Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=1)[CH:23]=O)[CH3:18]>>[CH2:29]([O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH2:17][CH3:18])[CH:27]=1)[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:30]
Reactant: CCOc1cc(C=O)cc(OCC)c1
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(OCC)c1
Yield: 33 %

Procedure:
The title compound (13 mg, 33%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3,5-diethoxybenzaldehyde. MS: 398.5 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][NH:27][CH:28]([CH3:29])[C:8]2=3)=[CH:4][CH:3]=1.Cl.C1(C2C=CC=CC=2)C=CC(CN2C(=O)C(C(NCC(OC(C)(C)C)=O)=O)=C(O)C3CNCC2=3)=CC=1.[S:68]1[CH:72]=[C:71]([C:73](Cl)=[O:74])[N:70]=[CH:69]1.CCN(CC)CC>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[O:15])=[C:10]([OH:25])[C:9]3[CH2:26][N:27]([C:73]([C:71]4[N:70]=[CH:69][S:68][CH:72]=4)=[O:74])[CH:28]([CH3:29])[C:8]2=3)=[CH:30][CH:31]=1
Reactant: CC1NCc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(Cc3ccc(Br)cc3)c21
Reactant: O=C(Cl)c1cscn1
Agent: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(-c4ccccc4)cc3)c1=O)CNC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1c2c(c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2Cc2ccc(Br)cc2)CN1C(=O)c1cscn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To tert-butyl N-{[1-(4-bromobenzyl)-4-hydroxy-7-methyl-2-oxo-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (1.344 g, 2.73 mmol, prepared in similar fashion to Intermediate 6 utilizing the appropriate starting materials) was added the product of Step A (0.403 g, 2.73 mmol) and NEt3 (0.38 mL, 2.73 mL). The reaction stirred at rt for about 17 h and was then diluted with EtOAc and washed with aq Na2CO3 (2 M) and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-65% EtOAc/hexane to afford the product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[N:17][C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 160 °C
Yield: 36 %

Procedure:
A mixture of (1-benzyl-piperidin-4-yl)-(6-chloro-pyridazin-3-yl)-amine (D1) (3 g, 9.9 mmol), zinc cyanide (2.09 g, 17.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.74 g, 2.3 mmol) in N,N-dimethylformamide (30 ml) was heated at 160° C. for 30 min., under microwave irradiation (Milestone MW-oven). The solvent was then evaporated in vacuo and an aqueous solution of potassium carbonate (10%) and ethyl acetate were added. The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 0 to 1.5% ammonia in methanol (7M)/dichloromethane) and then by HPLC to yield D2 (1.06 g, 36%) as a solid. C17H19N5 requires 293. Found 294 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[CH:15]=[CH:14]3)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[CH:15]=[CH:14]3)=[O:10])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1-n1ccc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc21
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1yl)-3cyanophenyl)acetate (0.043 g, 0.0837 mmol) in DCM (0.5 mL) was added TFA (0.50 mL, 6.49 mmol). The reaction mixture was stirred for 1 hour and then concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0.5% methanol/DCM with 0.5% AcOH to 5% methanol/DCM containing 0.5% AcOH to provide 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indol-1yl)-3-cyanophenyl)acetic acid as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56 (d, J=3.0 Hz, 1H), 7.24-7.34 (m, 5H), 6.84 (d, J=3.9 Hz, 1H), 3.83 (s, 2H), 3.62 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), MS(APCI)=458.1(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]([CH:26]=1)=[N:23][O:24][N:25]=2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[C:22]([CH:26]=2)=[N:23][O:24][N:25]=3)[N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCc1ccc2nonc2c1
Reactant: O=[N+]([O-])c1ccc(Nn2cncn2)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc3nonc3c2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-nitrophenyl)amino]-1H-1,2,4-triazole and 5-bromomethylbenzofurazan
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[CH2:3][CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]#[N:6]
Reactant: CC(C)(CO)CCC#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 16.13 g (0.127 mmol) of 4,4-dimethyl-5-hydroxyvaleronitrile in 250 mL of dry CH2Cl2 was added, at 20° C., in 2 min., 24.2 mL (0.139 mmol; 1.09 eq) of diisopropylethylamine, followed after 5 min. by 25.0 g (0.165 mmol; 1.3 eq) of solid t-butyldimethylsilyl chloride, all at once. Then, 1.55 g (0.0127 mmol; 0.1 eq) of 4-dimethylaminopyridine was added and the whole was stirred at 20° C. during 18h. After removing the solvent under vacuum (aspirator) the brown residue was taken up in H2O, followed by ethyl ether. The layers were separated and the aqueous one extracted three times with 200 mL of ether. The combined organic layers were back extracted with water (100 mL), HCl 1.2N (100 mL), 5% KHCO3 (2×100 mL), dried over Na2SO4 and concentrated under vacuum to give a faint yellow oil. Distillation at 94°-97° C. (0.7 mm) gave 21 g (69%) of the title compound. TLC: (Silica), Rf 0.59 (CH2Cl2), detection with molybdophosphoric acid blue on yellow.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>C1(C)C=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 100 °C
Yield: 89.28 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.51 g, 17.29 mmol, 1.0 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in toluene (70 mL) respectively and heated to 100° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, and the mixture was reacted for 4 h. White solid was obtained by filtration (6.50 g, yield: 89.28%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(C)c1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.851 g, 8.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.422 mL, 10.20 mmol). The solution was then cooled to 0° C. before 2,4-dimethylbenzoyl chloride (I53) (1.577 g, 9.35 mmol) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered, and analysis by LCMS showed impurities still to be present. The solid was thus further purified by flash chromatography (Isolera 100 g cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 1.482 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:21]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6]([CH:12]([OH:13])[CH3:21])=[N:7]2
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde (0.4405 g, 1.537 mmol) in THF (14.95 mL, 1.537 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.024 mL, 3.073 mmol) dropwise at 0° C. and the mixture was then allowed to warm to room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined orgainc layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1 H, dd, J=8.4, 1.2 Hz), 8.06 (1 H, dd, J=7.6, 1.4 Hz), 7.87 (1 H, dd, J=8.4, 7.6 Hz), 7.56-7.71 (3 H, m), 7.37-7.46 (1 H, m), 5.50 (1H, d, J=6.1 Hz), 5.04-5.13 (1 H, m), 1.48 (3 H, d, J=6.3 Hz); LC-MS (ESI) m/z 303.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:31]([C:2]1[CH:3]=[C:4]([CH2:5][N:6]2[C:10]([CH3:11])=[N:9][C:8]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=4)[N:13]=3)=[N:7]2)[CH:28]=[CH:29][CH:30]=1)=[CH2:32]
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 110 °C

