Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[K+].O.Cl>CS(C)=O>[CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a stirred solution of 0.73 g N-butyl-N-(3'-phenylpropyl)-4-methoxy-3-nitrobenzenesulfonamide in 10 ml dimethyl sulfoxide was added 10 ml of a 50% aqueous potassium hydroxide solution and the mixture was heated and stirred at 80° C. for 4 hours. The mixture was poured into water, acidified to pH 4-5 with 20% aqueous hydrochloric acid and extracted into chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to give 0.71 g N-butyl-N-(3'-phenylpropyl)-4-hydroxy-3-nitrobenzenesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.O.Cl>CC(C)=O.[OH-].[Na+]>[Cl:15][C:16]1[N:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 7.4 g (39.5 mMol) 6-hydroxy-1-naphthoic acid and 5.9 g (39.5 mMol) 2,4-dichloropyrimidin in 104 ml of acetone, 79 ml NaOH (1 M in H2O) are added dropwise. The mixture is stirred for 19 h at rt and finally 2 h at 50° C. Then it is poured into 1.3 l water and acidified by addition of 40 ml of a 2 M HCl solution. Filtration of the suspension, washing with water and drying gives the title compound: MS: [M+1]+=301.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([SH:11])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12]N(C)C=O.[H-].[Na+].IC>O>[CH3:12][S:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[N:10]=1
Reactant: Nc1ncnc2sc(S)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSc1nc2c(N)ncnc2s1
Reaction time: 4 h

Procedure:
To a stirred and cooled (below 25° C.) mixture of 13.9 parts of 7-aminothiazolo[5,4-d]pyrimidin-2-thiol and 180 parts of N,N-dimethylformamide were added portionwise 4.3 parts of a sodium hydride dispersion 50% while cooling. After stirring for 1 hour, 11.5 parts of iodomethane were added dropwise at a temperature below 25° C. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 5.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46). From the filtrate, the aqueous layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding a second fraction of 3.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:36]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1)(=[O:38])[CH3:37]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 97.2 %

Procedure:
To a reaction vessel charged with 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (0.5 g, 1.05 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.49 g, 1.36 mmol), Pd (PPh3)4 (0.061 g, 0.053 mmol) and toluene (5 mL) is purged with N2 and heated to 100° C. for 2 h. After cooling down to room temperature, the solvent is removed under vacuum and the residue is treated with acetonitrile (10 mL) and 1 N HCl (40 mL) for 1 h. The mixture is then extracted with EtOAc (3×30 mL) and the combined organic layer is washed with saturated aqueous KF solution (20 mL). The resulted precipitate is removed by filtration and washed with EtOAc (2×10 mL). The organic layer is washed with brine and dried (MgSO4). After filtering off the drying agent, the solvent is removed under vacuum and the residue is purified by flash column chromatography (silica gel, 0%˜50% EtOAc/hexane) to provide the titled compound 6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (450 mg, 95%). HPLC-MS calculated for C25H17ClN4O2 (M+1+): 441.1. Found: 441.1.
Reaction SMILES: C1(S([CH:10]([C:42]2[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]=2[CH3:50])[CH:11]=[C:12]([CH3:41])[CH:13](Cl)[CH2:14][CH2:15][C:16]([CH3:39])=[CH:17][CH:18]=[CH:19][CH:20]=[C:21]([CH3:38])[CH:22]=[CH:23][CH:24]=[C:25]([CH3:37])[CH:26]=[CH:27][C:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=2[CH3:36])(=O)=O)C=CC=CC=1.C[O-].[K+].O>C1(C)C=CC=CC=1>[CH3:50][C:43]1[CH2:44][CH2:45][CH2:46][C:47]([CH3:48])([CH3:49])[C:42]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]
Reactant: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC=C(C)CCC(Cl)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Yield: 79.8 %

