Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][S:12](O)(=[O:14])=[O:13]>S(=O)(=O)(O)N.O>[N+:8]([C:3]1[CH:4]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:10])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: NS(=O)(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
157.6 g (1.0 mol) of 2-chloronitrobenzene are added to 699 g (6.0 mol) of chlorosulfonic acid and 2 g of sulfamic acid such that the temperature does not exceed 40° C. After addition is complete, the mixture is heated to 100° C. and stirred at this temperature for 6 hours. The reaction mixture is dripped into water at 15° C., and the precipitated crystals are filtered off with suction and washed with water. 236.2 g of 2-nitrochlorobenzene-4-sulfonyl chloride having a water content of 1.5%, corresponding to 232.7 g of 2-nitrochlorobenzene-4-sulfonyl chloride (90.8% of theory), are obtained.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH3:10].Cl.C(=O)=O>>[ClH:4].[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([Cl:7])=[O:17])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)CCCCCC(=O)O
Agent: Cl
Agent: O=C=O
Product: CN(C)CCCCCC(=O)Cl
Temperature: 30 °C

Procedure:
Oxalyl chloride (3367.33 g, 26.53 mol) is placed in a 5000 mL three-necked round-bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, and argon inlet. 6-(N,N-Dimethylamino)hexanoic acidhydrochloride (1146.00 g, 5.86 mol) is added over 3 h while maintaining the reaction temperature between 25-35 ° C. As reaction takes place, HCl, CO2, and CO are swept away from the mixture with argon. After addition is complete, the mixture is cooled to room temperature over 45 min. Excess oxalyl chloride is removed first by rotary evaporation at 50° C. (water aspirator vacuum) and then by Kugelrohr distillation at 60° C. (0.3 mm Hg) for 3 h. A quantitative yield of 3 is isolated as a dark red oil that solidifies on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and benzylamine. ES-MS m/e (%): 476 (M+H+, 100).
Reaction SMILES: Cl.[CH:2]1([CH2:5][C:6]([F:15])([F:14])[CH2:7][C@H:8]([NH2:13])[C:9]([O:11]C)=[O:10])[CH2:4][CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(O)(C)C.C(#N)C.[BH4-].[Zn+2].[BH4-]>[CH:2]1([CH2:5][C:6]([F:15])([F:14])[CH2:7][C@H:8]([NH:13][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([F:26])([F:16])[F:27])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H](N)CC(F)(F)CC1CC1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CC#N
Solvent: CC(C)O
Product: O=C(O)[C@H](CC(F)(F)CC1CC1)N[C@@H](c1ccccc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 7.5 %

Procedure:
(S)-5-cyclopropyl-4,4-difluoro-1-methoxy-1-oxopentan-2-amine hydrochloride (250 mg, 10 mmol), trifluoroacetophenone (179 mg, 10 mmol), potassium carbonate (426 mg, 30 mmol) was charged in isopropanol (10 mL) under nitrogen. The reaction mixture stirred for 20 h at 60° C. When TLC showed an absence of starting material, is the mixture was filtered under hot and the solids were washed with isopropanol (20 mL) and the filtrates were combined and concentrated under reduced pressure. The residue (400 mg, 10 mmol) was dissolved in acetonitrile (5 mL) and methanol (1 mL) and transferred to a dropping funnel under nitrogen. The zinc borohydride suspension prepared as described above was cooled to −45° C. and treated with the imine solution which was added drop-wise and the reaction was stirred at same temperature for 1 h. Once the staring material was consumed, is the reaction mixture was quenched with 1N HCl solution (10 mL) at 0° C. and then allowed to warm to room temperature. The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts washed with water (50 mL) and brine (50 mL). The organic extracts were evaporated under reduced pressure, and the residue re-dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (50 mL). The solution was dried (MgSO4) and the solvent evaporated under reduced pressure to give (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid as a pale oil (265 mg, 71.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:17](=O)[NH:16][C:15](=O)[N:14]([CH3:20])[C:13]1=O.[H][H]>[Pt].C(OCC)(=O)C>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]2[CH:17]=[N:16][CH2:15][N:14]([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CN1CN=CN(c2cc(N)c(F)cc2Cl)C1

