Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10]O)=[CH:7][S:8][CH:9]=1.[ClH:17]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][Cl:17])=[CH:7][S:8][CH:9]=1
Reactant: OCc1cscc1Nc1c(Cl)cccc1Cl
Reactant: Cl
Product: ClCc1cscc1Nc1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
27.4 g (0.1 mole) of 4-(2,6-dichloroanilino)-3-thiophenmethanol are dissolved in 800 ml of concentrated aqueous hydrochloric acid, and the solution is left to stand for eight hours, poured onto ice and extracted with toluene. The organic phase is washed with sodium bicarbonate solution, dried and concentrated. Recrystallization of the residue from petroleum ether gives 3-(2,6-dichloroanilino)-4-chloromethylthiophen (m. 89° to 92°).
Reaction SMILES: [C:1](C1C(=O)N(CC(C)C)N=C(C2C=CC(F)=C(F)C=2)C=1)(O)=O.[C:23]([C:26]1[C:27](=[O:40])[NH:28][N:29]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:31]=1)([OH:25])=[O:24]>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[C:30]1[CH:31]=[C:26]([C:23]([O:25][CH3:1])=[O:24])[C:27](=[O:40])[NH:28][N:29]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1=O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Yield: 81.2 %

Procedure:
Following the procedure of Example 1 (5), 4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 81.2%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C@H:12]3[CH2:30][CH2:29][CH2:28][C@:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])[CH2:15]4)[CH2:13]3)[C:7]=2[CH:31]=1)#[N:2].C[Si](C)(C)[O-].[K+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C@H:12]3[CH2:30][CH2:29][CH2:28][C@:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])[CH2:15]4)[CH2:13]3)[C:7]=2[CH:31]=1)#[N:2]
Reactant: COC(=O)C(C)(C)CN1C[C@@]2(CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CN1C[C@@]2(CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)OC1=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 3-{(5S,7S)-7-[(6-cyano-1H-benzimidazol-1-yl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-3-yl}-2,2-dimethylpropanoate (1.06 g, 2.505 mmol) and potassium trimethylsilanolate (0.482 g, 3.76 mmol) in THF (12.5 mL) was stirred at RT overnight. LCMS showed the reaction was not complete. Additional potassium trimethylsilanolate (0.482 g, 3.76 mmol) was then added, and the reaction was stirred for one additional day. The reaction mixture was then concentrated to a light yellow solid. The solid was washed with a mixture of DCM and Et2O and dried under vacuum to give 3-{(5S,7S)-7-[(6-cyano-1H-benzimidazol-1-yl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-3-yl}-2,2-dimethylpropanoic acid as a light yellow solid. This product was used in the next step without any further purification. MS (m/z) 411.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[C:7]([C:8]([N:39]2[C:40]3[C:35](=[CH:34][C:33]([CH3:32])=[CH:42][CH:41]=3)[CH2:36][CH2:37][CH2:38]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1ccc(F)c(Cl)c1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A solution of 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (32.1 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (57 mg, 35 pt, 0.48 mmol, 4.0 equiv; [CAS RN 7719-09-7]) was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (77.6 mg, 102 μL, 0.60 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 6-methyl-1,2,3,4-tetrahydro-quinoline (21.2 mg, 0.14 mmol, 1.2 equiv; [CAS RN 91-61-2]) and the reaction mixture heated by microwave irradiation to 140° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 auto sampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 397.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:11]=1[OH:12])[C:5](OC)=[O:6].O.[NH2:18][NH2:19]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[C:11]=1[OH:12])[C:5]([NH:18][NH2:19])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Solvent: O
Product: NNC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Temperature: 0 °C

