Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20](=[O:35])[N:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[N:47][NH:48][CH:49]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH:47]1[CH:46]=[C:45]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:49]=[N:48]1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2Br)cc1F
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2-c2cn[nH]c2)cc1F
Temperature: 85 °C
Yield: 57 %

Procedure:
In a sealed tube, N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.064 g, 0.332 mmol), potassium carbonate (0.092 g, 0.664 mmol), and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 85° C. overnight. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were added. The reaction mixture was degassed with Ar and heated at 85° C. for 2 days. The mixture was diluted with EtOAc and extracted with sat. NaHCO3 (aq). The organic extract was washed with brine, dried and evaporated. The crude product was purified by silica gel chromatography (25 g) eluting with CH2Cl2/MeOH to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (69 mg, 56.9% yield). The hydrochloride salt was formed by suspending N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.069 g, 0.126 mmol) in acetonitrile (2 ml) and adding 0.1N HCl (1.51 mL, 0.151 mmol). The mixture was sonicated for 10 min. The solution was diluted with water (2 mL), frozen and lyophilized. The crude lyophilate was dried at 80° C. for 4 h under vacuum to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (0.069 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 9.15 (s, 1H); 8.49 (d, J=6.5 Hz, 1H); 8.43 (dd, J=12.5, 7.0 Hz, 1H); 8.33 (s, 2H); 7.93 (d, J=7.8 Hz, 1H); 7.69 (dd, J=10.8, 7.3 Hz, 1H); 7.48 (dd, J=8.8, 4.9 Hz, 2H); 7.37 (t, J=8.8 Hz, 2H); 7.25 (d, J=6.5 Hz, 1H); 6.56 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 508.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[C:15]([Br:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1.[C:24](O)(C(F)(F)F)=[O:25]>Cl>[Br:1][C:2]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[C:15]([Br:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:8]([OH:11])=[C:9]([CH:10]=1)[CH:24]=[O:25]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c1Br
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Temperature: 95 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
Hexamethylentetramine (197 mg, 1.4 mmol) was added to a solution of compound 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-isopropylphenol of Part 8C (250 mg, 0.56 mmol) and TFA (5 mL). The resulting reaction mixture was stirred for 16 hours at 95° C. The reaction mixture was cooled to room temperature and 1N HCl (10 mL) was added. After another hour of stirring, the reaction mixture was extracted with EtOAc (3×30 mL), the combined organic phases washed by 1N HCl (15 mL), H2O (20 mL) and brine (20 mL). After drying over Na2SO4, concentration and filtration through a pad of silica, 210 mg (79%) of 5-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde was obtained as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:40])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[OH-].[Li+].CN(C)C=O.SCC(O)=O>CCOC(C)=O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([F:40])[CH2:18][NH:19][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(NCC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (21.0 mg, 0.030 mmol; see representative procedure 4) was added lithium hydroxide (3.2 mg, 0.134 mmol), dimethylformamide (0.5 ml, 0.06 M) and mercaptoacetic acid (4.2 ul 0.060 mmol). After stirring at rt for 1 h the reaction mixture was diluted with EtOAc and washed sequentially with water, saturated sodium bicarbonate solution, water (3×) and brine. The organic layer was dried over Na2SO4, filtered and condensed. The crude reaction mixture was purified in 30% EtOAc/hexanes (+0.2% TEA), with 13.6 mg isolated. Yield=88%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=NC(=O)C)[N:21]([CH2:27][CH3:28])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:29]1CCOCC1.OS(O)(=O)=O>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:22](=[O:29])[N:21]([CH2:27][CH3:28])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCn1c(=NC(C)=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21

Procedure:
A mixture of the product of Example 5, N-[6-(3,5dimethoxy-phenyl)-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-ylidene]-acetamide, (43.5 g, 0.11 mol) and dioxane (200 mL) was heated with stirring to the boiling point at which point the solid dissolved. At the boiling point was added 100 mL of 15% aq. H2SO4 and the mixture refluxed for 2 minutes. The reaction mixture cooled in an ice bath and water was added (˜200 mL). Crystals formed that were collected by filtration and washed with water. The solid was dissolved in CH2Cl2 (400 mL), dried over K2CO3, charcoal added, and the mixture filtered through celite. The filtrate was evaporated under reduced pressure to give 33.0 g of the titled compound. mp 120–122° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OC1CCCC1
Product: N=C(OC1CCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and cyclopentanol there is obtained cyclopentyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, 1H-NMR(CDCl3): 1.5-2.1 (8H), 4.2 (s, 4H), 4.67 (broad s, NH), 5.1 (m, OCH), 7.3-7.7 (8H).
Reaction SMILES: O1CCOCC1.C(O)(=O)C.[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24](=[N:31][O:32][CH3:33])[C:25]([N:27]=[CH:28][NH:29][OH:30])=O)=[CH:14][CH:13]=1>CCOCC>[CH3:33][O:32][N:31]=[C:24]([C:25]1[O:30][N:29]=[CH:28][N:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:15]1[CH:34]=[CH:35][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: CON=C(C(=O)N=CNO)c1ccccc1COc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CON=C(c1ncno1)c1ccccc1COc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.7 %

