Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C=O)CCC=CCC1.[CH:10]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[C:18]12([O:28][CH2:29][C:30]3[NH:34][C:33]([CH:35]4[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]4)=[N:32][C:31]=3[C:42]([OH:44])=[O:43])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.[CH3:45][O:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>>[CH2:16]([O:17][C:42]([C:31]1[N:32]=[C:33]([CH:35]2[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]2)[NH:34][C:30]=1[CH2:29][O:28][C:18]12[CH2:25][CH:24]3[CH2:26][CH:20]([CH2:21][CH:22]([CH2:23]3)[CH2:27]1)[CH2:19]2)=[O:43])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:45][O:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:54][C:42]([C:31]2[N:32]=[C:33]([CH:35]3[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]3)[NH:34][C:30]=2[CH2:29][O:28][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:44])[CH:49]=1
Reactant: O=C(O)c1nc(C2CCC=CCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2
Reactant: O=CC1CCCCC1
Reactant: COC(=O)c1cccc(N)c1
Agent: O=CC1CCC=CCC1
Product: COC(=O)c1cccc(NC(=O)c2nc(C3CCC=CCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(OCc1ccccc1)c1nc(C2CCC=CCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2

Procedure:
5-(Adamantan-1-yloxymethyl)-2-cyclohept-4-enyl-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 216, steps a, b, c, d with the modification that cyclohept-4-enecarboxaldehyde (D. F. Murray et al. J. Org Chem. 1986, 51, 1) was used in step d instead of cyclohexanecarboxaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the resulting 5-(adamantan-1-yloxymethyl)-2-cyclohept-4-enyl-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid methyl ester according to the procedure of Example 20, step d to afford 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohept-4-enyl-1H-imidazole-4-carbonyl]-amino}-benzoic acid methyl ester. The methyl ester was hydrolysed according to the procedure of Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.90 (1H, br s), 12.40 (1H, br s), 9.87 (1H, br s), 8.44 (1H, s), 7.93 (1H, d), 7.63 (1H, d), 7.42 (1H, t), 5.81 (2H, m), 4.79 (2H, s), 3.04 (1H, m), 2.30 (2H, m), 2.11 (5H, m), 1.96 (2H, m), 1.76-1.53 (14H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 59.69; H, 7.90; N, 7.88%. C36H52N4O9.2.1 mols H2O requires: C, 59.81; H, 7.84; N, 7.75%.
Reaction SMILES: [CH:1]([S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4])=[CH2:2].[N+:13]([CH:16]([CH3:18])[CH3:17])([O-:15])=[O:14].C(N(C(C)C)C(C)C)C.Cl>CC(=O)OCC>[CH3:17][C:16]([N+:13]([O-:15])=[O:14])([CH3:18])[CH2:2][CH2:1][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: C=CS(=O)(=O)Oc1ccccc1
Reactant: CC(C)[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCS(=O)(=O)Oc1ccccc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.43 g of phenyl ethenesulfonate and 4.60 ml of 2-nitro-propane was heated to 80° C. and, at 80° C., 0.89 ml of ethyidiisopropylamine was added dropwise. The mixture was stirred at 80° C. for 4 hours and 30 minutes, left to stand at RT for 16 hours and then stirred at 80° C. for a further 2 hours. Cooling to RT was followed by addition of 250 ml of a 2N aqueous HCl solution and extraction 3 times with 150 ml of EA each time. Drying over Na2SO4 and removal of the solvent in vacuo were followed by coevaporation 3 times with 100 ml of toluene each time. 13.47 g of a pale yellow oil were obtained.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23]([NH2:26])[CH:24]=[CH2:25]>ClCCl>[CH2:23]([NH:26][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:8])[C:18]=1[N+:19]([O-:21])=[O:20])[CH:24]=[CH2:25]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 105.2 %

Procedure:
Triethylamine (17.0 mL, 123 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (20.0 g, 82.3 mmol) in dichloromethane (350 mL) followed by the dropwise addition of allylamine (5.90 mL, 78.2 mmol). The solution was allowed to stir and warm to room temperature overnight. The solvent was evaporated under reduced pressure and the resulting orange solid was suspended in water (300 mL). Solid sodium carbonate was added to adjust the pH to 10-11 and the suspension was stirred for 2 hours at 0° C. A yellow solid was isolated by filtration and dried under vacuum overnight to yield N-allyl-2-chloro-3-nitroquinolin-4-amine (21.7 g) that contained small amounts of an impurity and water.
Reaction SMILES: C([O:5][CH2:6][C:7]1[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][CH:12]=1)(C)(C)C.Cl[C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.[IH:24]>>[I:24][C:17]1[CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][OH:5])[CH:8]=2)[N:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OCc1cccc(B(O)O)c1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: OCc1cccc(-c2cc(I)ncn2)c1

