Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[OH:6][C:7]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>CCCCCC>[C:1]([C:13]1[C:14]([OH:16])=[CH:15][C:7]([OH:6])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(=O)O)c(O)cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a tert-butanol (14.3 mL, 11.12 g, 150 mmol) suspension of 2,4-dihydroxy-benzoic acid (F71-01: 2312 mg, 15.0 mmol), trifluoroacetic acid (8.0 mL, 11.84 g, 103.8 mmol) and sulfuric acid (0.43 mL, 0.79 g, 8.0 mmol) were added in this order under argon atmosphere while stirring at room temperature. The reacting solution was stirred at room temperature for 10 minutes and then at a bath temperature of 75° C. for 6 hours. Additional trifluoroacetic acid (8.0 mL, 11.84 g, 103.8 mmol) was added, and the reaction mixture was stirred at a bath temperature of 80° C. for further 2.5 hours. After completing the reaction, the reaction mixture was added to ice-water (160 mL) and stirred with the addition of hexane (20 mL). The deposited solids were collected by filtration, washed with water and hexane to obtain the title compound (F71-02: pale pink solid, 2.13 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[C:15]([O:29][CH3:30])[CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:30][O:29][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:12][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)[CH:3]=[C:4]2[N:10]=[C:9]1[NH2:11]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(Br)cnc43)cc2OC)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5cnn(C)c5)cnc43)cc2OC)cc1
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 144.4 %

Procedure:
To a stirred solution of 6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine (0.25 g, 0.53 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.14 g, 0.66 mmol), potassium phosphate tribasic (0.39 g, 1.84 mmol), tricyclohexylphosphine (0.015 g, 0.052 mmol), palladium(II) acetate (0.005 g, 0.026 mmol). The reaction mixture heated to 125° C. in a microwave reactor. After 15 min, the reaction mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 0.36 g of a greenish brown solid. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 1-10% 2M ammonia in methanol/dichloromethane) afforded 0.10 g (41%) of the product as a light green solid: 1H NMR (400 MHz, DMSO-d6) δ 8.12-8.08 (m, 2H), 7.83 (d, J=0.6 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.08 (d, J=1.9 Hz, 1H), 6.96-6.85 (m, 5H), 6.72 (dd, J=8.3, 1.9 Hz, 1H), 5.18 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H) ppm, (M+1)=471.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](Br)[C:13]([O:20][CH2:21][O:22][CH3:23])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:31]1[CH:32]=[CH:33][C:28]([C:26]([OH:27])=[O:25])=[CH:29][CH:30]=1)[C:13]([O:20][CH2:21][O:22][CH3:23])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COCOc1cc2cc(OCc3ccccc3)ccc2cc1Br
Product: COCOc1cc2cc(OCc3ccccc3)ccc2cc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Followed the coupling procedure described in Step 1 of Example 20, where the starting materials were 6-(benzyloxy)-2-bromo-3-(methoxymethoxy)naphthalene (Intermediate 11) and 4-methoxycarbonylphenylboronic acid and where the reaction was stirred at 90° C. for 3 hours. The desired product (1.30 g, yield 72%) was obtained as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:11][CH2:10]2)=[C:4]([O:32][C:33]([F:36])([F:35])[F:34])[CH:3]=1.C=O.[C:39](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:13][CH2:14]2)[CH3:39])=[C:4]([O:32][C:33]([F:35])([F:36])[F:34])[CH:3]=1
Reactant: CC(=O)O
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccc(Br)cc1OC(F)(F)F)C[C@H]1CC[C@H](CNc2nc(N(C)C)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step B of example 15 (290 mg, 0.52 mmol) in CH2Cl2 (3 mL) were added 37% aqueous formaldehyde (42 mg, 0.52 mmol), acetic acid (31 mg, 0.52 mmol), and NaBH(OAc)3 (165 mg, 0.78 mmol). The reaction mixture was stirred at ambient temperature for 19 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 25% EtOAc in hexane) to give trans-N2-(4-{[(4-bromo-2-trifluoromethoxy-benzyl)-methyl-amino]-methyl}-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (153 mg, 51%) as a pale yellow solid.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1>CO.[Pd]>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1
Reactant: COCCOCOCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COCCOCOCCOc1ccc(N)cc1
Yield: 96.2 %

