Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7](CC)CCCC)(=[O:4])C=C.C(#N)C=C.CC(C(OCCO)=O)=C.CC(N=NC(C#N)(C)C)(C#N)C.C1CCN(C[CH:46]2C(C3C=CC(Cl)=CC=3)=N[NH:50][C:48](=[O:49])[CH2:47]2)CC1.Cl.C(NN)(=O)CCCC(NN)=O>O.CC(O)C.CCC(C)=O>[C:48]([NH:50][C:1]([O:5][CH2:6][CH3:7])=[O:4])([CH:47]=[CH2:46])=[O:49]
Reactant: O=C1CC(CN2CCCCC2)C(c2ccc(Cl)cc2)=NN1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: C=C(C)C(=O)OCCO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: C=CC#N
Solvent: CCC(C)=O
Solvent: O
Product: C=CC(=O)NC(=O)OCC
Temperature: 75 °C

Procedure:
In the dropping tank of a reaction vessel (tank) equipped with a stirrer, a thermometer, a nitrogen-sealing tube, a condenser and a dropping tank were placed 8.0 parts of MMA, 15.0 parts of BA, 1.0 part of AA, 1.0 part of 2-ethylhexyl acrylate (referred to here-inafter as EHA), 10.0 parts of acrylonitrile (referred to hereinafter as AN), 5.0 parts of HEMA, 5.0 parts of DAAA, 1.0 part of AIBN, 25 parts of MEK and 25 parts of IPA and then uniformly mixed. Separately, in the reaction tank were placed 20.0 parts of PA-8, 8.0 parts of MMA, 15.0 parts of BA, 1.0 part of AA, 1.0 part of EHA, 10.0 parts of AN, 5.0 parts of HEMA, 5.0 parts of DAAA, 20 parts of MEK and 20 parts of IPA and then uniformly mixed. Subsequently, the reaction tank was heated to 75° C. and the liquid mixture in the dropping tank was dropped into the reaction tank over 5 hours. Thereafter, the resulting mixture was further subjected to reaction at the same temperature for 4 hours. Thereafter, 2.8 parts of TEA was added to the reaction mixture to sufficiently neutralize the same and then aqueous hydrazide consisting of 148 parts of distilled water and 4.7 parts of glutaric acid dihydrazide (referred to hereinafter as GDH) was added thereto to emulsify the reaction mixture. Thereafter, the MEK and the IPA present in the system were removed at 60° C. at 100 Torr to obtain an aqueous emulsion of a self-emulsifiable acryl-urethane copolymer having a solid content of 39.9% (the emulsion is referred to hereinafter as EA-11).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:29])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1>CO.CCOC(C)=O.[NH4+].[Cl-]>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]([OH:36])[C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[C:18]([F:29])=[CH:19][CH:20]=[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[C:4]=4[F:3])[CH:10]=3)[NH:15][CH:16]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(O)c4ccc(Cl)cc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
KOH (0.012 g, 0.22 mmol) was added to 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.37 mL, 0.074 mmol) in MeOH (0.4 mL), followed by the addition of 4-chlorobenzaldehyde (0.013 g, 0.096 mmol). The reaction mixture was stirred at room temperature overnight. The contents were then diluted with EtOAc and NH4Cl (aq.) and extracted with EtOAc (3×). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (5% MeOH/DCM) to afford N-(3-((4-chlorophenyl)(hydroxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (23 mg, 58%). 1H NMR (400 MHz, CD3OD) δ 8.41-8.42 (m, 1H), 8.28-8.29 (m, 1H), 7.60-7.67 (m, 1H), 7.46-7.49 (m, 2H), 7.34-7.36 (m, 2H), 7.09-7.14 (m, 1H), 6.06 (s, 1H), 3.09-3.13 (m, 2H), 1.82-1.91 (m, 2H), 1.03-1.07 (m, 3H); m/z (APCI-pos) M+1=535.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[NH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[I:33][C:15]1[C:13]2[N:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[NH:17][CH:16]=1
Reactant: c1ccc(COc2nc(OCc3ccccc3)c3[nH]ccc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Ic1c[nH]c2c(OCc3ccccc3)nc(OCc3ccccc3)nc12
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a stirred solution of 2,4-bis-O-benzyl-5H-pyrrolo[3,2-d]pyrimidine 15 (1.43 g, 4.3 mmol) in anhydrous CH2Cl2 (15 mL) under N2, NIS (1.069 g, 4.7 mmol) was added at which point the reaction mixture turned from pink to orange. The mixture was stirred overnight until the TLC indicated the absence of starting material. The reaction mixture was washed with aqueous Na2S2O3 (15 mL) followed by brine (15 mL). The organic layer was dried over MgSO4, loaded onto silica and purified using column chromatography eluting with 4:1 then 1:1 hexanes/EtOAc to obtain compound 16 as a pale-yellow solid (1.77 g, 3.88 mmol, 90%). Rf 0.4 in 1:3 hexanes/EtOAc. Mp 157.8-158.4° C. 1H NMR (400 MHz, CDCl3): δ 5.53 (s, 4H), 7.32-7.41 (m, 9H), 7.55-7.57 (m, 2H), 8.71 (br s, 1H, NH). 13C NMR: 57.3, 68.7, 69.3, 111.9, 127.9, 128.3, 128.6, 128.66, 128.7, 128.9, 132.4, 135.8, 137.2, 152.0, 156.9, 160.1. FAB-MS m/z for C20H16IN3O2 calculated [M+H]+ 458.0360. found 458.0357.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=70%.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccccc2F)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2′-fluoro-biphenyl-4-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([OH:16])([CH3:15])[CH3:14]>>[C:13]([O:16][C:10](=[O:11])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:12]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Yield: 100 %