Procedure:
A mixture of 1-(2-chloro-4-fluoro-5-nitrophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (28.5 g, 0.09 mol) and 5% platinum on activated carbon (1 g) in ethyl acetate is hydrogenated at 55 psi until hydrogen uptake is complete. The reaction mixture is then filtered and concentrated in vacuo to give the title product as a white solid, mp 244°-245° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23][CH:24](C)[CH3:25])[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(C)CCC(O)CCC)C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Agent: CCCC(O)CCN(C)Cc1ccccc1
Product: CCCC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, 1-(benzyl-methyl-amino)-hexan-3-ol affords the title compound: mass spectrum (ion spray) m/z=354 (M+1); 1H NMR (CDCl3) δ 7.45-7.41 (m, 2H), 7.29-7.20 (m, 7H), 6.81 (d, 1H), 4.58-4.53 (m, 1H), 3.47 (s, 2H), 2.54 (t, 2H), 2.20 (s, 3H), 2.03-1.90 (m, 2H), 1.88-1.60 (m, 2H), 1.53-1.38 (m, 2H), 0.93 (t, 3H).
Reaction SMILES: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](OC3C(=O)C4C(O)=CC(O)=CC=4OC=3C3C=CC(O)=C(O)C=3)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@@H]4C[C@H]5CC[C@H]6[C@@]7(O)CC[C@H](C8COC(=O)C=8)[C@@]7(C)CC[C@@H]6[C@@]5(C)CC4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O.[CH3:98][C@H:99]1[O:104][C@@H:103]([O:105][C@@H:106]2[CH2:111][C@H:110]3[CH2:112][CH2:113][C@H:114]4[C@@:119]5([OH:129])[CH2:120][CH2:121][C@H:122]([C:123]6[CH2:128][O:127][C:125](=[O:126])[CH:124]=6)[C@@:118]5([CH3:130])[C@H:117]([OH:131])[CH2:116][C@@H:115]4[C@@:109]3([CH3:132])[CH2:108][CH2:107]2)[CH2:102][C@H:101]([OH:133])[C@@H:100]1[O:134][C@@H:135]1[O:140][C@H:139]([CH3:141])[C@@H:138]([O:142][C@@H:143]2[O:148][C@H:147]([CH3:149])[C@@H:146]([O:150][C@@H:151]3[O:156][C@H:155]([CH2:157][OH:158])[C@@H:154]([OH:159])[C@H:153]([OH:160])[C@H:152]3[OH:161])[C@@H:145]([O:162]C(C)=O)[CH2:144]2)[C@@H:137]([OH:166])[CH2:136]1>>[CH3:98][C@H:99]1[O:104][C@@H:103]([O:105][C@@H:106]2[CH2:111][C@H:110]3[CH2:112][CH2:113][C@H:114]4[C@@:119]5([OH:129])[CH2:120][CH2:121][C@H:122]([C:123]6[CH2:128][O:127][C:125](=[O:126])[CH:124]=6)[C@@:118]5([CH3:130])[C@H:117]([OH:131])[CH2:116][C@@H:115]4[C@@:109]3([CH3:132])[CH2:108][CH2:107]2)[CH2:102][C@H:101]([OH:133])[C@@H:100]1[O:134][C@@H:135]1[O:140][C@H:139]([CH3:141])[C@@H:138]([O:142][C@@H:143]2[O:148][C@H:147]([CH3:149])[C@@H:146]([O:150][C@@H:151]3[O:156][C@H:155]([CH2:157][OH:158])[C@@H:154]([OH:159])[C@H:153]([OH:160])[C@H:152]3[OH:161])[C@@H:145]([OH:162])[CH2:144]2)[C@@H:137]([OH:166])[CH2:136]1
Reactant: CC(=O)O[C@H]1C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)O[C@H](C)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5CC[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Product: C[C@H]1O[C@@H](O[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3C[C@@H](O)[C@]3(C)[C@@H](C5=CC(=O)OC5)CC[C@]43O)C2)C[C@H](O)[C@@H]1O[C@H]1C[C@H](O)[C@H](O[C@H]2C[C@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](C)O2)[C@@H](C)O1