Procedure:
In a 50-ml round-bottom flask 2.01 g (purity: 40.9%, 1.15 mmoles) of 1-phenylsulfonyl-4-chloro-1,18-di(2,6,6-trimethyl-1-cyclohexen-1-yl)-3,7,12,16-tetramethyloctadeca-2,7,9,11,13,15,17-heptaene was reacted with 1.0 g (purity: 80%, 11 mmoles) of potassium methoxide in 4 g of toluene at 30° C. for 2 hours. Then water was added to the reaction mixture. The resulting organic layer was separated and washed with water, followed by removal of the solvent, to give 2.58 g (purity: 19.1%, 0.918 mmole, yield: 80%) of a crude β-carotene. To this product 10 g of water was added. The mixture was heat-refluxed for 10 hours and subjected to extraction with toluene to remove organic substances, followed by recrystallization of the residue from toluene-methanol solvent, to give 44 mg of a dark brown crystal. The crystal thus obtained was confirmed to be β-carotene by comparison with standard sample.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:41]4[C:32](=[CH:33][C:34]5[O:39][CH2:38][CH2:37][O:36][C:35]=5[CH:40]=4)[O:31][CH2:30]3)[C:22]2=[O:42])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-(trifluoromethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 204-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.74 (d, J=1.6 Hz, 1H), 7.82 (dd, J=8.1, 1.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 1H), 7.03-7.05 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.11 (d, J=16.0 Hz, 1H), 4.92 (d, J=16.1 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 149.0, 147.9 (q, J=139.5 Hz), 144.8, 141.2, 138.4, 136.5, 134.9, 132.1, 129.1, 124.4, 124.1, 121.4, 120.8 (q, J=10.8 Hz), 120.5, 111.4, 108.6, 99.6, 80.1, 64.5, 63.9, 58.0, 41.3; MS (ES+) m/z 429.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1.[BH4-].[Na+].CO>C(O)(=O)C>[CH3:29][N:18]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[C:15]1[N:14]=[N:13][C:12]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[OH:1])[CH:8]([OH:11])[CH2:7][CH2:6]3)=[CH:17][CH:16]=1
Reactant: CN(c1ccc(-c2cc3c(cc2O)C(=O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(c1ccc(-c2cc3c(cc2O)C(O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Example 35-1, 50 mg, 0.13 mmol), sodium borohydride (9.59 mg, 0.25 mmol) and MeOH (1.5 mL). The resulting suspension was stirred at RT for two hours. The reaction mixture was acidified with excess acetic acid and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford the title compound. MS [M+H+]=397.3, LCMS Rt=0.46 min [LCMS Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.11 (d, J=9.54 Hz, 1H), 7.64 (s, 1H), 7.31 (d, J=9.54 Hz, 1H), 6.99 (s, 1H), 5.16 (t, J=6.53 Hz, 1H), 5.01-5.13 (m, 1H), 2.95-3.08 (m, 4H), 2.73-2.86 (m, 1H), 2.41-2.54 (m, 1H), 1.91 (s, 1H), 1.53-1.78 (m, 4H), 1.41 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[C:11]([F:17])=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[C:11]([F:17])=[N:12][CH:13]=[C:14]([CH2:16][Br:1])[CH:15]=1
Reactant: Cc1cnc(F)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ncc(CBr)cc1Br
Yield: 22.3 %

Procedure:
N-Bromosuccinimide (4.732 g, 26.59 mmol) and benzoyl peroxide (0.1356 g, 0.5598 mmol) were added to a solution of 3-bromo-2-fluoro-5-methylpyridine (Matrix Innovation Inc., Montreal, Quebec, Canada 5.318 g, 27.99 mmol) in CCl4 (50 mL), and the mixture was heated at gentle reflux under a N2 atmosphere for 16 h. The mixture was filtered, washing with CCl4, and the residue concentrated and purified by flash chromatography on silica (1% to 1.5% EtOAc/hexane) to give 3-bromo-5-(bromomethyl)-2-fluoropyridine (1.593 g, 21.17% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H); 8.03 (dd, J=8.02, 2.15 Hz, 1H); 4.43 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −65.17 (br. s., 1 F). Sample did not ionize well in ESI+ mode.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C:9]([CH3:14])([CH3:13])[CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([O:35]N1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25](=[O:35])[N:11]([CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[CH3:12])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CNCC(C)(C)CNC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN(CC(C)(C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (2,2-Dimethyl-3-methylamino-propyl)-carbamic acid tert-butyl ester (compound PP) (1.05 g, 4.85 mmol) in CHCl3 (10 mL) at ambient temperature was added DIEA (0.84 mL, 4.85 mmol) followed by Cbz-OSu (1.21 g. 4.85 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture then was diluted with CHCl3 (100 mL), and washed with water (2×50 mL) and brine (50 mL). The organic layer was separated and dried over Na2SO4. The removal of the solvents in vacuo yielded crude compound QQ in quantitative yield (1.78 g, 4.85 mmol) as a foamy solid. LC-MS [M+H] 351.6 (C19H30N2O4+H, calc: 351.2). Compound QQ was used directly in the next reaction without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17](O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN(C)c1ccc(C(=O)C(O)c2cccc(Cl)c2)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)C(F)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution 6.7 g diethylaminosulfur trifluoride in 20 ml of dry dichloromethane was stirred at -78° C. under nitrogen as a solution of 12 g of 2-(3-chlorophenyl)-2-hydroxy-1-[4-(dimethylamino)phenyl]ethanone in 200 ml of dry dichloromethane was added dropwise. The mixture was warmed to room temperature and stirred for 72 hours. The mixture was poured into 200 ml of ice water and the layers separated. The organic layer was dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (8:1 hexane-ethyl acetate) and then recrystallized from ether-hexane to give 1.1 g of 2-(3-chlorophenyl)-2-fluoro-1-[4-(dimethylamino)phenyl]ethanone, mp 90°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([N:15]([CH:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:16][CH2:17][N:18]([CH2:29][CH2:30][C:31]1[C:39]2[S:38][C:37](=[O:40])[NH:36][C:35]=2[C:34]([OH:41])=[CH:33][CH:32]=1)[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:14])[CH:12]=[CH2:13]>C(O)C>[CH:42]1([N:15]([C:11](=[O:14])[CH2:12][CH2:13][NH:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:16][CH2:17][N:18]([CH2:29][CH2:30][C:31]2[C:39]3[S:38][C:37](=[O:40])[NH:36][C:35]=3[C:34]([OH:41])=[CH:33][CH:32]=2)[C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1
Reactant: NCCc1cccc(F)c1
Solvent: CCO
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1)C1CCCCCC1
Temperature: 50 °C
Reaction time: 32 h

