Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH3:12])[N:6]=[CH:5]2.C([Li])CCC.CON(C)[C:21]([C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][N:24]=1)=[O:22].C(=O)([O-])O.[Na+]>C1COCC1>[Cl:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=2)[N:7]([CH3:12])[N:6]=[CH:5]3)=[O:22])[CH:28]=1
Reactant: Cc1cc(Br)cc2cnn(C)c12
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.450 g (2.00 mmol) 5-bromo-1,7-dimethyl-1H-indazole in 25 mL THF were cooled to −75° C., combined with 1.40 mL (2.24 mmol) of a 1.6 molar n-butyllithium solution and stirred for 1 h at −75° C. Then 0.480 g (2.14 mmol) 6-chloro-pyrimidine-4-carboxylic acid methoxy-methyl-amide were added dropwise. The mixture was brought to 0° C. and stirred for a further hour. Then saturated sodium hydrogen carbonate solution was stirred in, the mixture was extracted with EtOAc, the organic phase was dried and evaporated down i. vac. The residue was triturated with DIPE, suction filtered and dried. The precipitate was purified by flash chromatography (Alox).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:38]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=O)C.[BH4-].[Na+].[NH4+].[Cl-]>CO>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][CH:11]([OH:12])[CH:6]([CH2:4][OH:3])[CH2:7]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C(CO)C1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (14 g) in MeOH (300 mL) was added NaBH4 (12 g) in 12 lots over 1 h period. After completion of addition, the reaction mixture was stirred for 30 min. Removed solvent under reduced pressure, to the residue was added saturated NH4Cl solution (300 mL) and was extracted with EtOAc (300 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with ethyl acetate to give 4-hydroxy-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (10.1 g, cis/trans mixture).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8](CO)[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(CO)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)Nc3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac) 2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-(hydroxymethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)acetic acid (Example 62, Step L) (12.6 mg, 0.025 mmol) in MeOH (1 mL) at room temperature was added DIEA (8.74 μL, 0.050 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 10% citric acid and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[N+:18]([C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:23]3[CH2:22][CH2:21][NH:24][C:1]32[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: NCCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C2(c3ccccc3)NCCN12

Procedure:
Condense 2-benzoyl-4-nitrobenzoic acid with ethylenediamine by the procedure of Example 1 to obtain 8-nitro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 203° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)(=[O:27])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][OH:8])[CH2:2]2)=[CH:32][CH:33]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: OCC1CNCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(N3CCOC(CO)C3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of morpholin-2-ylmethanol (30 mg, 0.256 mmol) in tetrahydrofuran (THF) (3 mL) stirred under nitrogen at room temperature was added triethylamine (0.071 mL, 0.512 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 minutes then N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (86 mg, 0.256 mmol) was added. The reaction mixture was stirred at room temperature overnight. LCMS analysis showed no product, so the solvent was removed under a stream of nitrogen and the crude treated with LiHMDS (1M in THF, 0.768 mL, 0.768 mmol) and THF (2 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 30 minutes. After cooling, LCMS analysis showed some conversion, so the reaction vessel was resealed and reheated by microwaves (Biotage Initiator) to 150° C. for a further 30 minutes. No further conversion was seen by LCMS, so ethyl acetate (10 mL) was added to the mixture and the organic phase washed with water (10 mL) then dried using a hydrophobic frit. Solvent was removed under a stream of nitrogen to give the crude product. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 4 mg. LCMS [LCMS2] Rt 1.29 min, m/z (ES+) 433 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 63.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (example 39 step 1) (1.75 g, 2.475 mmol) was deprotected in TFA/DCM (2/20 mL). This afforded 950 mg (63.3% yield) of the titled compound after purification by column (Silica gel 60/120) using 4% methanol in DCM as eluent. MS: m/z=608.0 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:33])[CH2:16][N:17]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([O-:27])=[O:26])[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[C:18]1=[O:32].[ClH:34]>C(O)(=O)C.O1CCOCC1.O>[ClH:34].[C:25]([CH2:24][CH:21]1[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[C:18](=[O:32])[N:17]([CH2:16][C:15]([NH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:33])[CH2:23][CH2:22]1)([OH:27])=[O:26]
Reactant: O=C([O-])CC1CCN(CC(=O)NCCCNc2nc3ccccc3[nH]2)C(=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC1CCN(CC(=O)NCCCNc2nc3ccccc3[nH]2)C(=O)c2ccccc21

