Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=[C:20]3[O:19][CH2:17][CH3:18])[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4ccc(F)cc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (example 17a, 41.4 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a light brown solid: 46.6 mg (61.7%), MS: m/e 472 (MH+).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>O1CCCC1>[C:16]1([CH2:15][CH2:14][S:10][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [S-2]
Reactant: BrCCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(CCSCCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
A solution of 7.65 g (32 mmol) of sodium sulfide nonahydrate and 8.7 ml (64 mmol) of 2-bromoethylbenzene in 150 ml of 1:1 tetrahydrofuran:methanol was heated at reflux under inert atmosphere. After 24 h, the solution was allowed to cool and concentrated in vacuo to give the crude desired compound.
Reaction SMILES: [OH-:1].[K+].O.[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@@H:31]2[O:35][C:34](=[O:36])[CH2:33][CH2:32]2)=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]>CO>[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@H:31]([OH:35])[CH2:32][CH2:33][C:34]([OH:36])=[O:1])=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: [OH-]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(OC[C@H](O)CCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A 1 N potassium hydroxide aqueous solution (0.1 mL, 0.1 mmol) and water (0.1 mL) were added to a solution of 5(R)-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (Example 19-(3); 2.8 mg, 0.006 mmol) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for one hour. The reaction solution was directly purified by silica gel chromatography (dichloromethane/methanol=8/3, saturated with water) to give the title compound (0.9 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47]Cl)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C>CC#N>[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][N:11]([CH2:10][CH2:9][CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21)C(=O)OC(C)(C)C
Yield: 76.5 %

Procedure:
Using the General Procedure for N-alkylation: A solution of (2S)-2-(tert-butoxycarbonylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoic acid tert-butyl ester (0.700 g, 1.67 mmol), 1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.690 g, 2.59 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) in CH3CN (16 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (50:1 CH2Cl2—MeOH) provided 0.830 g (77%) of 2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a tan foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[CH:10][C:9]2=[O:16])[C:5]([CH3:17])=[CH:4][N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(C)n(-c3cc(Cl)ncc3C)c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-4-hydroxy-6,5′-dimethyl-[1,4′]bipyridinyl-2-one of part A (1.5 g, 6.0 mmol) in N,N-dimethylformamide (10 mL) was added 4-methoxybenzylbromide (1.33 g, 6.6 mmol), potassium carbonate (2.1 g, 15.1 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product (1.37 g): MS (M+H) 372.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@@H:27]2[C@:44]3([CH3:45])[C@H:30]([C@H:31]4[C@H:41]([CH2:42][CH2:43]3)[C@:39]3([CH3:40])[C:34]([CH2:35][C@@H:36]([O:53][CH:54]5[CH2:59][CH2:58][CH2:57][CH2:56][O:55]5)[CH2:37][C@@H:38]3[O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:33][CH2:32]4)[CH2:29][CH2:28]2)[CH2:14][CH2:15][C@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])(=O)=O)=CC=1.[I-:60].[Na+].O.C(Cl)Cl>CC(C)=O>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][C@@H:38]1[C@@:39]2([CH3:40])[C:34](=[CH:33][CH2:32][C@@H:31]3[C@@H:41]2[CH2:42][CH2:43][C@@:44]2([CH3:45])[C@H:30]3[CH2:29][CH2:28][C@@H:27]2[C@H:13]([CH2:12][I:60])[CH2:14][CH2:15][C@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])[CH2:35][C@@H:36]([O:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[CH2:37]1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.220 g. (0.00026 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), and 0.165 g. (0.0011 mole) of sodium iodide in 2 ml of acetone was heated at 50° for 18 hr and cooled. The mixture was poured into water and the product was isolated with methylene chloride. The organic layers were washed with aqueous sodium sulfite solution, and saturated aqueous sodium bicarbonate solution. The organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([N:38]([CH3:39])[CH3:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (470 mg, 1.04 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (250 mg, 1.56 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine (2.0N in THF, 1.0 ml, 2.0 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was dissolved in ethyl acetate (30 ml) and extracted with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC (CH3CN: Water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (160 mg, 30%): mp 80-82° C.; 1H NMR: δ(CDCl3): δ 0.33-0.39 (m, 2H), 0.60-0.68 (m, 2H), 1.21-1.30 (m, 1H), 2.25 (s, 3H), 2.90 (s, 3H), 2.97 (dd, J=5 Hz, the other doublet is buried, 1H), 3.05 (s, 3H), 3.87 (d, J=7.5 Hz, 2H), 3.94 (dd, J=10 Hz, the other doublet is buried, 1H), 5.83 (dd, J=5, 10 Hz, 1H), 6.69 (t, JH-F=75 Hz, 1H), 7.12-7.15 (m, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.73 (d, J=8.5 Hz, 1H), 9.53 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.8, 25.6, 35.4, 36.1, 37.7, 51.9, 74.5, 112.6, 116.7, 120.8, 114.9, 116.0, 118.5, 120.9, 123.4, 125.3, 131.9, 136.4, 138.0, 138.6, 140.7, 151.2, 168.7, 169.8, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O6: C, 60.58; H, 5.28; N, 8.15. Found: C, 60.23; H, 5.26; N, 8.02.