Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[Cl:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCc1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(C)c3C)c2cc1OC
Yield: 83.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (127 mg, yield 77%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH3:2].[CH:9](OCC)=[O:10]>>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH:9]=[O:10])[CH2:6][CH3:7])[CH3:2]
Reactant: CCCC(=O)OCC
Reactant: CCOC=O
Product: CCOC(=O)C(C=O)CC

Procedure:
The title compound was prepared from butyric acid ethyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: N#Cc1ccc(N2CCN(CCO)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinonitrile (350 mg, 1.51 mmol) and imidazole (236 mg, 3.47 mmol) in anhydrous DMF (3 mL) was added TBDMS chloride (295 mg, 1.96 mmol) in anhydrous DMF (2 mL) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified on silica gel column chromatography eluting with 30% EtOAc/isohexane, and increasing the polarity to 50% EtOAc/isohexane to afford 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-yl}-nicotinonitrile as a pale yellow solid (394 mg, 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]2[C:17](=[O:19])[CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Yield: 85.5 %

Procedure:
The preparation comprises dissolving cis-8-benzyl-2,8-diazabicyclo[4,3,0]nonane (5.0 g, 23.1 mmol) in dichloromethane (50 mL) and triethylamine (5 mL) under stirring in ice bath, dropwise adding a solution of acetyl chloride (1.8 g, 23.1 mmol) in chloroform (10 mL), continuing with the stirring until the reaction finishes, distilling off the solvent, and chromatographing on silica gel with petroleum ether and ethyl acetate to give cis-8-benzyl-2-acetyl-2,8-diazabicyclo[4,3,0]nonane (5.1 g, 85.5%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][Si](C)(C)C)=[N:4][C:5]([O:8][Si](C)(C)C)=[N:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].II.[OH-].[Na+]>ClCCCl.O>[Cl:22][CH2:21][CH2:20][CH2:19][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:13])[NH:4][C:5]1=[O:8]
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Reactant: ClCCCBr
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1F

Procedure:
A mixture of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine (1 g, commercially available from Lancaster), 1-bromo-3-chloropropane (0.44 mL) and I2 (10 mg) in 1,2-dichloroethane (10 mL) was heated to reflux for 30 h. Then the reaction mixture was treated with water and the pH was brought to 7 using aqueous 6N NaOH solution, the mixture was extracted twice with DCM, the organic phase dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with DCM/MeOH 95/5 to give 35 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=[CH:14][C:15]=2[N+:16]([O-])=O)=[O:8])=[CH:5][CH:4]=1.C([OH:32])(C)C>C(Cl)Cl>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:32])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(SC)cc3)ccc2[N+](=O)[O-])cc1
Reactant: CC(C)O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(S(C)=O)cc3)ccc2N)cc1
Yield: 57 %

Procedure:
Following the same procedure as described in Example 10, step 2 (scheme 10), but substituting compound 120 for compound 209, the title compound 210 was obtained in 57% yield [after column chromatography (5% isopropanol in DCM)].
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: C=CCN
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([CH2:19][CH:20]=[CH2:21])([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][CH:6]=[CH2:7]>CO.[Pd]>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:9])=[O:10])([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH3:7]
Reactant: C=CCC(CC=C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide (326 mg, 1.0 mmol), (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)+; 1H NMR (300 MHz, CDCl3): δ0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9 Hz, 2H), 7.76 (d,J=9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16]1>>[CH3:14][C:15]1([CH2:20][NH:21][C:2]2[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CC1(CN)CCOC1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Product: CSc1ncc2ccnc(NCC3(C)CCOC3)c2n1

Procedure:
The title compound was prepared according to the method described for Preparation 175 using of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33) and (3-methyltetrahydrofuran-3-yl)methanamine at 130° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](Cl)=O)=[CH:16][C:3]1=2.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].N1C=CC=CC=1.Cl.[NH2:45][OH:46]>COCCOCCOC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH:18]=[N:45][OH:46])=[CH:16][C:3]1=2
Reactant: NO
Reactant: O=C(Cl)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Solvent: COCCOCCOC
Product: O=C1c2ccccc2COc2ccc(CC=NO)cc21
Temperature: -78 °C

