Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][CH2:17][CH2:18][C:19]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1)=[CH:13][C:12]([O:33][CH3:34])=[CH:11][CH:10]=2>ClCCl>[ClH:3].[ClH:3].[Cl:3][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][C:19]([CH2:18][CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:33][CH3:34])[CH:13]=3)[N:8]=[CH:7][C:6]=2[F:5])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:21]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCO)CC1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCCl)CC1
Product: Cl
Temperature: 20 °C

Procedure:
5.73 cm3 of thionyl chloride were added dropwise to a suspension of 0.6 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate in 10 cm3 of dichloromethane with stirring in the region of 20° C., and the mixture was stirred for 24 hours at a temperature in the region of 20° C. The reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was taken up in 3 times 30 cm3 of cyclohexane and evaporated to dryness as under the above conditions. 0.67 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate dihydrochloride was obtained in the form of a beige-colored solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[N:19][CH:20]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.Cl.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[OH:36].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[N:29]1[CH2:1][C:3]2[C:4](=[CH:9][C:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)=[N:19][CH:20]=3)=[C:11]([CH3:13])[CH:12]=2)[C:5]1=[O:6]
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1C=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cc3cc4c(cc3C)CN([C@@H]3CCCC[C@H]3O)C4=O)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
A solution of methyl 2-formyl-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate (0.06 g), trans-2-aminocyclohexanol hydrochloride (0.02 g), triethylamine (0.02 mL) and anhydrous magnesium sulfate (0.04 g) in THF (1.20 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (1.20 mL) and THF (1.20 mL), sodium triacetoxyborohydride (0.06 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.02 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1.[CH3:22][N+:23]([CH3:25])=[CH2:24].[I-]>ClCCl>[ClH:21].[OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:22][N:23]([CH3:25])[CH3:24]
Reactant: C=[N+](C)C
Reactant: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Agent: [I-]
Solvent: ClCCl
Product: COc1ccc(Cc2oc3ccc(CN(C)C)c(O)c3c2C)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (164) (Example 44) (1 g, 3.3 mmol) in 25 mL dichloromethane was added Eschenmoser's salt (0.6125 g, 3.3 mmol). The mixture was allowed to stir a room temperature for 20 h. The solvent was evaporated. The residue was chromatographed on silica gel (eluted with 20% EtOAc in hexane) to give the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[S:20][CH2:21][C@@H:22]([C:24](O)=[O:25])[N:23]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][N:29](C)[C:30](C1OC(C2C=CC=CC=2)=CC=1)=O>>[CH3:27][O:28][N:29]([CH3:30])[C:24]([C@@H:22]1[CH2:21][S:20][C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=[CH:12]3)=[N:23]1)=[O:25]
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)o1
Reactant: O=C(O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Product: CON(C)C(=O)[C@@H]1CSC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)=N1
Yield: 57.1 %

Procedure:
(R)—N-methoxy-N-methyl-2-(1-(phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxamide (65a) was prepared from 64a with the same method as used for 38d. 57.1% yield. 1H NMR (500 MHz, CDCl3) δ 7.92 (m, 2H), 7.77 (m, 3H), 7.51 (d, 1H, J=3.0 Hz), 7.46 (t, 1H), 7.35 (t, 1H), 6.61 (d, 1H), 5.58 (br, t, 1H) 3.82 (s, 3H), 3.73 (t, 1H), 3.43 (m, 1H), 3.21 (s, 3H). MS (ESI) m/z 452.1 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](Cl)=[O:4].[NH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[N:29][C:30]=3[NH2:32])[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=2)=[C:17]([F:46])[CH:16]=1>N1C=CC=CC=1>[NH2:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:24]=[C:23]([C:18]3[C:17]([F:46])=[CH:16][C:15]([NH:14][C:3](=[O:4])[C:2]([CH3:13])([CH3:1])[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:20]([O:21][CH3:22])[CH:19]=3)[C:31]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)C(C)(C)Cc1ccccc1
Reaction time: 5 h

Procedure:
2,2-Dimethyl-3-phenylpropanoyl chloride (52 mg, 0.264 mmol) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL). After 5 hours, the solvent was evaporated and the residue was first purified by flash column chromatography chromatography using dichloromethane/methanol (95:5 to 85:15) as mobile phase then by preparatory LC/MS to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (22 mg, 19%). 1H NMR (CDCl3-d) δ 1.33 (s, 6H), 1.57 (m, 2H), 1.92 (m, 2H), 2.15 (m, 6H), 2.30 (s, 3H), 2.49 (m, 4H), 2.66 (m, 3H), 2.95 (s, 2H), 3.84 (s, 3H), 4.76 (m, 1H), 5.51 (bs, 2H), 6.98 (d, J=6.86 Hz, 1H), 7.15 (m, 2H), 7.23 (m, 3H), 8.01 (s, 1H), 8.35 (s, 1H), 8.47 (d, J=11.88, 1H). LCMS LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=615.3, Rt=2.18 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: N#Cc1cccnc1Cl
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1cc(Br)ccc1=O
Temperature: 75 °C

