Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([NH2:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.C([O:23][C:24](=O)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:34]Br)C.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[N:19]1[CH2:34][C:26]2[C:25](=[C:30]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:28][CH:27]=2)[C:24]1=[O:23]
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC(F)F
Reactant: CCOC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC(F)F
Yield: 80.8 %

Procedure:
3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester was prepared by the procedure of example 11 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (7.3 g, 0.025 mol), 2-bromomethyl-6-nitro-benzoic acid ethyl ester (7.6 g, 0.028 mol) and triethyl amine (7 ml, 0.05 mol) in DMF (50 ml) to provide 3-(4-difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester as yellow oil (9.1 g, 81% yield). 1H NMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 3.09 (dd, J=6.8, 15 Hz, 2H, CH2CO), 3.29 (dd, J=6.8, 15 Hz, 1H, CH2CO), 3.65 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.26 (d, J=17 Hz, 2H, CH2N), 4.46 (d, J=17 Hz, 2H, CH2N), 5.80-5.86 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, OCF2H), 6.92 (dd, J=1.8, 8.2 Hz, 1H, Ar), 7.06 (d, J=1.8 Hz, 1H, Ar), 7.14 (d, J=8.25, 1H, Ar), 7.58-7.76 (m, 3H, Ar).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(O[CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(C(F)(F)F)c1)C(=O)OCC
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 3-(trifluoromethyl)aniline (40 mL, 0.32 mmol) and diethyl ethoxymethylmalonate was heated at 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature at which time the solution solidified to provide 102 g of diethyl 2-{[3-(trifluoromethyl)anilino]methylene}malonate as a cream colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=O)=[CH:12][N:11]=1.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][NH:27][C:20]([C:13]2[C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:11][CH:12]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Product: O=C(NCC1CC1)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Yield: 63 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (80 mg) and cyclopropylmethylamine (19 mg, ex Lancaster) afforded the title compound (58 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:33]=[C:32]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:33]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as an orange solid (103 mg).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCc1ccc(Cl)cc1
Yield: 62.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.029 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 63 (0.027 g, 0.05 mmol, 65%) as a white solid. LCMS m/z (%)=545 (M+H79Br35Cl35Cl, 65), 547 (M+H79Br35Cl37Cl37Br35Cl35Cl, 100), 549 (M+H81Br35Cl37Cl79Br37Cl37Cl, 45), 551 (M+H81Br37Cl37Cl, 6). 1H NMR (400 MHz, acetone-d6) δ: 8.23 (s, 1H), 8.17 (s, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 7.22 (d, J=9.0 Hz, 1H), 5.14 (AB quartet, J=12.3, 24.8 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: [OH-].[Na+].C1COCC1.[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)[CH:22]=2)[C:16]([O:18]C)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>CO>[N:8]1([C:13]2[CH:14]=[C:15]([CH:20]=[C:21]([C:23]3[N:27]=[CH:26][NH:25][N:24]=3)[CH:22]=2)[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1cc(-c2nc[nH]n2)cc(N2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2nc[nH]n2)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous 5 N sodium hydroxide solution (0.21 mL, 1.05 mmol) was added to a THF (0.7 mL)-methanol (0.7 mL) suspension of methyl 3-(1-pyrrolidinyl)-5-(1,2,4-triazol-3-yl)benzoate (95.8 mg, 0.35 mmol), and stirred at room temperature for 18 hours. 5 N hydrochloric acid (0.21 mL, 1.05 mmol) was added to the reaction mixture and concentrated under reduced pressure. 40% methanol/chloroform was added to the residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, the formed insoluble matter was taken out through filtration, washed and dried to obtain the title compound as a pale yellow solid.
