Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([CH3:18])=[C:11]([CH3:19])[C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Cu]Cl>[NH2:15][C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([Cl:20])[C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=1
Reactant: Cc1cc([N+](=O)[O-])c(OCc2ccccc2)c(Cl)c1C
Agent: Cl[Cu]
Solvent: CO
Product: Cc1cc(N)c(OCc2ccccc2)c(Cl)c1C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
1-Benzyloxy-2-chloro-3,4-dimethyl-6-nitrobenzene (3.00 g, 10.3 mmol) was dissolved in MeOH (420 mL) and cooled to +2° C. Copper(I) chloride (6.11 g, 30.8 mmol) was added followed by KBH4 (3.88 g, 72.0 mmol) portionwise added at +2° to +4° C. during 1.5 h. The reaction mixture was stirred at +2° C. for 1 h and more KBH4 (400 mg, 7.41 mmol) was added. After 1 h at +2° C. additional KBH4 (120 mg, 2.22 mmol) was added and the stirring was continued for another 20 min. Filtration and evaporation of the solvent gave a residue which was extracted between EtOAc (400 mL) and water (75 mL). Drying (MgSO4) and evaporation afforded 2.94 of crude product. Purification by flash column chromatography (SiO2, CHCl3) yielded the title compound (2.14 g). Mp: 57°-58° C.; 1H NMR (DMSO-d6): δ 7.54 (d, J=6.5 Hz, 2H), 7.42-7.34 (m, 3H), 6.52 (s, 1H), 4.83 (s, 2H), 4.79 (s, 2H), 2.12 (s, 6H); 13C NMR (DMSO-d6): δ 140.00, 138.91, 137.30, 133.00, 128.27, 128.22, 127.91, 127.33, 121.23, 115.35, 72.73, 20.24, 15.45; MS (EI, 70 eV): m/z (rel.int.) 286/284 (M+23,42/100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[H-].[Na+].I[CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:18])[C:11]([CH3:13])=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnc(C)n2C)ccc1Br
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
3-(4-Bromo-3-methylphenyl)-5-methyl-1,2,4-triazole (D62, 0.60 g, 2.4 mmol) was stirred under Ar in dry DMF (6 ml) as sodium hydride (80% dispersion, 0.21 g, 7.2 mmol) was added. After stirring for 30 min, iodomethane (0.3 ml, 4.8 mmol) was added. This mixture was stirred for 1 h, and treated with water (30 ml), giving a beige precipitate. This was filtered off and dried, giving the title compound (0.49 g, 77%) as a beige solid. 1H NMR (250 MHz, d6DMSO) δ(ppm): 7.92 (s, 1H), 7.65 (m, 2H), 3.80 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate (11.8 g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl>CN(C)C=O>[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46][O:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
490 mg (1.00mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 40 mL of dimethylformamide, 3.60 mg (26.0 mmol) of potassium carbonate and 2.88 g (20.0 mmol) of 2-dimethylaminoethyl chloride hydrochloride were added and the mixture was stirred at 50° C. for 12 hours. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 230 mg of 7-(2-dimethylaminoethoxy)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[OH:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=2[OH:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)c2ccc(Cl)cc2)c1
Temperature: 100 °C

Procedure:
p-Chlorobenzoyl chloride (33.25 g; 0.19 mole) was added with cooling during 20 minutes to a stirred solution of 2-(3-amino-4-hydroxyphenyl)propionitrile (28.35 g; 0.175 mole) in dry pyridine (200 ml.) at 0°-3° C. After addition was complete the mixture was heated at 100° C. for one hour. It was then evaporated under reduced pressure to yield crude 2-(3-p-chlorobenzamido-4-hydroxyphenyl)propionitrile as an oil. The oil was boiled for 30 minutes during which time the temperature of the vapour above the oil rose to 130° C. On cooling the residue solidified. Recrystallisation of the solid from methanol yielded 2-(2'-p-chlorophenyl-5'-benzoxazolyl)propionitrile (29.00 g.) m.p. 150°-153° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:6]=1[NH2:28])=[O:4].[OH-].[Na+]>C(O)C>[NH2:28][C:6]1[C:7]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[N:8][C:9]2[C:14]([C:5]=1[C:3]([OH:4])=[O:2])=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(N)c(-c2ccc(-c3cccnc3)cc2)nc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(-c2ccc(-c3cccnc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 20 °C
Yield: 81.4 %

Procedure:
