Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[O:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[NH3+]N.C(OCC)(=O)C>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[O:21][N:20]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCOc2noc(-c3ccc([N+](=O)[O-])cc3)n2)cc1OC
Agent: [Ni]
Agent: N[NH3+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCOc2noc(-c3ccc(N)cc3)n2)cc1OC
Temperature: 50 °C
Yield: 23.6 %

Procedure:
5 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyloxy}-5-(4-nitrophenyl)-1,2,4-oxadiazole (for preparation, see Example 67) were dissolved in 500 ml ethanol. 4 ml of hydrazinium hydroxide and a catalytic quantity of Raney nickel were added to the solution and the reaction mixture was heated at 50° C. for 30 minutes. The catalyst was then filtered off and the filtrate was concentrated to dryness. The remaining residue was reacted with 10% aqueous sodium carbonate solution and shaken with ethyl acetate. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude oily title compound that remained as a residue was purified by medium-pressure chromatography over silica gel (Lichroprep Si 60®) using 99:1 ethyl acetate/methanol as the eluent. 1.1 g of the title compound were obtained as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:20][C@H:19]3[CH2:21][C@H:22]([N:24]4[C:28]5[N:29]=[CH:30][N:31]=[C:32]([CH3:33])[C:27]=5[C:26]([C:34]#[C:35][Si](C)(C)C)=[CH:25]4)[CH2:23][C@H:18]3[CH2:17][O:16]2)=[CH:11][CH:10]=1>CO.CCOC(C)=O>[C:34]([C:26]1[C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[N:29][C:28]=2[N:24]([C@H:22]2[CH2:21][C@@H:19]3[O:20][CH:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=4)[O:16][CH2:17][C@@H:18]3[CH2:23]2)[CH:25]=1)#[CH:35]
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4cc(C#C[Si](C)(C)C)c5c(C)ncnc54)C[C@@H]3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cn([C@@H]2C[C@H]3COC(c4ccc(OC)cc4)O[C@H]3C2)c2ncnc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Potassium carbonate (191 mg, 1.38 mmol) was added to a solution of 7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-4-methyl-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (314 mg, 0.680 mmol) in MeOH (10.0 mL), and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an oil (215 mg, 81%). LC/MS: Rt=1.94 min, ES+ 390 (AA standard).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[CH:5]1[CH:18]([OH:24])[C:19]([O:21]CC)=[O:20])(=[O:3])[CH3:2].O[Li:26].O.[OH-].[Na+]>>[Li+:26].[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:6](=[O:17])[CH:5]1[CH:18]([OH:24])[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2]
Reactant: [Li]O
Reactant: CCOC(=O)C(O)C1C(=O)N(c2ccc(C)cc2)CCN1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCN(c2ccc(C)cc2)C(=O)C1C(O)C(=O)[O-]
Product: [Li+]
Yield: 87.6 %

Procedure:
According to the Step 1-2 in synthetic method for EXAMPLE 1, compound 109-3 (0.11 g) and LiOH—H2O (13.8 mg) were used instead of 1-1 (LP) and NaOH to obtain compound 109-4 (90 mg) as a beige amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[OH:29]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Product: O=C(Nc1ccccc1C(=O)O)c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
In analogy to example 2,-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and 2,4-difluoro-phenol. MS (m/e): 367.1 (M−H−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([NH:29][CH3:28])[CH2:27][OH:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CCO
Product: CNC(CO)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% methylamine in ethanol, the title compound was obtained as a light orange powder (165 mg) by flash chromatography of mixture of regioisomers which gave ABD783. 1H NMR (400 MHz, CDCl3): δ 2.10 (3H, s), 3.51 (1H, m), 3.60-3.62 (2H, m), 5.10 (3H, br s), 6.70-6.95 (3H, m), 7.10-7.15 (4H, m), 7.20-7.25 (1H, m), 7.34 (2H, d, J=8 Hz) and 7.73 (2H, d, J=8 Hz). MS, m/z: Calcd, 418.11. Found, 418.09 (M).
