Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[Cl-].C[Zn+].[CH3:36]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl.CCOC(C)=O>[CH3:25][N:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:36])=[CH:3][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCN(C)C1=O
Agent: Cl[Pd]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1[CH-]N(c2c(C(C)C)cccc2C(C)C)CC1
Agent: C[Zn+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (0.15 g, 0.317 mmol, example 12) in THF (2 mL) were added methylzinc chloride (0.238 mL, 0.476 mmol, 2M solution in THF), 1,3-dimethyl-2-imidazolidinone (0.4 mL, CAS RN 80-73-9) and (1,3-bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)palladium(II) dichloride (4.31 mg, 0.00635 mmol, Sigma-Aldrich) and the reaction was stirred at 50° C. (oil bath temperature) for 1 h. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc and the organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless oil (0.122 g; 85%). MS (ESI): m/z=453.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]COC)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccnc1C(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 85.8 %

Procedure:
A mixture of 2-(5-chloro-2-methoxymethoxybenzoyl)-3-cyanopyridine (1.50 g), hydrochloric acid (2.5 ml) and THF (17.5 ml) was stirred for 13 hours at room temperature. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and dried (anhydrous sodium sulfate), which was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-chloro-2-hydroxybenzoyl)-3-cyanopyridine (1.10 g) (Compound E-13). The physical properties and spectrum data are shown in Table 16 and Table 19.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[CH:17]=1>C1COCC1>[CH3:11][CH:12]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([OH:29])[C:18]=2[CH:17]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(O)(c1ccccc1)c1ccccc1-2
Temperature: 40 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, magnesium (280 mg, 11.5 mmol) was suspended in dehydrated THF (2 ml), iodine (45 mg, 0.18 mmol) was added, bromobenzene (390 μl, 3.70 mmol) was slowly added dropwise, and the suspension was stirred at 40° C. for 4 hr. To the reaction mixture was added the aforementioned 2-(3′,7′,11′-trimethyldodecyloxy)-9-fluorenone (300 mg, 0.74 mmol), and the mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the reaction was quenched with 1N hydrochloric acid (30 ml). The mixture was extracted with chloroform (40 ml), and the extract was washed three times with 1N hydrochloric acid (20 ml), three times with 5% aqueous sodium hydrogen carbonate solution (20 ml), and once with 20% brine (20 ml). The solvent of the organic layer was evaporated, and the obtained residue was purified and separated by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2-(3′,7′,11′-trimethyldodecyloxy)-9-phenylfluoren-9-ol (181 mg, 0.37 mmol, yield 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.N1C=CC=CC=1.ClCCl>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccccc1Oc1cccnc1
Reaction time: 48 h
Yield: 5.9 %

Procedure:
2-Bromophenol (355 mg, 2.05 mmol), 3-pyridyl-boronic acid (500 mg, 4.1 mmol), copper acetate (745 mg, 4.1 mmol) and pyridine (3.3 mL, 41 mmol) were added to dichloromethane (41 mL) and stirred for about 48 hours under air. The reaction was diluted with water (50 mL) and the layers separated. The organic layer was washed with 5N NaOH. The organic layer was concentrated, and chromatographed on silica gel (MeOH/dichloromethane) to yield 3-(2-bromo-phenoxy)-pyridine (30 mg, 6%) as a yellow oil. MS found 249.1 M+1. 3-(2-Bromo-phenoxy)-pyridine was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+): 256.1 (M+1)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][C:31]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:32])[CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (75 mg, 69%), MS (ISP) m/z=411.4 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyclopropyl-acetic acid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Br)=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[CH:2]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>CO>[CH2:12]([N:14]([CH2:15][CH3:16])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[CH:2][CH:1]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
P-nitrobenzyl bromide (5.0 g) was added to a methanol solution (50 mL) of diethylamine (16.9 g), and stirred at room temperature for 3 hours. Methanol was evaporated off from the reaction liquid under reduced pressure, and water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was extracted with 1 N hydrochloric acid, and the aqueous layer was neutralized with aqueous ammonium solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate, and then the solvent was evaporated off under reduced pressure to obtain N,N-diethyl-N-(4-nitrobenzyl)amine (4.8 g) as an orange oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([O:20][CH3:21])[CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([O:20][CH3:21])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(OC)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(OC)CCNC1
Yield: 70 %