Procedure:
A solution of 3,4-difluorophenyl isocyanate (2 g, 10.55 mmol) in t-BuOH (50 mL) was heated at 80° C. for 16 h. The mixture was concentrated by rotary evaporation to give a white solid which was triturated with toluene and evaporated to dryness. Addition of toluene (20 mL) and concentration under vacuum gave (3,4-difluorophenyl)-carbamic acid-tert-butyl ester as a white solid (2.43 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O.O>C(#N)C.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reaction time: 3 h
Yield: 92 %

Procedure:
In a 25 ml flask, 3-nitro-5-trifluoromethyl-pyridin-2-ol (300 mg, 1.44 mmol) was dissolved in acetonitrile (4.5 ml), and then phosphorus oxychloride (0.4 ml, 4.33 mmol) and benzyltrimethyl ammonium chloride (164 mg, 0.721 mmol) were added thereto. The mixture was stirred for 3 hours at 800. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid (300 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCOCC1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.133 g, 0.50 mmol) and morpholine (0.220 mL, 2.50 mmol) gives the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].CNC(=O)C(CO)NC(=O)C1C(I)=C(N)C(I)=[C:31]([C:38](O)=[O:39])C=1I.C(Cl)(=O)C>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:38](=[O:39])[CH3:31])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CNC(=O)C(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: CC(=O)Cl
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β-alanine methylamide . 1.1 H2O (IV f), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH2:2].[Si:10]([O:27][CH2:28][C:29](O)=[O:30])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Si:10]([O:27][CH2:28][C:29]([NH:2][NH:1][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:30])([C:23]([CH3:25])([CH3:26])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)NN
Reactant: CC(C)(C)[Si](OCC(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of ethyl hydrazino(oxo)acetate (3.58 g) in acetonitrile (100 mL) were successively added triethylamine (6.86 mL), {[tert-butyl(diphenyl)silyl]oxy}acetic acid (7.74 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.20 g) and 1-hydroxybenzotriazole (415 mg) under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.20 g, yield 30%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:25]1[O:34][C:33]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:26]1>C(OCC)(=O)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:29]([NH:30][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=4[N:13]=3)=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OCO4)nc21
Temperature: 200 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (3.70 mmol) of 3,4-methylenedioxyaniline was heated, with stirring, in a 200° C. oil bath. The resulting solution was heated for 5 minutes and cooled to room temperature. Ethyl acetate (2 mL) was added, and some traces of solids were filtered. The crystals that slowly developed in the filtrate were filtered and washed with 2 mL of ethyl acetate; wt 0.080 g. The solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform and then 50% hexane/ethyl acetate to obtain pure crystalline product; wt 0.054 g; mp 240°-241° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[C:15]([C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][N:13]=[CH:12][N:11]=1>>[CH3:6][N:4]([CH:3]=[C:17]([C:18](=[O:21])[CH2:19][CH3:20])[C:16]([C:15]1[C:10]([CH3:9])=[N:11][CH:12]=[N:13][CH:14]=1)=[O:22])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(=O)c1cncnc1C
Product: CCC(=O)C(=CN(C)C)C(=O)c1cncnc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To 181 mg of dimethylformamide dimethyl acetal was added 250 mg of 1-(4-methylpyrimidin-5-yl)pentan-1,3-dione. The mixture was stirred for 16 hours at room temperature and the volatiles removed by bulb-to-bulb distillation (80° C.; 0.01 mm Hg) to yield 278 mg of 2-(dimethylaminomethylene)-1-(4-methylpyrimidin-5-yl)pentan-1,3-dione as an oil.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:13]2[O:14][C:15]3[C:20]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1.I[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu]>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:8]1[C:13]2[O:14][C:15]3[C:20]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-c2ccccc2Nc2cccc3c2oc2c(C4CCCCC4)cccc23)cc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Product: COc1ccc(N(c2ccccc2-c2ccccc2)c2cccc3c2oc2c(C4CCCCC4)cccc23)cc1
Yield: 85.9 %

