Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:26]([CH3:36])[CH:25]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:36][C:26]1[CH:25]=[C:24]([CH2:23][N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:35]=[CH:34][C:27]=1[O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CSCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)COc1ccc(CN(CCSC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
To a solution of N-[2-(methylthio)ethyl]-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.27 g, 0.864 mmol) in anhydrous MeCN (22 mL) under nitrogen at room temperature was added methyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.248 g, 0.864 mmol) and N,N-diisopropyethylamine (0.15 mL, 0.864 mmol). The resultant mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×30 mL) and water (30 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge), eluted with 1:99–1:33 EtOAc:cyclohexane afforded the title compound as a yellow oil (249 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.O1CCOCC1.[C:22](OC([O-])=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl>C(=O)([O-])O.[Na+].C(#N)C>[C:25]([O:24][C:22]([N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)CNc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
226 mg (1.03 mmol) of DL-[3-(trifluoromethyl)phenyl]-glycine are dissolved in 10 ml of an aqueous 5% sodium hydrogen carbonate solution and treated with 4 ml dioxan. 261 μl (1.13 mmol) of tert.-butyl dicarbonate are added and the mixture stirred overnight at RT. For the workup, the solution is carefully acidified to pH 2 with 1 N hydrochloric acid. The precipitated product is redissolved by addition of acetonitrile, and purified by preparative HPLC (Method 20). 135 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([NH2:6])=[O:5].C[Si](C)(C)[O-:17].[K+].Cl>COCCOCCOC>[OH:17][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C[Si](C)(C)[O-]
Reactant: NC(=O)c1c(F)cccc1C(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: COCCOCCOC
Product: NC(=O)c1c(O)cccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-6-(trifluoromethyl)benzamide (500 mg, 2.41 mmol) in diglyme (8.05 mL) was added potassium trimethylsilanolate (1.08 g, 8.45 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mixture was acidified with 1N HCl (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% solution of LiCl in water, dried with MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by Combiflash™ chromatography (SiO2, 12 g, elution with 20-40% EtOAc/hexanes over 40 min) to afford the title compound as solid.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1([B-](F)(F)F)[CH2:11][CH2:10]1.[K+].Cl[C:18]1[C:23]2[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=2[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH:9]1([C:18]2[C:23]3[O:24][CH:25]([CH3:29])[C:26](=[O:28])[NH:27][C:22]=3[CH:21]=[C:20]([CH:30]=[O:31])[CH:19]=2)[CH2:11][CH2:10]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Temperature: 110 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a suspension of potassium phosphate, tribasic (0.141 g, 0.665 mmol), potassium cyclopropyltrifluoroborate (0.049 g, 0.332 mmol), 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.05 g, 0.222 mmol) in toluene (Ratio: 5.00, 5 mL) and water (Ratio: 1.000, 1.0 mL) was added PdOAc2 (3.73 mg, 0.017 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.016 g, 0.033 mmol) at 23° C. The reaction was stirred at 110° C. for 14 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was reconstituted in DCM (0.25 mL) and purified via medium pressure chromatography using a gradient eluant of 1-5% MeOH:DCM. The appropriate fractions were combined and solvent was removed via rotary evaporation. The late eluting fractions were dried in vacuo to provide the title compound as an off-white solid (0.0283 g, 0.122 mmol, 55.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69-0.81 (m, 2H) 0.91-1.04 (m, 2H) 1.48 (d, J=6.57 Hz, 3H) 2.15 (tt, J=8.49, 5.15 Hz, 1H) 4.85 (q, J=6.82 Hz, 1H) 7.13 (d, J=1.77 Hz, 1H) 7.19 (d, J=1.77 Hz, 1H) 9.79 (s, 1H) 10.89 (s, 1H). ESI-MS: m/z 232.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21].[OH-].[Na+]>ClCCl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:23]([N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Reactant: CCN(CC)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(CCC)C1CCc2cccc(CNC(=O)N(CC)CC)c2C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of dichloromethane under nitrogen. 0.81 g (6 mmol) of diethylcarbamoyl chloride was then added dropwise at a maximum of +25° C. The batch was then stirred for 26 h at room temperature. The batch was then stirred into 160 ml of ice water. The mixture was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was subsequently removed by distillation. The residue was purified by column chromatography. Diisopropyl ether/isopropanol/triethylamine, 80:19.5:0.5, was used as eluent. The final product could be crystallized from petroleum ether 30-50 and was dried at +40° C. in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:9](=[O:10])O[C:7]([C:16]([OH:18])=[O:17])=[C:6]2[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[NH3:31]>CO>[C:16]([C:7]1[NH:31][C:9](=[O:10])[C:11]2[C:5]([C:6]=1[C:19]1[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:13]([O:14][CH3:15])[CH:12]=2)([OH:18])=[O:17]
