Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[Na+]>C(O)C.O.[OH-].[K+]>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1
Yield: 46969.8 %

Procedure:
To a mixture of hydroquinone (20.0 g, 0.182 mmol), 2-iodopropane (30.9 g, 0.182 mmol) in ethanol (25 mL) at refluxing was added KOH (88%, 12.2 mg, 0.191 mmol) in water (30 mL) over a period of 60 min. The resulting mixture was refluxed for 3 hours. The mixture was poured into 1N NaOH and extracted with ether (1×). The aqueous layer was acidified with 10% HCl to pH ˜5 and extracted with ether (2×). The combined extracts were washed with brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (1:8) to give the desired product as a brownish liquid (13.01 g, 47.0%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:31])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1ccc(-c2ocnc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=429.03.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]([O:28]CC)=O)[C:9](=[O:24])[C@H:10]([NH:16]C(OC(C)(C)C)=O)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:32](F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:25][C:26](=[O:28])[NH:16][C@H:10]([CH2:11][C:12]([O:14][CH2:15][CH3:32])=[O:13])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](CC(=O)OC)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of Example 255C (50.75 g, 120 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid. The reaction was stirred overnight and then concentrated. Ammonia was added (7 N, methanol, 250 mL) and the solution was warmed to 70° C. for 2 hours. The reaction was concentrated and dichloromethane was added (500 mL). The solution stirred for 10 minutes before the salt was removed by filtration. The solution was then concentrated and purification via flash chromatography (3% 2 N NH3 in methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC(C)C)([CH3:18])[CH3:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CC1(C)[C@H](/C=C2\CCOC2=O)[C@H]1C(=O)O
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Solvent: CCO
Product: CC(C)OC(=O)[C@@H]1[C@@H](/C=C2\CCOC2=O)C1(C)C

Procedure:
Using the procedure of Example 17, 4 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 5 ml of isopropyl N,N'-diisopropylcarbamimidate were reacted to obtain 3.5 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+38.5°±1.5° (c=1% in ethanol).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:7]=1[N+:14]([O-])=O)C>C(O)(=O)C.[Fe]>[C:12]([C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][C:4](=[O:3])[NH:14]2)=[CH:11][CH:10]=1)#[N:13]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)NC(=O)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Iron powder (11.5 g, 205.2 mmol) was added to a saturated solution of ethyl(4-cyano-2-nitrophenyl)acetate (12 g, 51.3 mmol) in hot glacial acetic acid and the reaction mixture was stirred at 100° C. for 2 hours. The mixture was allowed to cool and poured into stirred ice water (1000 ml). The aqueous mixture was extracted with ethyl acetate, the extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The solid residue was recrystallised from ethyl acetate to give 6-cyanooxindole (6.94 g, 85%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34]C)=[O:33])[N:27]=2)[CH:7]=[CH:8][C:9]=1[Cl:10].O>C(O)C>[C:21]([O:20][C:18]([N:14]1[CH2:13][CH:12]([O:25][C:26]2[N:27]=[C:28]([C:32]([OH:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)[CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[O:17][CH2:16][CH2:15]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cccc(OC2CN(C(=O)OC(C)(C)C)CCOC2c2ccc(Cl)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(Oc2cccc(C(=O)O)n2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
2M Aqueous sodium hydroxide solution (1.7 mL) was added to a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-{[6-(methoxycarbonyl)pyridin-2-yl]oxy}-1,4-oxazepane-4-carboxylate (210 mg) in ethanol (5 ml), and the mixture was stirred at room temperature overnight and at 70° C. for 2 hr. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The obtained aqueous layer was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (69 mg).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@H:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]3[C@@H:15]([O:19][CH2:20][CH3:21])[C:16](=[O:18])[O:17][C@@H:8]23)[CH2:4][O:3]1.O>C(O)(=O)C>[OH:6][C@@H:5]([C@H:7]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]2[C@@H:15]([O:19][CH2:20][CH3:21])[C:16](=[O:18])[O:17][C@@H:8]12)[CH2:4][OH:3]
Reactant: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H]1COC(C)(C)O1
Solvent: O
Solvent: CC(=O)O
Product: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H](O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
2.62 g of 48 (8.28 mmol) are introduced into a 100 mL three-necked flask containing 16 mL of water and 16 mL of acetic acid. The medium is stirred for 24 h at RT and then the reaction medium is concentrated under vacuum. The residues are disintegrated with 25 mL of isopropyl ether, filtered and dried under vacuum. 2.15 g of expected product 49 (white solid) are obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[F:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:46]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=4)[C:9]=3[N:45]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: CN(C)C=C1CCCC(c2cccc(C(F)(F)F)c2)C1=O
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3ncc4c(n3)C(c3cccc(C(F)(F)F)c3)CCC4)cc2F)cn1