Procedure:
N-([1,1′-biphenyl]-2-yl)-6-cyclohexyldibenzo[b,d]furan-4-amine (8.3 g. 20.0 mmol), 4-iodoanisole (18.7 g, 80.0 mmol), potassium carbonate (5.5 g, 40.0 mmol), copper powder (1.3 g, 20.0 mmol), and 18-crown-6 ether (5.3 g, 20.0 mmol) were mixed. The resultant mixture was bubbled with nitrogen for 30 min. The mixture was refluxed for 20 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography using 15% DCM/hexane (containing 1% triethylamine) to yield N-([1,1′-biphenyl]-2-yl)-6-cyclohexyl-N-(4-methoxyphenyl)dibenzo[b,d]furan-4-amine (9.0 g, 86% yield) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:4]2[O:3]1.[H][H]>CO.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:5]2[C:4]=1[O:3][CH:2]([CH3:1])[CH2:6]2
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(C)O2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2c1CC(C)O2
Reaction time: 12 h
Yield: 91.9 %

Procedure:
Methyl 2-methyl-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 30a (100 mg, 0.42 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (10 mg, 10%), filled with hydrogen for three times. The reaction solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl 7-amino-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30b (80 mg, yield: 91.0%) as a colorless oil liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:15]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH3:17])[C:18](=[O:25])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n(C)c1=O
Yield: 73.1 %

Procedure:
A mixture of 5-chloro-2-methylaminobenzophenone (1.23 g), diethyl malonate (1.6 g) and piperidine (0.1 ml) was heated for 3 hours at 170°-180° C. After cooling, the mixture was treated with isopropyl ether to give crystals, which were recrystallized from ethanol to afford ethyl 6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylate (1.25 g, 73.1%). mp 124°-125° C. The product was identical with the compound obtained in Reference Example 12.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9 L) at −78° C. was added over 30 minutes a 2.5 M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than −55° C. during the addition. The reaction mixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) δ7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm−1; mp 102-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[NH2:8]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine (14.76 g, 61.70 mmol) in THF (80 mL) was added Pd/C (3.00 g). The reaction was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as an offwhite solid (11.99 g, 93%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[N:52]1([CH2:58][CH2:59][OH:60])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([N:55]5[CH2:56][CH2:57][N:52]([CH2:58][CH2:59][OH:60])[CH2:53][CH2:54]5)=[O:39])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(CCC(=O)N3CCN(CCO)CC3)cc2)cn1
Yield: 24.6 %

Procedure:
Using 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid (100 mg) obtained in Step A in Example 1-D-168 and 2-piperazin-1-yl-ethanol (23 mg) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one was obtained, and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-170) as a pale yellow powder (20 mg, 25%).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:25][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(c2ccccc2)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were dissolved in N,N-dimethylformamide (30 mL), and then K2CO3 (4.2 g) was added and the reaction stirred at room temperature for 60 hours. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with 2M aqueous Na2CO3 and brine, then dried over Na2SO4. After filtration and concentration, the crude material was purified by column chromatography using 1.5-2.0% ethyl acetate in hexanes.