Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]1[O:23][C:22]2[CH:21]=[CH:20][C:18]([O-:19])=[CH:17][C:16]=2[O:15]1.[Na+]>CS(C)=O.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:19][C:18]2[CH:20]=[CH:21][C:22]3[O:23][CH2:14][O:15][C:16]=3[CH:17]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(F)cccc1F
Reactant: [O-]c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Ethyl 2,6-difluorobenzoate (558 mg, 3.0 mmol) was added to dry sodium 3,4-methylenedioxyphenoxide (3.0 mmol, prepared as described in part A) in DMSO followed by addition of dry DMSO (2 ml). The reaction mixture was warmed to 50° C. forming a solution which turned from brown to green upon further heating. After 90 min., the reaction was cooled to 25° C., diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic extract was washed with water (2×7 ml) and brine (7 ml), dried (MgSO4) and concentrated to give a light yellow oil. The product was purified by flash chromatography on SiO2 (5-20% EtOAc/hexane) yielding 532 mg of ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate as a colorless oil (58% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(F)cccc1F
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1F
Yield: 83.2 %

Procedure:
2,6-Difluorophenol (8.6 g, 66 mmol) was treated with tert-butylchlorodimethylsilane (17.4 g, 0.12 mol) and imidazole (13.1 g, 0.19 mol) by the method in Example 1 to give 13.41 g (83%) of tert-butyldimethylsilyl 2,6-difluorophenyl ether.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.[CH3:15][O+:16]([CH3:18])C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2C(=O)[CH2:47][CH2:46][CH2:45][C:44]=2[OH:50])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2[C:44](=[O:50])[CH2:45][CH2:46][CH2:47][C:15]=2[O:16][CH3:18])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:40])([F:42])[F:41])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1

Procedure:
N,N-Diisopropylethylamine (450 μL, 2.59 mmol) and trimethyloxonium tetrafluoroborate (331 mg, 2.24 mmol) are added to a mixture of 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 44, 500 mg, 1.12 mmol) in dichloromethane (4.0 mL), and the mixture is stirred at room temperature for 20 min Dichloromethane (20 mL) is added, and the phases are separated. The organic layer is washed three times with water and concentrated under reduced pressure. Yield: 567 mg; ESI mass spectrum [M+H]+=462; Retention time HPLC: 1.09 min (Z018_S04).
Reaction SMILES: O.[CH:2]1[C:7](N=C=S)=[CH:6][C:5]2[C:11]([O:13][C:14]3([C:24]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=4[O:22][C:16]4[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]3=4)[C:4]=2[CH:3]=1)=[O:12]>O1CCCC1>[CH:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([C:14]2[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[O:22][C:23]3[C:24]=2[CH:25]=[CH:26][C:27]([CH:28]=3)=[O:29])[CH:3]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 1.05 h

Procedure:
A PNA or PNA derivative having a single free NH2 such as H2N-GCAT-COOH is dissolved in tetrahydrofuran:water to provide a solution that is 0.1 M in PNA and to this is added fluorescein isothiocyanate to give a solution which is 0.1-1.0 M in fluorescein isothiocyanate. The solution is. stirred for 0.1-2 hours, then evaporated to a solid and purified by preparative HPLC.
Reaction SMILES: OO.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][N:11]=[N+:12]=[N-:13])=[CH:6][CH:5]=1.C1(=O)OC(=[O:18])C=C1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[N+:9]([O-:18])[CH:8]=1)=[N+:12]=[N-:13]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccc(CN=[N+]=[N-])cn1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 756.4 %

Procedure:
After adding 30% aqueous hydrogen peroxide (7.5 ml, 6.6 mmol) dropwise to a solution of (6-methyl-3-pyridyl)methyl azide (8.9 g, 6.0 mmol) and maleic anhydride (6.5 g, 6.6 mmol) in methylene chloride (90 ml) over a period of 5 minutes while cooling on ice, the mixture was stirred at room temperature for 16 hours. Maleic anhydride (3.25 g) and 30% aqueous hydrogen peroxide (3.75 ml) were added in a similar manner while cooling on ice, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogencarbonate (100 ml) was added to the reaction mixture, NaHCO3 was further added to be basic, and extraction was performed with methylene chloride. The extract was washed with a brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off to yield crude 5-(azidomethyl)-2-methyl-1-pyridiniumolate (7.45 g). This was used without further purification for the following reaction.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C/C=C\COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC/C=C/COCc1ccccc1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
3.9 g of (Z)-4-benzyloxy-2-butenal was dissolved in 60 ml of ethanol, and 850 mg of sodium borohydride was added thereto under stirring at 0° C. The mixture was stirred at 0° C. for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate solution was washed sequentially with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure (2.0 mmHg, 142° C.) to obtain 2.2 g of (E)-4-benzyloxy-2-buten-1-ol as colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 120 °C

