Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].CC(C)([O-])C.[K+].[C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:36]4[CH:35]=[C:34]5[C:37]6([CH2:44][O:45][C:33]5=[CH:32][C:31]=4[CH2:30][CH2:29]3)[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]6)=[O:27])=[CH:22][CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)(=O)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:3][O:2][NH:4][CH:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:36]4[CH:35]=[C:34]5[C:37]6([CH2:44][O:45][C:33]5=[CH:32][C:31]=4[CH2:30][CH2:29]3)[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]6)=[O:27])=[CH:22][CH:21]=2)=[C:16]([CH3:46])[CH:15]=1)[CH3:12]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Reactant: CON
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: CONC(C)c1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.2 %

Procedure:
Methoxylamine hydrochloride (0.06 g, 0.7 mmol) was added to a stirred solution of potassium t-butoxide (0.06 g, 0.5 mmol) in methanol (10 ml) under argon. After 20 minutes at room temperature, the solution was treated with a solution of 5-(4'-acetyl-2'-methylbiphenyl-4-carbonyl)-1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E10, 0.16 g, 0.3 mmole) in methanol (10 ml) and stirred at room temperature for 18 hours, followed by 1 hour heating under reflux. The solution was allowed to cool, treated with 10% Na2CO3 solution (40 ml) and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (0.16 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11]3=[C:12]([CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15][CH2:16][N:10]3[CH2:9][CH2:8][CH:7]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1)([O-])=O>CO.[Pd]>[C:23]1([CH:7]2[C:6]3[C:11]4=[C:12]([CH:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:15][CH2:16][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:4]([NH2:1])[CH:5]=3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1

Procedure:
A solution of 9-nitro-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (Intermediate 3), (1.2 g, 7.06 mmol), in MeOH (100 mL) was subjected to hydrogenation reaction by the action of 10% Pd/C (120 mg) under H2 balloon at room temperature for 12 h. The mixture was filtered through Celite and freed of solvent under reduced pressure to get 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4) as a solid, (1.08 g, 98%).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])=[CH2:3].[CH3:10][C:11](=[CH:13][CH2:14][CH2:15][C:16](=[CH:18][CH:19]=O)[CH3:17])[CH3:12]>[O-2].[Zn+2].O>[CH3:3][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH:8]=[CH:19][CH:18]=[C:16]([CH3:17])[CH2:15][CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])=[CH2:1]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: C=C(C)CCCC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: C=C(C)CCCC(=O)C=CC=C(C)CCC=C(C)C
Temperature: 160 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of 150 parts of 2-methyl-1-hepten-6-one and 50 parts of citral is heated with 20 parts of zinc oxide in a round flask while stirring for 4 hours at 160° C and atmospheric pressure. Water thus formed is removed by distillation. The fractionation which follows gives 61 parts of 2,10,14-trimethylpentadeca-1,7,9,13-tetraen-6-one having a boiling point of 118° to 120° C at 10116 4 mm. The yield is 88% of theory based on citral, at a conversion of 81%.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)=[C:2]=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([NH:1][C:2](=[O:3])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[N:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C)c(C)c3)cc2)o1)C(C)C
Yield: 82 %

