Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Li].[CH:12]1([C:18]2[CH:19]=[C:20](Cl)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C)[CH:36]=[O:37]>O1CCCC1>[CH:12]1([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:36]=[O:37])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: Clc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Agent: [Li]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
Naphthalene (3.48 g, 27.2 mmol) was added to a suspension of 30% lithium dispersion (3.2 g, 138 mmol, pre-washed with tetrahydrofuran) in tetrahydrofuran (80 ml). The suspension was stirred until a green color appeared (approximately 1 hour). The reaction was cooled to −78° C., and a solution of the 3-cyclohexyl-4-morpholinoethoxy-chlorobenzene (8 g, 24.7 mmol) in tetrahydrofuran (20 ml) was added. After 1 hour, the reaction was warmed to 0° C. and stirred for an additional hour. Dimethylformamide (9.6 ml, 123.5 mmol) was added, the reaction was stirred at 0° C. for one more hour and then warmed to room temperature and stirred for another hour. The reaction was quenched with methanol (30 ml), added to 1N hydrochloric acid (300 ml) and extracted with ethyl acetate (400 ml). The organic layer was washed with water (300 ml), saturated sodium bicarbonate solution (300 ml) and brine (300 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, 40-60% ethyl acetate/hexanes) afforded 3 g (34%) of 3-cyclohexyl-4-morpholinoethoxybenzaldehyde as a light yellow oil.
Reaction SMILES: I[C:2]1[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH3:30])=[O:27])=[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(NC2CCOCC2)c1I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NC1CCOCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of 5-iodo-6-methyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine (10.0 g, 30.0 mmol) in DMF (200 mL) was added triethylamine (12.50 mL, 90.0 mmol) and ethyl acrylate (9.80 mL, 90.0 mmol) successively at room temperature. The reaction was purged with nitrogen for 5 min. and Pd(PPh3)4 (10 mol %, 3.50 g) was added. The reaction was heated to 95° C., stirred for overnight under nitrogen, and then cooled to room temperature. Nearly all DMF was evaporated under reduced pressure. The reaction was poured into ethyl acetate (500 mL) and H2O (300 mL). The organic layer collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (70% ethyl acetate/hexanes to 10% EtOH/ethyl acetate) to afford (E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-5-yl)acrylate, as a light yellow semicrystal (yield: 6.85 g, 75.0%). LC/MS: calculated for C15H22N4O3 (306.17). found: 307.2 (MH+). HPLC analytical purity: >97.0%.
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]3[N:32]=[C:33]4[C:38](=[C:39]5[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]5)[CH:37]=[CH:36][CH:35]=[CH:34]4)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6][C@:5]2([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:46][C@H:4]2[CH2:3]1.Cl>C(OCC)(=O)C.O1CCOCC1>[F:54][C:2]1([F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:17][C:18]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[O:19])[C:10](=[O:26])[N:9]2[CH2:27][C@H:28]([O:30][C:31]3[N:32]=[C:33]4[C:38](=[C:39]5[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]5)[CH:37]=[CH:36][CH:35]=[CH:34]4)[CH2:29][C@H:8]2[C:7](=[O:45])[NH:6][C@:5]2([C:47]([OH:49])=[O:48])[CH2:46][C@H:4]2[CH2:3]1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Reaction time: 24 h

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-tert-butyl 12,12-difluoro-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18h, 20 mg, 0.027 mmol) in ethyl acetate (100 μl) stiffing at rt was added 4N hydrogen chloride (134 μl, 0.536 mmol) in dioxane. The reaction mixture was stirred for 24 h, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (10% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-12,12-difluoro-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic (10.2 mg, 55%)
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:3])=[O:5])(=[O:9])=[O:10])([C:12]([N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)=[O:13])[CH3:16]
Reactant: C1CSCCN1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Product: CC(C)(C(=O)N1CCSCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with thiomorpholine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-[(tetrahydro-4H-1,4-thiazin-4-yl)carbonyl]ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 399 (M)+, as a colourless solid.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CN(C)CCN(C)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23](B(O)O)[CH:24]=1>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][CH:9]=3)[CH:24]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: c1ncc2[nH]cnc2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: O
Solvent: CO
Product: Oc1ccc(Cl)cc1-n1cnc2cncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of purine (0.24 g, 2.0 mmol), copper(II) acetate (0.36 g, 2.0 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.6 mL, 4 mmol) in a mixture of methanol (160 mL) and water (40 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (0.69 g, 4.0 mmol). The reaction mixture was stirred vigorously open to the atmosphere at ambient temperature for 2 h. The mixture was filtered over a pad of diatomaceous earth and the pad was washed with a mixture of dichloromethane (50 mL) and methanol (50 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in dichloromethane, followed by trituration in a mixture of ethyl acetate and hexanes, to afford 4-chloro-2-(9H-purin-9-yl)phenol as a tan solid in 20% yield (0.098 g): 1H NMR (300 MHz, DMSO-d6) δ10.65 (s, 1H), 9.26 (s, 1H), 8.95 (s, 1H), 8.76 (s, 1H), 7.73-7.67 (m, 1H), 7.49-7.41 (m, 1H), 7.17-7.09 (m, 1H); MS (ES+) m/z 247.0 (M+1), 248.9 (M+1).
