Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([OH:24])=O.O.[NH2:39][NH2:40]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:24]
Reactant: NN
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid from above (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (17 mg, 41%). LC-MS (M+H=483, obsd.=438).
Reaction SMILES: C[Si](C)(C)CC[O:5]C[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>O.C(#N)C>[NH4+:7].[OH-:5].[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][C:23]#[N:24])[CH:20]=2)=[N:14][CH:13]=1
Reactant: CCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 147.6 %

Procedure:
Into a 500 mL round bottom flask fitted with stir bar, condenser and nitrogen inlet was charged acetonitrile (58 mL), water (5.0 mL), 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile (2nd peak from chiral separation in step 2, 3.50 g, 8.24 mmol), and lithium tetrafluoroborate (7.88 g, 82.4 mmol). The mixture was warmed to reflux overnight. To the reaction mixture was charged 7.2 M of ammonium hydroxide in water (4.3 mL, 31 mmol) in portions over a period of 5 minutes at room temperature adjusting pH to 9-10. The resulting reaction mixture was stirred for 2 hours at room temperature. Solid was removed by filtration and the filtrate was purified on RP-HPLC (XBridge column C18, 30×100 mm 5 μM; with injection volume 5 mL and flow rate 60 mL/min; at a gradient of water and acetonitrile and 0.15% NH4OH) to give desired product (1.79 g, 74%). LCMS calculated for C16H19N6(M+H)+: m/z=295.2. Found: 295.2.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:10]=[CH:9][C:8]=1[F:22])C.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1>C1COCC1>[CH:24]1([NH:31][C:5]([NH:6][C:7]2[CH:12]=[C:11]([B:13]3[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]3)[CH:10]=[CH:9][C:8]=2[F:22])=[O:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCCC1
Reactant: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
Temperature: 60 °C
Yield: 77.9 %

Procedure:
Treat a solution of prop-1-en-2-yl(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.460 g, 1.432 mmol) in THF (5 mL) with cycloheptylamine (0.195 g, 1.719 mmol) followed by a catalytic amount of 1-methylpyrrolidine (0.012 g, 0.143 mmol) and heat at 60° C. for 2 h. Concentrate the mixture to dryness, add MeCN, collect the solid via filtration and dry to afford the title compound (420 mg, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (dd, J=9, 1.7 Hz, 1H), 8.33 (s, 1H), 7.16 (m, 2H), 6.60 (d, J=7.0 Hz, 1H), 3.64 (m, 1H), 1.80 (m, 2H), 1.50 (m, 10H), 1.26 (s, 12H); MS(ESI) m/z: 377.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[C:17]=1[F:26])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(C)C=CC=CC=1.O.C(O)C>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:12]=[CH:11][C:5]([C:4]3[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=[CH:2][CH:3]=3)=[CH:4][CH:3]=2)=[C:18]([F:25])[C:17]=1[F:26])[CH3:14]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
Ethyl 4-iodobenzoate (1) (25.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were added to a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction solution had been cooled to 25° C., it was poured into water (500 ml) and toluene (500 ml), and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was further purified by recrystallization from ethanol and dried to give ethyl 4-ethoxy-2,3-difluoro-4′-biphenylbenzoate (3) (18.8 g). The yield based on the compound (1) was 67.9%.
Reaction SMILES: C1(O)C2C(=CC=CC=2)C=CC=1.[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=O.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.C(N(CC)CC)C>[CH3:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[OH:12]
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: COC(=O)Cl
Agent: Oc1cccc2ccccc12
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1O
Yield: 80 %