Procedure:
The title compound was prepared from crude 6-[1-dimethylamino-methylidene]-2-(3-trifluoromethyl-phenyl)-cyclohexanone (172 mg, 0.5 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (134 mg, 0.37 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (106 mg, 61%). MS ISP (m/e): 468.3 [(M+H)+]. mp 207-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCc1ccccc1
Reaction time: 10 h
Yield: 63.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.02 ml (0.016 mol) of 2-phenylethylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. The product was crystallized in hexane/ethyl acetate. There were obtained 3.13 g (64%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-2H-benzo[e]indol-2-one as white crystals with m.p. 89°-90°.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
{4-[4-(2-tert-Butoxycarbonylaminoethoxy)phenyl]butyl}carbamic acid benzyl ester 1 (2.5 g, 5.60 mmol), ethanol (20 mL), and 10% palladium on carbon (1 g), were subject to one atmosphere of hydrogen for 4 h, and then allowed to stand overnight. After stirring under nitrogen purge, the catalyst was removed by filtering the reaction mixture through Celite and rinsing with methylene chloride. Evaporation followed by 2 h under high vacuum afforded the product (1.7 g, 98%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.47 (m, 2H), 1.61 (m, 2H), 1.75 (br s, 2H), 2.56 (t, 2H), 2.71 (t, 2H), 3.51 (m, 2H), 3.99 (t, 2H), 5.07 (br s, 1H), 6.80 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:25][CH:2]([CH3:1])[CH2:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-:34])=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)CC(C)C
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)CC(C)C

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-methyl-1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one (2.40 g, 7.10 mmol) by reaction with m-CPBA (3.9 g) to provide 6-methyl-1-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one followed by reaction with p-toluenesulfonyl chloride (2.0 g, 10.5 mmol) and ammonium hydroxide solution (75 mL) to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one as tan crystals after recrystallization from aqueous methanol, mp 136-138° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][CH2:22][C:6]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:4]1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:26].Cl>C(N(CC)CC)C>[O:20]=[C:19]1[C:9]2[S:8][CH2:7][C:6]3([CH2:22][CH2:23][CH:3]([NH:2][C:25](=[O:26])[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=4)[CH2:4][CH2:5]3)[O:11][C:10]=2[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:21]
Reactant: O=C(Cl)Oc1cccc(C(F)(F)F)c1
Reactant: NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O)Oc1cccc(C(F)(F)F)c1

Procedure:
Compound 108 was synthesized using 4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione hydrochloride, 3-(trifluoromethyl)phenyl chloroformate, triethyl amine to neutralize the hydrochloride and conditions outlined in procedure S. M.p.=198-199° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.08 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.83 (t, J=7.1 Hz, 1H), 7.78 (t, J=7.1 Hz, 1H), 7.66-7.43 (m, 4H), 3.56-3.47 (m, 1H), 3.04 (s, 2H), 2.16-2.05 (m, 2H), 1.94-1.80 (m, 2H), 1.78-1.66 (m, 7H), LCMS: 504 [M+H].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]1[CH2:37][O:36][C:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C@H:20]4[C@H:30]([C:31](=[O:35])[CH2:32]3)[C@:28]3([CH3:29])[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)([CH3:15])[O:13]1>>[CH2:37]1[CH2:12][O:13][C:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C@H:20]4[C@H:30]([C:31](=[O:35])[CH2:32]3)[C@:28]3([CH3:29])[C@H:23]([CH2:24][C@@H:25]5[O:6][C@@H:26]5[CH2:27]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)([CH3:15])[O:36]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Yield: 86.9 %