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]3[C:4]([N:5]=[C:6]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=24)=[CH:3][CH:2]=[N:1]3)=[CH:15][CH:14]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a solution of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol (60 mg, 0.2 mmol) in DMF (1 mL) was added 1-bromo-3-chloropropane (67 mg, 0.4 mol) and K2CO3 (45 mg, 0.3 mmol). The mixture was stirred at 80° C. for 5 hours, then cooled, diluted with EtOAc (3 mL) and washed with H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified via preparative LCMS to give 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (13 mg, 32% yield).
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:6]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)([CH2:7]1)[C:5](=[O:18])[N:4]([CH2:19][CH2:20][CH3:21])[C:3]2=[O:22].[H][H]>[Pd].C(OCC)(=O)C>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]23[CH2:8][C:2]([CH3:1])([CH2:7]2)[C:3](=[O:22])[N:4]([CH2:19][CH2:20][CH3:21])[C:5]3=[O:18])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CCCN1C(=O)C2(C)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2(C)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
1.0 g of 5% palladium-on-carbon catalyst is added to a solution of 10.0 g of 5-methyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 200 ml of ethyl acetate and the whole is hydrogenated under normal pressure and at 30°-35° in a hydrogen atmosphere. When the absorption of hydrogen is complete, the reaction mixture is diluted with 100 ml of methylene chloride and freed of catalyst by filtration over HYFLO Super-Cel®. The solvent is evaporated off in vacuo, and the residue is recrystallised from an ethyl acetate/n-hexane mixture, yielding the title compound in the form of white crystals having a melting point of 135°-136°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH3:25]I>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:25]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Product: COC(=O)c1cc(C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 96 %

Procedure:
In the same manner as described in Example 9, 0.30 g (0.860 mmol) of the product of Example 62 was alkylated with methyl iodide to give 0.30 g (96%) of the desired product as a white solid. Electrospray Mass Spec: 364 (M+H).