Procedure:
1-naphthol (5) was heated with twice its weight of KHCO3 at 200° C. for 5 hours (stainless steel bomb) whereby 1-hydroxy-2-naphthoic acid (9) was obtained in a yield of 60%. 1-Hydroxy-2-naphthoic acid (9) was treated with methyl chloroformate and triethylamine in THF, followed by sodium borohydride reduction, whereby 2-methyl-naphthol (I) was produced in a yield of 80%.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)[N:3]=[CH:2]1.ClCCCl.[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][N:33]([C:17]2[CH:16]=[C:11]3[C:12]4[C:7]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[CH2:19][N:18]=2)=[C:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[CH:15]=[CH:14][CH:13]=4)[CH:34]=1
Reactant: COCc1c[nH]cn1
Reactant: O=C1C=C2c3cccc(-c4cscn4)c3CCN2C(=O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4-c4cscn4)C3=C2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
Example 101. To a stirred solution of 9-(thiazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (160 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) POCl3 (0.096 mL, 1.03 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (4 mL), 4-(methoxymethyl)-1H-imidazole (172 mg, 1.53 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: Reprosil 70 NH2, 5 μm, 250×30 mm, Dr. Maisch; eluent: 14% MeOH/CO2 for 1 min, then from 14% MeOH/CO2 to 19% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) to yield the title compound as white powder (27 mg). UPLC-MS: MS 406.2 (M+H+); UPLC rt 0.78 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=5.9 Hz, 2 H), 3.42 (s, 3 H), 3.85 (t, J=6.1 Hz, 2 H), 4.39 (br. s., 2 H), 4.44 (s, 2 H), 6.61 (s, 1 H), 7.37-7.50 (m, 3 H), 7.68 (d, J=7.8 Hz, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 8.04 (s, 1 H), 8.95 (s, 1 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[O:14][CH3:15])([CH3:3])[CH3:2].[ClH:16]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:14][CH3:15])([CH3:3])[CH3:2].[ClH:16]
Reactant: COc1cc(NC(C)=O)ccc1C(C)C
Agent: Cl
Product: COc1cc(N)ccc1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Isopropyl-3-methoxy-phenyl)-acetamide (14.5 g, 69.9 mmol) in 200 ml 6 N HCl was heated to 95° C. for 3.0 hours. The reaction mixture was cooled to room temperature, and allowed to sit for 72 hours at room temperature, during which time crystals formed. The reaction mixture was filtered, and the crystals were washed 1 N HCl and dried under vacuum to give 4-Isopropyl-3-methoxy-phenylamine as an HCl salt (7.6 g, 60% ).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.C(=O)=O.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.C(O)CO.O>[CH3:24][S:25]([O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2ncsc2c1
Agent: O=C=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc2ncsc2c1

Procedure:
1,3-benzothiazol-6-ylmethanol (1.56 g, 0.00944 mol) and N,N-diisopropylethylamine (2.47 mL, 0.0142 mol) were stirred in methylene chloride (16 mL). The reaction mixture was cooled in an ethylene glycol/water (4/1)/dry ice bath. To the solution was added dropwise a solution of methanesulfonyl chloride (1.10 mL, 0.0142 mol) in DCM (2 mL). After 30 min the reaction mixture was quenched by adding water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in the next step without purification. LCMC: (M+H)+=244.2.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[NH:5]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7].C1(OC(=N)OC(=N)O1)=N>>[NH:5]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[NH:8][C:6]1=[O:7].[N:1]#[C:2][OH:3]
Reactant: NC(N)=O
Agent: N=c1oc(=N)oc(=N)o1
Agent: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Product: N#CO

Procedure:
under conditions sufficient to prepare the urea condensation mixture of cyanuric acid and cyamelide. The urea is first heated to produce isocyanuric acid and/or cyanic acid then reacted with urea to form biuret then further heated to form a mixture of cyanuric acid and cymelide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)Nc1cc(N)cc(Br)c1
Temperature: 80 °C

Procedure:
N-(3-bromo-5-nitrophenyl)acetamide (4 g, 15.44 mmol) was dissolved in ethanol (154 mL) and saturated NH4Cl(aq) (2 mL). Iron (2.59 g, 46.3 mmol) was added to the solution the reaction mixture was heated to 80° C. for 30 minutes. Upon completion, the reaction was cooled to room temperature and filtered through a short pad of silica gel (ethyl acetate wash). The organic was dried over sodium sulfate, filtered, and concentrated under reduced pressure. N-(3-amino-5-bromophenyl)acetamide was isolated as a beige foam (3.25 g, 14.19 mmol, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Yield: 85.6 %

