Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1-c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1c(-c2ccccc2)cccc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed and cooled to -78° C. and a 1.3 M s-BuLi solution in cyclohexane (2.2 eq) was added dropwise. The resulting reaction mixture was stirred at -78° C. for 30 min and TMSCl (1.2 eq) was added dropwise. The reaction was stirred at -78° C. for 30 min and allowed to warm to -30° C. The reaction was worked up in the usual manner. The crude product was purified by flash chromatography and recrystallization from hexanes to afford the title compound as a white solid (1.15 g, 39%). m.p. 159-160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10]O)[C:6]=2[CH:12]=1.S(Cl)([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:15][CH2:10][C:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1coc2ccc(F)cc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated successively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([CH2:9][NH2:10])[OH:8]>N1C=CC=CC=1>[OH:8][CH2:7][CH2:9][NH:10][CH:3]([CH3:4])[CH2:2][C:1]([OH:6])=[O:5]
Reactant: NCCO
Reactant: C/C=C/C(=O)O
Solvent: c1ccncc1
Product: CC(CC(=O)O)NCCO

Procedure:
A solution of 86 g of crotonic acid (1 mole) and ethanolamine (1 mole) in pyridine (200 ml) was refluxed for 2-3 hours and subsequently cooled. The resulting product was filtered and recyrstallized to yield the title compound having a m.p. (melting point) of 178-180° C. (compound 1.1, List of Compounds).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([CH2:17][CH:18]2[CH2:20][C:19]2([Cl:22])[Cl:21])=[C:11]([F:23])[C:10]=1[F:24]>CO.Cl>[Cl:22][C:19]1([Cl:21])[CH2:20][CH:18]1[CH2:17][C:12]1[C:11]([F:23])=[C:10]([F:24])[C:9]([CH2:8][OH:7])=[C:14]([F:15])[C:13]=1[F:16]
Reactant: Fc1c(F)c(CC2CC2(Cl)Cl)c(F)c(F)c1COC1CCCCO1
Agent: Cl
Solvent: CO
Product: OCc1c(F)c(F)c(CC2CC2(Cl)Cl)c(F)c1F

Procedure:
4-[(2,2-dichlorocyclopropyl)methyl]-2,3,5,6-tetrafluorobenzyl tetrahydropyran-2-yl ether (0.240 g) was heated at the reflux temperature for 3 hours in a mixture of methanol (5 cm3) and 2M hydrochloric acid (1 cm3). The solvent was evaporated under reduced pressure and water removed azeotropically from the sample by heating with toluene (2×10 cm3). The title product (0.15 q) was obtained as an orange oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12](=[O:20])(=[O:19])[N:11]=2)=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12](=[O:19])(=[O:20])[N:11]=2)=[CH:2]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: O=S1(=O)N=C(c2c[nH]c3ccccc23)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C2=NS(=O)(=O)c3ccccc32)c2ccccc21
Temperature: 80 °C

Procedure:
A solution of the product from example 1, step b (300 mg) was dissolved in DMF and treated with K2CO3 (166 mg, 1.2 mmol) followed by t-butyl bromoacetate (150 μL, 1 mmol). The reaction was heated to 80° C. for 1 h. Additional K2CO3 and t-butyl bromoacetate were added (1 mmol each) and the reaction was heated to 100° C. for 2 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed with water 3 times then dried over MgSO4 and concentrated to give the sub-title compound as a yellow solid. MS: ESI (positive): 397 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC.C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:15][C:23](=[O:24])[NH:11][C:10]1=[O:14]
Reactant: CCOC(=N)C(O)c1ccccc1Cl
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2Cl)O1
Reaction time: 1 h
Yield: 68 %