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@@H](O)Cc3ccccc3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to CH2Cl2 (8.0 mL). This mixture was added to a sample of 1-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(S)-propanol (320 mg, 0.67 mmol) in a 25 mL round-bottom flask with magnetic stirrer under N2. After stirring at room temperature overnight, the solution was concentrated in vacuo, the residue was diluted with water, and the solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product (300 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm particle size; UV detection at 254 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, methanol; 40-100% B in A in 8 min). The product-containing eluate was partially evaporated under reduced pressure to remove MeOH. The residual solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. Concentration gave the free amine (130 mg, 52%) as a yellow oil. LC-MS (ESI) m/z 375 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[ClH:7].[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13]O)[NH2:12]>C(Cl)Cl>[ClH:2].[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13][Cl:7])[NH2:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a stirred suspension of 104 g of phosphorous pentachloride in 550 ml of methylene chloride at -10° C., is added 70 g of L-serine methyl ester hydrochloride, in approximately 5 g portions, over a period of 40 minutes while the temperature is maintained between -10 and 0° C. The reaction mixture is then allowed to warm to room temperature with stirring. Stirring is continued for 2-3 hours and the mixture is then poured into 550 ml of stirred petroleum ether. The resultant mixture is filtered and the filter cake is washed with petroleum ether (3×100 ml) and then with ether (2×100 ml). The combined filtrate and washings are dried under vacuum over sodium hydroxide pellets to afford 71 g of β-chloroalanine methyl ester hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]#N)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Ba+2].[OH-:18].S(=O)(=O)(O)O>O>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]([OH:18])=[O:16])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC12CC1CN(Cc1ccccc1)C2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: O
Product: O=C(O)C12CC1CN(Cc1ccccc1)C2
Yield: 95.7 %

Procedure:
A mixture of 3-benzyl-1-cyano-3-azabicyclo-[3.1.0]hexane (2.77 g, 14.0 mmol) and barium hydroxide (4.47 g, 14.2 mmol) in water (100 ml) was heated to reflux for 18 hours. The reaction was then cooled and brought to neutral pH with sulfuric acid. The thick white mixture was filtered and washed twice with ethanol and twice with water. The filtrate was concentrated in vacuo, and the residue mixed with hot ethanol and filtered again. The filtrate was concentrated to provide the title product (2.91 g, 13.4 mmol, 96% yield). 1H NMR (D2O): 7.50 (bs, 5H), 4.36 (s, 2H), 3.9 (bs, 1H), 3.6 (m, 1H), 3.5 (bm, 2H), 2.14 (bs, 1H), 1.53 (bs, 1H), 1.09 (bs, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[OH:39][CH:40]1[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: OC1CCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCC(O)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-hydroxypyrrolidine were converted to the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:23])=[CH:18][C:15]=1[CH2:16][OH:17].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([C:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[CH3:24])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCCOCCOC2CCCCO2)c(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)CC(C)(C)c1ccc(OCCOCCOC2CCCCO2)c(C=O)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
The above benzyl alcohol (37 g, 0.08 mol) in dichloromethane (150 ml) was added dropwise to a suspension of pyridinium dichromate (36.25 g, 0.14 mole, Tetrahedron Letters, 399 [1979]) in dichloromethane (250 ml), with stirring. Stirring was continued overnight, and then the reaction mixture was diluted with ether and filtered through a magnesium sulfatesilica gel pad. The filtrate was washed with 1N hydrochloric acid and then it was evaporated in vacuo to give 31.2 g (87% yield) of 2-(2-[2-(2-tetrahydropyranyloxy)ethoxy]ethoxy)-5-t-octylbenzaldehyde, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2=[O:12].[C:13]12[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:18]C(=O)O[C:14]2=[O:15].CN(C1C=CC=CN=1)C.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[C:8](=[N:18][C:19]3[C:13]([C:14]1=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2cccc(F)c2-n2c1nc1ccccc1c2=O
Yield: 14 %

Procedure:
A solution of 7-fluoroisatin (300 mg, 1.8 mmol), isatoic anhydride (1.2 g, 7.3 mmol), and dimethylaminopyridine (222 mg, 2 mmol) in 5 mL of pyridine were heated at reflux temperature for 64 h. 50 mL of 0.2N HCl and 100 mL of chloroform were added and the chloroform layer was separated. The water layer was extracted with chloroform and the combined organic extracts were concentrated. Chromatography on silica gel eluting with chloroform gave the title compound in 14% yield: mp 264°-267° C.; 1H NMR (300 MHz, CDCl3) δ 8.46 (d, 1H) 8.02 (d, 1H) 7.82-7.92 (m, 1H) 7.79 (d, 1H) 7.64-7.74 (m, 1H) 7.52-7.64 (m, 1H) 7.40-7.49 (m, 1H).