Procedure:
A solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetyl chloride (15.00 g) in 150 ml of dry diglyme was stirred at -78° C. under nitrogen as lithium tri-tert-butoxyaluminohydride (104.6 ml of a 0.5M solution in diglyme) was added slowly dropwise over one hour. The reaction was stirred ten minutes at -78° C. and then quenched with 3 ml of glacial acetic acid added slowly dropwise. After warming the reaction to room temperature 50 ml of pyridine and 2 equiv. of hydroxylamine hydrochloride (7.27 g) was added and the slurry stirred at 50° C. for two hours. The solvent was evaporated using high vacuum and the residue taken up in chloroform and 1N HCl. The layers were separated and the aqueous phase extracted with chloroform. The combined organic phases were dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (silica; 5:2 hex-EtOAc) and recrystallized from ethyl acetate-hexane to give 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetaldoxime, as crystals, m.p. 132°-134° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([CH3:28])[NH2:27])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16].CO.[BH4-].[Na+]>C1C=CC=CC=1>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:27][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-trifluoromethylphenyl glyoxal (2.1 g) and 2-(4-carbomethoxyphenyl)-1-methylethanamine (2.0 g) in benzene (150 ml) was refluxed under Dean & Stark conditions for 2 hours. The solvent was replaced with methanol (150 ml), the mixture was cooled in ice and sodium borohydride (4.0 g) was added portionwise. The mixture was stirred at ambient temperature for 3 hours, the solvent was evaporated and the residue was partitioned between water (100 ml) and chloroform (100 ml). The aqueous phase was further extracted with chloroform (100 ml), the combined organic extracts were dried (Mg SO4) and evaporated to an oil which was crystallised from hexane to give the title compound, m.p. 80°-83° as a 25:75 mixture of diastereoisomers. (25% RR,SS:75% RS,SR). τ(CDCl3) 8.95 (3H,d,J=6 Hz) 6.6-7.6 (5H,m), 6.13 (3H,s), 5.3 (1H,m) 2.72 (2H,d,J= 8 Hz), 2.1-2.5 (4H,m), 1.92 (2H,d,J=8 Hz).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[CH:18]=1)=[O:16].[I:26]I>O1CCCC1.CCOC(C)=O>[CH3:13][O:14][C:15]([C:17]1[S:21][C:20]2[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=2[C:18]=1[I:26])=[O:16]
Reactant: II
Reactant: COC(=O)c1cc2c(s1)CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(c1I)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
A −78° C. solution of diisopropylamine (23.2 g, 230 mmol) in Tetrahydrofuran (THF) (100 mL) was treated with added n-BuLi (92 mL, 230 mmol) dropwise. The pale yellow solution was stirred at 0° C. for 30 min and recooled to −78° C. To above solution was added the solution of 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid methyl ester (25 g, 127 mmol) in 20 mL THF dropwise over a period of 5 min. The deep-red solution was stirred at −78° C. for 45 min, the solution of Iodine (48.5 g, 191 mmol) in 20 mL THF was added. The mixture was stirred at −78° C. for 30 min and then warm to room temperature, quenched with saturated aqueous NH4Cl (100 mL) and saturated aqueous Na2S2O3(100 mL). The aqueous layer was extracted with ethyl acetate (150 mL×2). The combined ethyl acetate solution was dried over Na2SO4 and concentrated, which was purified by silica gel chromatography eluted with PE:EtOAc=10:1 to afford title product (15 g, 36% yield). LCMS (m/z) ES+=323 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:34]=[CH:35][N:36]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:44]([C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:34]=[CH:35][N:36]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:52](=[O:53])[C:51]5[CH:55]=[CH:56][C:48]([C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:49][CH:50]=5)[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(N)c4)cn4ccnc34)cc2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (14) (2.35 