Procedure:
3-Methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester 4a in MeOH (2200 mL), was added 14 g of 10% Pd/C (˜50% in water). The reaction mixture was hydrogenated using H2 at ˜55 psi pressure (epen valve) for 1 overnight. The reaction mixture was filtered, dried to give 3-Methoxy-pyrrolidine-3-carboxylic acid methyl ester 11BH 126 g. (overall yield of 70% for 4 steps, no column purification).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)CCCc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NC(=O)CCCC1CCNCC1

Procedure:
The crude amide was dissolved in glacial acetic acid and hydrogenated at 60°/60 p.s.i. over a platinum oxide catalyst until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give crude 4-(piperid-4-yl)butyramide as an oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: N#CC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-Benzhydryl-azetidine-3-carbonitrile (0.25 g, 1.0 mmol) in dichloromethane (2 ml) is treated with 1-chloroethylchloroformate (0.12 ml, 1.1 mmol). The reaction mixture is stirred at room temperature for 3 hours, the solvent evaporated and the residue taken-up in methanol and refluxed for 1 hour. The reaction mixture is cooled to room temperature and stirred for a further 18 hours. The solvent is evaporated to afford crude azetidine-3-carbonitrile hydrochloride. The crude azetidine-3-carbonitrile is dissolved in dichloromethane (3 ml) and treated with triethylamine (0.25 ml, 2.0 mmol) and 3,4-dichlorobenzylbromide (0.24 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 2 hours, then washed with water, the organic phase dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica using hexane:ethylacetate 2:1 as eluent to afford 1-(3,4-Dichloro-benzyl)-azetidine-3-carbonitrile. [MH]+ 240.97
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:40]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of compound A (46.2 mmol) in EtOAc (175 mL) at room temperature was added piperidine (4.57 mL, 46.2 mmol) and the reaction mixture was stirred for 18 h at room temperature. Next the solvent was removed in vacuo and the resulting residue dissolved in minimum amount of EtOAc (˜50 mL) and hexane (˜1 L) was added. Precipitated crude product was filtered off and recrystallised again with EtOAc (˜30 mL) and hexane (˜750 mL). The precipitate was filtered off, washed with hexane and dried in vacuo to afford compound B (28.0 g, 46.2 mmol). LC-MS [M+H] 595.4 (C28H46N6O6S+H, calc: 595.3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58.6 mg), 2-hydroxy-5-methylbenzophenone (276 mg), and 4-dimethylaminopyridine (156 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (98.9 mg, yield 95%).
Reaction SMILES: [C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:72](Cl)([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[O:64][S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3O)c2ncn1Cc1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3OS(=O)(=O)C(F)(F)F)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 3',5'-di-O-trityl-1-benzylinosine (2.0 g, 2.4 mmol), 4-dimethylaminopyridine (290 mg, 2.4 mmol) and triethylamine (480 mg, 4.8 mmol) in methylene chloride (40 mL) is added triflyl chloride (800 mg, 4.8 mmol), and the mixture is stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using a mixture of tetrachloromethane and ethyl acetate (5:1 v/v) as the eluent to give 3',5'-di-O-trityl-2'-O-triflyl-1-benzylinosine as a foam (1.82 g, 78% yield), 1H NMR (Me2SO-d6) δ 2.92-2.96 (2H, m, H-5',5"), 3.62-3.69 (1H, m, H-4'), 4.41-4.43 (1H, m, H-3'), 5.23 (2H, s, CH2Ph), 5.89-5.95 (1H, m, H-2'), 6.66 (1H, d, H-1', J1',2' =6.3 Hz), 7.18-7.34 (35H, m, 2×Tr and CH2 Ph), 8.29, 8.32 (1H each, s, H-2, H-8). Analyses calculated for C56 H45F3N4O5S: C, 68.98, H, 4.65, N, 5.63. Found: C, 68.94, H, 4.76, N, 5.63.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][N:64]=[C:63]([O:67][CH3:68])[CH:62]=2)[C:50]=1[CH3:69].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:69])[C:51]([C:61]1[CH:66]=[CH:65][N:64]=[C:63]([O:67][CH3:68])[CH:62]=1)=[N:52]2
Reactant: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)ccn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 5-morpholinopyridin-3-amine (0.067 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline (0.1 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.075 g, 0.78 mmol) in toluene (3.1 mL) at 100° C. for 46.5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (1H, d, J=1.6 Hz), 8.30-8.34 (1H, dd, J=5.1, 0.6 Hz), 7.80 (1H, d, J=2.3 Hz), 7.64 (1H, m), 7.58 (1H, d, J=2.3 Hz), 7.43-7.51 (1H, m), 7.21 (1H, dd, J=5.2, 1.5 Hz), 7.03 (1H, s), 6.59 (1H, t, J=2.3 Hz), 3.92 (3H, s), 3.70 (4H, m), 3.08 (4H, m), 2.08 (3H, s). Mass Spectrum (ESI) m/e=464.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([I:18])[CH:11]=1)[C:2]1C=CC=CC=1.[CH3:20][N:21]1CCN[CH2:23][CH2:22]1.IC1C=C(C=C(OC)C=1)C(O)=O>>[I:18][C:12]1[CH:11]=[C:10]([C:9]([N:8]2[CH2:1][CH2:2][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:19])[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=1
Reactant: COc1cc(I)cc(C(=O)NCc2ccccc2)c1
Reactant: CN1CCNCC1
Agent: COc1cc(I)cc(C(=O)O)c1
Product: COc1cc(I)cc(C(=O)N2CCN(C)CC2)c1
Yield: 80 %