Procedure:
The product from Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl2 following the procedure from Example 5I giving the title compound as a white solid (1.42 g, 86%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.I[C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: Oc1cccnc1I
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccnc1C1=CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 2-iodo-3-hydroxypyridine (Aldrich, 0.177 g, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].C=C=O>>[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: C=C=O
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
This invention pertains to a process for the preparation of trifluoromethanesulfonic acid anhydride (triflic anhydride) by the disproportionation of a mixed anhydride comprising a trifluoromethane-sulfonyl acyl residue and a carboxyl residue. More particularly, this invention pertains to a process for the preparation of trifluoromethane-sulfonic acid anhydride by the steps of (1) forming a mixed anhydride comprising a trifluoromethanesulfonyl acyl residue and a carboxyl residue by contacting trifluoromethanesulfonic acid or a derivative thereof with a carboxyl compound selected from ketene, dialkyl ketenes, carboxylic acids, and derivatives of carboxylic acids and (2) subjecting the mixed anhydride to reactive distillation wherein the mixed anhydride undergoes disproportionation to produce triflic anhydride and a higher boiling carboxylic acid anhydride.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:14](=O)[CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].N.O>C(C(C)=O)C.C(O)C>[C:22]([C:19]1[CH:18]=[C:13]([C:14]2[N:1]=[C:2]3[N:6]([CH:15]=2)[CH2:5][CH2:4][S:3]3)[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:20]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: NC1=NCCS1
Agent: N
Solvent: CCO
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
In 300 ml of methyl ethyl ketone was dissolved 10.2 g of 2-amino-2-thiazoline and after adding 32.7 g of 3,5-di-tert-butyl-4-hydroxyphenacyl bromide was added portionwise to the solution followed by stirring for 30 minutes at room temperature, the resultant mixture was refluxed for one hour. Then, the solvent was distilled off under reduced pressure, the crystals thus formed were dissolved in 200 ml of ethanol, and the solution was refluxed for 4 hours. The reaction mixture was basified with the addition of aqueous ammonia and then 200 ml of water was added to the reaction mixture to precipitate crude crystals, which were recovered by filtration and recrystallized from ethanol to provide 23.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]\[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (intermediate E1.1) (13.2 g, 52.2 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (6.96 g, 57.4 mmol) in tetrahydrofuran (104 ml) was added at 23° C. titanium(IV) ethoxide (21.4 g, 19.5 ml, 93.9 mmol). The yellow solution was stirred at 70° C. for 3 hours. The cooled reaction mixture was poured into ice water, diluted with ethyl acetate and filtered through a pad of Dicalite. The organic layer was separated and washed with brine and then dried over Na2SO4. Removal of the solvent in vacuum left a yellow oil (18.25 g), which was purified by silica column chromatography 200 g, SiO2 with dichloromethane/heptane 1:1 to give (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (14.49 g, 40.7 mmol, 78.0% yield) as a yellow oil. MS (ISP): m/z=355.9 [M+H]+ and 357.9 [M+2+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:10][C:8]1([CH3:11])[O:7][CH2:6][C:5]2[S:12][C:2]([NH:1][C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])=[C:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:4]=2[CH2:9]1
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)Nc2ccccc2)sc2c1CC(C)(C)OC2
Yield: 30.6 %

Procedure:
To a solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.100 g, 0.353 mmol, 1 eq) in dry tetrahyrofuran (5 mL) under argon was added phenyl isothiocyanate (0.05 mL, 0.388 mmol, 1.1 eq). The mixture was heated at reflux for 16 hours. The solvent was evaporated in vacuo. Purification by reverse-phase chromatography (0-100% CH3CN: Water ramp over 20 min) afforded the desired product tert-butyl 5,5-dimethyl-2-(3-phenylthioureido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate as a yellow solid (0.045 g, 0.108 mmol, 30% yield). 1H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 11.05 (s, 1H), 7.50 (d, J=7.6, 2H), 7.42 (t, J=7.9, 2H), 7.26 (t, J=7.3, 1H), 4.61 (s, 2H), 2.65 (s, 2H), 1.53 (s, 9H), 1.23 (s, 6H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:15][NH2:16]>ClCCl>[OH:14][C:8]1[CH:7]=[CH:6][C:5]([S:2](=[O:4])(=[O:3])[NH:16][CH3:15])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml dichloromethane at RT was added dropwise 317 mmol methylamine (8 M solution in ethanol) and the mixture was allowed to stir at RT for 1 h. The mixture was then concentrated in vacuo. The residue was suspended in 1 M aq NaOH solution and extracted twice with ether. The aqueous phase was acidified with 5 M aq HCl, saturated with NaCl, and extracted 3 times with THF. The combined THF extracts were washed twice with saturated aqueous NaCl solution and dried with Na2SO4. Evaporation in vacuo yielded the title compound. MS (m/e): 249.0 (M+NH4+, 100%), 231.9 (M+H+, 63%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH3:33][O-:34].[Na+]>>[CH3:33][O:34][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:32][CH2:31][C:14]2([C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cnccc1Cl)CC2
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccncc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 194 from 8-(4-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in 199) and sodium methoxide. Off-white solid. MS (ESI): 486.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl)([O-:24])=[O:23]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(Cc3cccc([N+](=O)[O-])c3)c3ncccc23)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1 (35 mg, 0.14 mmole) was dissolved in 15 mL of DMF and sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added in small portion to the reaction mixture. After stirring for 30 minutes, m-nitro-benzyl chloride (30 mg, 0.14 mmole) was added to the reaction mixture and was stirred for 2 hours. The reaction mixture was poured into 50 mL of ice water and was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate followed by saturated potassium bisulfate and then brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield 42 mg (71%) of the titled compound as a white solid. MS(ESI) [M+H+]+=390.1.