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][N:24]1[CH2:28][CH2:27][CH:26](O)[CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH:26]3[CH2:27][CH2:28][N:24]([CH3:23])[CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CN1CCC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2, 639 mg, 2.0 mmol) in DCM (30 ml) was added 1-methyl-3-pyrrolidinol (658 μl, 6.0 mmol) and triphenyl phosphine (1572 mg, 6.0 mmol). The suspension was cooled to 0° C. under a nitrogen atmosphere. Di-tent-butyl azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM (20 ml), dropwise over the course of 15 minutes. The resulting light brown solution was allowed to warm to room temperature and was stirred overnight. The solution was evaporated, and the residue purified by chromatography, eluting with 0 to 5% methanol in DCM. The appropriate fractions were combined and evaporated, and the crude product (230 mg) re-dissolved in 1:1 methanol/DCM (5 ml). Ethereal HO (1M, 1.14 ml) was added, and the mixture evaporated. Crystallisation from ethanol diethyl ether gave the title product as a hydrochloride salt in the form of a white crystalline solid (154 mg, 16%); 1H NMR (hydrochloride salt): 2.30 (m, 1H), 2.65-2.75 (m, 1H), 2.88 (s, 3H), 3.30-3.80 (m, 3H), 3.85-4.05 (m, 1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51 (dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8.72 (s, 1H), 8.81 (s, 1H); Mass Spectrum: 403.3, 405.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].CO.C(N(CC)CC)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([OH:12])([CH3:11])[CH2:7][N:6]1[S:43]([C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44])=[O:4]
Reactant: COC(=O)C1CCC(C)(O)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(C)(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a mixture of 5-hydroxy-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.08 g) and 5 mL of methanol was added 10 drops of 12 M aqueous HCl. After stirring for 1 hour, the mixture was concentrated in vacuo, and the residue was dissolved in 1 mL of DMF. After cooling to 0° C., the mixture was treated with triethylamine (0.11 mL, 0.80 mmol) and 4-benzyloxy-benzenesulfonyl chloride (0.11 g, 0.40 mmol). After stirring for 2 h at room temperature, the mixture was diluted with ethyl acetate, washed 2× with 1M HCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography (2:1 hexane-ethyl acetate, 2 mm silica gel plate) affording 0.047 g of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid methyl ester as a colorless solid.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2cccc(F)n2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3cccc(F)n3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(6-fluoro-pyridin-2-yloxymethyl)-phenyl) acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 55-1-5 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (237 μL, 1.7 mmol) at room temperature, which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1→2:1) to obtain the title compound (59 mg, 23%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Agent: Cl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccncc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and isonicotinoyl chloride hydrochloride were combined to provide N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isonicotinamide as a white crystalline solid, m.p. 213.0-213.7° C. 1H NMR (300 MHz, DMSO-d6) δ8.76 (m, 1H), 8.69 (d, J=5.6 Hz, 2H), 8.22 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=5.7 Hz, 2H), 7.62 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.62 (broad s, 2H), 4.64 (t, J=6.8 Hz, 2H), 3.30 (m, 2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 360.1699 (360.1699 calcd for C20H20N6O).
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1.N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][O:18][C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CN(C)C=Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N=CN(C)C)nc(Br)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
The compound was produced as described in example 9. The following were used: compound from example 17 (250 mg, 0.65 mmol), pyridine (2 ml), 4,4′-dimethoxytrityl chloride (330 mg, 0.98 mmol). FC cf. 9. Colourless solid (260 mg, 58%). TLC (CH2Cl2/MeOH, 9:1): Rf 0.37. 1H-NMR ((D6)DMSO): 2.23, 2.68 (2m, H—C(2′)); 3.01, 3.09 (2s, CH3—N); 3.57, 3.58 (2s, CH3O); 3.84 (m, H—C(4′)); 4.33 (m, H—C(3′)); 5.24 (d, J=4.5 Hz, HO—C(3′)); 6.22 (“t”, J=5.8 Hz, H—C(1′)); 6.6-7.2 (m, aromat. H); 8.21 (s, H—C(8)); 8.69 (s, H—C(N═)). Anal. calc. for C34H35BrN6O5 (687.59): C, 59.39; H, 5.13; N, 12.22; found: C, 59.46; H, 5.40; N, 12.09.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]([O-])([CH3:22])[CH3:21].[K+].BrCC(C)=C>C1COCC1.O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:21][C:20]([CH3:22])=[CH2:19])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[O-]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 1-diphenylmethylazetidin-3-ol (239 mg, 1.0 mmol) in THF (3.6 mL) was cooled to 0° C. t-BuOK (1M in THF, 3.6 mL) was added dropwise and the reaction mixture was stirred at room temperature for 1 h then cooled to 0° C. 3-Bromo-2-methyl-1-propene (504 μL, 5.0 mmol) was added and the solution was stirred from 0° C. to room temperature overnight. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated to dryness to give the title compound (276 mg, 94%) as a yellow oil.