To a solution of 0.097 g of 3-amino-6-fluoro-2-[4-(3-pyridinyl)-phenyl]-4-quinolinecarboxylic acid methyl ester in 10 ml of ethanol was added 1.0 ml of 2.5N aqueous sodium hydroxide. The solution was stirred at reflux for 0.5 hour. The solution was concentrated to a small volume in vacuo and then diluted with 10 ml of water. The solution was acidified with 0.2 ml of glacial acetic acid, warmed briefly and cooled to 20° C. The solid was collected, washed with water, and dried in vacuo, giving 0.076 g of the desired compound as a yellow powder, mp 260°-268° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])Cl)[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)=[O:17].P(O)(O)([O-])=O.[Na+]>C(Cl)Cl>[CH3:7][C:8]1([CH3:36])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:15])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C@H:9]1[C:16]([O:18][C@H:19]([C:34]#[N:35])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reactant: OCC(F)(F)F
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reaction time: 1.5 h

Procedure:
2 ml of 2,2,2-trifluoroethanol were added at 20° C. to a solution of 2.14 g of the product of Step D in 8 ml of methylene chloride and the mixture was stirred for 90 minutes and was poured into aqueous monosodium phosphate solution. The decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure The residue was chromatographed over silica gel and was eluted with a 1-1 cyclohexane-ethyl acetate mixture to obtain 2.33 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate melting at 56° C. and having a specific rotation of [α]D20 =+42°±1° (c=1% in CHCl3).
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(O[C:29]1(O[Si](C)(C)C)[CH2:31][CH2:30]1)C.CC(O)=O.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH:1]1([N:4]([CH:20]2[CH2:21][CH2:22][N:23]([CH:29]3[CH2:31][CH2:30]3)[CH2:24][CH2:25]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(C3CC3)CC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (120 mg, 0.337 mmol, 1.0 equiv.), (1-ethoxycyclopropoxy)trimethylsilane (404 μL, 2.02 mmol, 6.0 equiv.) and AcOH (193 μL, 3.37 mmol, 10 equiv.) in MeOH (2.0 mL) was treated with NaBH3CN (95 mg, 1.52 mmol, 4.5 equiv.). After being stirred for 48 h at 25° C. and being refluxed for additional 24 h, the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-7% MeOH/CH2Cl2, gradient elution) gave the title compound as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.55 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.22-4.13 (m, 1H), 3.12 (d, J=11.5 Hz, 2H), 2.96 (s, br, 1H), 2.54-2.50 (m, 1H), 2.39-2.22 (m, 2H), 2.12-1.99 (m, 2H), 1.88-1.82 (m, 2H), 1.74 (s, 3H), 1.61-1.57 (m, 1H), 0.88-0.85 (m, 2H), 0.55-0.41 (m, 6H); MS(ESI) 398 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: C=CC[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: ClC(Cl)Cl
Product: C=CC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol (32) was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane to afford (33) as an amber oil after workup.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=2)=[C:5]([NH2:16])[NH:4][N:3]=1.[C:17]1([C:23](=O)[CH2:24][C:25](OCC)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:24][C:25](=[O:26])[NH:16][C:5]=23)=[CH:12][CH:11]=1)[CH3:15]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: CCOc1ccc(-c2c(C)nn3c(-c4ccccc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-ethoxyphenyl)-1H-pyrazol-5-amine and ethyl 3-phenyl-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound is yielded by column chromatography.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([C:18](OC)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH2:18][OH:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(CO)CCOCC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
At −78° C., 73.3 ml (73.3 mmol, 1.0M in toluene) of diisobutylaluminium hydride were added dropwise to a solution of 5.80 g (36.7 mmol) of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate in 220 ml of toluene such that the internal temperature did not exceed −70° C. The mixture was subsequently stirred at −78° C. for another 90 min and then further at room temperature overnight. The reaction was terminated by addition of 40 ml of methanol and 300 ml of 1N hydrochloric acid. The phases were separated and the aqueous phase was extracted three times with 150 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product corresponded to the title compound. Yield: 2.14 g (45% of theory)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2.[OH-].[Li+].Cl.Cl.[NH:42]1[CH2:45][CH:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]1.Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[O:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([N:42]3[CH2:45][CH:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2
Reactant: COC(=O)C1CNC1