Procedure:
Further, rutin is a flavonoid glycoside which is contained in buckwheat and tea leaves. Digitoxin is colorless white-crystalline powder which is contained in digitalis. Lanatoside C is much contained in digitalis lanata. Lanatoside C is hydrolyzed with alkali to obtain deslanoside. Deslanoside is removed of glucose by an enzyme reaction to obtain digoxin. Strophanthin is a glycoside contained in apocynaceae plants. Glycyrrhizin and glycyrrhizard are colorless crystal contained in licorice roots. Amygdalin is much contained in bitter almond and fruit nucleus. Arbutin exists in rhododendron plants, and plants such as cowberry and uva-ursi.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H48N5O4Cl2 [(M+H)+] 720.3078, observed 720.3072.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:19])[C:6]2[CH:11]=[C:10](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])[N:9]=[C:8]([O:17][CH3:18])[CH:7]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([NH:4][C:5](=[O:19])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:9]=[C:8]([O:17][CH3:18])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COC/C=C/c1cc(C(=O)NC2CC2)cc(OC)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C(=O)NC2CC2)cc(OC)n1
Reaction time: 4 h

Procedure:
To a solution of N-cyclopropyl-2-methoxy-6-[(1E)-3-methoxyprop-1-en-1-yl]isonicotinamide from the previous step (1 eq.) in EtOAc (0.2 M) was added palladium (10% w/w over activated carbon, 15% loading). The reaction vessel was evacuated and back-filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 4 h. The reaction was quenched with CH2Cl2, filtered through celite and the insolubles washed further with EtOAc. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:9][C:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:11][CH:12]=1)=[O:7])C.Cl>C(O)C.O>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][NH:14][C:13]([C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:24]
Reactant: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83 %

Procedure:
Aqueous 1M sodium hydroxide (16.3 mL; 16.3 mmole) was added to a stirring solution of (12(a)) (1.17 g; 3.3 mmole) in ethanol (70 mL). The reaction mixture was stirred at ambient temperature for 19 hours, reduced to a small volume, diluted with water and adjusted to pH 2 by addition of 2M hydrochloric acid. The filtered solid was washed with water and dried in vacuo to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid (12(b)) as a white solid (83%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:11][CH2:12][CH3:13])(C)[NH:5][S:6]([NH2:9])(=[O:8])=[O:7].[CH3:15][O-].[Na+]>CO>[CH2:11]([CH:4]1[N:5]([CH3:15])[S:6](=[O:8])(=[O:7])[NH:9][C:3]1=[O:2])[CH2:12][CH3:13]
Reactant: CCCC(C)(NS(N)(=O)=O)C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Reaction time: 15 h
Yield: 125.9 %

Procedure:
A solution of N-(aminosulfonyl)-2-propyl-DL-alanine methyl ester (10.66 g; 47.53 mmol) in methanol (100 ml) was added in one portion to a solution of sodium methoxide (prepared from 2.0 g of Na in 100 ml of dry methanol under nitrogen) and the resulting reaction mixture was stirred for 15 hours. The mixture was neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin with stirring (20 minutes), and filtered. The filtrate was concentrated in vacuo to yield an oil which was dried in vacuo (4 hours) to afford 8.96 g (98%) of 4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =propyl;R2 =CH3 ; R3 =H).
Reaction SMILES: [CH2:1]([C:13]1C=C[C:16]([OH:19])=[CH:15][CH:14]=1)CCCCCCCCCCC.[NH2:20][CH2:21][CH2:22][CH2:23][Si](OCC)(OCC)OCC.C=O>C1(C)C=CC=CC=1>[O:19]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:1][C:23]=2[CH:22]=[CH:21][NH:20]1
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
This benzoxazine was prepared from 4-dodecylphenol (26.2 g, 100 mmol), 3-aminopropyltriethoxysilane (22.1 g, 100 mmol), paraformaldehyde (6.3 g, 210 mmol), and toluene (150 mL). The method to prepare this compound was the same as that used to make the previous benzoxazines. The final product was a clear, faint yellow liquid. The yield was 92%.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7](Br)[CH2:6][CH2:5][C@H:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]1.[OH-].[Na+]>C(Cl)Cl>[CH3:12][N:11]([CH3:13])[C:9]([C@H:4]1[CH2:5][CH2:6][C@@H:7]2[C@@H:2]([O:1]2)[CH2:3]1)=[O:10]
Reactant: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
Methylene chloride (125 mL) was cooled to 0° C., and (1S,3S,4S)-3-hydroxy-4-bromo-N,N-dimethylcyclohexanecarboxamide (25 g) was then added thereto. Thereafter, a 25% sodium hydroxide aqueous solution (16 mL) was added to the above obtained solution, and the temperature of the obtained mixture was then increased to room temperature, followed by stirring the mixture for 3 hours. Thereafter, the organic layer was separated from the reaction mixture, and was then concentrated and dried to solidify. Thereafter, the resultant was dissolved in ethyl acetate (100 mL), and was then filtered over silica gel (25 g). The filtrate was concentrated and dried to solidify, and heptane (250 ml) was then added thereto, followed by crystallization, to obtain the title compound (13.91 g, yield: 82%).
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:27][CH3:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=2)[C:10]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:9]1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:36].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:27][CH3:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:36])[CH:13]=[CH:14][CH:15]=2)[C:10]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:9]1)[CH3:3]
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Reactant: O=C=O
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)Br
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(O)c12
Reaction time: 12 h
Yield: 39 %