Reactant: N
Reactant: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Solvent: CO
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of a solution of 6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-isocoumarin-3-carboxylic acid (the compound obtained in Reference Example 50) (2.4 g) in methanol (50 ml) and a 5.5M solution of ammonia in methanol (50 ml) is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure to remove the ammonia, and further the solvent is distilled off. The residue thus obtained is extracted with chloroform, and the extract is washed with water, dried, and concentrated under reduced pressure. To the residue is added a 4M solution of hydrogen chloride in ethyl acetate (30 ml), and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure, and the resulting residue is extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure to give 3-carboxy-6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (1.89 g) as listed in Table 8.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[N:21]=[C:22](N)[S:23][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]2[N:21]=[C:22]([C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:38][CH:37]=3)[S:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc2nc(N)sc2c1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 115 (300 mg, 0.78 mmol), 4-(trifluoromethoxy)benzaldehyde (123 μl, 0.86 mmol), and dibutyltin dichloride (24 mg, 0.08 mmol) in THF was added phenylsilane (106 μl, 0.86 mmol). The mixture was stirred overnight at room temperature under nitrogen, additional aldehyde and phenylsilane were added and the stirring continued until no more starting material was present. The THF was evaporated off the mixture and the residue was purified by flash column chromatography (EtOAc/hexane 30/70, then 50/50), to give the title compound 116 (314 mg, 72%). 1H-NMR (DMSO) δ: 9.77 (s, 1H), 8.89 (t, J=5.7 Hz, 1H); 8.69 (s, 1H); 8.29 (d, J=1.8 Hz, 1H); 7.84 (dd, J=8.4, 1.8 Hz, 1H); 7.50 (m, 5H); 7.37 (d, J=7.8 Hz, 2H); 7.17 (m, 2H); 4.69 (d, J=5.7 Hz, 2H); 1.47 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1>CN(C=O)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=2)[CH:51]=1
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
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: COc1cccc2cc(C(=O)Nc3cccc(-c4cnc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 59.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 59% yield: LCMS (ESI) m/z 423 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-chloroaniline (0.6 g, 4.69 mmol) (Fluka) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-chloro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.45 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47]3)[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:48]2[CH2:47][C:46]3[C:50](=[CH:51][CH:52]=[C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)[CH:45]=3)[CH2:49]2)=[O:9])[CH:10]=1
Reactant: CN1CCN(c2ccc3c(c2)CNC3)CC1
Reactant: O=C(O)c1cc(Cl)c(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc3c(c2)CN(C(=O)c2cc(Cl)c(O)cc2O)C3)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-2,4-dihydroxy-benzoic acid (176 mg, 0.93 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (179 mg, 0.93 mmol) then HOBt (126 mg, 0.93 mmol). After 45 minutes, the solution of the activated acid was added to a mixture 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride (290 mg, 0.78 mmol) and triethylamine (0.28 mL, 2 mmol) then the mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and brine then dried (MgSO4), combined and concentrated. Some insoluble material remained and this was dissolved in 1N hydrochloric acid and methanol then combined with the organic extracts. The pH was adjusted to 14 with solid sodium hydroxide and the mixture allowed to stand overnight. The pH was adjusted to 7 with 1N hydrochloric acid and the resulting precipitate was filtered off then subjected to purification by preparative HPLC to afford the title compound as a red solid. This was converted to its hydrochloride salt by treatment with 4M HCl in dioxane, concentration in vacuo and trituration with ether which gave a brown solid (91 mg, 27%). 1H NMR (DMSO-d6) 11.10 (1H, br. s), 10.50 (1H, br. s), 7.26-7.15 (2H, m), 7.02-6.93 (2H, m), 6.69 (1H, s), 4.72-4.61 (4H, m), 3.78-3.72 (2H, m), 3.45 (2H, br. s), 3.12 (4H, br. s), 2.78 (3H, s). MS: [M+H]+ 386/388.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)ccc1O
Temperature: 90 °C
Yield: 92 %

Procedure:
Vanillin (40 g, 263 mmol) was dissolved in pyridine (120 ml), and malonic acid (41 g, 395 mm ol) was added, followed by piperidine (4 ml). The mixture was heated at 90° C. for 6 hs under N2. After removal of pridine, the residue was poured into water (500 ml), acidified to PH=3 by aq.HCl. The precipitate was collected, washed by water (150 ml×3), and dried to give product (47 g, 91.8%). LC-MS: m/e 193 (M−1)
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])[CH3:3].CC(C)([O-])C.[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[CH3:3][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([S:24]([CH3:23])(=[O:26])=[O:25])[S:5]1(=[O:16])=[O:15])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(S(C)(=O)=O)S1(=O)=O
