Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]=[C:6]([CH2:12][C:13]#[N:14])[NH:7]2.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:10]1[CH:11]=[C:2]([Cl:1])[C:3]2[C:4]([NH:5]/[C:6](/[NH:7][C:8]=2[CH:9]=1)=[C:12](\[C:26]([C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:27])/[C:13]#[N:14])=[O:15]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: N#CCc1nc(=O)c2c(Cl)cccc2[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2c(Cl)cccc2N1
Yield: 27.2 %

Procedure:
To solution of 2-(5-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (26.4 mg, 120 μmol) and triethylamine (18.4 μL, 132 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (18.5 μL, 132 μmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin B (3) (12.8 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dd, J1=7.5 Hz, J2=1.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.55 (dd. J1=8.2 Hz, J2=1.9 Hz, 1H), 7.68-7.79 (m, 3H). 13C NMR (500 MHz, DMSO-d6) δ ppm 71.69, 114.6, 117.63, 118.45, 127.65, 128.1, 129.2, 129.65, 130.49, 133.35, 134.8, 135.47, 138.2, 154.81, 156.48, 188.71. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9582.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][CH3:4].Cl[C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][N:8]=1>O>[I:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:5][CH2:2][CH2:3][CH3:4])[CH:12]=1
Reactant: CCCO
Reactant: Clc1cc(I)ccn1
Agent: [Na]
Solvent: O
Product: CCCOc1cc(I)ccn1
Reaction time: 0.75 h

Procedure:
0.58 g (25 mmol) sodium are carefully added to 40 mL n-propanol in several portions. The mixture is stirred for 45 min. After that time, 6.0 g (25 mmol) 2-chloro-4-iodo-pyridine are slowly added to the mixture. The mixture is stirred at reflux for 3 h. Subsequently, water is added and the solvent is removed in vacuo. The residue is taken up in 20 mL DMF/MeOH, filtrated and the filtrate is purified by RP-HPLC (MeOH/H2O/NH3).
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=3[C:21]#[N:22])[CH2:7][CH2:6]2)[O:4]C1C.Cl.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CCOCC>[C:21]([C:12]1[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1)#[N:22]
Reactant: CC1COC2(CCN(c3ccc(C(F)(F)F)cc3C#N)CC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 24 (1.70 g, 5.20 mmol) in ether (20 mL) was treated with 6N aqueous HCl (50 mL). The mixture was stirred at room temperature (20 min). The reaction mixture was neutralized with sodium carbonate solution and solid sodium hydroxide. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (25).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)O)ccc21
Yield: 82.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide (97 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 1-amino-2-methyl-propan-2-ol (24 mg), HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.18 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.60 (s, 1H), 3.64 (s, 3H), 3.29 (d, 2H), 1.14 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:6][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:12])[N:1]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(C)cccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(C)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A stirred mixture of methyl 2-amino-6-methylbenzoate (1.50 g, 9.08 mM) and dimethyl acetylenedicarboxylate (1.40 g, 9.82 mM) in t-butanol (20 mL) was refluxed fpr 18 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and potassium t-butoxide (1.10 g, 9.82 mM) was added in one portion whereupon a precipitate formed. After refluxing this mixture for 1.5 hr, it was cooled to room temperature and filtered to separate the solids. The solids were dissolved in water and the resulting solution acidified with 1N H2SO4 to form a precipitate. The mixture was filtered and the collected solids were washed with water and dried to give the title compound (1.66 g, 66.4%) as a tan solid. An analytical sample of this material was obtained by recrystallization of a portion from ethyl acetate/hexane to give off white crystals, mp 167°-168° C.; MS(CI): 276 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][N:3]=1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(CCN2C(=O)c3ccccc3C2=O)ccn1
Solvent: CCO
Product: Cc1cc(CCN)ccn1
Reaction time: 8 h