Reaction SMILES: C1([C@H](N)CC)C=CC=CC=1.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[C:21]([O-:23])=[O:22].C1([C@H]([NH3+])CC)C=CC=CC=1>C(#N)C.C(OC)(C)(C)C>[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[C:21]([OH:23])=[O:22]
Reactant: O=C([O-])[C@H]1CCc2ccccc2O1
Agent: CC[C@@H](N)c1ccccc1
Agent: CC[C@@H]([NH3+])c1ccccc1
Solvent: CC#N
Solvent: COC(C)(C)C
Product: O=C(O)[C@H]1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Intermediate-1 (18.6 g, 104 mmol) in acetonitrile (91 mL), (R)-(+)-1-phenylpropylamine (9.14 g, 67.9 mmol) in methyl tert butyl ether (MTBE) (12 mL) solution was added in dropwise manner. After about half of the total amount of the (R)-(+)-1-phenylpropylamine solution was added. The reaction mixture was seeded with few crystals of ((R)-(+)-1-phenyl propyl ammonium (R)-(−)-chromane-2-carboxylate). The resultant thick slurry was diluted with MTBE (80 mL) and the mixture was further stirred for 6 h at RT. The salt was filtered, washed with MTBE and dried. The salt (13.7 g) was suspended in MTBE (80 mL) further aqueous HCl solution (1:1) (88 mL) was added and the mixture was stirred in cooling to 0° C. The aqueous layer was extracted with methyl tert-butyl ether (70 mL×2). The extracts were combined with organic layer and the solution was washed with 1:1 HCl solution (40 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as a white crystalline solid (6.5 g); m/z-178.02.
Reaction SMILES: I.[CH3:2][C:3]1[N:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](SC)=[NH:17])=[CH:11][C:10]=2[F:20])[N:4]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]([F:40])[F:39])=[CH:32][CH:31]=1)[C:27](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:57][NH2:58]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:58][N:57]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:5]3[C:6]([CH3:8])=[N:7][C:3]([CH3:2])=[N:4]3)=[C:10]([F:20])[CH:11]=2)[N:17]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]([F:40])[F:39])=[CH:32][CH:31]=1
Reactant: CSC(=N)Nc1ccc(-n2nc(C)nc2C)c(F)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(OCC(F)F)cc1
Reactant: NN
Agent: I
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)n(-c2ccc(Nc3n[nH]c(C(CCCCCl)c4ccc(OCC(F)F)cc4)n3)cc2F)n1

Procedure:
Methyl 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenylcarbamimidothioate, hydroiodide (600 mg, 1.47 mmol, from preparation T) and 6-chloro-2-(4-(2,2-difluoroethoxy)phenyl)hexanoic acid (475 mg, 1.55 mmol, from preparation AX) were coupled [N-methylmorpholine (0.810 mL, 7.37 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.231 mL, 7.37 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, crude 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown gummy oil. LC-MS (M+H)+ 534.4.
Reaction SMILES: [CH:1]1([Si:6](OC)([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([OH:18])([CH2:16][CH3:17])([CH3:15])[CH3:14].C[Si](C)(C)Cl>C[O-].[Na+]>[C:13]([O:18][Si:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:9][CH3:10])[O:7][CH3:8])([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCC(C)(C)O
Reactant: CO[Si](OC)(OC)C1CCCC1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCC(C)(C)O[Si](OC)(OC)C1CCCC1
Yield: 81.7 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 10.1 g (0.0531 mole) of cyclopentyl trimethoxysilane, 30.6 g (0.347 mole) of tert-amyl alcohol and 86.4 mg (1.6 m mole) of sodium methoxide, which were then reacted with each other in an oil bath of 105° C. for 4 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 10.7 g (0.0434 mole) of tert-amyloxy cyclopentyl dimethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 82%.