Procedure:
2-(3-Fluorophenyl)ethanamine (0.573 mL) was added to benzyl {2-[acryloyl(cycloheptyl)amino]ethyl}[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate, prepared as in Example 23 step ii), (0.786 g) in ethanol (15 mL). The resulting solution was stirred at 50° C. for 32 h. The volatiles were removed in vacuo and the crude material was purified by flash silica chromatography, elution gradient 0.5:0.5:19 to 1:7:13 7M NH3 in methanol:ethanol:ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (0.759 g) as a pale yellow foam.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:26](O)[CH3:27]>>[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 250 ml. of ethanol is added 20 ml. of concentrated sulfuric acid, followed by the addition of 13.3 g. of 4-benzoylindan-1-carboxylic acid. The mixture is refluxed for 5.5 hours. After cooling, the ethanol is distilled off under reduced pressure and water is added to the residue, followed by extraction with ether. The ethereal layer is washed with a 5 % aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (eluted with chloroform). The described procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([O:15][CH2:16][CH:17]=[CH2:18])([C:11]([O:13][CH3:14])=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:20]([O:22][SiH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([C:11]([O:13][CH3:14])=[O:12])([O:15][CH2:16][CH2:17][CH2:18][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCOC(CC(=O)OC)(CC(=O)OC)C(=O)OC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCOC(CC(=O)OC)(CC(=O)OC)C(=O)OC)(OCC)OCC
Temperature: 80 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
In a round-bottom flask, 3-allyloxy-3-methoxycarbonyl-pentanedioic acid dimethyl ester (2.74 g, 10 mmol) was introduced in 25 mL of dry toluene, followed by triethoxysilane (2.63 g, 16 mmol). Hydrosilylation catalyst, platinum-divinyltetramethyldisiloxane complex in xylenes solution (0.02 mL), was added and the mixture was stirred at 80° C. in a dry atmosphere for 16 hours. The volatiles were then removed in vacuo. The residue was dissolved in dry dichloromethane, a spatula of activated carbon was added, and the mixture was stirred for 3 hours under nitrogen. The mixture was then filtered over a 0.45 μm Teflon filter and the solution was evaporated to dryness to yield the title compound (3.75 g, 86%) as an oil that was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCOCC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and morpholine (29 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional morpholine (29 μL, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (25 mg, 50%). LCMS (Method 5): Rt 3.66 min, m/z 748.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.0 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.73 (2H, m), 1.75-1.98 (4H, m), 1.99-2.19 (2H, m), 2.42 (4H, t, J=4.0 Hz), 2.67 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.20 (1H, m, obscured by water), —3.30 (1H, m, obscured by water), 3.53 (4H, t, J=8.0 Hz), 4.12 (2H, t, J=8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.07-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.21 (0.5H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CC(OC(C)=O)=O>CCOCC>[CH2:1]([N:8]1[C:12]([NH2:13])=[CH:14][C:15](=[O:16])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NCc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Temperature: 77.5 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of benzylurea (33.3 mmol), 2-cyanoacetic acid (36.63 mmol) and Ac2O (20 mL) was heated at 75-80° C. for 2 hours. After cooling to room temperature, 30 mL of Et2O was added and the resultant suspension was stirred for 1 h. The solid intermediate was filtered, suspended in a mixture of water (30 mL) and ethanol (15 mL) and heated at 80-85° C. 5 mL of 10% NaOH were slowly added. After 30 minutes, the reaction mixture was concentrated, acidified with 10% HCl and the precipitate collected by filtration (Yellow solid. Yield 70-80%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[C:33]([CH:35]=1)[NH2:34].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:34][C:33]1[CH:35]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=1[CH3:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
6.9 g of sodium triacetoxyborohydride (32.5 mmol) was added to a solution of 5.08 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (27.1 mmol), 5 g of 5-fluoro-2-methylaniline (27.1 mmol) and 1.55 ml of acetic acid (27.1 mmol) in methylene chloride (270 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=8/1) to obtain 5.68 g of the title compound (yield: 71%).