Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:43]=[CH:42][C:15]([CH2:16][C@H:17]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:18][C@@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18][C@H:17]([CH2:16][C:15]1[CH:42]=[CH:43][C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCOCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 690 mg (1.15 mmol) di-tert-butyl (4S)-4-{4-[3-(benzyloxy)propyl]benzyl}-N-(tert-butoxycarbonyl)-L-glutamate in 17 mL of methanol, palladium (10% on charcoal) was added and the suspension was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered over celite, and the solvent was evaporated. The remaining material was used without purification.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][C:27]#[N:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN1CCCC1=O.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:12]/[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][C:27]#[N:28])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: N#CCCS(=O)(=O)c1ccc(Br)cc1
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CCCS(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Temperature: 135 °C
Yield: 70.1 %

Procedure:
To a suspension of sodium acetate (54 g, 0.66 mol) and 4-fluorostyrene (90 g, 0.74 mol) in 1-methyl-2-pyrrolidinone (500 mL) was added 3-[(4-bromophenyl)sulfonyl]propanenitrile (Step 1, 90 g, 0.33 mol) and palladium (II) acetate (1.4 g, 6.2 mmol). The mixture was plunged into an oil-bath at 100° C. and heated to 135° C. for 20 minutes. The cooled reaction mixture was diluted with water and EtOAc and filtered through Hyflo®. The organic layer of the filtrate was washed with water (×3) then concentrated in vacuo. The residue was triturated with isohexane to give 3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)propanenitrile (73 g). δH (360 MHz, CDCl3): 7.88 (2H, d, J 8.0), 7.69 (2H, d, J 8.3), 7.51 (2H, dd, J 5.6, 8.3), 7.22 (1H, d, J 15.0), 7.10–7.02 (3H, m), 3.39 (2H, t, J 7.7), 2.83 (2H, t, J 7.7).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:26][C:27]1[C:35]([OH:36])=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.CC(C)=O.FC1C(O)=CC=C2C=1C=C(C)N2.C(=O)([O-])[O-].[K+].[K+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:36][C:35]4[C:27]([F:26])=[C:28]5[C:32](=[CH:33][CH:34]=4)[NH:31][C:30]([CH3:37])=[CH:29]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (12.24 g, 33.5 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.54 g, 33.5 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (4.64 g, 33.5 mmol) was heated in N,N-dimethylacetamide (150 ml) at 85° C. for 4 hours. 4-Fluoro-5-hydroxy-2-methylindole (33 mg, 0.2 mmol) and potassium carbonate (108 mg, 57%) were added and the mixture heated for a further 1 hour at 85° C. and then stirred at ambient temperature overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a white solid which was suspended in acetone (150 ml) and heated at reflux for 1 hour. After cooling the mixture was filtered and the solid dried in air to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (10 g, 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[OH:22][CH:23]1[CH2:26][N:25]([C:27](=[O:29])[CH3:28])[CH2:24]1.CC(C)([O-])C.[K+]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:22][CH:23]2[CH2:26][N:25]([C:27](=[O:29])[CH3:28])[CH2:24]2)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: CC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), 1-(3-hydroxyazetidin-1-yl)ethan-1-one (1 g, 8.69 mmol) and potassium t-butoxide (500 mg, 5.21 mmol) in N,N-dimethylformamide (5 mL) kept under nitrogen in a 30-mL sealed tube was stirred overnight at room temperature. The reaction mixture was filtered through a frit filter and the filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 160 mg (29%) of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one as a yellow solid. LC-MS: m/z=+403 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:48])[CH:16]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:17]2[CH:30]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:29](=[O:38])[N:20]3[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:19]3[C:18]2=[O:39])=[CH:9][CH:8]=1)(C)(C)C.C(Cl)Cl.C(C(O)=O)(F)(F)F>>[C:46]([C:43]1[CH:44]=[CH:45][C:40]([CH:16]([N:17]2[CH:30]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:29](=[O:38])[N:20]3[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:19]3[C:18]2=[O:39])[C:15]([NH:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:49])=[O:5])=[CH:12][CH:11]=2)=[O:48])=[CH:41][CH:42]=1)#[N:47]
Reactant: CC(C)(C)OC(=O)c1ccc(CNC(=O)C(c2ccc(C#N)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(C(=O)NCc2ccc(C(=O)O)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Yield: 100 %