Reaction SMILES: [NH4+].[OH-].[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])(=[O:12])=[O:11])#[N:4]>[Ni].CO.C1COCC1>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[S:10]([N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:3][NH2:4])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])(=[O:11])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)N(CCCC#N)CCCCC#N)c(C)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCN)CCCCCN)c(C)c1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Raney nickel (W-2 grade, 7.60 g) and concentrated NH4OH (10 mL) were successively added to 38 (5.06 g, 14.6 mmol) in CH3OH (30 mL) and THF (30 mL) in a 200 mL Parr bottle, and a slow stream of NH3 was bubbled through the mixture for 30 minutes at 0° C. After hydrogenation in a Parr bottle was carried out at 50-55 psi for 8 hours, the suspension was filtered through Celite, and the solvents were removed in vacuo to give 4.70 g (91%) of 41 as an oil: NMR δ 1.14-1.24 (m, 10 H), 2.25 (s, 3 H), 2.6 (s, 6 H), 3.05-3.25 (m, 8 H), 3.45 (s, 4 H), 6.9 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][N+:7]([O-:9])=[O:8].C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1>CS(C)=O.CCOCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([N+:7]([O-:9])=[O:8])=[CH:25][NH:24][CH:23]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c[nH]cc1-c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h
Yield: 212.2 %

Procedure:
Sodium hydride (2.66 g of a 60% suspension in oil is rinsed with dry ether; 66 mmol) and suspended in 150 mL of dry ether. To this mixture is added over 15 minutes a mixture of 12.0 g (5.5 mmol) of 3,4-dichloro-β-nitrostyrene and 10.8 g (5.5 mmol) of (p-tolylsulfonyl)methyl isocyanide in 50 mL of DMSO and 150 mL of ether. The mixture is stirred for 1.5 hours and then diluted with 150-200 mL of water and additional ether. The ether layer is separated, dried over magnesium sulfate, and concentrated in vacuo. The resulting 10.6 g of crude product is purified by chromatography on silica gel using a 4:1 mixture of chloroform and ethyl acetate. A 7.2 g solid fraction is recrystallized from chloroform-ethyl acetate-hexane to give 3.0 g of yellow solid, m.p. 187°-188° C. (dec.).
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[O:10]([CH2:11][CH2:12][Br:13])[C@@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](OCCBr)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 92.9 %

Procedure:
A solution of NaOMe (0.1M, 0.3 mL) was added to a suspension of 4h (See FIG. 6) (300 mg, 0.66 mmol) in MeOH (3 mL) under N2 and stirred vigorously. After 4 hours, the resulting solution was passed through a Dowex 50W(H+) plug (2×1 cm, eluant MeOH) and the solvent removed to give 2-bromoethyl β-D-glucopyranoside 4c (See FIG. 6) (176 mg, 93%) as a white solid that was used directly in the next step. A sample was recrystallized from EtOH/EtOAc to give a colorless, crystalline solid; mp 74-78° C. (EtOH/EtOAc) [lit., (Helferich et al., Just. Lieb. Ann. Chem., 541:1-16 (1939), which is hereby incorporated by reference) mp 74-75° C. (EtOH/EtOAc)]; [α]26D=−22.4 (c 1.63, H2O) [lit., (Helferich et al., Just. Lieb. Ann. Chem., 541:1-16 (1939), which is hereby incorporated by reference) [α]19D=−26.1 (c 3.0, H2O)]; 1H NMR (400 MHz, CD3OD) δ 3.30 (t, J 8.4 Hz, 1H, H-2), 3.39-3.49 (m, 3H), 3.64-3.80 (m, 31H), 3.97 (br d, J6,6′ 11.7 Hz, 1H, H-6′), 4.02 (dt, Jt 6.5 Hz, Jd 11.3 Hz, 1H, —OCHH′—), 4.23 (dt, Jt 6.5 Hz, Jd 11.3 Hz, 1H, —OCHH′—), 4.44 (d, J1,2 7.9 Hz, 1H, H-1). NaSSO2CH3 (100 mg, 0.75 mmol) was added to a solution of 4c (See FIG. 6) (176 mg, 0.61 mmol) in DMF (7 mL) under N2 and warmed to 50° C. After 15 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1c (See FIG. 6) (144 mg, 74%) as a hygroscopic foam; [α]27D=−15.8 (c 0.88, H2O); IR(KBr) 3400 cm−1 (OH), 1310, 1131 cm−1 (S—SO2); 1H NMR (500 MHz, D2O, COSY) δ 3.07 (dd, J1,2 8.1 Hz, J2,3 9.4 Hz, 1H, H-2), 3.16 (dd, J3 4 9.0 Hz J4,5 9.8Hz, 1H, H-4), 3.24 (ddd, J4,5 9.8 Hz, J5,6 6.0 Hz, J5,6′ 2.3Hz, 1H, H-5), 3.27 (t, J 9.0 Hz, 1H, H-3), 3.30-3.33 (m, 2H, —CH2S—), 3.34 (s, 3H, CH3SO2—), 3.50 (dd, J5,6 6.0 Hz, J6,6′ 12.4 Hz, 1H, H-6), 3.69 (dd, J5,6 2.3 Hz, J6,6′ 12.4 Hz, 1H, H-6′), 3.81 (dt, Jt 5.8 Hz, Jd 11.5 Hz, 1H, —OCHH′—), 4.00 (dt, Jt 5.7 Hz, Jd 11.4 Hz, 1H, —OCHH′—), 4.30 (d, J1,2 8.1 Hz, 1H, H-1); 13C NMR (50 MHz, D2O) δ 36.9 (—CH2S—), 51.0 (CH3SO2—), 62.0 (—OCH2—), 69.5, 70.9, 74.3, 76.7, 77.3 (C-2, C-3, C-4, C-5, C-6), 103.7 (C-1); HRMS m/z (FAB+): Found 341.0351 (M+Na+); C9H18O8S2Na requires 341.0341.