Procedure:
Dioxane (2 ml) and acetic acid (1.5 ml) were added to 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-α-methoxyiminophenylacetamide (0.36 g, 1 mmol), and the mixture was stirred at 120° C. for 4 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-5-yl ketone O-methyloxime (0.14 g, 40.8%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccnc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (50 mg, 68%), MS (ISP) m/z=296.5 [(M+H)+], mp 239° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][CH3:17])[CH2:11][C:10]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=O)CCCCCCC>>[C:1]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][CH3:17])[CH2:11][C:10]1=[O:18])(=[O:8])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:19]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC1CCCN(C(=O)c2ccccc2)C(=O)C1
Product: CCCCCCCC(=O)N1CCCC(OC)CC1=O

Procedure:
Synthesized as for N-benzoyl-3-methoxycaprolactam (Example VII) using octanoyl chloride (Aldrich) in place of benzoyl chloride.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:27][CH2:28][O:29][CH3:30])[CH2:21][C:22]#[C:23][C:24]([OH:26])=O.[Br:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([NH2:49])[CH:47]=3)[N:42]=[CH:41][N:40]=2)[CH:35]=[CH:36][CH:37]=1>O1CCCC1.N1C=CC=CC=1>[Br:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([NH:49][C:24](=[O:26])[C:23]#[C:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:27][CH2:28][O:29][CH3:30])[CH:47]=3)[N:42]=[CH:41][N:40]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: COCCN(CC#CC(=O)O)CCOC
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCN(CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1)CCOC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (0.963 g, 9.52 mmol) were added to an ice cold solution of 2.100 g (9.52 mmol) of 4-[bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.660 g of 4-[Bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 512.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc2nc(N)c3ncccc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc(C(=O)O)cc2c2cccnc12
Temperature: 80 °C
Reaction time: 36 h

Procedure:
Ethyl 5-aminobenzo[f][1,7]naphthyridine-9-carboxylate (Example 8) (1.0 eq.) was mixed with 1N NaOH (2.0 eq.) in ethanol (0.12 M). The reaction was heated to 80° C. and stirred for 36 hours. The solvent was removed en vacuo. The residue was suspended in water, and the pH was adjusted to neutral using 5% citric acid aqueous solution. The suspension was centrifuged (2500 rpm, 5 min), and the supernatant was removed. The resulting solids was re-suspended in water by vortexing, centrifuged (2500 rpm, 5 min), and the supernatant was removed. The re-suspension, centrifugation, and removal of supernatant steps were repeated with hot methanol, hot ethyl acetate, and ether to give a pure solid. 1H NMR (DMSO): δ 12.86 (s, 1H), 9.15 (d, 1H), 9.00 (s, 1H), 8.97 (d, 1H), 8.07 (d, 1H), 7.88-7.91 (dd, 1H), 7.56-7.59 (m, 3H). LRMS [M+H]=240.1
Reaction SMILES: [CH2:1]([N:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]CC)=[O:12])[NH:7][C:6]=2[C:5]([N:16]([CH3:25])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])=[CH:4]1)[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[NH:7][C:6]=2[C:5]([N:16]([CH3:25])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc2c([nH]1)c(N(C)S(=O)(=O)c1cccs1)cn2CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylate (1.0 g), tetrahydrofuran (8 mL) and ethanol (8 mL) was added 8N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated, 6N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether to give 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid (780 mg, yield 85%) as colorless crystals.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][N:17]([CH3:24])[CH2:18][C:19]#[C:20][C:21](O)=[O:22].[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([C:36]#[N:37])=[C:29]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1>O1CCCC1.N1C=CC=CC=1>[Br:45][C:41]1[CH:40]=[C:39]([NH:38][C:29]2[C:28]3[C:33](=[CH:34][CH:35]=[C:26]([NH:25][C:21](=[O:22])[C:20]#[C:19][CH2:18][N:17]([CH3:24])[CH3:16])[CH:27]=3)[N:32]=[CH:31][C:30]=2[C:36]#[N:37])[CH:44]=[CH:43][CH:42]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Isobutyl chloroformate (0.260 g, 1.91 mmol) and N-methylmorpholine (0.594 g, 5.88 mmol) were added to an ice cold solution of 0.370 g (2.94 mmol) of 4-dimethylamino-2-butynoic acid in 50 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.144 g (21%) of yellow solid; ESMS m/z 448.0 (M+H+); mp 114-118° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([CH:21]([CH:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]([OH:24])=[O:23])[CH2:17][CH2:18][CH2:19][CH3:20].O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>COCCOC>[CH2:16]([CH:21]([CH:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22]([OH:24])=[O:23])[CH2:17][CH2:18][CH2:19][CH3:20].[C:35]1(=[O:40])[NH:34][C:38](=[O:39])[CH2:37][CH2:36]1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCC(O)C(CCCCC)C(=O)O
Solvent: COCCOC
Product: O=C1CCC(=O)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dicyclohexylcarbodiimide (27 g) dissolved in 1,2-dimethoxyethane (300 cc) is added, in the course of 40 minutes, to a solution, kept at 0° C., of 2-n-pentyl-3-hydroxynonanoic acid (29.1 g) and N-hydroxysuccinimide (14.1 g) in 1,2-dimethoxyethane (300 cc). The reaction mixture is stirred at 0° C. for 3 hours and then kept at 4° C. for 21 hours. The precipitate formed is filtered off and washed twice with 1,2-dimethoxyethane (100 cc in total). The filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 50° C. The concentrate is taken up in a mixture of diisopropyl ether (300 cc) and acetic acid (3 cc). After standing for 2 hours at 20° C., the precipitate formed is filtered off and washed twice with diisopropyl ether (40 cc in total). The filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 50° C. Succinimide 2-n-pentyl-3-hydroxynonanoate (42.6 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CCO>[F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:33][CH:34]([O:36][CH3:37])[CH2:35]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: COC1CN(c2ncc(N3CCN(c4cccc(CN5C(=O)c6ccccc6C5=O)c4F)CC3)cn2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC1CN(c2ncc(N3CCN(c4cccc(CN)c4F)CC3)cn2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHCl3) to obtain 1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methanamine (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[C:4]([F:11])[N:3]=1.Cl.N[C@@H]1CC[CH2:17][CH2:16][C@H:15]1[OH:20].C[Si](C)(C)N[Si](C)(C)C.[Na].IC1COC1>C(O)(C)C.CCO.[Ni](I)I>[F:1][C:2]1[CH:7]=[C:6]([CH:16]2[CH2:15][O:20][CH2:17]2)[CH:5]=[C:4]([F:11])[N:3]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Fc1cc(C2COC2)cc(F)n1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 390 %