Procedure:
A mixture of 34.5 g of N-(3-bromophenyl)-6-nitro4-quinazolinamine and 16.8 g of iron powder in 150 mL of ethanol and 150 mL of glacial acetic acid was heated in an oil bath at 120° C. for 2 hours. After filtration of the solid, solid sodium carbonate was added to the filtrate giving a solid. This was filtered, and the solid was extracted with methanol. The extracts were treated with charcoal and evaporated to a solid. After washing the solid with ether 27.5 g of N-(3-bromophenyl)-4,6-quinazolindiamine was obtained: mass spectrum (m/e): 315.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([CH:7](O)[CH3:8])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:10][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][CH2:8][O:30][N:31]2[C:35](=[O:36])[C:34]3[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]2=[O:41])[CH2:4][O:3]1
Reactant: CC(O)C1COC(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(CCON2C(=O)c3ccccc3C2=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:15])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O.CCOCC>[C:9]1([CH2:8][CH2:7][C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CNC(=O)CCc1ccccc1
Yield: 85.2 %

Procedure:
Glycine (1.5 g, 20 mmol) and hydrocinnamoyl chloride (3.37 g, 22 mmol) were reacted in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 5 Part A. The crude product was extracted into chloroform, dried (MgSO4) and freed of solvent in vacuo leaving a near white solid (3.53 g, 85%). This was recrystallized from EtOAc (13 ml) to give title compound (2.66 g, 64%) m.p. 112°-114° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH2:11][C:3]=12.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:13][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:3]2[CH2:11][C:10]([CH3:12])=[N:9]1
Reactant: OB(O)c1ccccc1
Reactant: CC1=NN(C)c2ncnc(Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=NN(C)c2ncnc(-c3ccccc3)c2C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
The 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g), phenyl boronic acid (682 mg) and potassium carbonate (771 mg) were dissolved in toluene (15 mL) and water (1.5 mL). After the reaction mixture was degassed with nitrogen for 30 minute, Pd(PPh3)4 (323 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using MeOH/CHCl3 (0.8:9.2) as eluent to afford 1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (500 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.89 (s, 3H), 3.37 (s, 3H), 3.52 (s, 2H), 7.47-7.57 (m, 5H), 8.60 (s, 1H).
Reaction SMILES: [C:1]1([CH2:15][OH:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH:15]=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2cc3ccccc3cc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2cc3ccccc3cc12
Yield: 67.9 %

Procedure:
To a 2 L round bottom flask equipped with condenser and magnetic stirring bar was added (1-anthryl)methanol (21.0 g, 0.10 mol), CH2Cl2 (1200 mL) and pyridinium chlorochromate (Aldrich, 32.33 g, 0.15 mol). The mixture was then refluxed for 5 h. The reaction was cooled and then filtered through 400 g plug of silica gel using PhCH3 as eluting solvent. The first 1 L of solution was collected and concentrated to give 16 g of crude product. This material was purified by preparative HPLC using PhCH3 as eluting solvent. The solvent was removed and the pure material recrystallized from PhCH3 /hexane to give 14.0 g (67%) of 1-anthracenecarbaldehyde mp 130°-131.5°, (C, H), (lit. mp 126.5°-127.5°, P. H. Gore J. Chem. Soc. 1616 (1959)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9].CN(C)C1C=CC=CC=1.[Br:31][CH2:32][C:33](Br)=[O:34].[Cl-].[NH4+]>ClCCl>[Br:31][CH2:32][C:33]([NH:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9])=[O:34]
Reactant: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1N
Reactant: O=C(Br)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CSc1cc(C)nc(SCCO[Si](C)(C)C(C)(C)C)c1NC(=O)CBr
Yield: 78 %