Procedure:
Analogously to Example II, the tert-butyl ester (Example IX) in glacial acetic acid was cleaved using 4N HCl in dioxane. After stripping off the solvent, the residue was dissolved in water, clarified with active carbon and then lyophilized; 0.72 g of white amorphous residue; ESI-MS [M+H+]: 450.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:13]=2[CH:26]=1)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[CH3:17][C:15]1([CH3:18])[CH:14]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:13]2[CH:26]=[C:9]([NH2:8])[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=2[O:16]1
Reactant: Cc1ccc(C2c3cc(NCc4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C2c3cc(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of N-benzyl-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 138 (6.60 g, 17.8 mmol) in ethanol (70 mL) was added 12 N hydrochloric acid (0.1 mL) and 10%-palladium carbon (hydrous 50%, 0.33 g), and the mixture was stirred under hydrogen condition of 5 atmosphere pressure at room temperature for 2 hours. The catalyst is filtered off, and the solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, was washed with a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 4.42 g (yield 88%) of the title compound as an oily matter.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5]/[O:6][CH3:7].CNC(=O)/C(/C1C=CC=CC=1O)=N\OC>>[CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5][O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1O
Agent: CNC(=O)/C(=N\OC)c1ccccc1O
Product: CNC(=O)C(=NOC)c1ccccc1O

Procedure:
9.68 g of crude product (0.0339 mol of methyl E/Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate, in particular compound II-1c from process step 6, HPLC: 43.7% E isomer of log p=1.48; 29.4% Z isomer of log p=2.37) are dissolved in 100 ml of tetrahydrofuran and cooled to 10° C. With cooling, methylamine is introduced. After about 30 minutes, 50 ml of methanol are added, the solution is saturated with methylamine and the mixture is allowed to stand at 10° C. overnight. The solvents are distilled off under reduced pressure and the residue is mixed with a mixture of 30 ml of 2N hydrochloric acid and 30 ml of saturated sodium chloride solution and extracted three times with 50 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 8.5 g of crude product which, according to HPLC, contains 52.6% N-methyl-E-2-(2-hydroxyphenyl)-2-methoxyimino-acetamide of log p=0.98 and 31.9% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl>[C:2]([N:31]1[CH2:32][CH2:33][C:27]2[C:28](=[N:29][C:24]([N:21]3[CH2:20][CH2:19][CH:18]([O:17][C:16]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=4[F:8])[CH2:23][CH2:22]3)=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[N:26]=2)[CH2:30]1)(=[O:1])[CH3:4].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(C#N)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (1.0 mL) was added acetyl chloride (0.013 mL, 0.188 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (8.7 mg, 16%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.86-1.96 (m, 2H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.10-2.21 (m, 2H), 2.61 (t, J=5.6 Hz, 0.9H), 2.73 (t, J=5.2 Hz, 1.1H), 2.88-2.98 (m, 2H), 3.23-3.31 (m, 2H), 3.66-3.76 (m, 2H), 4.09-4.17 (m, 1H), 4.40 (s, 1.1H), 4.43 (s, 0.9H) 4.80-4.87 (m, 1H), 5.59-5.67 (m, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.68 (dq, J=8.6, 1.7 Hz, 1H), 7.86 (dt, J=11.2, 1.7 Hz, 1H); ESI-MS m/z [M+H]+ 453.5.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[C:8]([O:19][CH3:20])=[N:7][C:6]=1[CH2:21][O:22][CH3:23])=[O:4]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Yield: 77.8 %

