Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:3]1.[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH:4]([N:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]2=[O:16])[CH2:3]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)(c2ccccc2)C1
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A solution of Example 58A (1.00 g, 4.36 mmol) and THF (20 mL) was cooled to <−70° C. and phenylmagnesium chloride (2.40 mL, 4.80 mmol) was added at <−70° C. After 2 hours, saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with MTBE (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was puridifed by flash column chromatography (0-20% EtOAc/hexanes, gradient elution), to provide the title compound (370 mg, 1.20 mmol, 27.6% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.Cl[NH2:19].CCOCC>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([NH2:19])[C:12]([CH3:17])=[CH:11]2
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc2cc(F)ccc2n1N
Temperature: 23 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A solution of potassium tert-butoxide (1.84 g, 16.43 mmol) and 5-fluoro-2-methylindole (1.21 g, 8.09 mmol) in DMF (20 mL) is stirred under N2 at rt for 60 min. A solution of monochloroamine in ether (65 mL, 9.75 mmol) is added via an addition funnel over 10 min. The resulting mixture is stirred at 23° C. for 2 hours, and then concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford 5-fluoro-2-methyl-indol-1-ylamine (290 mg, 22%) as a solid. MS: 165 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.24-7.19 (m, 1H), 7.12 (dd, 1H), 6.92 (dt, 1H), 6.12 (s, 1H), 4.23 (br s, 2 H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CC(N(C)C)=O.[CH:51]1([O:57][C:58](=[O:64])[O:59][CH:60](Cl)[CH2:61][CH3:62])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(=O)([O-])O.[K+]>O.C(OCC)(=O)C>[CH:51]1([O:57][C:58](=[O:64])[O:59][CH:60]([O:16][C:14]2[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=[C:11]([C@H:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:4][CH:5]=3)[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=3[F:35])[N:15]=2)[CH2:61][CH3:62])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(OC(=O)OC1CCCCC1)Oc1nc([C@H](Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a mixture of N-[1-amino-1-(4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 12b, 200 mg) and DMA (2 mL), carbonic acid 1-chloropropyl ester cyclohexyl ester [CAS No. 108098-53-9] (300 mg) and potassium hydrogen carbonate (100 mg) were added, and the resulting mixture was stirred at 55° C. for 36 hours. The resulting mixture was poured into ethyl acetate and water. After shaking the mixture, the organic layer was collected, sequentially washed twice with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was crudely purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a crudely purified product (120 mg).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][C@H:12]([NH:20][C:21](=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:47][C@H:48]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49][CH2:50][C:51](=[O:53])[OH:52].CCN(C(C)C)C(C)C.Cl>C(#N)C.O>[C:57]([O:56][C:54](=[O:55])[C@@H:48]([NH:47][C:9](=[O:8])[CH2:10][CH2:11][C@@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21](=[O:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:49][CH2:50][C:51]([OH:52])=[O:53])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-2-(17-tert-Butoxycarbonylheptadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (0.5 g, 0.766 mmol) was dissolved in acetonitrile (20 mL). This solution was added to a solution of H-Glu-OtBu (0.171 g, 0.84 mmol) in water (30 mL) pH was adjusted to 10 with DIPEA. The mixture was stirred at RT for 15 min, then acidified to pH 7 with HCl (2M) and evaporated in vacuo. The residue was partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to dryness. This afforded (S)-2-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]pentanedioic acid 1-tert-butyl ester as an oil. LC-MS (electrospray): m/z=741 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[F:26][C:27]1[CH:32]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 2-fluoro-4-methylsulfonyl-phenylboronic acid following a procedure analogous to that described for Example 2; PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex is the preferred catalyst used. LC (method 1): tR=1.30 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[O:12])[CH:9]2[C:4](=[CH:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.I[CH2:15][CH3:16].[H-].[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.CCCCCC>[CH2:15]([CH:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1([CH3:13])[CH3:1])[CH3:16]
Reactant: CC1(C)CC(=O)C2CCCC=C2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4, -tetrahydro-2,2-dimethyl-4-quinolinone (EXAMPLE 325) (0.10 g, 0.36 mmol) and iodoethane (0.50 mL, 6.3 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) and the resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded a mixture of products, which was treated with TFA (0.50 mL) in methylene chloride (1.0 mL) for 3 h. The reaction was neutralized to pH 10 by 5% NaOH and was extracted with EtOAc (2×20 mL). Chromatography (silica gel, EtOAc/hexane, 3/7) afforded 30 mg (41%) of (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (30 mg, 0.15 mmol) as a colorless oil. The quinolinone (30 mg, 0.15 mmol) was treated with Et3SiH (1.0 mL) and BF3 -OEt2 (0.05 mL, 0.4 mmol) in CH2Cl2 (1.0 mL) at 100° C. for 15 h in a sealed tube. Purification of the crude product by chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg (71%) of (R/S)-3-ethyl-1,2,3,4,-tetrahydro-2,2-dimethylquinoline. Data for (R/S)-3-ethyl-1,2,3,4,-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.5, 1H), 6.96 (t, J=7.5, 1H), 6.61 (t,J=7.5, 1H), 6.44 (d,J=7.5, 1H), 3.60 (s, 1H), 2.90 (dd, J=16.7, 5.2, 1H), 2.41 (dd, J=16.7, 10.7, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 1.23 (m, 1H), 1.22 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:6]=2[CH:18]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(Cl)ccc1S2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C=C(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