Procedure:
To a solution of 3-amino-2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthiopyridine (synthesized by the method disclosed in Example 30 in WO96/26925) (1.50 g, 4.35 mmol) in dichloromethane (30 ml) were added N,N-dimethylaniline (0.63 g, 5.22 mmol) and bromoacetyl bromide (1.05 g, 5.22 mmol) with ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was mixed with a saturated ammonium chloride solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 100 g, developing solvent; hexane:ethyl acetate=3:1) to provide 1.57 g (yield 78%) of 2-bromo-N-[2-(2-tert-butyldimethylsilyloxyethylthio)-6-methyl-4-methylthio-3-pyridyl]acetamide as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].C1COCC1.[CH3:26][NH2:27]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:27][CH3:26])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.10 g, 3732 μmol, see Example 2) was dissolved in 2M methanamine in THF (9331 μL, 18661 μmol). The resulting mixture was stirred at 60° C. for 16 hours and then diluted with 100 mL of EtOAc. The resulting mixture was added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 20 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4 and concentrated in vacuo to give the title compound (131 mg) as a white solid after purification via preparatory LC. MS m/e=280 (M+H)+. Calculated for C14H14ClNO3 279.07.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.Cl[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([Cl:23])[CH:14]=1)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Cl:23][C:15]1[CH:14]=[C:13]([S:10]([NH:2][C:3]2[S:4][C:5]([Cl:8])=[CH:6][N:7]=2)(=[O:12])=[O:11])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of 2-amino-5-chlorothiazole hydrochloride (2.62 g, 15.3 mmol, 3 eq) in pyridine (10 ml) was added methyl 4-(chlorosulfonyl)-2-chlorobenzoate (2.28 g, 5.1 mmol, 1 eq) portionwise and the reaction mixture stirred at room temperature for 1 hour. The solution was added to 6M HCl (40 ml) and the resultant precipitate collected by filtration. The crude material was triturated with t-butylmethyl ether to yield the title compound (410 mg, 1.1 mmol, 22%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4].CN(C=O)C.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][CH3:42])[CH:32]=1)=[O:30]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][C:33]=3[O:41][CH3:42])(=[O:39])=[O:38])[C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(-c3ccccn3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.2 g of sodium hydride as a 60% dispersion in oil is added to a mixture of 1 g of 5-ethoxy-1,3-dihydro-3-(pyrid-2-yl)-2H-benzimidazol-2-one, 25 ml of DMF and 25 ml of THF and the mixture is stirred for 30 minutes at RT. 1 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1 g of the expected product, which is used as such in the next step.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[C:15]3[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH2:29][C:30]([N:6]1[C:7]2[C:3](=[C:2]([F:1])[C:10]([C:11]3[C:15]4[C:16]([NH2:20])=[N:17][CH:18]=[CH:19][C:14]=4[O:13][CH:12]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:31]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nc1nccc2occ(-c3ccc4c(c3F)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 3-(4-fluoro-2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (190 mg, 0.555 mmol), 2,5-difluorophenylacetic acid (100 mg, 0.583 mmol), HATU (232 mg, 0.611 mmol), and Hunig's base (0.388 mL, 2.221 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was stirred at room temperature for 2 hours. HPLC indicated complete consumption of starting material, so the mixture was poured into water (30 mL), the suspension was stirred for a few minutes, and the precipitate was collected by vacuum filtration and dried in the vacuum oven overnight to give 3-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (209 mg, 0.469 mmol, 84% yield) as a light tan solid. LC/MS (ES) m/z=424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.26-3.31 (d, J=8.34 Hz, 2H), 3.97 (s, 3H), 4.38 (t, J=8.46 Hz, 2H), 5.48 (s, 2H), 6.95 (d, J=5.81 Hz, 1H), 7.14-7.35 (m, 4H), 7.87 (d, J=6.06 Hz, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.96 (s, 1H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22](Cl)(=[O:24])=[O:23].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22]([NH2:1])(=[O:24])=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c1=O
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(N)(=O)=O)c2)c1=O

Procedure:
With stirring, 1.6 g (93.8 mmol) of ammonia gas were, at 0° C., introduced into a mixture of 18 g (44.6 mmol) of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]-benzenesulfonylchloride in tetrahydrofuran (THF). Then, at 10° C., ethyl acetate was added and the mixture was acidified with 1N hydrochloric acid. The phases were separated and the aqueous phase was extracted, and the combined organic phases were then washed, dried and the solvent was removed. Customary purification methods gave 14.4 g (82.4% of theory) of the title compound (m.p.: 257-258° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([CH3:10])=O.[NH2:11][O:12][CH:13]1[CH2:16][N:15]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>C(O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]2[CH2:16][CH:13]([O:12]/[N:11]=[C:8](\[CH3:10])/[CH2:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:14]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NOC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)Cc1ncccn1
Solvent: CCO
Product: C/C(Cc1ncccn1)=N\OC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 100.7 %

Procedure:
A solution of 1-pyrimidin-2-ylacetone (27 mg, 0.2 mmol; which may be prepared as described in Step 1) and 3-(aminooxy)-1-(diphenylmethyl)azetidine (51 mg, 0.2 mmol; which may be prepared as described in Step 3) in ethanol (2 mL) under nitrogen was stirred at 80° C. overnight. The crude mixture was concentrated to dryness to give the title compound (75 mg, quantitative) as a brown oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([C:20]([NH:22]C(=O)OCC)=S)[OH:19])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C([O-])(=[O:30])C>>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]([N:18]([OH:19])[C:20]([NH2:22])=[O:30])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)NC(=S)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)[O-]
Product: CC(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N(O)C(N)=O

Procedure:
[[[1-[3,5-bis (1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]hydroxyamino]-thioxomethyl]carbamic acid, ethyl ester, acetate;
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)#[N:3].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[ClH:1].[CH2:15]([S:22][C:2]([CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[NH:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(CC#N)o1
Reactant: SCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CC(=N)SCc2ccccc2)o1

Procedure:
Gaseous hydrogen chloride is passed for 30 minutes at 10° C. through a solution of 94.5 g (0.53 M) of ethyl 5-cyanomethylfuran-2-carboxylate and 61.9 ml (0.53 M) of benzyl mercaptan in 2000 ml of diethyl ether.