Procedure:
85%-m-Chloroperoxybenzoic acid (14.74 g) was added to a stirred solution of 20,20-ethylenedioxy-5α-pregn-2-en-11-one (26.0 g) at 20° to 25° during 15 minutes. After 45 minutes the solution was washed with 5% sodium hydrogen carbonate solution (2×300 ml) and water (300 ml). Evaporation of the solvent and crystallisation of the residue from 1% pyridine in methanol (300 ml) gave the title compound (23.6 g) m.p. 159°-160°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCN3CCCC3)C(=O)C3CC3)cc(Cl)c1O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.44 mL, 4.8 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) and the reaction mixture was stirred at 55° C. for 2 h. It was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.280 g, (81.63%); 1H NMR (DMSO-d6): δ 0.71 (bs, 2H, CH2), 0.88 (bs, 2H, CH2), 1.87 (bs, 2H, CH2), 2.01 (bs, 2H, CH2), 2.70 (s, 3H, CH3), 3.00 (bs, 2H, CH2), 3.18 (bs, 2H, CH2), 3.57 (bs, 2H, CH2), 3.70 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.04 (bs, 2H, CH2), 5.38 (s, 2H, CH2), 7.78 (s, 1H, Ar), 7.98 (s, 1H, Ar), 8.19 (s, 1H, Ar). 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14].[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[CH:31])([CH3:18])([CH3:17])[CH3:16]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[C:31][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-1-fluoro-4-(propylsulfonyl)benzene (Intermediate 106; 541 mg; 1.93 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 467 mg; 1.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (49 mg; 0.07 mmol) and TEA (728 μL; 5.2 mmol) was heated at 60° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with a sat. NH4Cl aqueous solution and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=O)[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.CO.[BH4-].[Na+].Cl.[NH3:31]>>[NH2:31][CH:12]([C:11]1[C:2]([OH:1])=[C:3]2[CH:23]=[CH:22][C:21]([CH3:25])([CH3:24])[O:20][C:4]2=[C:5]2[C:10]=1[O:9][C:8](=[O:16])[CH:7]=[C:6]2[CH2:17][CH2:18][CH3:19])[CH2:13][CH3:14]
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(=O)oc2c(C(N)CC)c(O)c3c(c12)OC(C)(C)C=C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
5-Hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (1.0 g, 2.9 mmol, 1.0 eq) was dissolved in 7 N ammonia in methanol (100 mL, 0.7 mol, 241 eq). The mixture was stirred overnight at ambient temperature. Solvent and excess of ammonia were removed under vacuum and the residue re-dissolved in methanol (100 mL). The solution was cooled to 0° C. and sodium borohydride (550 mg, 14.6 mmol, 5.0 eq) added portionwise. The mixture was allowed to warm up room temperature and stirred for 3 h. The mixture was then poured into ice-water and pH adjusted to 8.5 with concentrated hydrochloric acid. The product was extracted into ethyl acetate (3×50 mL). The extracts were combined and washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel column eluted with 5-10% methanol in dichloromethane to yield 612 mg of 24a (61% yield). 1H NMR (CDCl3): 0.97 (t, J=7.5 Hz, 3H), 1.03 (t, J=7.5 Hz, 3H), 1.47 (s, 3H), 1.49 (s, 3H), 1.67 (m, 2H), 1.78 (m, 2H), 2.89 (m, 2H), 4.85 (t, J=7.0 Hz, 1H), 5.52 (d, J=10.0 Hz, 1H), 5.88 (s, 1H), 6.67 (d, J=10.0 Hz, 1H); 13C NMR (DMSO-d6): 10.17, 13.99, 23.54, 26.24, 27.23, 27.31, 37.99, 49.84, 76.35, 96.60, 102.88, 103.95, 107.80, 118.29, 123.55, 150.87, 153.82, 158.66, 160.26, 167.83; IR: 1683 cm−1; MS (ACPI+): 344 (M+1), 327 (M-NH3+1); Anal. Calcd. for C20H25NO4: C 69.95, H 7.34, N 4.08; Found C 69.97, H 7.30, N 4.08.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.[CH:30]([O:33]C(C)C)(C)[CH3:31]>C(OC(=O)C)(=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:30](=[O:33])[CH3:31])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reactant: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of acetic anhydride are addedt o 0.06 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzoisothiazol-3(2H)one 1,1-dioxide, and the mixture is stirred at room temperature for 12 hours. It is then evaporatd to dryness, isopropyl ether is added and the mixture is stirred for 1 hour. It is then filtered and the colourless crystals are dried in vacuo.
Reaction SMILES: [C:1]([C:3](=[CH:9]OCC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:9]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)C(C#N)=CNc1ccc(C(=O)OCC)cc1
Temperature: 150 °C

Procedure:
The mixture of ethyl 2-cyano-3-ethoxyacrylate (28.5 g, 0.168 mol) and 4-aminobenzoic acid ethyl ester (26.5 g, 0.16 mol) was heated at 150° C. for 2 h, detected by HPLC. After cooling to room temperature, the reaction mixture was dried under reduced pressure to give 4-(2-cyano-2-ethoxycarbonyl-vinylamino)-benzoic acid ethyl ester as a grey solid. LC-MS m/e 289 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=O)[O:5][N:4]=[C:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Br)(Br)([Br:15])=O.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Br:15][C:6]1[O:5][N:4]=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]=1[CH3:1]
Reactant: CCOC(=O)C1=NOC(=O)C1C
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1noc(Br)c1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Ethyl 4-methyl-5-oxo-4,5-dihydroisoxazole-3-carboxylate (42.5 g, 248 mmol) and phosphorous oxybromide (199 g, 695 mmol) were stirred together and heated to 80° C. Triethylamine (34.6 mL, 248 mmol) was added dropwise over 15 mins and the reaction mixture was stirred at 80° C. for 3 hours. The resulting mixture was cooled to room temperature. DCM (400 mL) was added and the mixture was poured into ice (˜400 mL) with stirring. 2M NaOH (aq) (1250 mL) was added until pH 7 and the resulting layers were separated. The aqueous layer was extracted with DCM (2×300 mL) and the resulting organic extracts were combined, washed with water (400 mL), sodium thiosulfate (5% w/v solution, 400 mL), water (400 mL) and brine (400 mL). The organics were dried over MgSO4 and charcoal, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane afforded the title compound;