Reaction time: 64 h

Procedure:
To 200 ml of acetonitrile was added with stirring 24 g(0.1 mole) of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide and 11.8 g (0.105 mole) of potassium t-butoxide. The resultant mixture was heated to reflux, cooled, and 8.0 ml (0.105 mole of methanesulfonyl chloride in 100 ml of acetonitrile was added dropwise over a 0.5 hr period. The mixture was stirred 64 hours, filtered, and the solvent removed from the filtrate in vacuo. The crude product, 31.5 g, was washed with 2-50 ml-portions of methanol to afford 18.8 g of analytically pure 3-(1-methylethyl)-1-methylsulfonyl-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide. m.p. 156°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15](O)[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.CCCCCC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[NH:13][C:14](=[O:17])[C:15]=2[Cl:24])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C2=C(Cl)C(=O)Nc3ccccc3S2)cc1
Yield: 64.8 %

Procedure:
Under a nitrogen blanket, a 2.0 g sample of dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4(5H)-one (6.8 mmol) was refluxed neat with 20 mL of thionyl chloride (27.6 mmol) for approximately 2 hours. Then, 50 mL of hexane and about 20 mL of ether were added, and solid product was filtered off. The solid was dried under vacuum to obtain 1.4 g of 2-(4-methoxyphenyl)-3-chloro-1,5-benzothiazepin-4(5H)-one (66 percent yield of theory).
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH2:31][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)CCN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCN(C)C)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
Sodium hydride (0.7 g) is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (8.0 g) in anhydrous dimethylformamide (125 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. and then treated with a solution of 4-dimethylamino-2-butanone (3.5 g) in anhydrous dimethylformamide (5 cc). The mixture is stirred for 3 hours at a temperature in the region of 20° C., and is then poured into distilled water (500 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is dissolved in ethyl acetate (400 cc) and the solution obtained is extracted with 1 N aqueous hydrochloric acid solution (2×100 cc). The aqueous phases are combined, washed with ethyl acetate (50 cc), alkalinized with 10 N aqueous sodium hydroxide solution to a pH in the region of 11 and extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with distilled water (3×30 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in acetonitrile, 3-(4-dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.6 g), m.p. 140° C., is obtained.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([Si:11]([CH3:31])([CH3:30])[O:12][CH:13]1[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C:15]([OH:29])(CO)[CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CO>[C:7]([Si:11]([CH3:31])([CH3:30])[O:12][CH:13]1[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][C:15](=[O:29])[CH2:14]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(CO)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium periodate saturated water (28.5 mL) was added to the diol 15 (1.8 g, 4.7 mmol) in methanol (124 mL) at 0° C. The solution was stirred for 1 h, then poured into water and extracted with ether. The combined ether fractions were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give 16 (1.5 g, 90%). No further purification was required. 1H NMR (CDCl3, 500 MHz) 6 0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.15 (s, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 1.94 (m, 2H), 2.35 (m, 2H), 2.54 (m, 2H), 4.35 (m, 2×1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12].CCN(C(C)C)C(C)C.[Br:26][CH2:27][C:28](Br)=[O:29]>C1COCC1>[Br:26][CH2:27][C:28]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH2:14][CH2:15][OH:16])=[O:12])=[O:29]
Reactant: O=C(Br)CBr
Reactant: Nc1sc2c(c1C(=O)NCCO)CCCC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Reaction time: 0.5 h
Yield: 43 %

Procedure:
2-Amino-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (4.6 g, 19.14 mmol) and DIPEA (4.95 g, 6.33 mL, 38.3 mmol) were dissolved in THF (100 mL) and the mixture purged with nitrogen and cooled in an ice bath. 2-Bromoacetyl bromide (3.86 g, 1.667 mL, 19.14 mmol) dissolved in THF (5 mL) was added dropwise and the reaction monitored by TLC. After 30 min TLC indicated 3:1 product: starting material with a faint spot for bis-acylated material. An additional quantity of 2-bromoacetyl bromide (0.97 g, 0.417 μL, 4.79 mmol) was added and stirring continued for a further 30 min. The mixture was quenched by addition of water before removal of THF under reduced pressure. The mixture was then partitioned between EtOAc/water and the organic layer collected—additional DCM was added to aid solubility. The aqueous layer was further washed with DCM. Combined organics were dried and concentrated to give a thick dark oil which was purified on silica eluting with 20-60% EtOAc/heptane. Desired fractions were collected and concentrated to yield the desired product as a light yellow solid (2.96 g, 8.23 mmol, 43%). The sample was used directly in the next step without any further purification.