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([C:6]([F:9])([F:8])[F:7])[CH2:4][OH:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[F:1][C:2]([F:11])([F:12])[C:3]([CH3:10])([C:6]([F:7])([F:9])[F:8])[CH:4]=[O:5]
Reactant: CC(CO)(C(F)(F)F)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C=O)(C(F)(F)F)C(F)(F)F
Temperature: 100 °C

Procedure:
3,3,3-Trifluoro-2-methyl-2-trifluoromethyl-propan-1-ol, 1 gm, 5.1 mM, and Dess-Martin Periodinane, 4.3 gm, 10.2 mM, 2 eq. was added to ten ml of 1,1,1,3 tetrachloroethane and the mixture stirred for several hours. A short path distillation head was added and the receiver flask was cooled in dry ice-acetone bath. The mixture was heated to 100° C. and the pressure lowered to 180 Ton. The desired product 3,3,3-Trifluoro-2-methyl-2-trifluoromethyl-propionaldehyde condensed in the receiver flask and was used without further purification in the above reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:20])[N:12]=[C:13]([NH:16][N+:17]([O-:19])=[O:18])[NH:14][CH:15]=2)=[CH:5][N:4]=1.[CH3:21]I>C(Cl)(Cl)Cl>[CH3:21][N:14]1[CH:15]=[C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[C:11](=[O:20])[N:12]=[C:13]1[NH:16][N+:17]([O-:19])=[O:18]
Reactant: COc1ncc(Cc2c[nH]c(N[N+](=O)[O-])nc2=O)cn1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: COc1ncc(Cc2cn(C)c(N[N+](=O)[O-])nc2=O)cn1
Temperature: 23 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
A solution of 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-(nitroamino)-4(1H)-pyrimidinone (200 mg, 0.719 mmol) in chloroform (5 mL) was mixed with methyl iodide (0.054 mL, 0.863 mmol). The reaction mixture was stirred at 23° C. overnight. Purification via a reverse phase Biotage then provided the title compound (35 mg, 16.66% yield). LCMS: rt=1.62 min, [M+H+]=293.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccn1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1ccccn1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 2-(2-aminoethyl)pyridine (35 mg) according to Method B to give the title compound (56 mg). 1H-NMR (400 MHz, CD3OD) d 8.52 (d, J=4.6 Hz, 1H), 7.97 (m, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.46-7.17 (m, 8H), 7.03 (d, J=8.6 Hz, 1H), 4.78 (s, 2H), 4.46 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.4 Hz, 1H), 3.41 (m, 1H), 2.74 (dd, J=8.9 Hz, J=13.6 Hz, 1H), 1.35 (s, 9H); HRMS m/z 634.2651 (calc. of monoisotopic mass for C33H38N4O9 gives 634.2639).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CC2CCC1C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Norbornaneacetic acid (66 mg) was dissolved in thionyl chloride (0.5 ml) under a nitrogen atmosphere, followed by stirring at 50° C. for 1 hr. The reaction mixture was concentrated under a reduced pressure to provide a crude product of 2-norbornaneacetyl chloride. The crude product of 2-norbornaneacetyl chloride was dissolved in acetonitrile (5 ml) under a nitrogen atmosphere, and then potassium thiocyanate (84 mg) was added thereto at 50° C., followed by stirring at the same temperature for 1 hr. The reaction mixture was cooled down to room temperature, and then 4-(4-amino-2-fluorophenoxy)-2-[(dimethylamino)carbonylamino]pyridine (50 mg) was added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:4). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (5 ml) was added to precipitate crystals. A suspension containing the crystals was diluted with hexane (10 ml). The crystals were filtered off and dried under aeration to provide the titled compound (39,7 mg, 48%) as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1>COCCOC.O.