Procedure:
To a mixture of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 11, Step 1; 200 mg, 0.42 mmol), tributyl(vinyl)stannane (159 mg, 0.50 mmol) and K2CO3 (174 mg, 1.26 mmol) in 1,4-dioxane (5 mL), was added Pd(PPh4)3 (28 mg, 0.025 mmol). The reaction mixture was heated in a sealed vial at 110° C. under inert atmosphere for 12 h, cooled to RT, diluted with H2O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC to give the title compound as a white solid; MS (ES+) C21H16F3N5O2 requires: 427. found: 428 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=9 Hz, 2H), 7.61 (d, J=9 Hz, 2H), 7.48 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 7.21 (d, J=7 Hz, 1H), 6.76 (m, 1H), 5.87 (d, J=17.5 Hz, 1H), 5.57 (s, 2H), 5.31 (d, J=11.5 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11].Br[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>CN(C)C=O>[CH2:17]([N:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11])[CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: C=CCCCBr
Reactant: O=C1CCCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCN1CCCCCCC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a stirred suspension of sodium hydride (0.9 g, 37.5 mmole) in dimethylformamide (50 mL) was added azocan-2-one (3.83 g, 30 mmole). The mixture was stirred at room temperature for 15 minutes, and then 5-bromo-1-pentene (5.03 g, 33.7 mmole) was added slowly. The reaction mixture was stirred at room temperature for 30 minutes, and then at 80° C. for 16 hours. The solvent was removed under reduced pressure and water was added to the residue. The mixture was extracted with ethyl ether, the organic phase was washed with water, dried (magnesium sulfate) and concentrated to give 1-pent-4-enyl-azocan-2-one (5.53 g,) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH4+:10].[OH-]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:10])=[O:8]
Reactant: [NH4+]
Reactant: O=C(Cl)Cc1cccs1
Agent: [OH-]
Product: NC(=O)Cc1cccs1
Yield: 64 %