Procedure:
The above-described cyclized products 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid tert-butyl ester (diastereomers A and B) were treated with a 1:1 CH2Cl2 /CF3CO2H solution according to General Method 3 to afford 27 mg (100%) of 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid (diastereomer A) and 35 mg (100%) of 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid (diastereomer B).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.Cl>C(OCC)C>[NH2:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 2-(2-oxo-2,3-dihydrobenzo[d]imidazol-1-yl)ethylcarbamate (200 mg) was added to 15 mL of hydrogen chloride solution in diethyl ether (1 M) and the mixture was stirred at rt for 5 h. Evaporation of the solvent give the title compound as a white hydrochloride salt (100%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCC1OCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CNCC1OCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxolane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight. After this time the mixture was cooled and filtered. The filtrate was then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine having a boiling point of 125° C at 0.1 mm of Hg pressure.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]=3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[CH2:23][CH:22]=[C:21]([C:16]2[C:15]([CH:13]3[CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:14]3)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.100 g, 0.225 mmol, SCHEME 5) CH2Cl2 (1 mL) and TFA (0.174 mL, 2.255 mmol) was stirred at RT for 1 h. LCMS showed the product and no more starting material was present. The mixture was concentrated in vacuo and neutralized with Na2CO3. The mixture was extracted with a mixture of CHCl3:i-PrOH (3:1) three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (77 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)CCC.[Ni]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]2[CH:8]=[CH:9][N:10]=[C:3]12
Reactant: Cc1cccn2ccnc12
Agent: [Ni]
Solvent: CCCCO
Product: CC1CCCn2ccnc21
Temperature: 65 °C
Reaction time: 96 h
Yield: 79.9 %

Procedure:
1 g of 8-methylimidazo[1,2-a]pyridine [3-1] was dissolved in 20 mL of 1-butanol, and a catalytic amount of Raney nickel of was added thereto. The mixture was stirred under a hydrogen atmosphere (5 atmospheric pressure) at 65° C. for 4 days. After cooling the reaction mixture back to room temperature, the insolubles were filtered through celite, and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, to obtain 823.3 mg of 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [46-1].
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].O1CC[CH2:14][CH2:13]1.C([Al](CC)CC)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.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.CO>[CH2:13]([C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11])[CH3:14]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Br
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Al](CC)CC
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1c(C)c[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture composed of 4-bromo-2,3,5-trimethylpyridine 1-oxide (5.76 g), tetrahydrofuran (60 mL), a 15% solution of triethylaluminum in toluene (40 mL) and tetrakis(triphenylphosphine)palladium (0) (1.54 g) was heated under reflux for six hours. After leaving to cool to room temperature, toluene (60 mL), methanol (12 mL) and subsequently a saturated ammonium chloride solution (18 mL) were added, and the mixture was heated under reflux for one hour. After leaving to cool to room temperature, the insoluble matter was separated off by filtration, and the filtrate was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (3.84 g, 87%) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc2c(c1)OCO2
Yield: 83 %

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and D-leucine methyl ester hydrochloride. Yield: 83%. 