Procedure:
To 20 ml of diethyl ether containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 3.92 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-chloroindazole, 2.06 g of isopropyl bromide and 20 ml of diethyl ether. Into the mixed solution were introduced dried oxygen gas and dried carbon dioxide gas for 12 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.46 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-hydroxyindazole having the following analytical values in a yield of 39%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: Nc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CNc2ccccc2)cc1
Yield: 90 %

Procedure:
200 parts of aniline, 108 parts of benzyl alcohol and 10 parts of triphenyl phosphite are heated for 20 hours at 240° C in a stirred autoclave. The autoclave is then let down and the water of reaction which has formed, the excess aniline and the unconverted alcohol are distilled off under reduced pressure. 165 parts of N-benzylaniline, corresponding to a yield of 90% of theory, distil at a boiling point of 125° C/0.2 mm Hg.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(−)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3Br)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+:17]>C1COCC1.C(OCC)(=O)C.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[C:8]3[CH:9]=[CH:4][CH:5]=[CH:6][N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Brc1ncoc1-c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncoc2-c2ccc3c(c2)OCO3)nc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a degassed solution of 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (50 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol, 0.05 equiv) in THF (2 mL) was added 2-zinc bromo -pyridine (1 mL, 0.5 M in THF, 0.500 mmol, 2.6 equiv). The resulting reaction mixture was heated to reflux overnight, cooled to ambient temperature, treated with saturated aqueous ammonium chloride, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (50% ethyl acetate in hexane) provided 2-(5-Benzo[1,3]dioxol-5-yl-oxazol4-yl)-pyridine (22.7 mg, 46%). [LCMS: Rt=1.79 min, M+H=267.1]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28]Br)=[CH:23]2>>[Br:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:28][O:16][C:4]1[CH:5]=[C:6]([C:8]3([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:7]=[C:2]([F:1])[CH:3]=1)=[CH:23]2
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: BrCc1ccc2c(Br)cccc2c1
Product: COC1(c2cc(F)cc(OCc3ccc4c(Br)cccc4c3)c2)CCOCC1
Yield: 52 %

Procedure:
Using the procedure described in Example 5, 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with 5-bromo-2-bromomethylnaphthalene to give 4-[3-(5-bromonaphth-2-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyran in 52% yield, as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1>[C].[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 200 °C
Reaction time: 7.5 h

Procedure:
Into a reaction vessel were charged 6.00 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 96.5% ee) and 1.62 parts by weight of 5% palladium-carbon (STD-type, manufactured by N. E. Chemcat Corporation), thereby obtaining a mixture. The reaction vessel was sealed, the gas in the reaction vessel was replaced with nitrogen, and then the mixture was stirred at 200° C. for 7.5 hours to obtain a reaction mixture. Thereafter, the obtained reaction mixture was cooled and filtered. The obtained solid was washed with 20 parts by weight of 2-propanol. The washing liquid recovered after washing and the filtrate obtained by filtration were combined. The combined mixture was concentrated under reduced pressure to obtain 5.06 parts by weight of 1,1,3-trimethyl-4-aminoindane. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 3.3% ee and a recovery rate of 84.3%.