Procedure:
In a 50 mL 3-neck RBF equipped with N2 Bubbler and gas purger; to a suspension of Pd—C (1.0 g) in methanol (10 mL) was added 1-(2-((2-methoxyethoxy)methoxy)ethoxy)-4-nitrobenzene (5.0 g) in methanol (20 mL) under nitrogen atmosphere. Hydrogen gas was bubbled through the reaction mixture for 2 h at room temperature. The reaction was monitored on TLC using ethyl acetate:hexane (5:5) as mobile phase. After completion of the reaction, the reaction mixture was filtered using Celite and washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 4.28 g of 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline as a brown liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
4-Hydroxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.8 mmol) was dissolved in dry THF (15 mL) and sodium hydride (60% disp. in mineral oil; 0.076 g, 1.9 mmol) added and the mixture stirred for 1 hour. Methyl iodide (0.16 mL; 2.7 mmol) was then added and the mixture stirred overnight. Brine was added and the product extracted into ethyl acetate, dried over sodium sulphate, filtered and the solvent removed by evaporation. The residue was purified by flash chromatography on silica eluting with 0-10% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a clear colourless oil (0.35 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Cu][C:16]#[N:17].C(N)CN>CN(C=O)C.[Cu]I>[OH:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCO[C@H]2CCO
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A suspension of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (300 g, 1.17 mol), copper(I) cyanide (209 g, 2.34 mol), and copper(I) iodide (33.3 g, 0.18 mol) in dry DMF (1.16 L), under an atmosphere of nitrogen, was heated to 140° C. After 8 h at this temperature, HPLC analysis of an aliquot indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into an aqueous solution of ethylenediamine (3 L, v/v 3/1) then extracted into toluene. The combined organic layers were washed with water and concentrated in vacuo to give the crude title compound. This material is used without further purification in the subsequent step.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 4-methoxyphenol according to the procedure described in Example 74 to afford 2-(4-methoxyphenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=457 (M++1); Rt=4.50 min; 1H-NMR 500 MHz (CDCl3): δ 3.85 (s, 3H), 6.95 (d, J=9 Hz, 2H), 7.05. (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz, 2H), 7.25-7.30 (m, 4H), 7.39 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Zn+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(-c2ccccn2)c1
Reaction time: 8 h

Procedure:
To an argon purged solution of methyl 3-bromo-5-iodobenzoate (834 mg, 2.45 mmol) and Pd(PPh3)4 (142 mg, 0.12 mmol) in THF (20 mL) was added 2-pyridylzinc chloride (0.5 M, 7.4 mL, 3.7 mmol). The mixture was stirred overnight and then poured into a large volume of water (100 mL). The resulting solution was extracted with EtOAc (3×20 mL) and the combined organics were successively washed with water (1×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified via automated flash chromatography (silica gel; 0 to 25% EtOAc in hexanes) to afford methyl 3-bromo-5-(pyridin-2-yl)benzoate. MS m/z=292, 294 [M+1]+; Calc'd for C13H10BrNO2: 292.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[I:21]I>C1COCC1.CCCCCC>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[I:21]
Reactant: II
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cccc(Br)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of diisopropylamine (76 mL, 0.4 mol) in dry THF (664 mL) and n-hexane (220 mL) was added 2.5 M/L n-BuLi (160 mL. 0.4 mol) dropwise at −78° C. during a period of 1 h. The mixture was stirred for 1 h at −78° C. Then a solution of 1-bromo-3-fluoro-benzene (69 g, 0.4 mol) in dry THF (300 mL) at −78° C. was added to the above mixture dropwise. After stirring for an additional 1 h at −78° C., the mixture was added a solution of iodine (101 g, 0.4 mol) in dry THF (400 mL) dropwise at −78° C. The temperature was raised from −78° C. to rt during 2 h. After stirring for 18 h at rt, the mixture was concentrated in vacuo to give crude product (120 g) which was distilled under reduced pressure to afford 1-bromo-3-fluoro-2-iodo-benzene (110 g). 1H NMR (400 MHz, DMSO): 7.24-7.19 (t, 1H), 7.38-7.32 (m, 1H), 7.55-7.53 (d, 1H).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][C:58]5([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCNCC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6(C)COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 92.1 %

Procedure:
To 377 mg (0.559 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 127 mg (0.466 mmol) of 2-chloro-5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 17, and 154 mg (1.11 mmol) of potassium carbonate, 1 ml of 1,4-dioxane was added, and the reaction mixture was stirred at 120° C. for 26 hours. After completion of the reaction, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=89/11-68/32 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 391 mg of the title compound as a foam (yield: 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C[C:29]([N:31](C)C)=O>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([C:5]1[N:4]=[CH:3][C:2]([C:29]#[N:31])=[CH:7][N:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(c1ccccc1)c1ncc(Br)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(C(=O)c2ccccc2)nc1
Temperature: 150 °C
Yield: 42 %