Procedure:
The title compound was synthesized analogous to Example 1, using 4-isocyanato-1,2-dimethylbenzene and intermediate 1. Yield: 82%; 1H NMR (DMSO-d6, 300 MHz): δ 8.97 (d, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.79 (s, 1H), 7.77 (d, 2H), 7.61 (d, 2H), 7.24 (dd, 1H), 7.19 (dd, 1H), 7.04 (d, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.28 (m, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 0.95 (d, 6H); MS (ES+): m/z 465 (M+1).
Reaction SMILES: Cl[C:2]([C@H:4]1[C@H:6]([CH:7]=[C:8]([Cl:13])[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].N1C=CC=CC=1.[C:22]([CH:24]([OH:38])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>O>[Cl:13][C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C@@H:6]1[C@H:4]([C:2]([O:38][CH:24]([C:22]#[N:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=2)=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the residue of (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (obtained in Example 18) was added a mixture of pyridine (0.12 g) and (+)-α-cyano-3-phenoxybenzyl alcohol (0.33 g) and the mixture thus obtained was stirred for a period of 16 hours at the ambient temperature. Water (20 ml) was added and the mixture extracted with diethyl ether (3×10 ml). The combined extracts were washed with water, saturated sodium bicarbonate solution, and water and dried over anhydrous sodium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was subjected to preparative thick-layer chromatography, using 2 mm thick silica on glass with chloroform as eluent, to yield (+)-α-cyano-3-phenoxybenzyl (+)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (Rf 0.52), and the corresponding trans isomers (Rf 0.42), each containing about 90-95% of the Z-isomer. Spectral data: infra red (CHCl3) 1740, 1660, 1590, 1480, 1460 cm-1 ; n.m.r. (CCl4): 6.90-7.50π, 1.60-2.70π, 1.50-1.00τ, and specific peaks at 6.3 τ (benzylic H), 6.85, 6.50, 6.11 and 5.84 π (vinylic H) tentatively assigned to the Z-cis, E-cis, Z-trans and E-trans isomers respectively.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C@@H:8]([NH:18][C@H:19]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])[CH3:20])[CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])C>C(O)C>[C:6]([C@@H:8]([NH:18][C@H:19]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])[CH3:20])[CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([OH:7])=[O:5]
Reactant: CCCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2.0 ml quantity of a 1N aqueus solution of sodium hydroxide was added with ice cooling and stirring to a solution of 373 mg of the N-[(R)-1-ethoxycarbonyl-2-heptylthioethyl]-alanyl-(S)-proline (β-isomer) prepared in Example 17 in 4 ml of ethanol. The mixture was stirred at room temperature for 3 hours and applied to a column (Dowex 50W-X8(H+)). The reaction product was sufficiently washed with water and was eluted with a 4% aqueous solution of pyridine. Fractions of the title compound were collected and lyophilized. The powdery substance thus obtained was reprecipitated with ethanol-ether, giving the title compound.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)#[N:3].C(NCC)C>CN(C=O)C>[NH2:3][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)=[S:1]
Reactant: S
Reactant: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
H2S gas was passed slowly through a solution of methyl 2-(5-{3-[(5-cyano-2-pyridinyl)oxy]propoxy}-1H-indol-1-yl)propanoate (Example 67, 0.50 g, 1.32 mmol) in DMF (7.80 mL) for 20 minutes at rt. Diethylamine (0.21 mL, 2.37 mmol) was added in one portion, and the resultant light green solution was heated at 60° C. for 3 h. The reaction mixture was purged with a stream of argon, and then concentrated under reduced pressure. The desired compound (0.49 g, 90%) was isolated by column chromatography (50% hexanes in EtOAc) as a bright yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.63 (dd, 1H), 8.16 (dd, 1H), 7.25-7.08 (m, 3H), 6.86-6.74 (m, 2H), 6.46 (d, 1H), 5.16 (qt, 1H), 4.59 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[CH2:9]C=C)[C:5]([CH:19]=[CH2:20])=[C:4]([NH:21][CH3:22])[N:3]=1>C1C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:22])[C:5]2[CH:19]=[CH:20][CH2:9][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([OH:12])[C:6]=2[N:7]=1
Reactant: C=CCC(O)(c1ccccc1)c1nc(Cl)nc(NC)c1C=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: c1ccccc1
Product: CNc1nc(Cl)nc2c1C=CCC2(O)c1ccccc1
Temperature: 85 °C
Yield: 91.5 %

Procedure:
To a solution of 1-(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)-1-phenylbut-3-en-1-ol (60 mg) in benzene (5 mL) was added Grubbs I (16 mg), and the reaction mixture was heated at 85° C. for 1 h. The solvent was removed, and the residue was purified by preparative TLC eluting with 40% EtOAc/Hexanes to give the title compound as a colorless oil (50 mg). 1H NMR (500 MHz, CDCl3) δ ppm 7.4 (5H, m), 6.25 (1H, m), 6.07 (1H, m), 5.14 (1H, br. S), 4.52 (1H, s), 3.10 (3H, d<J=5.0 Hz), 2.99 (2H, m). 13C NMR (125 MHz, CDCl3) 164.32, 159.38, 158.85, 144.15, 128.24, 128.02, 127.83, 125.51, 117.54, 108.14, 60.51, 38.50, and 28.57. HRMS calcd. for C15FH15ClN3O (M+H) 288.0904. found: 288.0899.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH:13](=[N:1]/[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:12])\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(Cl)cc2c1COC2=O
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccc3)cc(Cl)cc21