Procedure:
To 5-bromo-2-pyridone (1.0 g) and 2-chloro-3-cyanopyridine (1.0 g) in dry N,N-dimethylformamide (20 ml) was added caesium carbonate (2.73 g), and the mixture heated at 75° C. under a nitrogen atmosphere for 24 h. The solvent was removed in vacuo from the mixture and the residue partitioned between ethyl acetate and water. The organic layer was evaporated and the residue purified by chromatography (silica gel, 0 to 4% MeOH/CH2Cl2) to give the title compound, crystallised from diethyl ether/isohexane: 1H NMR (400 MHz, CDCl3) δ 8.81 (1H, dd, J 2.0, 5.1), 8.17 (1H, dd, J 1.8, 7.6), 7.67 (1H, d, J 2.7), 7.56 (1H, dd, J 4.9, 7.6), 7.49 (1H, dd, J 2.5, 10.0), 6.62 (1H, d, J 9.8); MS (ES+) m/z 276 and 278 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[Cl:11]C1C(CCl)=CC(Cl)=C(Cl)N=1>>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([Cl:11])=[C:4]([Cl:10])[N:3]=1
Reactant: O=Cc1ccc(Cl)nc1Cl
Reactant: ClCc1cc(Cl)c(Cl)nc1Cl
Product: O=Cc1cc(Cl)c(Cl)nc1Cl

Procedure:
Obtained analogously to the process described for 2,6-dichloropyridine-3-aldehyde, using 2,5,6-trichloro-3-chloromethylpyridine instead of 2,6-dichloro-3-chloromethylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC
Reaction time: 1 h

Procedure:
While cooling with ice, a solution of 485.2 gm of 3,4-dimethoxyphenyl-acetic acid chloride in 1.1 liters of methylene chloride at 15° C. to 20° C. was added dropwise to a solution of 246.2 ml of aminoacetaldehyde dimethyl acetal and 315 ml of triethylamine in 2.2 liters of methylene chloride, and the mixture was stirred for one hour at 16° to 18° C. Then, it was extracted with water several times, dried over magnesium sulfate and concentrated by evaporation. The oil thus obtained slowly crystallized.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:14]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of crude methyl-8-hydroxy-octanoate (7, 1.24 g, 7.13 mmol, 1.0 equiv.) in CH2Cl2 (15 mL, 0.48M) at 0° C. was treated successively with CBr4 (3.07 g, 9.27 mmol, 1.3 equiv.) and PPh3 (2.61 g, 9.98 mmol, 1.4 equiv.) and the reaction mixture was stirred at 4° C. for 10 h. The, reaction mixture was then concentrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, hexanes) afforded 8 as a clear, colorless oil (1.25 g, 1.69 g theoretical, 74.0%): 1H NMR (CDCl3, 250 MHz) δ3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J =6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, CH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 6H, alkyl protons).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].Cl.[OH2:21]>>[CH3:3][N+:2]([O-:21])([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: O
Reactant: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: Cl
Product: COc1cccc(C2(O)CCCCC2C[N+](C)(C)[O-])c1

Procedure:
Tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted its free base in basified water (pH>9) and then extracted with ether. The solid was then heated under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 (use of Pt/C is suggested for its ease of removal) on carbon was then added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru filter aid. The filtrate was concentrated under vacuum while being heated to a temperature <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:5]2.S(Cl)([Cl:21])=O>O1CCCC1>[Cl:21][C:5]1[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: Clc1ccc(-c2cc3cc(Cl)cc(Cl)c3[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Clc1ccc(-c2[nH]c3c(Cl)cc(Cl)cc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
(1.0 g, 3.38 mmole) A solution of 5,7-dichloro-2-(p-chlorophenyl)-indole(in tetrahydrofuran is treated dropwise with 1.0 mL of thionyl chloride, stirred for 16 hours at room temperature, poured over ice and filtered. The filtercake is air-dried to afford the title product as a yellow solid, 0.85 g (76% yield), mp 148°-149° C., identified by IR, 1HNMR and elemental analyses.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:20]([O:19][C:17]([NH:24][C@H:25]([CH3:26])[C:27]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])=[O:28])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](N)CO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (5.0 g, 32.0 mmol), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmol), Boc-D-Alanine (6.06 g, 32 mmol), and DCC (7.26 g, 35.2 mmol) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 86% of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)-3-hydroxypropanoate.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[O:16])[CH3:15])[N:6]=1.O[Li:19].O>C1COCC1.O>[C:14]([C:7]1[N:6]=[C:5]([CH2:4][C:3]([O-:17])=[O:2])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=12)(=[O:16])[CH3:15].[Li+:19]
Reactant: COC(=O)Cc1nc(C(C)=O)c2ccccn12
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc(CC(=O)[O-])n2ccccc12
Product: [Li+]
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of (1-acetyl-imidazo[1,5-a]pyridin-3-yl)-acetic acid methyl ester (1.12 g, 4.82 mmol) in THF (15 mL) and water (7.5 mL) was added LiOH.H2O (202 mg, 4.82 mmol). The reaction was stirred at RT for 5.5 h until completion of the reaction. The mixture was concentrated under reduced pressure and the material thus obtained was used in the next step without further purification: MS (UPLC/MS): 219.2 [M+H]+, 241.2 [M+Na]+, 217.2 [M−H]−; tR (HPLC conditions f): 1.03 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(OCc2ccccc2)c1
Yield: 26.6 %