Procedure:
(5-Bromo-pyrimidine-2-yl)-phenyl-methanone (1.6 g, 6.08 mmol) is dissolved in dimethylacetamide (20 mL), and potassium hexacyanoferrate(II) trihydrate (0.57 g, 1.34 mmol) is added, followed by Na2CO3 (0.64 g, 6.08 mmol), and palladium (II) acetate (68 mg, 0.3 mmol). The mixture is heated to 150° C. under N2 for 3 h, and then cooled to rt. EtOAc (30 mL) is added and the mixture is filtered. The filtrate is washed with water (2×15 mL) and 5% aqueous NH4OH (15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 70% EtOAc in heptane to afford 2-benzoyl-pyrimidine-5-carbonitrile (0.53 g, 42%) as a solid. MS: 210 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:19]=3[C:20]([NH2:24])=[N:21][C:22]=2[CH:23]=1.N12CCCN=C1CCCCC2.O>C(Cl)(Cl)Cl>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:19]=3[C:20]([NH2:24])=[N:21][C:22]=2[CH:23]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc2c(N)nc3cc(OCCCN4CCCS4(=O)=O)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
3-Chloropropanesulfonyl chloride (0.206 mL, 1.69 mmol) was added dropwise to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (17 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.316 mL, 2.11 mmol) was then added, and the reaction was stirred for 18 hours. The reaction was poured into water, and the mixture was extracted twice with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 97:3 dichloromethane:methanol) followed by recrystallization from acetonitrile to provide 0.237 g of 7-[3-(1,1-dioxidoisothiazolidin-2-yl)propoxy]-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as needle-like, white crystals, mp 142-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: C1=COCCC1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 77.6 %

Procedure:
A round-bottom flask was charged with 4-bromo-6-(trifluoromethyl)-1H-indazole (1.00 g, 3.8 mmol), TsOH monohydrate (27 mg, 0.15 mmol), 3,4-dihydro-2H-pyran (1.59 g, 18.9 mmol), and THF (25 mL). The reaction mixture was degassed with nitrogen and heated under reflux for 18 h, and then the solvent was removed in vacuo. The residue was purified by SiO2 chromatography to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (1.03 g, 78%) as a yellow oil. MS (ESI) m/z: 265.2 [(M−THP group)+1]+.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([CH2:6]Cl)=[O:5].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14][CH2:6][S:4]([CH3:3])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)CCl
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CS(=O)CSc1ccccc1
Temperature: 60 °C
Yield: 87.6 %

Procedure:
Potassium hydroxide (460 mg) was added in an atmosphere of nitrogen to a mixture of 560 mg of chloromethyl methyl sulfoxide and 616 mg of thiophenol, and then the mixture was heated at 60° C. for 13.5 hours. With addition of 3 ml. of water, the mixture was extracted with chloroform. The extract was dried using anhydrous sodium sulfate, and then subjected to column-chromatography [silica gel, chloroform-ethyl acetate (9:1 )] to yield 812 mg of methyl phenylthiomethyl sulfoxide having a boiling point of 148° C./0.5 mmHg and an nD25 of 1.6053 as a colorless liquid in a yield of 87.3%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCCN2CCN1CCOCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCCN2CCN1CCOCC1)c1cccs1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A solution of compound 4 (0.23 g, 0.88 mmol) in dry ethanol (20 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.502 g, 1.76 mmol) at room temperature and was stirred for 3 hours. The mixture was diluted with saturated sodium bicarbonate solution (50 mL) and was extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL) and dried (Na2SO4). The concentrated crude product was subject to flash chromatography on silica gel using 5% methanol/CH2Cl2, which resulted in a brown foam, compound 64 (0.194 g, 59%). 1H NMR (CDCl3) δ 7.66 (d, J=3.9 Hz, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.06 (dd, J=3.6, 5.1 Hz, 1H), 6.53 (s, 2H), 6.46 (s, 1H), 6.21 (brs, 2H), 3.57 (t, J=9.3 Hz, 4H), 3.24 (t, J=11.4 Hz, 2H), 3.65 (t, J=12.6 Hz, 2H), 2.45-2.41 (m, 6H), 1.88-1.80 (m, 2H); MS-ESI (m/z, %): 372 (11), 371 (MH+, 100), 258 (9); ESI-HRMS calculated for C20H27N4OS (MH+): Calculated: 371.1914, Observed: 371.1900.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][CH:22]([CH3:26])[C:23](O)=[O:24]>C(OCC)(=O)C.CCCCCC>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:23](=[O:24])[CH:22]([O:21][CH3:20])[CH3:26])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(C)C(=O)O
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 2-methoxypropionic acid. m.p.: 169-171° C. (ethyl acetate/hexane)