Procedure:
The compound was prepared according to Example 1 using 3-tert-butyloxymethylphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:38][NH2:39]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:38][N:39]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][C:16]([S:19]([N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=S(=O)(c1ccc(N=C=S)cc1)N1CCCCC1
Reactant: NN
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1)N1CCCCC1
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-(4-Isothiocyanato-benzenesulfonyl)-piperidine (2.0 g, 7.4 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-[4-(piperidine-1-sulfonyl)-phenyl]-amine as brown solid in 29% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:26][N:27]1[CH:31]=[C:30](I)[CH:29]=[N:28]1>CN(C=O)C>[CH3:26][N:27]1[CH:31]=[C:30]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]2)[CH:29]=[N:28]1
Reactant: Cn1cc(I)cn1
Reactant: COC(=O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(-c2cnn(C)c2)n1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
Into a solution of methyl 1H-pyrazole-3-carboxylate (10 g, 79.3 mmol) in DMF (80 ml), cuprous oxide (0.567 g, 3.96 mmol), salicylaldoxime (1.08 g, 7.93 mmol), Cs2CO3 (64.4 g, 198.4 mmol) and 1-methyl-4-iodo pyrazole (16.5 g, 79.9 mmol) were added and the mixture was stirred at 110° C. for 48 h. The reaction mixture was quenched with saturated solution of aqueous NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by flash-chromatography. Yield 2.9 g. 1H-NMR (400 MHz; DMSO-d6): δ 3.83 (s, 3H), 3.88 (s, 3H), 7.90 (s, 1H), 8.29 (d, 2H). LC-MS: [M+H]=207.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:27])[CH3:2].[O:30]1[CH2:35][CH2:34][N:33]([C:36]([CH2:38][CH2:39][C:40]#[CH:41])=[O:37])[CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:41]#[C:40][CH2:39][CH2:38][C:36]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)=[O:37])[CH:13]=2)[C:8]([OH:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:27])[CH3:2]
Reactant: C#CCCC(=O)N1CCOCC1
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(C#CCCC(=O)N1CCOCC1)cc2C(F)(F)F
Yield: 106 %

Procedure:
The title compound (65.2 mg, 88%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(phenyl)oxindole (57.2 mg) and 4-morpholinocarbonyl-1-butyne (31.1 mg) by the procedure similar to that described in Reference Example 21. The compound obtained was further purified by reverse phase HPLC with water-acetonitrile-trifluoroacetic acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O=[Th]=O>[C:1]1([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:5]1[C:6]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[O:7][C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: Oc1ccccc1
Agent: O=[Th]=O
Product: c1ccc(Oc2ccccc2)cc1
Product: c1ccc2c(c1)oc1ccccc12

Procedure:
However, it is more desirable to prepare diaryl ethers by the dehydration of phenols. The dehydration was first reported by P. Sabatier and A. Mailhe (Compt. Rend., 151, 1910, 492-494). They passed phenol over a thoria catalyst at 410° C. and atmospheric pressure to obtain diphenyl oxide and dibenzofuran as a byproduct.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([C:37]([N:39]3[CH2:42][CH:41]([O:43][C:44]4[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=4)[CH2:40]3)=[O:38])=[N:34][N:33]=2)=[CH:28][CH:27]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[N:8]1([CH2:48][C:47]2[CH:46]=[CH:45][C:44]([O:43][CH:41]3[CH2:42][N:39]([C:37]([C:35]4[O:36][C:32]([C:29]5[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)=[N:33][N:34]=4)=[O:38])[CH2:40]3)=[CH:51][CH:50]=2)[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Reactant: C1CNC2(C1)CCOC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC56CCOC6)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
7-Oxa-1-azaspiro[4.4]nonane TFA salt (0.07 g, 0.29 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.044 ml, 0.32 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.11 g, 0.29 mmol) and finally sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.072 g (51%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62-1.74 (m, 3H), 1.79-1.9 (m, 2H), 2.10 (dd, 1H), 2.42 (dd, 1H), 2.53-2.55 (m, 1H), 3.41 (d, 1H), 3.48 (d, 1H), 3.63 (d, 1H), 3.69 (q, 1H), 3.80 (d, 1H), 3.88 (s, 3H), 3.91 (td, 1H), 4.09 (dd, 1H), 4.54 (dd, 1H), 4.62 (ddd, 1H), 5.08 (ddd, 1H), 5.15 (ddd, 1H), 6.84 (d, 2H), 7.17-7.21 (m, 2H), 7.25 (d, 2H), 8-8.05 (m, 2H). MS (APCI+) m/z 491.2 [M+H]+, LC purity: 96%
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:32][C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:36]([F:39])([F:38])[F:37])[C:34]=1[CH3:35])#[N:29]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:36]([F:39])([F:37])[F:38])[O:32][C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 540 mg (1.48 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 500 mg (1.59 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 50° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 160 mg of a black powder (yield: 17.7%; mp: 176-178° C.)
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](O)=[O:5])[CH3:2].S(Cl)(Cl)=O.ClN1C(=O)CCC1=O.[ClH:23].[Cl:24]Cl>>[Cl:23][C:3]([CH2:1][CH3:2])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([Cl:24])=[O:5]
Reactant: ClCl
Reactant: CCCCC(CC)C(=O)O
Reactant: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O=S(Cl)Cl
Product: CCCCC(Cl)(CC)C(=O)Cl
Temperature: 70 °C
Yield: 17.6 %