Reactant: COC(=O)c1ccc(COc2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CN(C(=O)c2ccc(COc3cccc(CN(C(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A stirred solution of methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate (419 mg, 0.84 mmol) in THF (2 mL) and methanol (2 mL) was added with an aqueous solution of 1 N lithium hydroxide (1.7 mL, 1.68 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. This crude material was dissolved in dimethylformamide (5 mL) and ⅔ of the solution was used in the next step. Methyl azetidine-3-carboxylate hydrochloride (104 mg, 0.69 mmol), 4-(dimethylamino)pyridine (38 mg, 0.32 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol) were then added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water. The organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound as an oil that solidifies on standing (190 mg, 52% yield over two steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:16][C:17]1([F:21])[CH2:20][NH:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][C:17]([F:21])([F:16])[CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3-difluoroazetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88%). To a solution of 4-(3,3-difluoro-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[Si:11]([O:3][NH2:2])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.48 g) and triethylamine (7 ml) were stirred for 0.25 hours in DMF (50 ml) at 0° C. tert-Butyldiphenylsilyl chloride (13 ml) was added and the mixture was stirred for 1 hour. The mixture was partitioned between pentane (500 ml) and water (100 ml), the layers separated and the aqueous phase extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with brine (50 ml), dried over magnesium sulphate and the solvent was removed in vacuo. The crude product was triturated with pentane (20 ml) yielding the pure title compound as white solid (4.04 g), m.p.t. 85°-87° C.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][N:12]([CH3:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][N:39]=1)[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([NH:29][C:27](=[O:28])[C:26]1[CH:37]=[CH:38][N:39]=[C:24]([NH:23][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([N:12]([CH3:22])[CH3:11])=[CH:14][CH:15]=2)[CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: CN(C)c1ccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)cc1
Yield: 7 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-(dimethylamino)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-(dimethylamino)benzamido)-isonicotinamide was obtained as a colorless solid in 7% yield: mp 160-165° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.28 (t, J=5.9 Hz, 1H), 8.54 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 7.93 (d, J=9.0 Hz, 2H), 7.46 (dd, J=5.1, 1.4 Hz, 1H), 7.36-7.16 (m, 5H), 6.70 (d, J=9.1 Hz, 2H), 4.43 (d, J=5.9 Hz, 2H), 2.96 (s, 6H); MS (ES+) m/z 375.5 (M+1).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C(N(CC)CC)C>[NH2:8][C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
1.0 gram of 4-(N-benzylamino)-1-isobutyl-1H-imidazo(4,5-c)quinoline is added to 10 mL of ethanol, followed by the addition of 0.03 gram triethylamine and 0.2 gram of Pearlman's catalyst (20% Pd(OH)2/C). The mixture is stirred at 40° C. under 1 atm hydrogen until completion. The mixture is then filtered through Celite® and the filtrate, containing 4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline (imiquimod), is concentrated in vacuo.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:23][N:22]([CH2:30][C:31](O)=[O:32])[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)CCCN=C=NCC.O>ClCCl>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:31](=[O:32])[CH2:30][N:22]1[CH2:23][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21]1)([CH3:13])[CH3:12]
Reactant: O=C(O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 8.9 %

Procedure:
130 μl (0.69 mmol) of 2,6-diisopropylaniline are added to a solution of 180 mg (0.65 mmol) of (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid in 20 ml of dichloromethane. The solution is cooled to −10° C. and 132 mg (0.69 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added. The medium is allowed to return to room temperature and stirred for 4 h and then at reflux for one day and again at room temperature for 5 days. The medium is then poured into water and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 90/10, v/v). 25 mg of N-(2,6-diisopropylphenyl)-2-(1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid. M.p. 151-3° C., yield=8.8%.