27.4 G. of 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)one, 400 ml. of absolute benzene and 40 g. of 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone are stirred under an atmosphere of argon at 20° C. To the mixture, there are added dropwise over a period of 60 minutes, 9.3 ml. of titanium tetrachloride in 200 ml. of absolute benzene. The mixture is subsequently heated at reflux for 3.5 hours and, after cooling to about 40° C., poured on to a saturated, aqueous sodium bicarbonate solution and stirred for an additional 30 minutes. The suspension obtained is filtered and the benzene phase separated. The aqueous phase is back extracted with 100 ml. of benzene. The combined benzene extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. By recrystallization from acetonitrile, there is recovered from the residue still unchanged 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one. The mother liquor is evaporated and the residue recrystallized from benzene, whereby there is obtained 3-[2-[4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 194°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH2:27])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (1.5 g, 0.005 mol) was dissolved in dry N,N-dimethylformamide under argon and cooled to 0° C. 1,1′-Carbonyl-diimidazole (1.4 g, 0.009 mol) was added to the mixture and the reaction stirred for one hour while the temperature rose from 0° C. to room temperature. Ammonium acetate (5.6 g, 0.073 mol) was added and the reaction was stirred for one hour at room temperature. Water was added dropwise to the mixture and a precipitate appeared. The solid was filtrated, washed with water and dried under vacuum to yield 1.36 g (0.0041 mol, 91% of theory) of the title compound as a white solid. MS (m/e)=329.3(M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[CH:12]([C:15]([CH3:17])=[O:16])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:12]([CH3:14])([CH3:13])[C:15](=[O:16])[CH3:17])=[CH:6][CH:5]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(C)Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
254 g (4 mols) of potassium hydroxide powder (88% pure) are suspended in 1 liter of toluene. To this are slowly added 40 g of tetrabutylammonium bromide and a mixture of 644 g (4 mols) of 4-chlorobenzyl chloride and 430 g (5 mols) of methyl isopropyl ketone at 85° C. The reaction mixture is stirred a further 3 hours at 85° C. After cooling down, it is filtered and the filtrate is washed to neutrality. 732.5 g (87% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-3-butanone of boiling point 87°-90° C./0.05 mbar are obtained by fractional distillation under high vacuum.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8](=[CH2:17])[C:9]([O:11]C(=O)C(C)=C)=[O:10].O=O>>[CH3:3][CH:2]([CH2:4][CH2:17][C:8](=[CH2:7])[C:9]([OH:11])=[O:10])[C:1]([OH:6])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: O=O
Product: C=C(CCC(C)C(=O)O)C(=O)O
Temperature: 120 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a mechanically stirred solution of 2 moles of hydroxyquinone dissolved in 3 moles of methacrylic acid at 120° C. and atmospheric pressure was added dropwise (30 min) 1 mole of methylacrylic acid anhydride and the mixture was maintained at 120° C. with stirring for additional 4 hrs (NMR analysis). Throughout the course of the reaction 8% oxygen was admitted to the system. At the end of the reaction, the methacrylic acid was recovered by distillation under reduced pressure (110° C. and 200 mmHg), and the unreacted excess hydroquinone was precipitated out by the addition of toluene (1 liter) to the reaction mixture. A low level (1-2%) of the monomer 2-methyl-5-methylenehexanedioic acid was formed. This monomer was separated from the mixture by a washing step with distilled water. After phase separation, the desired 4-hydroxyphenyl methacrylate was obtained at 97% yield by the distillation of toluene under reduced pressure. {mp. (Uncorrected) 120° C.; Anal. Calcd. For C10H10O3: C, 67.41: H, 5.66; O, 26.94. Found: C, 67.37; H, 5.62}.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.B.N.[Cl:15][CH2:16][CH2:17][CH2:18][C@H:19]([CH2:34][CH:35]=[CH2:36])[C:20](N([C@@H](C)[C@@H](O)C1C=CC=CC=1)C)=[O:21]>C1COCC1>[Cl:15][CH2:16][CH2:17][CH2:18][C@H:19]([CH2:34][CH:35]=[CH2:36])[CH2:20][OH:21]
Reactant: C=CC[C@@H](CCCCl)C(=O)N(C)[C@@H](C)[C@@H](O)c1ccccc1
Agent: B