Procedure:
The title compound was prepared by the same method as N-benzyl-3-iodo-5-methoxy-benzamide. 4-Methylpiperazine was used instead of benzylamine. Starting with 3.1 g of 3-iodo-5-methoxybenzoic acid, 3.2 g (80% yield) of the title compound was obtained.
Reaction SMILES: O.[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15]/[C:16](=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])/[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15][C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCC/C=C1\SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCC[C@@H]1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 117 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
400 ml of purified water, 12.85 g of 20% palladium hydroxide on carbon (50% wet), 900 ml of a methanol solution containing 249.5 g of ethyl (5Z)-5-[(3aS,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-yliden]pentanoate were added successively in this order, and the atmosphere was replaced with 490 kPa hydrogen three times. Moreover, 627 kPa hydrogen pressure was applied at 6.5° C., and the mixture was stirred at 500 rpm. The reaction temperature and the pressure became 92.5° C. and 843 kPa at 50 minutes after initiation of heating, 117° C. and 921 kPa after 4 hours, and 116° C. and 853 kPa after 11 hours, so that hydrogen was charged up to 882 kPa. After 24 hours, the reaction mixture was cooled at 115° C. and 892 kPa, washed with methanol, and the catalyst was filtered off. The filtrate was concentrated, 400 ml of toluene was added to the residue, and replacement and concentration were carried out three times with an outer bath at 65° C. To the above-mentioned residue were added 1206 ml of methanol, 402 ml of water and 53.3 g of sodium hydroxide, the resulting mixture was stirred at 40° C. for 2 hours. To the reaction mixture was added 300 g of 10% aqueous hydrochloric acid, the mixture was neutralized to pH 7, 6 g of activated charcoal was added to the mixture and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was subjected to precoat filtration with 6 g of activated charcoal. Methanol was distilled of under reduced pressure, and 600 ml of ethyl acetate was added. 10% aqueous hydrochloric acid was added to the mixture to carry out extraction (pH of the aqueous layer was 0.7), and the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and when no ethyl acetate was distilled off, the residue was subjected to replacement with 170 ml of mesitylene and concentration two times to give 170.1 g of (3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-pentanoic acid as colorless oily product.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:15][C:16]1[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:15][C:16]2[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3C(F)(F)F)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure I using 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 1.6 mmol, 1 eq) in DMF (5 mL), NaH (60%, 0.138 g, 3.5 mmol, 2.2 eq), and 3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline (0.58 g, 1.7 mmol, 1 eq) in DMF (3 mL). After purification, 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as white solid. 1H NMR (DMSO-d6) δ ppm 8.27 (1 H, s), 7.99 (1 H, s), 7.88 (1 H, d, J=7.8 Hz), 7.73-7.79 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.51-7.61 (3 H, m), 7.28-7.35 (1 H, m), 5.41-5.54 (2 H, m), 2.60 (3 H, s). Mass Spectrum (ESI) m/e=561.0 (M+1).