Procedure:
A solution of 2-[2-(2-methyl-pyridin-4-yl)-ethyl]-isoindole-1,3-dione (2.58 g, 9.69 mmol) in 20 mL of ethanol was heated to reflux for 5 hours. The reaction was allowed to cool and stirred overnight. The resulting slurry was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and extracted several times with 10% aqueous hydrogen chloride solution. The aqueous layers were combined and neutralized with sodium carbonate and extracted with a mixture of chloroform and isopropanol (3:1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the tile compound as a clear colorless oil. MS(ES): m/e (EI*) 137.1 [M+H]
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:7][CH3:8])[CH3:6].[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([O:22]CC)=O)[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].Cl>ClCCl>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:7]([CH2:5][CH3:6])[CH3:8])=[O:22])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: CCNC
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 1.33 h
Yield: 87.2 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) (2.40 ml, 2.47 mmol) was dropwise added at room temperature to a dichloromethane (8 ml) solution of N-ethylmethylamine (146 mg, 2.47 mmol), followed by stirring for 80 minutes. Subsequently, a dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (400 mg, 1.23 mmol) was dropwise added, followed by stirring for 19 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, then the reaction liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (362 mg, 87%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[CH:5]1([S:8](Cl)(=[O:10])=[O:9])[CH2:7][CH2:6]1.[Cl-]>N1C=CC=CC=1>[CH:5]1([S:8]([O:4][CH:2]([CH3:3])[CH3:1])(=[O:10])=[O:9])[CH2:7][CH2:6]1
Reactant: CC(C)O
Reactant: O=S(=O)(Cl)C1CC1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
IPA (11 L) was added to pyridine (1850 g; 1890 mL) at 20° C. with stirring for 1 hour. The solution was cooled to between −10° C. and 2° C. and cyclopropane sulfonic chloride (1100 g) was added dropwise followed by stirring at this temperature for 70 hours. NMR analysis showed 85% of sulfonic chloride was consumed in the reaction. The reaction was cooled to 0° C. and NaOH (312 g) in water (600 mL) was added dropwise. The resultant product was concentrated to dryness and 45° C. and diluted with EtOAc (2750 mL), MTBE (1375 mL). The solution was stirred for 10 minutes and filtered. Heptane (1375 mL) was added, filtered and the filtrate was concentrated to dryness giving 1080 g of product as a red liquid (84% yield). 1H NMR (CDCl3, 400 MHz): δ 4.86 (m, 1H), 2.83 (m, 1H), 1.33 (d, 6H), 0.98-1.10 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li][CH2:13][CH2:14]CC.C(I)C>>[CH2:13]([C:9]1[S:8][C:7]2[CH:11]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[CH:10]=1)[CH3:14]
Reactant: [Li]CCCC
Reactant: COc1ccc2ccsc2c1
Solvent: CCI
Product: CCc1cc2ccc(O)cc2s1
Yield: 90 %

Procedure:
This material was prepared from 6-methoxybenzo[b]thiophene 1a (2.63 g, 16 mmole) by treatment with n-BuLi and ethyl iodide (7.80 g, 50 mmole) in a manner as previously described for example 1b to give a white solid (2.78 g, 90%). 1H NMR (DMSO-d6) δ 7.58 (1H, d, J=8.7 Hz), 7.44 (1H, d, J=2.3 Hz), 7.02 (1H, s), 6.92 (1H, dd, J=2.3, 8.7 Hz), 2.84 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH3:1])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (8 ml) stirred under argon at 0° C., was added n-butyl lithium (“n-BuLi”) (2.5 M in hexane) (0.74 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (made as described in EP 1,731,512) (500 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl iodide (0.14 ml) and the reaction mixture was stirred at −85° C. for 1 hour. More methyl iodide (0.08 ml) was added and the reaction mixture was stirred at −85° C. for a further 30 minutes. Then the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15) to give 4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 7.98-7.92 (m, 1H), 7.58-7.38 (m, 5H) 4.22-4.05 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.58-1.56 (m, 3H), 0.94-0.92 (m, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(Br)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 108.4 %

Procedure:
A solution of 4-bromo-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (5.81 g, 15.2 mmol) in ethanol (100 mL) was treated with 3.0 M sodium hydroxide in water (50.8 mL, 152 mmol) and stirred at 20° C. for 16 h. The reaction mixture was concentrated in vacuo to remove most of the ethanol. The remaining aqueous layer was neutralized with concentrated HCl to pH ˜7 and extracted with ethyl acetate (2×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated to give the desired product (3.74 g, quantitative) which was used without further purification. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 227.0, 228.9.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.Br>CC(O)=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: COc1ccccc1-c1cccc([N+](=O)[O-])c1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccccc2O)c1

Procedure:
2-Methoxy-3'-nitrobiphenyl (9.00 g, 3.9 mmol) was heated at reflux with HOAc (50 mL) and 48% HBr (50 mL) for 8 h. The solution was then concentrated in vacuo, poured into ice-cold H2O (300 mL) and extracted with CH2Cl2. The organic layer was dried, evaporated and recrystallized (50% aq MeOH) to afford 2-hydroxy-3'-nitrobiphenyl as yellow needles; 6.12 g (73%); mp 99.5°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH:14]=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(-c2ccccc2F)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(-c2ccccc2F)ncc1[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-fluoro-phenyl)-4-methyl-5-nitro-pyridine (5.4 g, 23 mmol) in DMF (30 mL) was treated with N,N-dimethylformamide dimethyl acetal (3.6 g, 30 mmol), and the mixture was stirred at 115° C. for 1 h, cooled, and concentrated in vacuo to yield crude {2-[2-(2-fluoro-phenyl)-5-nitro-pyridin-4-yl]-vinyl}-dimethyl-amine as a brown solid. The solid was dissolved in THF (100 mL), and water (100 mL), and then sodium periodate (14.06 g, 66 mmol) was added. The suspension was stirred at room temperature for 24 h. The reaction mixture was filtered, and the filtrate was concentrated, and then diluted with EtOAc. The organic extract washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), and concentrated in vacuo to yield crude title compound as a solid. The crude solid was purified by column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc) to yield 2-(2-fluoro-phenyl)-5-nitro-pyridine-4-carbaldehyde, the title compound as a yellow solid.
Reaction SMILES: O[C:2]1[C:3](=[O:12])[N:4]([CH2:9][CH2:10][CH3:11])[C:5](=[O:8])[NH:6][CH:7]=1.BrN1C(=O)CCC1=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>C(O)C>[CH2:9]([N:4]1[C:3](=[O:12])[C:2]2[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28][C:7]=2[NH:6][C:5]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCn1c(=O)[nH]cc(O)c1=O
Reactant: Nc1ccccc1S
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Product: CCCn1c(=O)[nH]c2c(c1=O)Nc1ccccc1S2
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of the 5-hydroxy-3-propylpyrimidine-2,4(1H,3H)-dione (0.85 g) in ethanol (40 ml), N-bromosuccinimide (0.98 g) was added in portions at room temperature. The mixture was stirred for 30 min. 2-Aminobenzenethiol (0.94 g) was added and the mixture was heated at reflux for one hour. After cooling, the precipitate was collected to give 1,5-dihydro-3-propyl-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (1.20 g, 87% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.[Na]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chicrite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1.O.CN([CH:22]=[O:23])C>>[CH3:6][O:7][C:8]1[C:17]([CH:22]=[O:23])=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)OCCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1C=O)OCCO2
Reaction time: 2 h