Procedure:
Ethyl 1-(2-chlorophenyl)-1-hydroxymethanecarboximidate hydrochloride (13 g., 52 mmoles) was combined with 350 ml. of tetrahydrofuran and cooled in an ice-water bath. Triethylamine (16.77 g., 0.166 mole) was added and the stirred mixture perfused with phosgene for 45 minutes at 0° C. After an additional 1 hour at the same temperature, the reaction mixture was poured slowly over 1 l. of crushed ice, with isolation and recrystallization from toluene according to Example 3 to yield 5-(2-chlorophenyl)oxazolidine-2,4-dione (7.43 g., 68%; m.p. 106°-108° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([C:9]3[O:10][C:11]([CH3:14])=[N:12][N:13]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:21][CH:20]=1)=[O:18].[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]([CH3:14])=[N:12][N:13]=2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1
Reactant: Cc1nnc(-c2ccc(C)c(Br)c2)o1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
Methyl 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate Methyl 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylate was prepared from 2-(3-bromo-4-methylphenyl)-5-methyl-1,3,4-oxadiazole and [4-(methoxycarbonyl)phenyl]boronic acid using method D. NMR; δH CDCl3 8.12,(2H, d), 7.94, (1H, dd), 7.90,(1H, d), 7.43,(3H, m), 3.96,(3H, s), 2.61,(3H, s), 2.33,(3H, s). LCMS; retention time 3.37 min, MH+ 309.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10].[CH3:12][O:13][CH2:14][CH2:15][C:16]#[CH:17].C(OCC)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][C:16]#[C:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10]
Reactant: C#CCCOC
Reactant: CC(=O)Oc1cnccc1I
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCC#Cc1ccncc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 mmol Palladium dichloride bis-triphenylphoshine and 0.97 mmol cupric chloride are dissolved in 64 ml tetrahydrofuran under an argon atmosphere. A solution of 30 mmol acetic acid 4-iodo-pyridin-3-yl ester [289473-46-7] and 38 mmol 4-methoxy-but-1-yne [36678-08-7] in 50 ml tetrahydrofuran is added in one portion and the reaction mixture is stirred at room temperature for 1 hour. 300 ml of diethyl ether are added and the precipitate is filtered off. The filtrate is washed successively with saturated, aqueous ammonium chloride solution (3×), water (2×) and brine. The organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: Cl[C@H:2]1[C@H:6]([Cl:7])[C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[O:3]1.[C:16]([O-])([O-])=O.[K+].[K+]>CCO>[Cl:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:4]=2[O:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)O[C@@H](Cl)[C@@H]2Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(Cl)coc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
trans-Methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate (58 mg, 0.23 mmol) is dissolved in EtOH (2 ml), treated with K2CO3 (187 mg, 1.35 mmol) and stirred at RT overnight. The mixture is concentrated to dryness, the residue is dissolved in 50% saturated NaCl (10 ml) and extracted with CH2Cl2 (3×10 ml). The combined organics are dried (K2CO3), filtered, and concentrated in vacuo to a yellow oil. The crude material is chromatographed over 10 g slurry-packed silica gel, eluting with 25% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 30 mg (58%) of ethyl 3-chloro-1-benzofuran-6-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.44, 4.43, 7.66, 7.79, 8.07, 8.21 ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[C:6]1([CH:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:15][CH:14]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CCC(Oc1ccc(N)cc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)CCC(Oc1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.25 g of N,N-dimethyl-γ-(4-aminophenoxy)benzenepropanamine in 30 ml of pyridine cooled to 10° C. by means of an external ice bath was treated with 1.86 ml of methanesulfonylchloride under a nitrogen atmosphere. The ice bath was removed and the reaction mixture stirred at room temperature overnight. The solution was poured into 30 ml of water, treated with acid and evaporated in vacuo. The residue was purified by high pressure liquid chromatography over silica gel eluting with methylene chloride/methanol/ammonium hydroxide (100:5:1). The appropriate fractions were combined and concentrated in vacuo providing 4.15 g of an oil which crystallized upon cooling. Recrystallization from ethanol provided 2.5 g of the desired title product as off-white crystals, m.p. 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13](Br)=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[Cu](C#N)[C:19]#[N:20]>CN(C)C(=O)C>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([C:19]#[N:20])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: CCCCCOC(=O)c1cc(Br)cc(C)c1N
Solvent: CC(=O)N(C)C
Product: CCCCCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 95.2 %

Procedure:
The above-described method (Example 2) was repeated to react pentyl 2-amino-5-bromo-3-methylbenzoate (2.3 g, 7.59 mmol) with copper cyanide (0.69 g, 7.74 mmol) in N,N-dimethylacetamide at 170° C. for 6 hours. Following working up similar to Example 2 and additional extraction with ethyl acetate and washing with aqueous 5% ethylenediamine solution, pentyl 2-amino-5-cyano-3-methylbenzoate (1.78 g, 89.2% of theory, 93.6 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)nc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)nc2cccnc21