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[S:16][CH2:17][CH2:18][N:19]=1.C(Cl)[Cl:21].C([C:25]1[C:34]([C:35](N)=[O:36])=[C:33]([OH:38])[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:39][CH3:40])[CH:31]=2)[N:26]=1)C>C1(C)C=CC=CC=1>[ClH:21].[S:16]1[CH2:17][CH2:18][N:19]=[C:15]1[NH:14][C:35]([C:34]1[CH:25]=[N:26][C:27]2[C:32]([C:33]=1[OH:38])=[CH:31][C:30]([CH2:39][CH3:40])=[CH:29][CH:28]=2)=[O:36]
Reactant: CCc1ccc2nc(CC)c(C(N)=O)c(O)c2c1
Reactant: NC1=NCCS1
Reactant: ClCCl
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: CCc1ccc2ncc(C(=O)NC3=NCCS3)c(O)c2c1
Product: Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
45.36 ml of 1.1 M of triisobutyl aluminum in toluene were added with stirring over 10 minutes at 7° to 10° C. to a mixture of 10.2 g of 2-amino-thiazoline and 500 ml of methylene chloride and the mixture was stirred at 7° to 10° C. for one hour. 4.88 of ethyl 6-ethyl-4-hydroxy-3-quinolin-carboxamide were added to the mixture which was then refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was taken up to 100 ml of aqueous N hydrochloric acid solution. The solution was heated at 70° C. for 2 hours and was treated with activated carbon and filtered. The filtrate was allowed to crystallize and was then vacuum filtered. The recovered product was washed with aqueous N hydrochloric acid solution and was dried under reduced pressure and crystallized from acetic acid to obtain 2.2 g of N-(4,5-dihydro-thiazol-2-yl)-6-ethyl-4-hydroxy-3 -quinoline-carboxamide hydrochloride melting at >260° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11])#[CH:2].C[Mg]Br.[CH:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1COCC1>[OH:20][CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11]
Reactant: C#Cc1ccc(F)c(F)c1F
Reactant: CCCCC=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(O)C#Cc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Under nitrogen replacement, 110 g of 1-ethynyl-2,3,4-trifluorobenzene was dissolved in 440 mL of THF. To this, 846 mL of methylmagnesium bromide (1.0 M in Toluene/THF=4/1) was added dropwise for 1 hour while ice-cooling, and stirred for 30 minutes. To this, 72.8 g of pentanal was added dropwise for 1 hour, warmed to room temperature, and stirred for 1 hour. After the reaction solution was poured into 300 g of ice/300 mL of concentrated hydrochloric acid, and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure to obtain a brown oily material. This was purified by column chromatography (silica gel, toluene) to obtain 183 g of 1-(3-hydroxy-1-heptynyl)-2,3,4-trifluorobenzene as a reddish brown oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]=[C:27]=[O:28])=[CH:20][CH:19]=1>>[CH2:25]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C=NCCc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NCCc4ccccc4)cc23)CC1
Yield: 64.1 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) 2-phenethyl isocyanate, 15.8 mg (65%) of the title compound were recovered.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][CH2:10][CH:11]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]=O>ClCCCl>[CH2:2]([O:9][CH2:10][CH:11]([CH2:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:12][CH2:22][Cl:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Reactant: Cl
Solvent: ClCCCl
Product: ClCOC(COCc1ccccc1)COCc1ccccc1
Temperature: 21 °C
Reaction time: 21 h

Procedure:
Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of 1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) and paraformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-dichloroethane at 0° C. The solution was then stored in a stoppered flask for 21 hours at 4° C. Next, the solution was dried over magnesium sulfate with warming to 21° C. then filtered and concentrated to give 17.5 g of 1,3-di-O-benzyl-2-O-chloromethylglycerol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH2:9][NH:8][C:7]=2[CH:11]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27])#[N:22].O>ClCCl>[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:34]([F:35])([F:37])[F:36])[C:31]=1[O:32][CH3:33])[C:26]([N:8]1[C:7]2[CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[CH:5][C:6]=2[S:10][CH2:9]1)=[O:27])#[N:22]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: FC(F)(F)c1ccc2c(c1)NCS2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(C#N)cc(C(=O)N2CSc3ccc(C(F)(F)F)cc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (5 mL), and triethylamine (0.56 mL) and 3-cyano-4-methoxy-5-trifluoromethylbenzoyl chloride (839 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (479 mg) as a pale yellow amorphous product.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[C:3]#[N:4].C(OCCCC)(=O)CCC>CCCCCC.C(O)CCC>[OH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[C:3]#[N:4]
Reactant: N#C[C@H](O)c1cccc(Oc2ccccc2)c1
Agent: CCCCOC(=O)CCC
Solvent: CCCCO
Solvent: CCCCCC
Product: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
The racemic ester, (R,S)-Cyano(3-phenoxyphenyl)methyl butyrate, (750 g) prepared by the method described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu, G.; DeshpandeA Tetrahedron Asymmetry 2000, 11, 3303–3309) is dissolved in a mixture of hexane (11 lit) and n-butanol (700 ml). The enzyme lipase from Candida rugosa (EC 3.1.1.3, Type VII, Sigma, USA) was immobilized in gelatin matrix according to the procedure described in literature by Fadnavis and Koteshwar (Fadnavis, N. W. and Koteshwar, K. Biotechnology Progress, 1999, 15, 98–104). The enzyme powder of average particle size 1 mm (1.5 Kg powder, 250 g enzyme) was placed in the reactor and the reaction mixture of the racemic ester in hexane was circulated at a flow rate of 85 ml/min through the enzyme reactor. The reaction temperature was maintained at 25° C. by means of a constant temperature circulating water bath. The progress of the reaction was monitored by chiral HPLC as described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu. G.; Deshpande. A. J. Chromatography A 2000, 189–193). The reaction was continued till almost all of the (R)-ester had reacted (8 h, 49% conversion) and the reaction came to a standstill. The reaction mixture was then drained from the bioreactor and the cycle was repeated The recovered reaction mixture consisting of unreacted (S)-ester, (R)-α-hydroxy-3-phenoxy-benzeneacetonitrile and butyl butyrate was then treated further to obtain (S)-α-hydroxy-3-phenoxy-benzeneacetonitrile as described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu, G.; Deshpande, A. Tetrahedron Asymmetry 2001, 12, 1695–1699). The enzyme placed in the bioreactor was used over 50 cycles over a period of one month without loss of activity (<5%).
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][Cl:6].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19]1[N:20]=[CH:21][C:22]2[CH2:28][NH:27][CH2:26][CH2:25][C:23]=2[N:24]=1.C(N(CC)CC)C>O1CCCC1.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19]1[N:20]=[CH:21][C:22]2[CH2:28][N:27]([C:1]([O:2][CH2:3][CH2:4][CH2:5][Cl:6])=[O:7])[CH2:26][CH2:25][C:23]=2[N:24]=1
Reactant: O=C(Cl)OCCCCl
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 2 h

Procedure:
Add a solution of 3-chloropropyl carbonochloridate (0.55 mL; 1.2 equiv; 4.51 mmoles) in tetrahydrofuran (25 mL) over 1 hour to a mixture of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1.00 g; 1.0 equiv; 3.75 mmoles) and triethylamine (1.10 mL; 2.1 equiv; 7.88 mmoles) in tetrahydrofuran (25 mL). Stir for 2 hours, then dilute with dichloromethane and saturated sodium bicarbonate and separate the layers. Further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts over sodium sulfate, filter, and concentrated to dryness to give a yellow oil. Purify the crude product by column chromatography (10% methanol in dichloromethane) to 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (1.146 g; 79%): MS (m/z): 387(M+1).