mmol), triethylamine (3.53 mmol), and tetrahydrofuran (20 mL) is treated dropwise with a solution of 4-t-butylbenzoyl chloride (2.35 mmol) in tetrahydrofuran (10 mL). The mixture is stirred at room temperature for 1 hr. Water (50 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The extracts are washed with water (2×50 mL) and brine (1×50 mL), dried over magnesium sulfate, and evaporated in vacuo. The residue is triturated with diethyl ether to give 4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15) as a cream solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([CH2:9][S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=[O:7].[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:25]>CN(C=O)C>[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:3].[Cl:25][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:9]=1[CH:6]=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)CSc1ccccc1C(=O)O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=Cc1sc2ccccc2c1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
Vilsmeier reagent was prepared via the dropwise addition of POCl3 (7.9 mL, 84 mmol) into ice-cold DMF (14 mL). A solution of 2-carboxymethylsulfanyl-benzoic acid (3.0 g, 14 mmol) in DMF (15 mL) was added dropwise to the Vilsmeier reagent. The resulting mixture was warmed to room temperature and then heated to 80° C. for 3.5 h. The reaction mixture was cooled to ambient temperature. Crushed ice was added until a bright yellow precipitate appeared. The solid was isolated by filtration. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate 3:2) gave the title compound (1.87 g, 68%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.59-7.53 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1.O.C(Cl)Cl>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(OCCc2cccc(NC)n2)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CNc1cccc(CCOc2ccc(C[C@@H](CC(=O)O)c3cccnc3)cc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
2.0 M NaOH (15 mL, 30 mmole) was added to a solution of ethyl (S)-4-[4-[2-[6-(methylamino)pyridin-2-yl]ethoxy]phenyl]-3-(pyridin-3-yl)butanoate (9.2 g, 22 mmole) in dioxane/H2O (100 mL), and the mixture was heated at 50° C. After 18 hr, the reaction was cooled to RT, acidified with 10% HCl (25 mL), and concentrated to 1/3 volume to precipitate a gum. The supernatant was decanted and the gum was partitioned between H2O and CHCl3. The layers were separated and the aqueous layer was extracted with CHCl3 (3×). The combined organic layers were dried (MgSO4)and concentrated, and the residue was taken up in H2O and 2 M NaOH (30 mL). The solution was washed with Et2O (3×), and the Et2O extracts were discarded. The aqueous solution was acidified with 10% HCl (50 mL), concentrated to 1/3 volume, and extracted with CHCl3 (3×). The organic layers were combined, dried (MgSO4), and concentrated to leave a foam. This foam was taken up in CH2Cl2, and the solution was diluted with hexanes and concentrated. This process was repeated three times. The resulting solid was dried in vacuo at 65° C. to afford the title compound (7.96 g, 92%): 1H NMR (400 MHz, MeOH-d4) δ 88.28 (narrow m, 1 H), 8.21 (d, J=1.7 Hz, 1 H), 7.68 (narrow m, 1 H), 7.48 (dd, J=8.5, 7.3 Hz, 1 H), 7.30 (dd, J=7.9, 4.9 Hz, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.72 (d, J=8.6 Hz, 2 H), 6.56 (d, J=7.3 Hz, 1 H), 6.44 (d, J=8.5 Hz, 1 H), 4.20 (t, J=6.6 Hz, 2 H), 3.31-3.42 (m, 1 H), 3.02 (t, J=6.6 Hz, 2 H), 2.97 (dd, J=13.6, 6.5 Hz, 1 H), 2.87 (s, 3 H), 2.77 (dd, J=13.6, 8.9 Hz, 1 H), 2.71 (dd, J=15.6, 6.4 Hz, 1 H), 2.62 (dd, J=15.6, 8.9 Hz, 1 H); MS (ES) m/e 392 (M+H)+. Anal. Calcd for C23H25N3O3.0.1H2O: C, 70.25; H, 6.46; N, 10.68. Found: C, 70.32; H, 6.50; N, 10.32.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([CH:10]=1)[O:4][CH2:3][CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(F)cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Yield: 84.4 %