Reaction SMILES: [Li+].CC(O[Al-](OC(C)(C)C)OC(C)(C)C)(C)C.[C:18]1([C:26](OCC)=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1>C1COCC1.C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1([CH2:26][OH:27])[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: CC(C)(C)O[Al-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CC1
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of lithium aluminum-tri-tert-butoxyhydride 1.0M in THF (28.5 mL, 28.5 mmol) is added to a solution of diethyl 1,1-cyclopropanedicarboxylate (2.0 mL, 11.4 mmol) in anhydrous THF (85.0 mL). After stirring the reaction mixture for 4 h, 10 mL of lithium aluminum-tri-tert-butoxyhydride 1.0M solution in THF is added and the solution is stirred overnight. The reaction mixture is diluted with DCM, washed with 1N HCl, saturated NaHCO3 solution and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressure affords 1.60 g of 1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester that is used in the next step without further purification. Yield: 85%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88 (2H, q, J=4.1 Hz), 1.21-1.33 (5H, m), 2.59 (1H, t, J=6.9 Hz), 3.63 (2H, d, J=7.2 Hz), 4.17 (2H, q, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH:8]([OH:11])[CH2:9]Br)[O:5][N:4]=1.[F:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>C(O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:9][CH:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)[OH:11])[CH2:21][CH2:20]2)=[O:18])=[CH:25][CH:26]=1
Reactant: COc1cc(C(O)CBr)on1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)on1

Procedure:
A solution of 3.5 g of 1-(3-methoxy-isoxazol-5-yl)-2-bromoethanol and 4.9 g of 4-(4'-fluorobenzoyl)piperidine and 5.4 ml of N-ethyldiisopropylamine in 160 ml of absolute ethanol was refluxed for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C1CCN2C(=[N:15]CCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:15])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1
Temperature: 65 °C
Yield: 107 %

Procedure:
A solution of 4-fluoroaniline (1.00 ml, 10 mmol) and diisopropylethylamine (1.74 mL, 10 mmol) in anhydrous DMF (10 mL) was warmed to 60° C., then a solution of tert-butyl bromoacetate (1.47 mL, 10 mmol) in anhydrous DMF (10 ml) was added drop-wise over 1 hour. After addition, the reaction mixture was kept at 60° C. for 4 hours. The reaction mixture was then concentrated by rotary evaporation, then partitioned between EtOAc and water. The organic layer was washed with water, then evaporated to yield a dark brown liquid (1.96 g, 87%) TLC (EtOAc/hexanes, 1:4) Rf=0.31; ESI-MS m/z=225.9 [M+H]+. The disubstituted aniline derivative (0.41 g, 2.31 mmol) and was then coupled to 6-chloronicotinoyl chloride (0.52 g, 2.31 mmol) in anhydrous DMF (2 mL) using DBU (344 ml, 2.31 mmol). The reaction mixture was heated to 65° C. for 48 h. The reaction mixture was diluted with EtOAc, and the organic layer washed with H2O. The crude material was concentrated by rotary evaporation, and purified by flash chromatography (EtOAc/hex 1:2) to yield 387 mg (46%) of 6-chloronicotinamide intermediate XIV as a clear oil. TLC (EtOAc/hexanes, 1:2) Rf=0.28; ESI-MS m/z=364.9 [M+H]+.
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[C:14]([C:17]#[N:18])[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[F:19].C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:17]([C:14]1[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]([F:19])=[C:2]([C:25]([O:27][CH2:28][CH3:29])=[CH2:26])[C:15]=1[CH3:16])#[N:18]
Reactant: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Under nitrogen atmosphere, bis(triphenylphosphine)palladium chloride (435 mg, 620 μmol) was added to a toluene (125 ml) solution of 6-bromo-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-127) (4.04 g, 12.4 mmol), tributyl(1-ethoxyvinyl)tin (5.37 g, 14.9 mmol) and 2,6-di-tert-butyl-p-cresol (about 20 grains), and heated under reflux for 20 hours. After cooling, the solvent was evaporated away under reduced pressure, then n-hexane was added to the resulting residue and stirred at room temperature for 1 hour. Next, the precipitated solid was collected by filtration and subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (1:1, v/v) gave 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (3.20 g, 81%) as a yellow solid. The fraction containing impurities was recovered and purified in the same manner, and 3.57 g (91%) of 4-cyano-6-[1-(ethoxy)ethenyl]-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide was obtained in total. The analytical data are shown below.