Procedure:
A mixture of 4-amino-6-chloroisobenzofuran-1(3H)-one (1 g, 5.46 mmol), benzaldehyde (0.72 g, 6.79 mmol) and magnesium sulfate (6 g) in dichloromethane (80 mL) was stirred at reflux overnight. The mixture was evaporated under reduced pressure and the residue was dried in vacuum. A crude product was obtained (740 mg) and used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30]C)=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([C:24]([F:27])([F:26])[F:25])([OH:23])[CH2:11][NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:7]=1.B(Br)(Br)Br.C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([C:24]([F:25])([F:26])[F:27])([OH:23])[CH2:11][NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1nccc2ccccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(CNc1nccc2ccccc12)C(F)(F)F)c1cc(F)ccc1O
Yield: 52.1 %

Procedure:
Analogously to Example 2, 65 mg (0.15 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(isoquinolin-1-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is reacted with 2.7 ml of 1 M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane-ethyl acetate (0-80%), 33 mg of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CON(C)[C:13](=[O:27])[CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13](=[O:27])[CH:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C#N)cc1)C(C)(C)C
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a dried and cleaned 10 L cryo reactor was added 4-bromobenzonitrile (321 g; 1.74 mol; 2.5 eq) and THF (995 mL; 5.0 vol). The stirred mixture was inerted under a nitrogen atmosphere and cooled (Tj −20° C.). To the cooled mixture at Tj −13° C. Turbo Grignard reagent (Turbo Grignard Reagent from Chemetall equal to iPrMgCl/LiCl 14% w/w in THF; 1.81 L; 2.5 eq) was charged under the nitrogen atmosphere while maintaining the temperature below approx −10° C. during 1 h 14 min. The reaction intermediate was left at approx 0° C. for 3 h giving a conversion of >97% (analytical sample quenched with 15% w/w aq NH4Cl). The mixture was cooled to Ti −20° C. and a solution of tert-butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (191 g; 0.70 mol; 1.0 eq) in THF 496 mL; 2.6 vol) was charged to the reactor for 28 min at approx-10° C. to −6° C. (exothermal reaction). The vessel was rinsed with THF (221 mL; 1.3 L), the reaction mixture warmed to 20° C. and left overnight affording a conversion (HPLC) of approx 90%. The mixture was cooled to 0° C. (Tj-10) and a solution of potassium sodium tartrate (Rochelle salt) (153 g; 1.05 eq) in water (10 vol) was drop wise added during 30 min keeping the temperature at 0 to 10° C. giving an orange coloured slurry. Tj was set to 40° C. and stirring was stopped at Ti 30° C. and the phases allowed to separate. The red coloured organic layer was recovered and the yellow slurry-like water phase was extracted twice at Tj 30° C. with iPrOAc (2×1.91 L; 2×10 vol). The organic layers were combined (7.5 L) and washed at Tj 30° C. three times with a brine-water mixture (3+3 vol; 5+5 vol; 3+3 vol). The washed organic layer was concentrated in vacuo at Tj 60° C. to approx 1.5 L volume and diluted (iPrOAc) to 2 L. The product solution was taken to the next step (example 3, method 2) without further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:18][N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15](=[O:24])(=[O:23])[C:14]=2[CH:25]=1.C(Cl)Cl>CN(C=O)C>[CH3:1][N:18]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:25][C:14]=2[S:15](=[O:23])(=[O:24])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17]1
Reactant: COC(=O)C1=NNc2ccc(C)cc2S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1=NN(C)c2ccc(C)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
Potassium carbonate (2.25 g) and iodomethane (0.60 g) is added to a solution of methyl 6-methyl-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 39, 0.83 g) in DMF (20 mL). The mixture is stirred at room temperature for 5 hours and then added to CH2Cl2 (120 mL) and washed with water (4×100 mL). The organic layer is dried with Na2SO4, filtered and the solvent evaporated. The crude solid is recrystallized (1% CH2Cl2/MeOH) to obtain 0.74 g (85%) of the title compound as a yellow crystalline solid. Physical characteristics: MS (ESI+) m/z 269 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([CH3:28])=[CH:4][N:3]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:32][CH2:33][CH3:34])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([CH3:28])=[CH:4][N:3]=1
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3C)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1nc(Cl)ncc1C
Reaction time: 0.5 h
Yield: 361.4 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 408, 800 mg, 0.25 mmol) in DMF (20 mL) was added portion wise NaH (118 mg, 2.97 mmol, 60% dispersion in mineral oil) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodopropane (0.39 mL, 3.96 mmol) was added. After 18 h of stirring at rt, the excess NaH was quenched by the slow addition of brine (40 mL) [H2 evolution]. The product was then extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (4:1 hexanes/EtOAc) to yield the product (403 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.30 (t, 3H), 1.65 (t, 2H), 1.74-1.79 (m, 1H), 2.06-2.11 (m, 2H) 2.27 (s, 3H), 2.37-2.45 (m, 2H), 2.70-2.74 (dd, 1H), 2.84-2.91 (m, 2H), 3.45-3.55 (m, 3H), 3.73 (t, 2H), 3.97 (t, 2H), 4.16 (q, 2H), 6.68 (d, 1H), 6.6.74 (s, 1H), 7.05 (d, 1H), 7.79 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][C:12]2=[O:11])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(C2CCCC2O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cccc(C2CCCC2=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of oxalic chloride (9.0 ml) in methylene chloride (200 ml) was added dimethyl sulfoxide (9.6 ml) at -78° C. After 10 minutes, to the solution was added a solution of 1-hydroxy-2-(3-methoxyphenyl)cyclopentane (13 g) in methylene chloride (20 ml) at the same temperature. After 15 minutes, to the mixture was added triethylamine at -78° C. and the mixture was warmed at 0° C. for 1 hour. The reaction mixture was washed with water and brine and dried over magnesium sulfate. The organic solution was concentrated and the residue was purified by column chromatography on silica gel to give 2-(3-methoxyphenyl)cyclopentanone (8.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][C:11]([O:14][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:16])([CH3:13])[CH3:12].[H-].[Na+]>O1CCCC1>[C:21]([O:20][C:18]([N:17]([CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)[C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 82.2 %

