Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:25]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:25])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 16 %

Procedure:
To a solution of 2-phenylbenzo[d]oxazole-7-carboxylic acid in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr. To the resulting mixture, water (10 mL) and aqueous hydrochloric acid (1 N) was added to pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated and dried in vacuum. The crude product was purified by pre-HPLC to obtain 2-phenylbenzo[d]oxazole-7-carboxamide as a white solid (40 mg, yield 16% for 2 steps). 1H-NMR (400 MHz, DMSO-d6) δ 7.48-7.52 (t, J=8 Hz, 1H), 7.62-7.68 (m, 3H), 7.81-7.83 (dd, J1=8 Hz, J2=1 Hz, 1H), 7.88-7.92 (d, J=8 Hz, 2H), 7.96-7.99 (dd, J1=8 Hz, J2=1 Hz, 1H), 8.30-8.33 (dd, J1=8 Hz, J2=2 Hz, 2H); LC-MS (ESI) m/z 239 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:27][CH:26]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
The product of Example 1, Step 3 (15.2 g, 78.7 mmol), 4-benzyloxyaniline HCl (15.6 g, 78.7 mmol) and Et3N (27 mL, 196.9 mmol) were combined in DMF (125 mL) and heated to 60° C. for 1 h. The reaction mixture was cooled and H2O (200 mL) was added dropwise over 1 h. The resulting yellow/orange precipitate was filtered and washed with Et2O to provide the title compound as a yellow powder (25.8 g, 92%). MS (ES+) m/e 356 [M+H]+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:4]2[CH:3]=[C:2]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C)CC1
Reactant: C1CCNC1
Product: COC(=O)c1ccc(N2CCCC2)cc1OC1CCN(C)CC1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
The methyl 4-fluoro-2-(1-methylpiperidin-4-yloxy)benzoate (10.6 g, 40 mmol) was mixed with pyrrolidine (14 g, 200 mmol) and heated at 70° C. for 3 hours, then heated at 100° C. for 1 hour before concentrating under vacuum. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (100 mL). The combined organic layer was dried over MgSO4 and concentrated to 12.5 g of an oil which was purified by flash chromatography, using THF/Hex/Et3 N 20/75/5 then 40/55/5 and finally 60/35/5, to give 11.9 g (37 mmol, 93%) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1ccc(F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluoro-α-(R)-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 521 (M+H).
Reaction SMILES: [Na+].[CH:2]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([O-:24])(=O)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].P(Cl)(Cl)(Cl)(Cl)Cl.[Na+].[Cl-]>ClCCl.C1(C)C=CC=CC=1>[CH:2]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:33])(=[O:24])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 4′-isopropoxycarbonylaminobiphenyl-4-sulfonic acid sodium salt (283 g, 0.79 mol), toluene (700 ml) and pyridine (35 ml, 0.43 mol) was stirred vigorously at RT and POCl3 (215 ml) was slowly added dropwise such that the internal temperature was kept between 30° C. and 45° C. Subsequently, PCl5 (100 g) was added at 35° C. in about 6 portions and the mixture was heated to 60° C. within 30 min. Afterward, further PCl5 (100 g) was added at 70° C. within 15 min and the mixture was left to stir without further heating for 1 h. In this time, the internal temperature fell to about 30° C. The mixture was diluted with dichloromethane (500 ml) and then worked up. To this end, a mixture of ice-water (5 kg), saturated NaCl solution (1000 ml) and dichloromethane (1000 ml) was initially charged with vigorous stirring and the reaction mixture was slowly added dropwise. In this time, the temperature was kept at from 15° C. to 25° C. by adding ice (2 kg). Subsequently, stirring was continued for 1 h, in the course of which the temperature was allowed to rise up to 30° C. The phases were separated and the aqueous phase was extracted twice using dichloromethane (1500 ml). The combined organic phases were reextracted using water (8000 ml), dried over Na2SO4 and concentrated by evaporation under reduced pressure. About 360 g of crude product were obtained as beige crystals. These were taken up in dichloromethane and filtered through a silica gel layer (15×30 cm, 70–200 μm), the layer was rinsed using dichloromethane and the filtrate was concentrated by evaporation. 270 g (96%) of isopropyl(4′-chlorosulfonylbiphenyl-4-yl)carbamate were obtained as yellow crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>C(O)C.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Agent: [Pd]
Solvent: CCO
Product: BrCCCCCCOCCCCCCc1ccc2ccccc2n1
Yield: 73.5 %