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b]pyridin-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Li+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCCC(Oc1cccc(C#N)c1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(Oc1cccc(C#N)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.00 g (36.5 mmol) of ethyl 2-(3-cyanophenoxy)pentanoate in 10 ml of methanol is treated with a solution of 1.29 g (54.0 mmol) of lithium hydroxide in 10 ml of water and the mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo, extracted with ethyl acetate, and the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. A colourless solid is obtained; FAB 220
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=[N:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NN1CCOCC1
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Solvent: ClCCl
Product: Cc1c(C=NN2CCOCC2)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (the compound of Example 115-b) (420 mg) in dichloromethane (50 ml) was added 4-aminomorpholine (380 mg) at room temperature. After stirring overnight, the mixture was washed with water (20 ml), NH4Cl solution (20 ml) and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography developed by dichloromethane and methanol to give the title compound as a colorless oil (340 mg). ESI-MS: m/z 423 (MH+); 1H-NMR (CDCl3): δ 1.98-2.07 (2H, m), 2.23 (3H, s), 2.30 (3H, s), 2.59 (2H, t, J=6.9 Hz), 3.21-3.26 (4H, m), 3.53 (2H, s), 3.88-3.92 (4H, m), 4.10 (2H, t, J=5.9 Hz), 6.58 (1H, d, J=7.6 Hz), 7.03-7.15 (3H, m), 7.58-7.63 (2H, m), 8.40-8.51 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH2:9]1.[C:25]([OH:27])([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CCOCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CNCC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 9.99 mmol) was dissolved in Methylene chloride (50.0 mL, 7.80E2 mmol) and the reaction mixture was treated with Trifluoroacetic Acid (6.0 mL, 78 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was then removed en vacuo to afford the -Piperidin-3-yl-morpholine as a TFA salt. (M+H)=171.06. The crude product contained TFA which was neutralized in the next step. Crude NMR showed evidence of product formation. 1H NMR (400 MHz, DMSO, d6) δ 8.99 (m, 1H), 3.68 (m, 2H), 3.48 (m, 2H), 3.28 (m, 5H), 3.10 (m, 2H), 2.81 (m, 2H), 1.97 (m, 2H), 1.66 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: Ic1ccc(-c2cc[nH]c2)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]ccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 (5.15 g, 19.1 mmol) in DMF (6.1 mL) and CH2Cl2 (140 mL) under argon was cooled to 0° C. and then POCl3 (2.11 mL, 22.6 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 2.5 M NaOH (100 mL). The mixture was poured into water (500 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (Na2SO4), and the solvent was removed in vacuo. 1H NMR spectroscopy showed two regioisomers in a ˜6:1 ratio. The minor isomer exhibited signals at δ 7.21 and 7.39 ppm, compared with signals at δ 6.42 and 7.14 for the major isomer. The most downfield signal (7.39 ppm) is assigned to the proton adjacent to a formyl group, which occurs in the 2-formyl-4-aryl substituted pyrrole. Recrystallization from ethyl acetate afforded an orange solid corresponding to the major aldehyde (2.25 g). The mother liquor was concentrated and purified by flash column chromatography [silica, hexanes/ethyl acetate (3:1)]. The first fraction corresponded to the major aldehyde (1.25 g). The total yield of the title compound was 3.50 g (62%): mp 153-154 ° C.; 1H NMR δ 6.42 (m, 1H), 7.14 (m, 1H), 7.22 (m, 2H), 7.76 (m 2H), 9.59 (s, 1H), 10.72 (br, 1H); 13C NMR δ 93.5, 104.3, 111.4, 125.8, 128.6, 130.8, 133.1, 137.8, 179.4; FAB-MS obsd 296.9663, calcd 296.9651; Anal. Calcd for C10H8INO: C, 44.5; H, 2.7; N, 4.7. Found: C, 44.4; H, 2.7; N, 4.6.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(CC5(C(F)(F)F)CC5)CC4)oc3cn2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and methanesulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester following a procedure analogous to that described for Example 17. LC (method 1): tR=0.65 min; Mass spectrum (ESI+): m/z=484 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:30][CH2:29][CH:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCC1CCOCC1

Procedure:
The method described in Part E of Example 1 can be used to treat 7-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (7-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine. The same method can be used to treat 6-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (6-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22](=[CH:23][CH2:24][C@:6]12[CH3:7])[C:21]1[CH2:20][CH2:19][C:18](=[O:25])[CH2:17][C:16]=1[CH2:15][CH2:14]3)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]12[CH3:7])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=[O:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)C3=CC[C@]2(C)[C@H]1OC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
3.2 g of 17β-acetoxy-16α-ethyl-5(10),9(11)-estradien-3-one is dissolved in 120 ml of toluene and 40 ml of methylene chloride and combined at room temperature dropwise with a solution of 5.5 g of dichlorodicyano-p-benzoquinone in 80 ml of toluene and 20 ml of methylene chloride. The mixture is stirred for 16 hours at room temperature, filtered over neutral aluminum oxide, and concentrated. After crystallization from diethyl ether, 2.8 g of 17β-acetoxy-16α-ethyl-4,9,11-estratrien-3-one is obtained, m.p. 95°-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH:29]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29][NH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c(N)c2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c(NCc1c(Cl)cccc1Cl)c2=O
Temperature: 25 °C

Procedure:
To a solution of 3-amino-9-(2-hydroxy-4-methyl-pentyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (100 mg, 0.29 mmol) and 2,6-dichlorobenzaldehyde (130 mg, 0.74 mmol) in 1 mL each of HOAc and CH2Cl2 was added NaBH(OAc)3 (110 mg, 0.52 mmol). The mixture was stirred at 40° C. for 50 min before a second portion of NaBH(OAc)3 (110 mg) was added. After a total of 2 h, the mixture was quenched with NaHCO3 (5 g) in H2O (15 mL) slowly and was allowed to stir over night at room temperature. Partition between CH2Cl2 and H2O followed by extraction with CH2Cl2 afforded the organic residue that was purified on silica (0–5% MeOH in DCM) to yield the desired product as an yellow foam. M+1 503.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])[CH:18]=[N:19][CH:20]=1)=O)(C)(C)C>CCOCC.CO>[ClH:1].[NH:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C@@H:22]2[CH2:24][C@H:23]2[CH2:25][OH:26])[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C[C@@H]2C[C@H]2CO)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OC[C@@H]1C[C@H]1Cc1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2M anhydrous HCl in ether is added to a stirred solution of (1R,2S)-2-[[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]methyl]cyclopropylmethanol in dry MeOH at 0° C. The mixture is stirred at room temperature overnight and the conversion of starting material confirmed by TLC. The above solution is concentrated and purified by HPLC to obtain the title compound.