carbamic acid tert-butyl ester (1.50 mmol), morpholine (130 μL, 1.50 mmol) and triethylamine (417 μL, 3.00 mmol) in ethanol (5 mL) was stirred at RT for 1 hour then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording [2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (quantitative). LCMS: RT=3.89 min, [M-CH2CH2NMeBoc+H]+=250/252/254.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:42])([F:41])[F:40])[N:26]=[CH:27][C:28]=2[CH:29]2[CH2:31][CH2:30]2)=[CH:18][C:17]=1[CH3:43])C)(C)(C)C>C(Cl)Cl>[CH:29]1([C:28]2[CH:27]=[N:26][N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][C:39]([F:42])([F:40])[F:41])[C:24]=2[CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[C:17]([CH3:43])[CH:18]=2)[CH2:31][CH2:30]1
Reactant: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1ccc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)cc1C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
HCl/dioxane (4 N, 3.7 mL) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-carbamic acid tert-butyl ester (1.92 g, 3.71 mmol) in methylene chloride (40 mL) at room temperature. After 2 h of stirring, the mixture is concentrated and worked up with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layers are washed with brine and dried over sodium sulfate to provide 1.50 g (97%) of the title compound as an oil. MS m/e 418.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: CON
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Product: CON=Cc1cccc(F)c1
Yield: 94 %

Procedure:
Reaction of 3-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil. (94% yield). HPLC indicated a 88:12 mixture of E- and Z-isomer. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.98 (3H, s, OCH3), 7.03-7.08 (2H, m, aromatics), 7.26-7.36 (2H, m, aromatics), 8.02 (1H, s, CH).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].ClC1C(C(OO)=[O:43])=CC=CC=1>C(Cl)Cl>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:15]2)=[O:43])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)CC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 44 %

Procedure:
The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 3 (0.15 g, 0.0003 mol) and m chloroperbenzoic acid (0.062 g, 0.0003 mol) in methylene chloride (3 ml). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.070 g (45%) of the desired product as an oil.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: NCCS
Reactant: OCc1cncs1
Agent: Br
Agent: Cl
Product: NCCSCc1cncs1

Procedure:
The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteamine hydrochloride (1.99 g.) in aqueous hydrobromic acid by the method described in Example 1(i)(a) gave 5-((2-aminoethyl)thiomethyl)thiazole dihydrobromide (4.85 g.) m.p. 191°-4° (from methanol).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 84.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example R-2, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.16 g of the title compound as a solid, mp 221-222° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:38][OH:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:41][C:42]#[N:43]>CN(C)C=O>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:38][O:39][CH2:41][C:42]#[N:43])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCCl
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Potassium carbonate (4.84 g.) was added to a stirred solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.) in N,N-dimethylformamide (22.0 ml.). Chloroacetonitrile (2.64 g.) was added dropwise to the solution under nitrogen atmosphere and stirred at room temperature for 5 hours. After removing the insoluble substance from the resultant mixture by filtration, water (300 ml.) was added to the filtrate and extracted with ethyl acetate (300 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and concentrated in vacuo. The residue was pulverized with a mixture of n-hexane, ethyl acetate and acetone (4:4:1) and then the precipitates were collected by filtration and washed with n-hexane to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-cyanomethoxyiminoacetate (syn isomer, 9.58 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
2-Chloro-8-fluoroquinoline (5.00 g, 27.5 mmol) was dissolved in THF (60 mL) and cooled to −78° C. To this solution was added freshly prepared and titrated lithium diisopropylamide (1M solution in THF, 30 mL, 30 mmol, 1.1 eq) over 5 min. The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (2.3 mL, 41.3 mmol, 1.5 eq.) was added via syringe over 30 seconds (exothermic). After 30 min at −78° C., the reaction was quenched with 50% saturated NH4Cl solution and diluted with EtOAc. The layers were separated and washed with brine, dried over MgSO4, and filtered. The crude reaction mixture was deposited on 30 g of silica gel and passed through a plug of 60 g of silica gel, eluted with 8:2 hexanes:EtOAc. Fractions containing product and a closely (second) eluting regioisomer were collected. The fractions were concentrated and the crude solid was slurried in 140 mL of 9:1 hexanes:EtOAc at reflux for 30 min. After cooling to rt, the solid was filtered and washed with a small amount of cold 9:1 hexanes:EtOAc to afford pure 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (3.1 g, 13.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH2:10][C:11]([CH3:13])=[CH2:12])=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.S(=O)(=O)(O)O.O>[CH3:12][C:11]1([CH3:13])[CH2:10][C:4]2[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][O:1]1
Reactant: C=C(C)Cc1c(O)cccc1CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2c(O)cccc2CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
3-(hydroxymethyl)-2-(2-methylallyl)phenol (Intermediate 169, 360 mg, 2 mmol) was dissolved in ethyl acetate (20 ml), two drops of sulfuric acid were added to the solution that was stirred for 4 hours at room temperature. After this time the reaction was diluted with water (40 ml) and ethyl acetate (40 ml). Phases were separated and the organic layer was dried over Na2SO4 and evaporated in vacuo to afford a colourless oil. The oil was triturated with cyclohexane to obtain a white solid that was filtered, washed with cyclohexane (20 ml) and dried in vacuo to afford the title compound (130 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: CCCc1c(O)ccc(C(=O)NC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OCC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 10 (418 mg, 2.0 mmol), the compound of Example 11 (895 mg, 2.0 mmol), and potassium carbonate (552 mg, 4.0 mmol) were added to 3.0 ml DMF, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, and dried over magnesium sulfate. Evaporation of the volatiles afforded a crude oil which was purified by chromatography using 50/50 ethyl acetate/hexane as eluant to give the product as a white solid.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([Cl:33])=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:23]=2)[O:7][C@@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:33][C:21]1[S:20][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:34][OH:35])[O:7]2)=[CH:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)sc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a suspension of acetate 19 (1.37 g, 2.41 mmol) in MeOH (20 mL) was added NaOMe (25 wt % in MeOH, 0.3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 20 (604 mg, 63%).