Procedure:
To a mixture of concentrated NH4OH (100 mL) and ice was added 2-thiopheneacetyl chloride (13.0 g, 80.9 mmol). The desired compound crystallized from the reaction mixture. Recrystallization from hot water gave 2-thiopheneacetamide (8.08 g, 64% yield) as white crystals. mp 146°-147° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: ClCCN1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (0.217 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% to 20% (2.0 M NH3 in methanol) in acetone to give the title compound: MS ES+ 397.2 (M+H)+, HRMS calcd for C22H29N4O3 397.2240 (M+H)+, found 397.2223, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.6 min, 99.0% purity.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(C)(C)SSC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of (R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-Cys(StBu)-OH) (Compound SP639) (280 mg, 0.708 mmol) in methylene chloride (1.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (371 μL, 2.12 mmol) and acetic anhydride (66.8 μL, 0.708 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-Cys(StBu)-OH) (Compound SP640) (270 mg, 0.617 mmol, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:20])[CH:15]=[C:16]([NH:18][CH3:19])[CH3:17].N1C=CC=CC=1.Cl.N1C=CC=CC=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)/[C:16](=[N:18]/[CH3:19])/[CH3:17]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: CNC(C)=CC(=O)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-methyl-benzoyl chloride (40.0 mmol) in tetrahydrofuran (300 mL) wad added 3-methylamino-but-2-enoic acid methyl ester (5.12 g, 40.0 mmol), followed by pyridine (3.2 mL, 40.0 mmol), and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride coated the flask, so the mixture was decanted, and the solid was washed three times with EtOAc. The combined solutions were concentrated and diluted with EtOAc (500 mL), and the mixture was washed three times with water. The aqueous layer was separated and back-extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([NH:25][S:26](=[O:29])(=[O:28])[NH2:27])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH3:45][C:46]1([CH3:55])[C@H:51]2[CH2:52][C@@H:47]1[CH2:48][CH2:49][C@@H:50]2[CH2:53][OH:54]>>[Cl:17][C:18]1[C:19]([O:54][CH2:53][C@H:50]2[CH2:49][CH2:48][C@H:47]3[CH2:52][C@@H:51]2[C:46]3([CH3:55])[CH3:45])=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([NH:25][S:26](=[O:29])(=[O:28])[NH2:27])=[O:24]
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Reactant: NS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CC1(C)[C@H]2CC[C@H](COc3cc(F)c(C(=O)NS(N)(=O)=O)cc3Cl)[C@@H]1C2

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-sulfamoylbenzamide and adamantan-1-ylmethanol with ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol, the title compound was obtained as a colorless solid (0.09 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.58 (s, 2H), 7.22 (d, J=12.4 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.49-2.38 (m, 1H), 2.10-2.03 (m, 1H), 2.19-1.65 (m, 5H), 1.48-1.34 (m, 2H), 1.22 (s, 3H), 0.86 (s, 3H); MS (ES−) m/z 403.2, 405.2 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].O.Cl>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 130 °C
Yield: 87.3 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (0.51 mmol) and 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid (0.61 mmol) in acetonitrile (2.5 mL) and aqueous sodium carbonate solution (0.4 M, 2.5 mL) is degassed with nitrogen for 5 minutes before addition of tetrakistriphenylphosphine palladium (0) (29.5 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 30 minutes. To the reaction mixture is added 2 mL of water, the pH is adjusted to about 7 using 2 N aqueous HCl and this mixture is extracted three times with ethyl acetate (30 mL). The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid as a solid (205 mg, 75%). LC/MS: RT=2.39 minutes, MS: 460 (M+H); 1H NMR [300 MHz, (CD3)2SO]: δ 12.38 (1H, s), 7.36-8.00 (7H, m), 6.58 (1H, s), 3.84 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.54 (6H, s).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:12])[CH:6]=1)#[N:4].[CH2:13](I)[CH3:14].O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)#[N:4]
Reactant: CCI
Reactant: Cc1ccc(C#N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a reaction vessel was charged sodium hydride (4.8 g, 0.12 mol) and N,N′-dimethylformamide (40 ml), and a solution obtained by dissolving 4-cyano-2-hydroxytoluene (14) (13.3 g, 0.1 mol) in N,N′-dimethylformamide (40 ml) in an ice bath was dropped on this, and the solution was stirred for 1.0 hour at room temperature. Subsequently, ethyl iodide (18.7 g, 0.12 mol) was dropped in an ice water, and the solution was stirred for 1.5 hours at room temperature. To the reaction liquid was added water and extracted with ethyl acetate, then, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure, to obtain 4-cyano-2-ethoxytoluene (15) (16.1 g, yield from (14) is 99%).