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CC[C@H](CO)CCCCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A magnetically stirred solution of diisopropylamine (184 mL, 1.29 mol) in THF (600 mL) was cooled to −78° C. nBuLi (2.5M in hexane, 482 mL, 1.21 mol) was added dropwise over 35 min using an addition funnel. The cloudy mixture stirred at −78° C. for 15 min and then was warmed to 0° C. for 15 min during which time the solution became clear and light yellow. Borane-ammonia (90%, 42 g, 1.24 mol) was added in four equal portions, one minute apart. (Caution: vigorous evolution of gas). The cloudy mixture was warmed to room temperature for 20 min and then was recooled to 0° C. (R)-2-(3-chloropropyl)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpent-4-enamide (100.2 g, 309 mmol) in THF (300 mL) was added dropwise over 10 min using an addition funnel. The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was cooled to −10° C. and was quenched with HCl (3M, 1500 mL). The phases were separated and the aqueous phase was extracted with Et2O (2000 mL total). The combined organic layers were washed with 3N HCl, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as a yellow oil. The crude material was purified by flash chromatography (ISCO; 330 g column; Hexane to 30% EtOAc/Hexane) to provide (R)-2-(3-chloropropyl)pent-4-en-1-ol as a clear, viscous oil (32.6 g, 200 mmol, 65%); 1H NMR (400 MHz. CDCl3) δ 5.82 (m, 1H), 5.07 (m, 2H), 3.78 (m, 1H), 3.58 (d, J=8.0 Hz, 2H), 3.54 (t, J=8 Hz, 2H), 2.14 (m, 2H), 1.85 (m, 2H), 1.64 (m, 1H), 1.49 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1.[CH3:17][Mg]Br.O>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1
Reactant: C[Mg]Br
Reactant: C=CCN1c2ccccc2C(C)NS1(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1c2ccccc2C(C)(C)NS1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Aminoacetophenone(5.6 g, 41.5 mmol)and sulfamide (4 g, 41.5 mm) were added to diglyme (70 ml, dried over 4A molecular sieves) and the solution heated under nitrogen at 150° C. After 1 hour a solid forms but heating was continued for 2 hours in total. After cooling, ether was added followed by 2N sodium hydroxide which dissolved the solid formed. The aqueous phase was collected, diluted with ethanol and (prop-2-en-1-yl) bromide (8 ml) added, stirring being continued overnight. After concentration under vacuo the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried, over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a yellow oil, 3,4-dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 3,4-Dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(2.4 g, 10 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen and the solution cooled to -78° C. in an acetone/dry ice bath. Methyl magnesium bromide (5 ml, 3M solution in ether) was added at this temperature and kept for 30 minutes when it was allowed to come to room temperature. After stirring for 2 hours, water was added and the solution concentrated. Partitioning between ethyl acetate and dilute HCl(aq) and collection of the organic extracts followed by drying, filtering and removal of solvent gave a product showing 75% conversion to product. Column chromatography eluting with ethyl acetate/hexane gave product, 3,4-dihydro-4,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. This compound (1.85 g, 7.3 mmol) was dissolved in N-methylpyrrolidine (30 ml) under nitrogen and sodium hydride (350 mg) was added at room temperature resulting in a vigorous effervescence. After the gas evolution had subsided (30 minutes), methyl iodide (300 mg) was added and the solution stirred overnight. The reaction was poured onto water and extracted with ethyl acetate(3×50 ml). Organic phase was washed with water (2×100 ml), dried, filtered and vacced to an oil, 3,4-dihydro-1-(prop-2-en-1-yl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[C:23]([OH:25])=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26]OC(C1C=CC(OCC2C=CC=CC=2)=C(C=1)C(O)=O)=O>CO>[CH3:26][O:24][C:23]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:20]([OH:22])=[O:21])=[O:25]
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
H2SO4 (0.8 ml, 11.02 mmol) was added dropwise to a solution of 4-[(phenylmethyl)oxy]-1,3-benzenedicarboxylic acid (may be prepared as described in Description 48; 3 g, 11.02 mmol) in methanol (40 ml). The mixture was stirred at room temperature for 3 h before being poured into ice-water (40 ml). The precipitate was collected and added to a saturated NaHCO3 solution. The mixture was filtered to remove the insoluble residue and the pH of the filtrate was adjusted to pH=4.8 by HCl (6 mol/L). The precipitate was collected to afford crude product. The crude product was added to a silica gel column (300 g), and was eluted with dichloromethane/methanol=100:1 (3 L) to afford a mixture of 5-[(methyloxy)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid and the title compound as a white solid. 1 g.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:19])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH:3]([CH3:19])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(CCl)CN1c2cccc3cccc(c23)S1(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4 g), triethylamine (5.1 cc), sodium iodide (5.4 g) and 4-(4-fluorophenyl)piperazine (6.5 g) in toluene (130 cc). The mixture is heated at boiling point for 16 hours, then cooled to a temperature of about 20° C. After purification by flash chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluants, and recrystallization from boiling acetonitrile (20 cc), 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methylpropyl}naptho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained m.p. 133° C.