Procedure:
3,4-Dihydroxy-5-sulfobenzoic acid, methyl ester (15.0 g, 52.9 mmoles) was dissolved in 100 ml of hydrazine hydrate and refluxed for 15 hours. The mixture was then evaporated in vacuo, the residue dissolved in water and the pH adjusted to 1.0 with 2N hydrochloric acid. The mixture was chilled at 0° C. for 15 hours and the white precipitate which formed was filtered and dried to give 12.83 g of the title compound as a white solid, m.p >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:4][C:3]=1[CH2:16][CH3:17].[F:18][C:19]([F:32])([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:20]([F:23])([F:22])[F:21]>C1CCCCC1.CCOCC.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:10][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:19]([F:18])([F:32])[C:20]([F:21])([F:23])[F:22])[CH:25]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[CH2:16][CH3:17]
Reactant: FC(F)(F)C(F)(F)c1cccc(CBr)c1
Reactant: CCc1cc(Oc2cccc(N)c2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCc1cc(Oc2cccc(NCc3cccc(C(F)(F)C(F)(F)F)c3)c2)ccc1Cl
Temperature: 25 °C
Yield: 35.1 %

Procedure:
EX-66° C.) A solution of 3-(4chloro-3-ethylphenoxy)aniline (1.7 g, 6.9 mmol) was prepared in cyclohexane (13 mL). A solution of crude 3-pentafluoroethyl benzylbromide (1 g, 3.5 mmol) product from EX-660B in cyclohexane (10 mL) was added dropwise over 3 min. The reaction mixture was refluxed under N2 for 24 h and then was cooled to room temperature. The mixture was diluted with Et2O and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with Et20. The organic layer was washed with brine, dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes in ethyl acetate (95:5) which gave 0.56 g (35%) of the desired N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl] methyl]amine product as an amber oil. 1H NMR (CDCl3) δ 7.53 (m, 4H), 7.27 (d, 1H), 7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H), 4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). 13C NMR (CDCl3) δ 158.6, 156.1, 143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8, 108.8. 103.9, 48.5, 27.5, 14.1. 19F NMR (CDCl3) δ −85.1 (s, 3F), −115.2 (s, 2F). HRMS calcd. for C23H19CIF5NO: 456.1154 [M+H]+, found: 456.1164.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=O)[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[NH2:29][O:30][CH2:31][CH3:32].Cl>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[O:30][CH2:31][CH3:32])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1C(=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: CCON
Agent: Cl
Product: CCO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 90 %

Procedure:
17,17-Bis(ethylendioxy)-6(E)-ethoxyiminoandrostane was prepared in 90% yield starting from 3,3:17,17-bis(ethylendioxy)androstan-6-one and NH2OCH2CH3.HCl by the procedure described above in Prepn. 21. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.99 (2H, q), 3.92-3.75 (8H, m), 3.25 (1H, dd), 2.25 (1H, m), 1.99-0.94 (18H, m), 1.17 (3H, t), 0.82 (3H, s), 0.75 (3H, s).
Reaction SMILES: [C:1]1([N:7]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:8]([C:10]2[C:11]([CH2:16][CH3:17])=[N:12][O:13][C:14]=2[CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC>[Pd].C(O)C>[C:14]([C:10](=[C:11]([NH2:12])[CH2:16][CH3:17])[C:8]([N:7]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:9])(=[O:13])[CH3:15]
Reactant: CCc1noc(C)c1C(=O)N(CCN(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: CCC(N)=C(C(C)=O)C(=O)N(CCN(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 51.2 grams (0.17 mole) of N-phenyl-N-(2-dimethylaminoethyl)-3-ethyl-5-methyl-4-isoxazole carboxamide and 5.2 grams of 10% palladium on carbon in 200 milliliters ethanol is hydrogenated at 50 pounds per square inch at room temperature overnight. The catalyst is removed by filtration and the solvent is evaporated in vacuo. The residue obtained is then treated with hexane and the resulting crystals triturated with ether to give 2-acetyl-3-amino-N-(2-dimethylaminoethyl)-N-phenyl-2-pentenamide, m.p. 103°-105° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH2:12][CH3:13])=[C:10]([CH2:14][CH3:15])[C:9]([CH2:16][CH3:17])=[C:8]2[C:4]=1[C:5](=[NH:19])[NH:6][C:7]2=N)[CH3:2].[ClH:20].[CH:21]([NH:24][C:25]1[S:26][CH2:27][C:28](=[NH:30])[N:29]=1)([CH3:23])[CH3:22].N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:20].[NH:19]=[C:5]1[C:4]2[C:8](=[C:9]([CH2:16][CH3:17])[C:10]([CH2:14][CH3:15])=[C:11]([CH2:12][CH3:13])[C:3]=2[CH2:1][CH3:2])[C:7](=[C:27]2[S:26][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[N:29][C:28]2=[NH:30])[NH:6]1
Reactant: CCc1c(CC)c(CC)c2c(c1CC)C(=N)NC2=N
Reactant: CC(C)NC1=NC(=N)CS1
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: CCc1c(CC)c(CC)c2c(c1CC)C(=N)NC2=C1SC(NC(C)C)=NC1=N