Procedure:
A solution of 2-[6-[(6-bromohexyl)oxy]-1-hexynyl]quinoline (2.29 g) in ethanol (120 ml) was hydrogenated at room temperature and pressure over pre-reduced 10% palladium on carbon (1 g) for 20 min. The catalyst was removed by filtration through hyflo and the filtrate evaporated in vacuo to a brown oil. Purification by FCC eluting with hexane-ether (2:1) gave the title compound as a pale brown oil (1.70 g), t.l.c. (hexane:ether 2:1) Rf 0.21.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(Cl)nc1NCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (8.00 g, 49.1 mmol) and 3-amino-1-propanol (4.50 mL, 58.9 mmol) in ethanol (200 mL) was added sodium carbonate (26.0 g, 245 mmol). The solution was vigorously stirred at rt for 24 h. The mixture was filtered over Celite® and the filtrate concentrated under reduced pressure. The resulting solid was triturated with Et2O to give the product as a white solid (9.80 g, 99%). 1H NMR (400 MHz, CDCl3) δ 1.86 (qt, 2H), 2.00 (s, 3H), 3.55 (t, 2H), 3.64 (t, 2H), 4.92 (broad, 2H), 7.68 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1.[F:20][C:21]([F:34])([F:33])[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:30](=[O:31])[CH2:29][CH2:28][C:25]3[CH:26]=[N:27][C:22]([C:21]([F:20])([F:33])[F:34])=[CH:23][CH:24]=3)[CH:15]=2)[N:10]=1
Reactant: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc(C(F)(F)F)nc1)Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of the product of Step B (307 mg, 1.2 mmol), the product of Step E (404 mg, 1.2 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 10 mL methylene chloride was added 4-dimethylaminopyridine (222 mg, 1.8 mmol) followed by 1-(3-dimethylaminopropyl)3-ethylcarbodiimide HCl (349 mg, 1.82 mmol). The resulting mixture was stirred at r.t. for 3 days. The solvent was removed under vacuum and residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate/triethylamine (1:7:0.1) to afford the product, MS: m/z 455 (MH+), as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:12][S:11][C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]2[CH3:20])=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:20])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CN1C(=Nc2ccccc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3)n2C)ccc1Cl

Procedure:
8.52 g (0.02 mole) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-phenyliminothiazolidin-4-ol in 100 ml of glacial acetic acid are heated at the boil for 3 hours, the solvent is distilled off and the residue is made to crystallize using water. Melting point 180° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F.F.F.C(N(CC)C(C)C)(C)C.[F:59]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34][F:59])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CO)nn2)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CF)nn2)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.C[Si](OS(O[Si](C)(C)C)(=O)=O)(C)C.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: OCCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: BrCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.8 %

Procedure:
A mixture of 100 g 1-bromodecan-10-ol, 2.1 g bis(trimethylsilyl)sulphate, 43 g 3,4-dihydro-2H-pyran and 500 ml dichloromethane is stirred for 6 hours at room temperature. Several drops of pyridine are added and the reaction mixture evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent to yield 58 g of 1-bromo-10-[tetrahydropyranyloxy]decane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C>[Cu]I.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.O1CCCC1>[CH:12]1([C:10]2[CH:11]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]3([CH3:18])[CH3:17])[CH2:14][CH2:13]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1

Procedure:
Following general procedure D and using 6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32, 0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (3 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.025 g, 0.1 3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2].[OH:22]O>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:22])[C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:21]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Reactant: OO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccc([N+](=O)[O-])cc1C=C2

Procedure:
400 Mg. 8-nitrodibenzo[b,f]thiepin-3-carboxylic acid is stirred for 24 hours in 200 cc. acetic acid and 1.5 cc. 30% hydrogen peroxide. The product is filtered, washed with water and dried to yield 315 mg. (74%) of pure product, m.p. 278°-281° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([CH2:24][CH3:25])([OH:23])[CH2:21][CH3:22])=[C:14]([CH3:26])[CH:13]=1)[CH2:10][CH3:11])[CH3:8].O>O1CCCC1>[CH2:7]([C:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)([C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([CH2:21][CH3:22])([OH:23])[CH2:24][CH3:25])=[C:14]([CH3:26])[CH:13]=1)[CH2:10][CH3:11])[CH3:8]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(C=Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)CC
Yield: 62.3 %