Procedure:
3.3 eq. of dry DMF are placed in a three-necked flask and then, using a dropping funnel, 1.3 eq. of phosphorus oxychloride are added at 0° C. After returning to ambient temperature, the compound obtained in Step B (4 g: 20.59 mmol) is dissolved in 6.5 ml of DMF and then added to the previous solution. Heating is carried out for 2 hours at 110° C. After cooling, the mixture is hydrolysed with water and extracted with dichloromethane.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:9]=2[S:8](=[O:22])(=[O:21])[CH:7]=1)C.[OH-].[Li+].Cl>CO>[CH3:20][S:17]([NH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][S:8](=[O:21])(=[O:22])[C:9]=2[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (Example 8g, 0.245 g, 0.680 mmol) in methanol (15 mL) was cooled to 0° C. in an ice-water bath and treated with 2.0 M aqueous lithium hydroxide solution (1.7 mL, 3.40 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The reaction was poured into 0.5 M aqueous hydrochloric acid solution (50 mL) on ice, extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give an orange solid. The crude solid was triturated with diethyl ether to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (0.175 g, 0.526 mmol, 77% yield) as a light orange solid. LC-MS (ESI) calcd for C11H12N2O6S2 332.4, found 333.3 [M+H+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:28]O>C(Cl)Cl>[CH2:37]([O:36][C:34]([NH:26][C@@H:27]([CH2:28][I:25])[C:30]([O:32][CH3:33])=[O:31])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CI)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
A mixture of triphenylphosphine (23.3 g, 0.890 mol) and imidazole (6.0 g, 0.89 mol) in DCM (100 mL) was cooled to 0° C. and iodide (22.6 g, 0.890 mol) was added in small portions over 0.5 h. The cooling bath was removed and the mixture was stirred for 0.5 h. After the mixture was re-cooled to 0° C., a solution of Cbz-L-Ser-OMe 15.0 g, 0.590 mol) in DCM (100 mL) was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature and stirred for 1.5 h. The mixture was filtered and the filtrate was concentrated to remove most of the solvent. MTBE (400 mL) was added to the residue and the mixture was filtered to remove triphenylphosphine oxide. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=50:1 to 10:1) to afford (R)-methyl 2-(benzyloxycarbonylamino)-3-iodopropanoate (12.3 g, 57% yield) as a colorless solid.
Reaction SMILES: O[C:2]1[CH:6]([CH2:7][OH:8])[O:5][C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1.C1(C)C=CC=CC=1.CN(C)C=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(O)(=O)C>[OH:8][CH2:7][CH:6]1[O:5][C:4](=[O:9])[CH:3]=[C:2]1[NH:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: O=C1C=C(O)C(CO)O1
Reactant: NCc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=C(NCc2ccc(Cl)nc2)C(CO)O1
Yield: 22.3 %

Procedure:
905.0 mg (6.95 mmol) of 4-hydroxy-5-hydroxymethylfuran-2(5H)-one (VII-1a) and 991.8 mg (6.95 mmol) of 3-aminomethyl-6-chloropyridine are stirred in the mixture of 100.5 ml of toluene and 10 ml of N,N-dimethylformamide (DMF), and 10 mg of para-toluenesulphonic acid and 0.5 ml of acetic acid are added. With stirring, the entire reaction mixture is then heated at reflux on a water separator for about 18 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm; mobile phase: cyclohexane/acetone=1:1) gives 394.2 mg (22.2% of theory) of 5-hydroxymethyl-4-{[(6-chloropyridin-3-yl)methyl]amino}furan-2(5H)-one.