Procedure:
When equivalent amounts of 4,5,6,7-tetraethyl-1,3-diiminoisoindoline and 2-isopropylamino-4-imino-2-thiazoline hydrochloride are substituted for the 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, in the procedure described in Example 9, part B above, there is obtained as the product 1-imino-4,5,6,7-tetraethyl-3-(2-isopropylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11](=[O:20])[NH:10][C:9]=3[N:4]2[N:3]=1.[Li]C.[C:24](OCC)(=O)C>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:21]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11](=[O:20])[NH:10][C:9]=3[N:4]2[N:3]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: CCOC(C)=O
Agent: O=[Mn]=O
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial, Compound (1-3) (0.15 g, 0.543 mmol, 1.0 eq.) was dissolved in THF (10 mL). The solution was cooled to −78° C. and MeLi (15 mL of 1.6 M THF solution, 24 mmol, 44.19 eq.) was added dropwise and the reaction mixture was stirred for 16 hours at 0-20° C. The reaction mixture was carefully and slowly poured into ethyl acetate 20 (mL) and stirred for 10 minutes. The quenched reaction mixture was concentrated. The residue was treated with 100 mL of THF and the THF solution was separated from the solid by filtration. The organic solution was stirred with MnO2 (0.47 g, 5.4 mmol, 10 eq.) for 4 hours at room temperature. The reaction was filtered and the solids washed with CHCl3/MeOH (10%) (50 mL). The combined organic solution was concentrated and the crude was purified by silica gel chromatography using CHCl3/MeOH (10%) as the eluant to give Compound (19-1).
Reaction SMILES: [CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[OH:15])([CH3:3])[CH3:2].O[CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([O:39]CC)=[O:38])[CH:31]=[CH:30]2>>[CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[O:15][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([OH:39])=[O:38])[CH:31]=[CH:30]2)([CH3:3])[CH3:2]
Reactant: CC(C)N(c1ccc(C(F)(F)F)cc1O)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1ccc2cc(CO)ccc2c1
Product: CC(C)N(c1ccc(C(F)(F)F)cc1OCc1ccc2cc(C(=O)O)ccc2c1)S(=O)(=O)c1ccccc1

Procedure:
By using 2-(N-isopropyl-phenylsulfonylamino)-5-trifluoromethylphenol (prepared in Reference Example 24.) and ethyl 6-hydroxymethyl-2-naphthate, the title compound having the following physical data was obtained by the same procedure as Reference Example 18(b)→Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([N:35](C(OC(C)(C)C)=O)[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C(=O)OC(C)(C)C)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 mg 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]phenyl}-vinyl]phenoxy}ethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (2c) were dissolved in 2.5 mL dichloromethane. 252 μL trifluoroacetic acid were added and the mixture was stirred for 5 h at room temperature. The solvent was removed under reduced pressure. The crude product was washed with hexane and diethyl ether and dried under reduced pressure 84 mg 2f were obtained as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH2:23][CH2:24][O:25][CH3:26])[N:13]=[CH:12][N:11]=[C:10]2[O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(O)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Yield: 33.8 %