Procedure:
A suspension of 8.00 g of 2-(2-chloroethoxy)-4-fluoroanisole, 5.75 g of phthalimide and 3.24 g of potassium carbonate in 15 ml of N,N-dimethylformamide was heated for 2 hours at 120°-130° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered to give 10.4 g of N-[2-(5-fluoro-2-methoxyphenoxy)ethyl]phthalimide as colorless crystals, which were recrystallized from ethanol as colorless needles, m.p. 134.5°-136° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7](O)[C:6]=1[O:14][CH2:15][CH2:16][I:17].[C:18]([O:26]CC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1CCCCC1.C(O)C>[I:17][CH2:16][CH2:15][O:14][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][I:1])[O:26][C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: O=Cc1ccc(OCCI)c(OCCI)c1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCCI)c(OCCI)cc2oc1=O

Procedure:
To 1.73 g (10.8 mmol) of the bis-iodoethoxy-hydroxybenzaldehyde from Example 33 was added diethyl malonate, 2.1 g (4.6 mmol), and this mixture was heated on a steam bath. When the mixture had become homogeneous, two drops of piperidine were added. After the mixture had cooled, a precipitate formed. The solution was diluted with a few milliliters of ethanol and reheated to boiling on the steam bath. After the solution had cooled, it was filtered and the precipitate product retained. The product was a solid with a m.p. of 162°-165° C. Proton NMR confirmed the structure of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[C:12]([NH:15][NH2:16])(=O)[CH3:13]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:12]([CH3:13])=[N:15][N:16]=[C:10]1[SH:11]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CC(=O)NN
Product: Cc1cccc(C)c1-n1c(C)nnc1S

Procedure:
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 2,6-dimethylphenyl isothiocyanate and acethydrazide are reacted to produce 4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol which is converted to 4-(2,6-dimethylphenyl)-3-methyl-4H-1,2,4-triazole. This triazole (1.87 g 0.01 mole) in 100 ml of tetrahydrofuran at -60° C. bath temperature is reacted with 6.9 ml of 1.6N n-butyllithium in hexane. The resulting mixture is stirred for fifteen minutes. Then using the procedure of Example 1, Part A above, this anion is reacted with 1-(β-phenethyl)-4-piperidinone to produce the product, which is recrystallized from ethyl acetate-hexane to give the subtitled product, mp 189°-192° C., with a C:H:N ratio of 73.30:7.77:14.27.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]2[O:21][CH2:22][C:23]([CH2:26][OH:27])([CH3:25])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:23]1([CH2:26][OH:27])[CH2:22][O:21][C:20]([C:17]2[CH:18]=[N:19][C:14]([O:10][CH2:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][CH:2]3[CH3:1])=[CH:15][CH:16]=2)=[N:24]1
Reactant: CC1(CO)COC(c2ccc(Cl)nc2)=N1
Reactant: CC1CCCN1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(CO)CO2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of 3-(2-methylpyrrolidin-1-yl)propan-1-ol (1.9 g, 13.4 mmol) in dry DMF (40 ml) is treated at 0° C. with sodium hydride (60% dispersion in mineral oil, 536 mg, 13.4 mmol) and stirred 15 minutes at 0° C. Then, a solution of [2-(6-chloropyridin-3-yl)-4-methyl-4,5-dihydro-1,3-oxazol-4-yl]methanol ax55 (1.8 g, 7.9 mmol) in dry DMF (40 ml) is added dropwise over 15 minutes and the resulting mixture is stirred at room temperature for 1 day. The mixture is then poured into ice-cold water (250 ml) and extracted with ethyl acetate (4×50 ml). The organic layers are combined, dried over sodium sulfate and concentrated. The residue is dried under high-vacuum with heating to leave a solid. This solid is taken up in ethyl acetate, washed with brine and filtered. After phase separation, the aqueous layer is extracted twice with ethyl acetate, the combined organic phases are washed three times with water, dried over magnesium sulfate and concentrated to afford 1.4 g of 80% pure (4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazol-4-yl)methanol ax56.