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>[F:7][C:8]1[N:13]=[CH:12][C:11]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(F)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of sodium carbonate (5.79 g), tetrakis(triphenylphosphine)palladium(0) (0.631 g), 6-fluoropyridin-3-ylboronic acid (5 g) and 3-bromopyridin-2-amine (4.72 g) in DME (75 mL) and water (15 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane, then NH silica gel, eluted with EtOAc in hexane) to give the title compound (4.53 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[F:17][C:18]1[C:23]([O:24][CH3:25])=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[Sn](C)(C)C.[F-].[Cs+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:22]([C:26]([F:28])([F:29])[F:27])=[C:23]([O:24][CH3:25])[C:18]=2[F:17])[N:6]=1)=[O:4]
Reactant: COc1c(C(F)(F)F)ccc([Sn](C)(C)C)c1F
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(OC)c2F)cc(NC(C)=O)c1Cl
Yield: 10 %

Procedure:
In an oven dried, nitrogen flushed 100 mL 3 neck flask equipped with a condenser and a magnetic stirbar was dissolved methyl-4-acetamido-3,6-dichloropyridine-2-carboxylate (1.2 g, 4.6 mmol) and (2-fluoro-3-methoxy-4-trifluoromethylphenyl)trimethyl stannane (1.7 g, 4.6 mmol) in acetonitrile (15 mL) and the resulting solution was de-aerated with a purge of nitrogen for 15 minutes. Cesium fluoride (2.1 g, 13.9 mmol), 1,4-bis(diphenylphosphino)butane (0.2 g, 0.46 mmol) and palladium acetate (0.1 g, 0.46 mmol) were added and the head space of the reaction was purged with nitrogen as the reaction was heated to reflux with stirring. The reaction was then stirred under an open nitrogen atmosphere for 5 hours by which time TLC (hexane:ethyl acetate/1:2) indicated complete consumption of starting material. The cooled reaction was filtered through celite with ethyl acetate and the filtrate concentrated and purified by flash silica gel chromatography (hexanes:ethyl acetate/2:1) to give 4-acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylic acid methyl ester (0.19 g, 0.46 mmol) as an oil: 1H NMR (CDCl3): δ 9.03 (d, 1H), 8.02 (bs, 1H), 7.68 (bt, 1H), 7.42 (bd, 1H), 4.03 (d, 3H), 4.01 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH2:37])[CH2:35][CH3:36]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:37][CH2:34][CH2:35][CH3:36])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and propylamine. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:34]>O1CCCC1>[OH:34][CH:33]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:45])([CH3:44])[CH3:46])=[N:37][CH:38]=[CH:39][CH:40]=1)[CH:16]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]1)[C:15]([O:14][CH3:13])=[O:30]
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A solution of diisopropylamine (6.0 mL, 43 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. A 2.5M solution of n-butyllithium in hexanes (17.0 mL, 43 mmol) was added to the mixture drop-wise. Mixture was held at −78° C. with stirring for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (9.3 g, 36 mmol) in tetrahydrofuran (35 mL) was added to the mixture drop-wise. Mixture was held at −78° C. for 1.5 hours. In a separate flask, 60% sodium hydride in mineral oil (1.57 g, 39 mmol) was washed in hexanes and then suspended in tetrahydrofuran (70 mL). Mixture was cooled to 0° C. A solution of N-(3-formylpyridin-2-yl)pivalamide (6.74 g, 33 mmol) in tetrahydrofuran (20 mL) was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 2 hours. Mixture was warmed to room temperature and then added to the butyllithium containing solution drop-wise. Reaction mixture was held at −78° C. with stirring for 2 hours. Mixture was allowed to slowly warm to room temperature. Mixture stirred at room temperature for 14 hours. Reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate (2×100 mL). Organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white foam in 93% yield. (M+H)+=464.2.