Procedure:
Using the procedure described in Example 46, 3-aminophenol (1.21 g, 11.1 mmol) and 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.85 g, 10.6 mmol) were reacted to give 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline (1.22 g, 3.58 mmol, 34%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.09 (t, 1H), 6.50 (d, 1H), 6.53 (s, 1H), 6.40 (d, 1H), 5.30 (br s, 2H), 4.33 (t, 2H), 3.97 (s, 3H), 3.77 (t, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]#[N:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[NH:24][C:23]4[C:18]([N:16]=3)=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1N
Reactant: N#CC1CCCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCCC(c3nc4ncccc4[nH]3)CC2)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
Polyphosphoric acid (PPA) (10 g) was heated to 160° C. Intermediate (1) (0.0467 mol) and 2,3-diaminopyridine (0.0513 mol) were added. The mixture was stirred at 180° C. for 1 hour, poured out on K2CO3 solid and ice, washed with K2CO3 10% and extracted with DCM. The aqueous layer was washed with DCM. The organic layer was dried, filtered and the solvent was evaporated.This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.5). The pure fractions were collected and the solvent was evaporated. Part of this fraction (6 g) was crystallized from DIPE and 2-propanone. The precipitate was filtered off and dried, yielding 3.16 g of (±)-2-[hexahydro-1-(phenylmethyl)-1H-azepin-4-yl]-1H-imidazo[4,5-b]pyridine (compound 69).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23]([O:28][C@@H:29]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]4[O:31][C:32](=[O:34])[CH3:33])=[N:24][NH:25][C:26]=3[CH3:27])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23]([O:28][C@@H:29]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[C@@H:40]([O:41][C:42](=[O:44])[CH3:43])[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]4[O:31][C:32](=[O:34])[CH3:33])=[N:24][NH:25][C:26]=3[CH3:27])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(-c3ccc(O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 58.2 %

Procedure:
To a solution of 4-({4-[4-(benzyloxy)phenyl]phenyl}methyl)-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.14 g) in methanol (3 mL) was added 10% palladium-carbon powder (0.030 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 11 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=1/1-1/5-dichloromethane/methanol=10/1) to give 4-{[4-(4-hydroxyphenyl)phenyl]methyl}-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.071 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10](C)(C)[C:9]2[C:4](=[CH:5][C:6]([NH2:14])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:16]1[N:21]=[C:20]2[NH:22][C:23](=[O:35])[N:24]([C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[C:25](=[NH:26])[C:19]2=[CH:18][N:17]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]=1[N:24]1[C:25](=[NH:26])[C:19]2[C:20](=[N:21][C:16]([NH:14][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:17][CH:18]=2)[NH:22][C:23]1=[O:35]
Reactant: Cc1cccc(Cl)c1-n1c(=O)[nH]c2nc(Cl)ncc2c1=N
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: Cc1cccc(Cl)c1-n1c(=O)[nH]c2nc(Nc3ccc4c(c3)CN(C)CC4)ncc2c1=N

Procedure:
35 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine obtained in Production Example 22 was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2-chloro-6-methylphenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 2 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: CO.[CH:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1>[Rh].C(O)(=O)C>[CH:6]1([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)[C@H](O)C1CCCCC1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 200 mL methanol were added 38.0 g of R-(−)-mandelic acid, 2.5 mL acetic acid, and 7.5 g rhodium on carbon (5%, Engelhard 5864). The mixture was sealed in an autoclave, purged with nitrogen, and then filled with hydrogen gas. Hydrogenation was carried out at room temperature for 8 hours at 1400 psi. The reaction mixture was then removed from the autoclave and filtered. The filtrate was concentrated and recrystallized from toluene. The colorless crystals were collected by filtration and dried under vacuum to give 19.8 g of (R)-(−)-2-cyclohexyl-2-hydroxyacetic acid (92.0% yield from 20.7 g R-(−)-mandelic acid). 1H NMR (DMSO-d6): δ (ppm) 3.71 (d, 1H), 1.69-1.52 (m, 6H), 1.16-1.09 (m, 5H). 13C NMR (DMSO-d6): δ (ppm) 175.27, 74.19, 41.15, 28.86, 26.74, 25.84, 25.76, 25.57. IR (KBr): ν (cm−1) 3442, 2935, 2854, 1716, 1452, 1280, 1261, 1232, 1112, 1099. Anal. Calcd. for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.89; H, 8.90. mp 124-126° C. [α]D20=−12.0° (c=1.0, CH3OH).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]/[CH2:27][C:28]([O:31][Si](CC)(CC)CC)([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][C@@H:9]1[C@@:43]2([CH3:44])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:25]=[CH:26]/[CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([OH:46])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 96.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-{4-triethylsilyloxy-4-methyl-(2E)-pentenyloxy}-20-methylpregna-5,7,16-triene (136 mg, 0.173 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (74 mg, 97%) as a colorless foam.