Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>O1CCCC1.CO>[CH:23]1([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:11]([C:8]3[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=3)=[CH:12]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a cooled solution (ice/methanol bath) of 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (4.0 g, 10 mmol) in tetrahydrofuran (80 ml) and methanol (80 ml) was added sodium borohydride portion-wise. The reaction was stirred for a further 20 minutes and then quenched with 1M hydrochloric acid (20 ml). The methanol and tetrahydrofuran were removed in vacuo and dichloromethane (200 ml) and 2M hydrochloric acid (50 ml) were added. The organics were separated and washed with brine (50 ml), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography eluting with 50% (v/v) diethyl ether in heptane to give [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (3.15 g, 8.8 mmol) as a light pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:27][C@H:28]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=452.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline, 3,5-difluorophenyl sulfonylchloride and (R)-1-aminoindane.
Reaction SMILES: CN(C)[C:3]1[C:4]([NH:14][S:15]([C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:13]=1.[CH2:31]([N:33](CC)[CH2:34]C)C.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:33]([C:8]1([CH3:40])[C:7]2[CH:13]=[CH:3][C:4]([NH:14][S:15]([C:18]3[S:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:5][C:6]=2[CH2:12][CH2:11][NH:10][CH2:9]1)[CH3:34]
Reactant: CCN(CC)CC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN(C)c1cc2c(cc1NS(=O)(=O)c1ccc(-c3ccc(Cl)cc3)s1)CCNCC2
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1(C)CNCCc2cc(NS(=O)(=O)c3ccc(-c4ccc(Cl)cc4)s3)ccc21
Reaction time: 0.08 h

Procedure:
To a suspension of the intermediate D10, in 1,2-dichloroethane (1 ml) at room temperature was added triethylamine (0.3, excess) followed by 37% aqueous formaldehyde (0.2, excess). After vigorous stirring for 5 minutes, sodium triacetoxyborohydride (100 mg, excess) was added portionwise over 5 minutes and the resultant solution stirred for a further 2 hours. The reaction was partitioned between water and dichloromethane and the organic phase washed with water, brine and dried over anhydrous MgSO4. The solution was evaporated to dryness affording the title compound E16 as a pale yellow solid (20 mg, 99% ). M-H 477. 1H NMR: δ CDCl3 2.36 (3H, s), 2.44 (6H, s), 2.54 (4H, m), 2.84 (2H, m), 2.91 (2H, m), 6.87 (1H, s), 7.12 (1H, d), 7.33–7.51 (6H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)CC.O>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:14]=[C:13]([C:15]([OH:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:19])[F:18])[CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Temperature: 85 °C

Procedure:
To a mixture of tert-butyl 3-bromo-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (1.2 g, 2.8 mmol) from Example 2.11 step B, (4-methylphenyl)boronic acid (0.5 g, 3.7 mmol), Pd[P(Ph3)]4 (0.16 g, 0.14 mmol), and K2CO3 (1.2 g, 8.5 mmol) under N2 was added 28 mL of degassed n-Propanol/water (4:1). The reaction was heated to 85° C. overnight. The mixture was cooled to room temperature, filtered over celite and concentrated. The crude material was taken up in EtOAc and sat. NaHCO3. The organic layer was extracted (3×) and washed with brine. The final organic layer was dried over Na2SO4, filtered and concentrated to 1.0 g of crude material. Purification using automated flash chromatography (SiO2, 120 g, 0-5% MeOH/DCM) gave, upon concentration, title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH:12]([CH3:14])[CH:11]([O:15][CH3:20])[CH2:10]2)[CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)C(C)O2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC1)CC(OC)C(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 93 mg 8-ethoxycarbonyl-3-hydroxy-2-methyl-1-oxa-8-azaspiro[4.5]decane in 1 ml N,N-dimethylforamide was cooled in ice, 16.7 mg oily sodium hydride (60%) was added, and the resulting mixture was stirred for 30 minutes under ice cooling. Methyl iodide (26.2 μl) was then added, and the mixture was stirred at room temperature for about 24 hours and poured into 5 ml ice water. After extraction with chloroform, the extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was purified by silica gel column chromatography using, as eluent, a mixed solvent of ethyl acetate/n-hexane (1:1 by volume), giving 47 mg 8-ethoxycarbonyl-3-methoxy-2-methyl-1-oxa-8-azaspiro[4.5]decane as oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[S:17](=[O:20])(=[O:19])=[O:18].O1CCOCC1>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([S:17]([OH:20])(=[O:19])=[O:18])[C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: O=S(=O)=O
Reactant: COc1cc(CC(=O)Cl)ccc1OC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(C(=O)Cl)S(=O)(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of 4-acetoxy-3-methoxyphenylacetyl chloride (2.42 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide - dioxane complex (15 mmole) dichloroethane at 0° C. This mixture was stirred at room temperature for eighteen hours and evaporated to afford a yellow gum. νmax. (CHCL3) 1800, 1748 cm-1.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].N(C(C)(CC)C([O-])=O)=NC(C)(CC)[C:33]([O-])=[O:34]>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:24]([OH:29])(=[O:28])[C:25]([CH3:27])=[CH2:26].[C:1]([O:6][CH:7]([CH3:10])[CH2:8][O:34][CH3:33])(=[O:5])[CH3:2]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: C=C(C)C(=O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 51.2 g (0.36 mol) of tert-butyl methacrylate, 21.1 g (0.12 mol) of benzyl methacrylate, 10.3 g (0.12 mol) of methacrylic acid and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in propylene glycol monomethyl ether acetate, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A′1-8 (tert-butyl methacrylate/benzyl methacrylate/methacrylic acid) as a propylene glycol monomethyl ether acetate solution.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:15].C1(C)C=CC=CC=1>O>[CH:4]1[CH:3]=[CH:2][C:1]([C:7]2[C:8]([O-:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=1.[K+:15]
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1-c1ccccc1