Procedure:
To a stirred solution of bromomethylbenzene (24.39 g, 143 mmol), 3-bromophenol (24.92 g, 144 mmol) in acetone (20 ml) was added potassium carbonate (59.72 g, 430 mmol). The suspension was refluxed overnight and then evaporated. To the residue was added H2O (100 ml) and extracted with EtOAc (3×80 ml). The combined EtOAc extracts were back washed with Na2CO3 and then dried over MgSO4, filtered and evaporated to get an off-white solid, which was purified via flash column chromatography (10% CH2Cl2 in hexane) to give 1-benzyloxy-3-bromo-benzene as a white solid (10 g, 67%): 1HNMR (DMSO-d6) 7.46-7.00 (m, 9H, Ar), 5.12 (s, 2H, CH2). The product was carried over to the next step.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9](O)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.S(Cl)([Cl:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([Cl:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCN(C2CCCCC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClC1CCN(C2CCCCC2)C1

Procedure:
To a stirred solution of 169 g. of N-cyclohexyl-3-pyrrolidinol in 600 ml. of chloroform, acidified with gaseous hydrogen chloride, is added 130 g. of thionyl chloride. This solution is refluxed for four hours, then poured onto ice water and made basic with sodium carbonate. The organic layer is dried over sodium sulfate, concentrated, and the residue distilled in vacuo to give N-cyclohexyl-3-chloropyrrolidine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11].FC1C=CC([B:22]([OH:24])[OH:23])=C(O[C@H](CC=C)C)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11])=[C:2]([B:22]([OH:24])[OH:23])[CH:7]=1
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1Br
Product: C=CC[C@H](C)Oc1ccc(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared from (S)-2-bromo-4-fluoro-1-(pent-4-en-2-yloxy)benzene in 100% yield following the same procedure as (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[CH:21][CH:20]=[N:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nccnc4c3O2)C1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.856 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.639 g, 3.222 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.248 g (77%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.36 (silica, methanol:ethyl acetate 1:9); mp>220° C. dec.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:18])[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A solution of 2.67 g of N-benzyloxycarbonyl-4(R)-thiazolidinecarboxylic acid in 42 ml of dry tetrahydrofuran was stirred and cooled to -15° C. in an ice/salt bath while there were added 1.15 g of N-ethylmorpholine followed after 2 minutes by 1.87 g of isobutyl chloroformate. After a further 3 minutes 0.73 g of tert.butylamine was added dropwise and the mixture was then allowed to warm to room temperature and was stirred overnight. Tetrahydrofuran was removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane The solution was washed in sequence with water, 10% citric acid solution, water, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulphate, filtered and evaporated to give 2.85 g of 3-(benzyloxycarbonyl)-N-tert.butyl-4(R)-thiazolidinecarboxamide as a solid which melted at 96°-98° C. after recrystallization from diethyl ether/n-hexane.
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].[Si]([O:22][CH2:23][CH2:24][O:25][CH2:26][N:27]1[C:35](I)=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])(C(C)(C)C)(C)C>>[OH:22][CH2:23][CH2:24][O:25][CH2:26][N:27]1[C:35]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]
Reactant: Cc1c(I)n(COCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Reactant: C#C[Si](C)(C)C
Solvent: C#Cc1ccccc1
Product: Cc1c(C#C[Si](C)(C)C)n(COCCO)c(=O)[nH]c1=O

Procedure:
In place of phenylacetylene in Example 38 (2), 0.82 ml (6 mmol) of trimethylsilylacetylene was used to react with 880 mg (2 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine for producing 1-[(2-hydroxyethoxy)methyl]-6-(2-trimethylsilylethynyl)thymine in the same manner as Example 38 (2). The obtained compound was dissolved in 100ml of methanol, was added to 1 ml of 1N sodium hydroxide aqueous solution and allowed to react for two minutes at room temperature. Then the reaction solution was neutralized with hydrochloric acid and concentrated. The resultant was distributed between ethyl acetate and aqueous layers, and the ethyl acetate layer then concentrated to dryness. The residue was crystallized from toluene/ethanol to obtain 170 mg of the target compound (Yield: 38%).