1H NMR (500 MHz, CDCl3): δ 0.98 (m, 6H); 1.63-1.67 (m, 1H); 1.71-1.76 (m, 2H); 3.76 (s, 3H); 4.83 (m, 1H); 6.03 (s, 2H); 6.38 (d, 1H); 6.83 (d, 1H); 7.32 (s, 1H); 7.33 (d, 1H). MS (M+H, 294). m.p: 89-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:50][C:51]([C:53]1[C:54]2[CH:55]=[CH:56][N:57]=[CH:58][C:59]=2[CH:60]=[CH:61][CH:62]=1)=[NH:52]>CN(C)C=O>[Cl:15][C:9]1[CH:8]=[C:4]([C:5]2[O:7][N:52]=[C:51]([C:53]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:54]=3[CH:55]=[CH:56][N:57]=[CH:58]4)[N:50]=2)[CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CCCOc1c(Cl)cc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1c(Cl)cc(-c2nc(-c3cccc4cnccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3,5-dichloro-4-(propyloxy)benzoic acid, (Maybridge) (150 mg, 0.603 mmol), HATU (232 mg, 0.610 mmol), Hunig's base (0.263 mL, 1.506 mmol) and N,N-dimethylformamide (DMF) (1 ml) was stirred for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 94 mg, 0.502 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was left to stir for 2 hrs at room temperature and then heated to 120° C. for 2 hr in a microwave. The cooled reaction mixture was concentrated in vacuo and the residue purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)) to give the title compound (23 mg)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][C:5]([N:7]4[C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=5[O:11][CH2:10][CH2:9][CH2:8]4)=[O:6])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)=[CH:23][CH:24]=1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:33]1[C:37]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH3:37])=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C)c1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0187 g (0.277 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0505 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3,N-dimethyl-benzamide (I-190) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].[ClH:24]>[Pd].C(O)C>[ClH:24].[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CNC[C@H]1c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of trans-ethyl-1-benzyl-4-phenylpyrrolidine-3-carboxylate (1.69 g, 5.47 mmol), concentrated HCl (36% in H2O, 610 mg) and palladium on activated carbon (10 wt %, 169 mg) in ethyl alcohol (27 mL) was put on hydrogenator at 50 psi for overnight. The mixture was filtered through Celite pad and washed with ethyl alcohol. The filtrated was concentrated to give the title compound as a off-white solid (quantitative yield). 1H NMR (400 MHz, CD3OD) δ 1.11 (3H, t, J=6.8 Hz), 3.36–3.42 (2H, m), 3.63–3.75 (4H, m), 4.06–4.11 (2H, m), 7.29–7.39 (5H, m). HPLC purity (retention time): 95% (1.05 min, method C). MS: 220.23 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][S:15][CH2:2][C:3]1[O:7][C:6]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)=[O:18])[CH3:21]
Reactant: O=[N+]([O-])c1cccc2cc(CBr)oc12
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1cc2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromomethyl-7-nitrobenzo[b]furan (512 mg), ethyl mercaptoacetate (0.24 ml) and potassium carbonate (552 mg) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 2 hours. To the reaction mixture was added cold water and the separated solid was collected, washed with water and dried to give 2-ethoxycarbonylmethylthiomethyl-7-nitrobenzo[b]furan (546 mg).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[C:46]([CH2:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:48])[NH2:47]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:53]2[CH2:54][CH2:55][CH2:56][N:50]([CH2:49][C:46](=[O:48])[NH2:47])[CH2:51][CH2:52]2)=[O:29])[CH2:10]1
Reactant: NC(=O)CN1CCCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Yield: 82.3 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 5.69 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 2.48 g of N,N'-carbonyldiimidazole and 5.89 g of N-carbamoylmethylhomopiperazine bis(trifluoroacetate), 4.88 g of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc(Cl)cc4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 4-chloroaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 443 (M+H)+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[F:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH2:23])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])[C:15]=1[F:33].O>C(Cl)Cl.C1COCC1>[F:33][C:15]1[C:16]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:6](=[O:7])[NH:23][C:17]=2[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]=1[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
For scale up synthesis, CDI(92.4 g, 570 mmol) was added to a solution of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine (153.6 g, 380.1 mmol) in 1500 mL of DCM at 0° C. The solution was then warmed to room temperature and stirred for approximately 48 hours. Analysis showed 0.3% remaining of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine with 86.1% purity. The solution was filtered to give crude gray solid with 96.4% purity. The crude was dissolved in 1.5 L of THF and then water (1.5 L) was added. The suspension was then concentrated to 1.7 L and filtered to give 87 g of product with 98.0% purity (53.2% yield). 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (bs, 1H), 8.09 (d, 1H), 7.94 (dd, 1H), 7.76 (d, 1H), 7.47 (t, 1H), 7.19 (d, 1H).