Procedure:
A solution of 3-bromobenzylbromide (7.5 g, 30 mmol) and di-tert-butyliminodicarboxylate (6.5 g, 30 mmol) in anhydrous tetrahydrofuran (80 ml) was treated portionwise with sodium hydride (1.2 g, 60% dispersion in mineral oil). After stirring at ambient temperature for 7 hours the reaction mixture was partitioned between saturated aqueous ammonium chloride solution (90 ml) and ethyl acetate (2 lots of 250 ml). The combined organic layers were washed with brine (75 ml ), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of pentane and dichloromethane (2:1, v/v) to give 3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-bromobenzene as a pale yellow oil (9.52 g). A sample of this material (2.0 g, 5.2 mmol) was dissolved in anhydrous dimethylsulfoxide (30 ml) and the solution was treated with potassium acetate (1.52 g, 15.5 mmol), bis(pinacolato)diboron (1.45 g, 5.7 mmol), and [1,1′-bis-(diphenylphosphino)ferroceno]-dichloropalladium (II)-dichloromethane complex (0.13 g, 0.16 mmol). This mixture was stirred at 80° C. under an atmosphere of nitrogen for 5 hours, then cooled and then partitioned between water (100 ml) and diethyl ether (4 lots of 75 ml). The combined organic layers were washed twice with brine (75 ml), then dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of pentane and dichloromethane (2:1, v/v) to give B-{3-[N,N-bis-(tert-butoxycarbonyl)-aminomethyl]-phenyl}-pinacolato-boron as a colorless oil (1.08 g). 1H NMR (CDCl3, 500 MHz): δ 7.78 (s, 1H), 7.70 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H), 4.79 (s, 2H), 1.27 (s, 18H), 1.35 (s, 12H). MS(EI): 434(M++H).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:18])[CH2:9]P(OCC)(OCC)=O)(C)(C)C.[C:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][CH:20]([CH3:22])[CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:8]([OH:7])=[O:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CC(C)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(CC(=O)O)c1ccccc1
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (60%, 1.2 g) was added at 0° C. to a tetrahydrofuran solution (30 mL) of tert-butyldiethylphosphonoacetate (4.9 g). After 10 minutes, the temperature of the mixture was naturally returned to room temperature, and the mixture was stirred. After 1 hour, a tetrahydrofuran solution (10 mL) of isobutyrophenone (4.0 g) was added. After stirring for 13 hours, the organic layer was separated by adding water and ethyl acetate thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. 5.48 g among the resulting crude product (6.1 g) was dissolved in methanol (30 mL), a catalytic amount of 10% palladium carbon (250 mg) was added, and the mixture was reacted under pressuring by hydrogen (3.9 kg/cm2). After 1.3 hours, the catalyst was filtered off, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system). The resulting product (3.0 g) was dissolved in acetone (50 mL) and 5N hydrochloric acid (20 mL), and the mixture was stirred for 3 hours under reflux conditions. The solution was evaporated, to give the title compound as a reddish yellow oil (1.96 g, 58%: 3 steps).