Procedure:
A 1 M solution of LiAlH4 in tetrahydrofuran (5.28 mL, 5.28 mmol) was added to a solution of 4-{1-ethyl-1-(4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl)-propyl}-2-methyl-phenol (Example 1-(4); 800 mg, 2.11 mmol) in tetrahydrofuran (8 mL) at room temperature. The mixture was heated under reflux for 18 hours and cooled, and then water was added. The mixture was filtered, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=7/1) to give the title compound (500 mg, 62%).
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:17])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:17])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)SCCCCCCCCCCCC(=O)Nc1ccccc1OCCCC(=O)O
Yield: 17.1 %

Procedure:
A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 mL) was treated at room temperature under a nitrogen atmosphere with 2.5N sodium hydroxide solution (0.6 mL). Methanol (2×2 mL) was used to clear the mixture, and the reaction allowed to continue until TLC analysis showed no ester remained. The filtered mixture was concentrated in vacuo and the residue obtained stirred with water (30 mL). After aging, the mixture was filtered (The cake is the sodium salt of the product (100 mg), and the stirred filtrate acidified with dilute hydrochloric acid, aged, filtered, washed with water and dried to give product 8 (0.02 g) as a white solid. M.P. 82°-84° C., with softening from 66° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:19])[CH3:18]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.768 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.01 g) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. 4-Bromobutyl acetate (1.26 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (80 mL), and extracted with ethyl acetate (100 mL×3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (1.084 g) as a colorless transparent oil.
Reaction SMILES: CN(C)CCN(C)C.Br[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:43]=[CH:42][C:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH:40]=[O:41])[CH:38]=4)[CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(OCC)C>[F:18][C:19]1[CH:43]=[CH:42][C:22]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([N:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH:40]([OH:41])[C:10]5[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][CH:11]=5)[CH:38]=4)[CH2:33][CH2:32]3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: COc1cccc(Br)n1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: CN(C)CCN(C)C
Solvent: CCOCC
Product: COc1cccc(C(O)c2ccc3c(c2)N(C2CCN(CCc4ccc(F)cc4)CC2)CC3)n1
Yield: 76.5 %

Procedure:
Tetramethylethylenediamine (0.26 ml) was added to 6-bromo-2-methoxypyridine (0.32 g) synthesized in accordance with the method described in Tetrahedron, 1373 (1985). and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.4 g) and diethyl ether was employed as the solvent. The resultant mixture was treated as in Example 93 to give the title compound (0.401 g) as colorless crystals (yield: 76.5%).
Reaction SMILES: [Li][CH3:2].[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C:5](=[O:11])[CH2:4]2.O>C(OCC)C>[CH3:2][C:5]1([OH:11])[CH:6]2[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]2)[CH2:4]1
Reactant: O=C1CN2CCC1CC2
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a well-stirred solution of MeLi [3.0M/diethyl ether] (67.0 mL, 201 mmol) in anhydrous diethyl ether (150 mL) at −78° C. was added, dropwise, a solution of quinuclidin-3-one (12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting solution was maintained at −78° C. for 1 hour, then at room temperature for 18 hours. Water (60 mL) was added dropwise at 0° C. and the mixture was concentrated in vacuo to give a residue, which was purified by neutral aluminum oxide column chromatography (0-20% MeOH in CHCl3) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To stirred acetonitrile (250 mL) at 0° C. was slowly added concentrated sulfuric acid (100 mL). The resulting solution was added dropwise to a mixture of 3-methylquinuclidin-3-of (9.10 g, 64.5 mmol) in acetonitrile (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 60 hours, then cooled with an ice bath and basified with aqueous sodium hydroxide solution to pH 10. The mixture was extracted with 5:1 (v/v) CHCl3/i-PrOH. The organic layer was concentrated to afford a residue which was diluted with 2N aq. HCl and washed with 5:1 (v/v) CHCl3/i-PrOH. The remaining aqueous layer was then basified with 2N NaOH and extracted with 5:1 (v/v) CHCl3/i-PrOH. The combined organic layers were washed with water, dried (Na2SO4) and concentrated to give 9.5 g (82%) of the desired compound as a light yellow oil. The 2 enantiomers of the above intermediate are separated from each other by using chiral column on supercritical fluid chromatography (SFC) system.