Procedure:
To a well stirred solution of (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (1.11 g, 3.4 mmol) and 4-(N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in CH2Cl2 (200 mL) was added powdered 4-nitrophenyl chloroformate (0.891 g, 4.42 mmol) at room temperature. Solvent was evaporated and the residue was purified by column chromatography on silica gel using CHCl3/EtOAc (20%-50%) as the eluent to give (+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (1.30 g, 78%) as a viscous oil. [α]D=+262.2 (c=2.3 g in 100 mL CHCl3).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[C:12]([CH3:20])=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]2[CH2:25][CH2:26][N:21]([C:11]3[C:10]([CH3:27])=[C:9]([O:8][CH3:7])[C:17]4[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=4[C:12]=3[CH3:20])[CH2:22][CH2:23]2)=[CH:30][CH:31]=1)[CH3:37]
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)(C)C4)CC2)cc1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol) synthesized in Reference example 96 and 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 123 mg (yield 22%). That is, sodium t-butoxide (398 mg, 4.14 mmol) was added to a mixture of toluene (30 mL) containing 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol), 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), palladium acetate (15 mg, 0.069 mmol) and BINAP (129 mg, 0.207 mmol), and the mixture was stirred under argon atmosphere and under heated reflux for 12 hours. After cooled to room temperature, saturated saline was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-80:20). Crystallization was performed using ethyl acetate-hexane to give 123 mg of the title compound as a colorless crystal (yield: 22%). Melting point was 152 to 154° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:2]2[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:3]=2)[CH:19]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1nc(Cl)cc(Nc2ccc(Cl)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Temperature: 92.5 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a mixture of 6-chloro-N*4*-(4-chloro-phenyl)-pyrimidine-2,4-diamine (0.5 g, 1.96 mmol), 5-chloro-2-methoxy-phenyl boronic acid (0.73 g, 3.92 mmol), palladium (II) acetate (0.066 g, 0.294 mmol), and triphenylphosphine (0.154 g, 0.588 mmol) was added a solution of sodium carbonate (0.63 g, 5.88 mmol) dissolved in water (6 ml) followed by glyme (20 ml). The reaction mixture was stirred under an argon atmosphere at 90-95° C. for 18 hours. After cooling to room temperature, the mixture was filtered through a pad of celite under suction and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (0.350 g, 49% yield) as a white powder. 1H NMR (CDCl3) δ 3.86 (s, 3H, CH3), 4.90 (s, 2H, NH2), 6.58 (s, 1H, NH), 6.71 (s, 1H, Ar), 6.91 (d, 1H, J=8.8 Hz, Ar), 7.32-7.41 (m, 5H, Ar), 7.87 (d, 1H, J=2.7 Hz, Ar).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.O[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([O:40][CH2:41][C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])[CH:37]=[N:38][CH:39]=1>C(Cl)Cl>[I:20][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([O:40][CH2:41][C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])[CH:37]=[N:38][CH:39]=1
Reactant: II
Reactant: CN1CCC[C@H]1COc1cncc(CCCCCCO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1cncc(CCCCCCI)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a stirred solution of PPh3 (300 mg, 1.14 mmol) in dry CH2Cl2 (7 mL) was added I2 (295 mg, 1.16 mmol) in one time. After 15 min, imidazole (90 mg, 1.32 mmol) was added. The mixture was stirred at room temperature for 20 min, and then 5-(6-hydroxy-1-hexanyl)-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (150 mg, 0.52 mmol) in CH2Cl2 (1 mL) was added in dropwise. After stirred at room temperature for additional 3 h, the reaction mixture was quenched by addition of brine and diluted with CH2Cl2 (50 mL). The organic phase was separated, washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography with EtOAc-Et3N (1:0 to 25:1) to give an oil (190 mg, 92%). 1H NMR (CDCl3) δ 8.23 (s, 2H), 7.19 (s, 1H), 3.99 (dd, 1H, J=9.3, 5.4 Hz), 3.92 (dd, 1H, J=9.3, 5.4 Hz), 3.25 (t, 2H, J=6.8 Hz), 3.14-3.08 (m, 1H), 2.69-2.61 (m, 1H), 2.48 (s, 3H), 2.46 (t, 2H, J=6.6 Hz), 2.35-2.26 (m, 1H), 2.10-1.95 (m, 1H), 1.90-1.65 (m, 5H); 13C NMR (CDCl3) δ 154.41, 144.55, 137.10, 123.04, 120.82, 92.51, 77.83, 71.15, 63.97, 57.65, 41.65, 32.33, 29.09, 28.48, 22.99, 18.35, 5.97.
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:13]2[N:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:12]2[C:11]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:10][N:9]=1.[K+].[Br-]>>[NH2:7][C:8]1[N:13]2[N:14]=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:12]2[C:11]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:10][N:9]=1
Reactant: CCC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)n2nc(-c3ccco3)nc12
Agent: [Br-]
Agent: [K+]
Product: CCC(=O)c1cnc(N)n2nc(-c3ccco3)nc12

Procedure:
Compound 158 (338 mg, yield: 69%) was obtained as a white solid using 780 mg (1.91 mmol) of Compound 157 obtained in Example 157 by carrying out a procedure similar to that in Example 153. 1H NMR (δ ppm, DMSO-d6): 8.50 (s, 1H), 7.98 (dd, J=1.7 Hz, 0.7 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 6.76-6.74 (m, 1H), 3.34-3.28 (m, 2H), 1.12 (t, J=6.9 Hz, 3H); Mass (m/z): 257 (M+); IR (KBr, cm−1): 3440, 3017, 1641, 1531, 1412, 1227; Melting point: 279.5-283.0° C.; Elemental analysis: C12H11N5O2 0.2EtOH; Found (%): C, 55.83, H, 4.40, N, 26.24; Calcd.(%): C, 55.89, H, 4.61, N, 26.28.