Procedure:
A mixture of 526.36 grams (3.092 moles) of 2-phenylphenol, a 45% aqueous solution containing 171.79 grams (3.062 moles) of potassium hydroxide and 2000 ml. of toluene was heated to reflux under nitrogen, with stirring, and the water which passed over was collected in a Dean-Stark trap. When all water had been removed by azeotropic distillation, the mixture was cooled and anhydrous potassium 2-phenylphenate was isolated in nearly quantitative yield by filtration and dried under vacuum at 120° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH-].[NH4+:13]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH2:13])[CH:7]=1
Reactant: ClCCCOc1cccnc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cccnc1
Temperature: 100 °C
Yield: 20.1 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (1.98 g, 11.6 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.70% 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.354 g (20.1%) of an oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A mixture of 7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmole) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.12 mmole) in anhydrous ethanol (0.6 ml) was stirred at 130° C. in a CEM microwave synthesizer for one hour before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (22 mg). LC-MS ESI+: 460 (M+1)+; ESI−: 458 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OCC)=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:26]([NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27].C1(O)C=CC=CC=1>C(OC(O)C)C>[C:26]([NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)NCCCN
Reactant: CCOc1c(-c2ccc(OC(F)(F)F)cc2)cnc2cc(Cl)ccc12
Agent: CCOC(C)O
Solvent: Oc1ccccc1
Product: CC(C)(C)NCCCNc1c(-c2ccc(OC(F)(F)F)cc2)cnc2cc(Cl)ccc12
Yield: 59 %