Procedure:
To 100 g of 2-ethylhexanoic acid (0.693 moles) was added 247.5 g of thionyl chloride (2.080 moles) over 30 minutes and then the solution was heated at 70° C. for 2 hours. To the cooled solution was added 185.2 g of N-chloro succinimide (1.387 moles), 165.0 g of thionyl chloride (1.387 moles) and 2.0 ml of concentrated HCl. The mixture was heated at 80° C. for 2 hours, after which time there was no more apparent Cl2 gas being given off. The mixture was cooled and filtered. The filtrate was distilled at atmospheric pressure to remove the SOCl2 and then distilled to give a major fraction at 95°-105° C. (20 mm) weighing 28.00 g. Purity was determined by GLC analysis. Purity (area %) was 85.7%; yield was 17.6%. The product had a satisfactory IR, and the NMR showed no detectable extra chlorination.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Li])[CH2:16][CH2:17][CH3:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: [Li]CCCC
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: CCCCC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (3.92 g) and butyl lithium (1.56M hexane solution, 15 ml) to give 1-(3,4,5-trimethoxyphenyl)-1-pentanone (2.84 g).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:17].[Cl:32][C:33]1[N:38]=[C:37]([Cl:39])[C:36]([CH2:40]I)=[CH:35][N:34]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH:20]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:40][C:36]1[C:37]([Cl:39])=[N:38][C:33]([Cl:32])=[N:34][CH:35]=1)[CH3:17]
Reactant: CCOC(=O)Cc1cc(OC)ccc1OC
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)ccc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 2,5-dimethoxyphenylacetic acid ethyl ester (2.24 g, 10.0 mmol) (Aldrich) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(2,5-dimethoxy-phenyl)-propionic acid ethyl ester as a colorless oil. (Yield 1.00 g, 51.9%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
Thymidine (1.918 g, 8.0 mmol) was dried under reduced pressure for a while, pyridine was then added in an argon atmosphere, and the mixture was stirred. 4,4′-Dimethoxytrityl chloride (DMTr-Cl) was added at 0° C., and the mixture was allowed to return to room temperature over about 2 hours with stirring. After confirmation of completion of the reaction by TLC, the reaction was quenched with water. This solution was concentrated under reduced pressure, the concentrate was dissolved in dichloromethane, and the solution was washed with a saturated aqueous solution of copper sulfate and with brine. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH:CH2Cl2=1:9). The eluate fraction was evaporated under reduced pressure, and the residue was dissolved in a small amount of ethyl acetate. Hexane was added to this solution for reprecipitation to give the title compound 5′-DMTr-Thd. Yield 3.67 g, 82.7%.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:25]([N:28](C(C)C)[CH2:29]C)(C)C.Cl.CNC.O>CN(C=O)C>[CH3:25][N:28]([CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=12)=[O:24]
Reactant: O=C(CCCCCl)NCCc1c2n(c3ccccc13)C(=O)CCC2
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCCC(=O)NCCc1c2n(c3ccccc13)C(=O)CCC2
Reaction time: 48 h

Procedure:
15 g 6-Oxo-10-[2-(5-chlorovaleryl)aminoethyl]-6,7,8,9tetrahydropyrido[1,2-a]indole (D 3 of EP-0213696), 14.6 ml diisopropylethylamine, 1 g KI and 3.5 g dimethylamine hydrochloride were dissolved in 100 ml DMF and stirred for 48 hours at room-temperature. After further stirring for 7 hours at 40° C. the reaction mixture was dissolved with water and extracted with ethyl acetate. After acid-base separation the product was crystallised from diisopropylether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:43](OCC)(OCC)OCC.Cl.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[CH:43]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2ncn3Cc2cc(-c3ccc(F)cc3)no2)cc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthoformate (2.6 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined at heated at reflux for 24 hours. An analysis by HPLC indicated the reaction was incomplete. Therefore, pyridine hydrochloride (0.25 g) was added, and the reaction vessel was fitted with a Dean-Stark trap. The reaction was heated at reflux for an additional 1.8 days, and additional triethyl orthoformate (1 mL) was added and heating was resumed. After the reaction was heated for a total of three days, it was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over magnesium sulfate; and filtered. The solution was purified by column chromatography on silica gel (eluting with 5% ethyl acetate in dichloromethane) to provide 2.0 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a pale yellow solid.