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27].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>CN(C=O)C>[CH3:22][NH:21][C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([NH:7][CH:5]3[CH2:6][N:3]([C:23](=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27])[CH2:4]3)[C:13](=[O:14])[NH:12][CH:11]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CC/C=C/C(=O)O
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
Agent: Br
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: CC/C=C/C(=O)N1CC(Nc2cc(-c3ccnc(NC)c3)c[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (Example 14, Step 4, 80 mg, 0.19 mmol), in DMF (1 mL) was added (E)-pent-2-enoic acid (28 mg 0.28 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.923 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep. HPLC to afford (E)-2′-(methylamino)-5-((1-(pent-2-enoyl)azetidin-3-yl)amino)-[3,4′-bipyridin]-6(1H)-one (34 mg, 42%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.97 (dt, J=15.3, 6.4 Hz, 1H), 6.62 (dd, J=5.3, 1.6 Hz, 1H), 6.38 (d, J=1.8 Hz, 2H), 5.85 (dt, J=15.3, 1.7 Hz, 1H), 5.48 (d, J=6.6 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.60 (t, J=7.9 Hz, 1H), 4.55-4.46 (m, 1H), 4.33 (dt, J=12.5, 6.3 Hz, 1H), 4.07 (m, 2H), 2.97 (d, J=4.9 Hz, 3H), 2.22 (m, 2H), 1.06 (t, J=7.4 Hz, 3H); MS (ES) m/z 354 (M+H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:22]=[O:23])=[CH:11][CH:10]=1.[CH3:24][NH:25][CH3:26]>CO>[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([N:25]([CH3:26])[CH3:24])=[O:23])=[CH:11][CH:10]=1
Reactant: CNC
Reactant: O=C=Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Solvent: CO
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude intermediate from Step A in 4 mL of methanol was treated with 4 mL of 40% aqueous dimethylamine. After stirring at room temperature for 15 minutes, the reaction mixture was evaporated under vacuum and the residue dissolved in 4 mL of methanol and treated with 1 mL of 10% methanolic p-toluenesulfonic acid. After 15 minutes at room temperature, the reaction mixture was treated with saturated aqueous sodium bicarbonate. The mixture was diluted with water then extracted with methylene chloride. The organic layer was dried and evaporated under vacuum; the residue was purified by preparative thin layer chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to afford 133 mg of product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[C:13]1([C@H:19]2[CH2:21][C@@H:20]2[N:22]2[C:30](=[O:31])[C@@H:25]3[CH2:26][NH:27][CH2:28][CH2:29][N:24]3[C:23]2=[O:32])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:27]1[CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]([C@H:20]3[CH2:21][C@@H:19]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:30](=[O:31])[C@@H:25]2[CH2:26]1)=[O:11]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
2,3-Dichlorophenyl isocyanate (1.1 eq.) was added to a stirred solution of D2 and DIPEA (3.0 eq.) in DCM (0.09 M) and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 67% yield, 92% de by SFC. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.80 (1H, s), 7.45-7.42 (2H, m), 7.34-7.28 (3H, m), 7.23-7.18 (3H, m), 4.35 (1H, dd, J=12.9, 4.2 Hz), 4.14-4.09 (2H, m), 3.92 (1H, dd, J=13.0, 2.7 Hz), 3.07-2.99 (2H, m), 2.91 (1H, td, J=12.6, 3.0 Hz), 2.68 (1H, m), 2.39 (1H, ddd, J=9.8, 6.8, 3.2 Hz), 1.51 (1H, ddd, J=9.5, 5.7, 4.3 Hz), 1.41 (1H, dd, J=14.0, 7.1 Hz). MS (ES+) C22H20Cl2N4O3 requires 458, 460, found: 459, 461 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:31]Br.O>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([Br:31])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.1 g, 1 eq.) and sodium acetate (761 mg, 3 eq.) in acetic acid (15 ml), was added bromine (158 ul, 1 eq.) and the reaction was stirred at room temperature for 4 h. Water was added and the product extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.44 g) as a yellow solid.
Reaction SMILES: C(N=C(N)N)#N.C(O)(=O)C.C(O)(=O)C.C(N)=N.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=1[N+:28]([O-])=O>[Ni].CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[NH2:28]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N#CN=C(N)N
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Cl)c(N)c1

Procedure:
3 g of dicyanodiamide, 3 g of acetic acid, 2 g of Raney nickel (60%, aqueous), and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. Under a hydrogen pressure of 4 bar and a temperature of 25° C., the dicyanodiamide is hydrogenated to the formamidine acetate. 40.8 g of 1-chloro-2,4-dinitrobenzene are then added to the autoclave, and the hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 98% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.