Procedure:
(2,6-difluoro-4-pyridyl)boronic acid (4.0004 mmol; 635.67 mg), Nickel(II) iodide (0.12001 mmol; 37.503 mg), Trans-2-aminocyclohexanol hydrochloride (0.12001 mmol; 18.382 mg), and Sodium hexamethyldisilazane (4.0004 mmol; 748.56 mg) were weighed into a CEM microwave vial. The mixture was capped then placed under a nitrogen atmosphere. Isopropanol (15 mL) was added and the mixture was stirred under nitrogen for 5 minutes. 3-Iodooxetane (2.0002 mmol; 368 mg) in Isopropanol (1.5 mL) was then added. The vial was heated at 100° C. under microwave for 20 minutes. The mixture was diluted with EtOH (15 mL) and filtered through Celite. The filter cake was washed with EtOH (2×10 mL). The mixture was concentrated and the residue was purified on silica eluted with 0 to 50% EtOAc in DCM to afford 2,6-difluoro-4-(oxetan-3-yl)pyridine (80.1 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](O)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C[CH2:27][N:28](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:28][CH3:27])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (vi) (15 g, unpurified from the previous step) in DMF (300 mL) was added DIPEA (27.7 mL, 0.16 mol), HATU (23.9 g, 0.06 mol) and methylamine (2.0M solution in THF, 60 mL, 0.12 mol). The reaction mixture was stirred for 2 h at RT and then poured onto the ice. The precipitate was then separated by filtration and the solid obtained was dissolved in DCM (300 mL), dried (Na2SO4) and the volatiles removed in vacuo to give (vii) (16.5 g with purity 86.5% by HPLC analysis), which was used unpurified in subsequent steps. ESI-MS m/z calculated for [M+H]+: 371.1. found: 371.0. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.74 (s, 1H), 7.62-7.45 (m, 4H), 5.91 (brs, 1H), 3.09-2.97 (m, 3H), 2.40-2.28 (m, 1H), 1.04-0.95 (m, 2H), 0.73-0.65 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([CH:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])(=O)[CH3:12]>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[C:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Product: COC(=O)CC(C(=O)OC)=C(C)Nc1ccc2c(c1)CCC2
Reaction time: 72 h
Yield: 53.8 %

Procedure:
2,3-dihydro-1H-inden-5-amine (10 g; 75 mmol) and dimethyl acetylsuccinate (12.82 g; 68 mmol) were mixed in a flask placed in a dessicator and the homogeneous mixture was stirred under vacuum (3 mbars) for 3 days. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0 to 20%) in heptane furnished 11.1 g (48%) of dimethyl 2-(1-(2,3-dihydro-1H-inden-5-ylamino)ethylidene)succinate as a deep orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[C:5]2[OH:16].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[C:5]2[OH:16]
Reactant: COC(=O)c1cc(O)c2cc(Cl)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(O)c2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
6-Chloro-4-hydroxy-2-methoxycarbonylnaphthalene (J. Chem. Research (S), 1995, p. 638) (473 mg) was dissolved in ethanol (10 ml), and a 1N aqueous solution (4.0 ml) of sodium hydroxide was added to stir the mixture for 24 hours at room temperature. Thereafter, the reaction mixture was stirred for 1 hour at 60° C. and 6 hours at 70° C., and the solvent was distilled off under reduced pressure. An 1N aqueous solution of hydrochloric acid and ethyl acetate were added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (442 mg) as a pale yellow solid.