Procedure:
The first step involves the selective iodination of position 3 of the quinolone nucleus with iodine in the presence of n-butylamine in DMF to give 7-chloro-3-iodoquinolin-4-ol (B) according to the procedure of Hart (Hart, J Med Chem 49, 1101-1112 (2006) incorporated by reference herein), in approximately 59% yield. Without further purification, this material is converted cleanly to the corresponding 4,7-dichloro-3-iodoquinoline (C) in approximately 99% yield according to the procedure of Andersag (Andersag, Chem Ber 81, 499-507, (1948), incorporated by reference herein). The iodoquinoline is then treated in THF with potassium ethoxide in the presence of a catalytic amount of 18-crown-6 ether to give pure 7-chloro-4-ethoxy-3-iodoquinoline (D) in approximately 90% yield as shown, for example, by GC-MS and NMR. In the next step, Suzuki coupling conditions (Mphahlele, J Chem Res 2008, 437-440 (2008) incorporated by reference herein) may be used to react 4-(trifluoromethoxy)-phenyl)boronic acid with the iodoquinoline intermediate (D) in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and 2M potassium carbonate in DMF. The reaction is allowed to proceed at 85° C. to give 7-chloro-4-ethoxy-3-(4-(trifluoromethoxy)phenyl)quinoline (E) in approximately 63% yield as white crystalline material after flash chromatography. Finally, the desired compound (Compound 1) is obtained by reacting the 4-ethoxy quinoline derivative (E) with N-tert-butyl propane 1,3 diamine in the presence of phenol according to the procedure of Andersag supra, in a Carius tube using 2 ethoxyethanol as a solvent at 180° C. for 4 days. The crude product is further purified by flash chromatography followed by crystallization in ethyl acetate to give Compound 1 as transparent white rectangular plates in approximately 59% yield.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[C:19]([CH3:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:26][CH3:27])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[C:19]([CH3:25])[C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:26][CH3:27])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1C
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 4.0 g (10.3 mmol) 4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and washed with ACN. After drying 1.3 g (32%) of the desired product are obtained a solid material.
Reaction SMILES: [F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[OH:14]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10]([CH3:11])=[O:14])=[N:7][C:6]=2[CH:12]=1
Reactant: O=S([O-])OO
Reactant: CSc1nc2cc(F)c(F)cc2s1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1nc2cc(F)c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 240 mg (1.1 mmol) 5,6-difluoro-2-methylsulfanyl-benzothiazole in 8 mL methanol under nitrogen at 0-5° C., was added drop wise a solution of 1.019 g (1.658 mmol) oxone in 4 mL water. The reaction mixture was stirred at 0° C. for 1 h. The suspension was diluted with water (10 mL). The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered, concentrated in vacuo and purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 130 mg (50.6%) of the title compound as white solid. MS(m/e): 234.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[O:36][CH2:35][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2([C:4]3[C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]=4[CH:11]=[CH:2][C:3]=3[O:36][CH2:35]2)[C:13]1=[O:34]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)OCCO3
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (2.1 g, 4.24 mmol) was suspended in methanol (20 mL) and ethyl acetate (80 mL) in a steel bomb and palladium on carbon (20% w/w, 0.45 g) was added. The bomb was pressurized with hydrogen gas (120 psi) and the mixture was stirred at 60° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated with ethyl acetate to afford 2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (0.522 g, 42%) as a colorless solid: mp 259-261° C.; 1H NMR (300 MHz, CD3OD) δ7.27-7.18 (m, 1H), 7.09-6.88 (m, 3H), 6.70 (d, J=8.7 Hz, 1H), 6.39 (d, J=8.7 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.59 (d, J=9.0 Hz, 1H), 4.12-3.90 (m, 4H); 13C NMR (75 MHz, CD3OD) δ 181.0, 157.5, 142.4, 141.3, 139.6, 133.9, 129.8, 124.5, 124.0, 119.0, 117.1, 111.0, 102.9, 82.4, 66.0, 65.2, 59.1; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:14])[CH3:13]>CO.O1CCCC1>[CH2:12]([NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:13]
Reactant: ClCCCOc1cccnc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCCOc1cccnc1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (1.00 g, 5.84 mmol) was dissolved in methanol (50 mL) and added to a 2.0 M solution of ethylamine in tetrahydrofuran (5 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 400 mg (38.1%) of an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:12][C:13](C)([O-])[CH3:14].[K+]>>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:13]#[CH:12]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Product: C#CCn1cnc2ccccc21

Procedure:
The procedure for Example 648 was used, substituting pyrrolidin-2-one for 1H-benzimidazole and sodium hydride for potassium tert-butoxide to provide Example 649. MS (ESI): m/z 124 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:34]1([CH2:40][NH2:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:40]([N:41]1[C:7](=[O:9])[C:6]2[C:5]([CH3:12])=[C:4]([O:13][CH3:14])[S:3][C:2]=2[NH:1][C:19]1=[O:25])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(N)sc(OC)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1sc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution (30 mL) of ethyl 2-amino-5-methoxy-4-methylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1-phenylmethanamine (1.5 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.2 g, 84%).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]2[S:12](=[O:13])[CH:11]=[N:10][C:9]=2[CH:14]=1)([O-:4])=[O:3].Br[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH3:15][C:7]1[C:8]2[S:12](=[O:13])[CH2:11][N:10]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]=2[CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c1S(=O)C=N2
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)N1CS(=O)c2c(C)cc([N+](=O)[O-])cc21

Procedure:
0.69 g (0.03 g atom) of sodium is dissolved in 100 ml of ethanol. 6.3 g (0.03 mol) of 5-nitro-7-methylbenzothiazolone and then 7.17 g (0.03 mol) of diethyl bromomalonate are added to the solution. The reaction mixture is heated under reflux for 8 hours, poured onto ice and the precipitated product is recrystallized from a little ethanol. 4 g 36% of theory) of 7-methyl-5-nitro-3-(bis-ethoxycarbonyl-methyl)-benzothiazolone are obtained in the form of colorless needles of melting point 97° C.