Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24])[CH3:2].Br[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:24])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)c2ccc(Oc3ccc(O)cc3)cc2C1=O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Oc2ccc3c(c2)C(=O)N(CC(=O)OCC)C3=O)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of [5-(4-hydroxy-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid ethyl ester (2.479 g, 7.26 mmol), 1-bromopropane (1.32 mL, 14.52 mmol), potassium carbonate (2.01 g, 14.52 mmol), and acetone (25 mL) was refluxed overnight. After cooling to ambient temperature the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.485 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.77 (q, 1H, J=8.1 Hz), 7.3-6.8 (m, 6H), 4.38 (s, 2H), 4.20 (q, 2H, J=7.0 Hz), 3.93 (t, 2H, J=6.4 Hz), 1.82 (q, 2H, 6.6 Hz), 1.28 (t, 3H, J=7.0 Hz), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([NH2:28])=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]#[N:28])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: NC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred slurry of 2-{trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetamide (45 mg, 0.11 mmol), from Example 30, in THF (1 mL) was added DMF (0.002 mL) and oxalyl chloride (0.05 mL, 0.6 mmol). After two hours of stirring at room temperature, the reaction was quenched with aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 34 mg. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.63 (br s, 2H) 7.22 (m, 4H), 4.57 (m, 2H), 3.90 (m, 2H), 2.43 (m, 3H), 1.78 (m, 4H), 1.63 (m, 1H), 1.43 (m, 2H), 1.08 (m, 2H). m/z=378.3 (M+1). IC50 64.3 nM (range 51.2-91.1 nM).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28]C)=[O:27])#[N:23]>>[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](/[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[N:3]\[O:2][CH3:1])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27])#[N:23]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(F)cc1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc(F)cc1
Yield: 15.46 %

Procedure:
Compound 34 was synthesized from (1Z)-1-(4-fluorophenyl)-2-[4-(hydroxymethyl)phenoxy]ethanone O-methyloxime (0.4 g, 1.46 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.46 mmol) by following the procedure described in scheme 18 (0.06 g, yield: 15.46%); Purity: 95.29%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.30 (m, 4H), 3.75-3.78 (m, 3H), 4.08-4.13 (m, 4H), 6.89-6.96 (m, 3H), 7.19-7.44 (m, 5H), 7.64-7.80 (m, 1H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O>[N:20]1([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc2n2c(=O)[nH]nc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 0.5 g (~1.89 mmol) 8-fluoro-7-nitro[1,2,4]triazolo[4.3-a]quinoxaline-1,4(2H,5H)-dione in 10 ml dry N,N-dimethylformamide was added 0.4 g (~5.9 mmol) imidazole. The reaction mixture was stirred at 120° C. for 2h. Evaporation in vacuo gave the title compound as an oil, which was solidified by stirring with water. Yield: 0.34 g (58%). M.p.>300° C. decomp.
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:9])=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32].Cl>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)=[O:9])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: CCCn1cncc1CSc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
To (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfenyl}phenylamine di-p-toluoyl-D-tartarate monohydrate (5 g) were added 1N hydrochloric acid (25 ml) and ethyl acetate (15 ml) to effect reverse extraction. To the aqueous layer was added aqueous 25% potassium carbonate solution (25 ml) (pH 9) and the mixture was extracted with 25 ml of ethyl acetate-IPA (4:1) three times. The organic layer was washed with saturated brine (25 ml) and dried with magnesium sulfate. The solvent was distilled off to give (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}-phenylamine.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][CH:6]([CH:12]([CH3:14])[CH3:13])[CH2:7][S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: CC(=O)OCC(CS(N)(=O)=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(CO)CS(N)(=O)=O
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
7.0 g of 3-acetoxy-2-isopropyl-1-propanesulfonamide was dissolved in 50 ml of methanol. While stirring the solution at room temperature (15° to 20° C.), 6.5 g of 28 w/w % sodium methoxide was added, and reaction was carried out for 30 minutes. The reaction mixture was concentrated to dryness; the residue was then subjected to column chromatography using 100 g of silica gel and eluted with chloroform:methanol (9:1) to yield 4.4 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[Cl:26])(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3n2)c(Cl)c1
Temperature: 95 °C
Yield: 15.7 %

Procedure:
2-Chloro-5-fluoroquinolin-6-ol (Intermediate 16, 1.0 mmol) and 4-borono-3-chlorobenzoic acid (1.1 mmol) were mixed with 5% (Ph3P)4Pd and 4.0 mmol of NaHCO3 in 20 ml 50% dioxane/water. The mixture was degassed three times by evacuation and argon filling and heated at 95° C. overnight. The reaction was diluted with 20 ml of water and filtered. The filtrate was acidified with 1N HCl to pH=4. The precipitate was filtered and washed with water, dried. The crude was purified by column using AcOH/MeOH/EtOAC (1/5/94) as solvent B and hexanes as solvent A with gradient 2 to 100%. The fractions with compound were pooled and evaporated to obtain white solid. The solid was triturated with diisopropyl ether. 50 mg of final product was obtained. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 10.55 (b, 1H), 8.47 (d, 1H), 8.01-8.03 (m, 2H), 7.79 (m, 3H), 7.56 (t, 1H). MS (ESI): m/z=316.3 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28].N12CCCN=C1CCCCC2>ClCCl>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27](=[NH:28])[O:14][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[N:8]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:11]=1)[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 4 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (2.5 g, 6.94 mmol) and trichloroacetonitrile (6.95 mL, 69.4 mmol) in dichloromethane (50 mL) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.66 mmol). After stirring for 4 h, the reaction was concentrated and purified by column chromatography (12% EtOAc/Hex+0.1% Et3N) to give 3.1 g, (89%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 6.67 (q, J=6.6 Hz, 1H), 5.73 (s, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.80 (d, J=6.6 Hz, 3H), 0.93 (m, 2H), −0.05 (s, 9H). Mass spec.: 526.90 (MH)+.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[C:12]=2[Cl:14])[NH:7][CH:6]=1)C.[C-:17]#[N:18].[K+].CI>>[C:17]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[C:12]=2[Cl:14])[NH:7][CH:6]=1)#[N:18]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CI
Product: COc1ccc2[nH]cc(CC#N)c2c1Cl
Yield: 91.2 %

Procedure:
Reaction of 3-dimethylaminomethyl-4-chloro-5-methoxy-indole (2.00 g, 8.40 mmol) with potassium cyanide (2.08 g, 32.0 mmol) and methyl iodide (4.72 g, 33.0 mmol) and subsequent workup as described in 1 (d) gave 3-cyanomethyl-4-chloro-5-methoxyindole (1.69 g), m.p. 138°-9° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][O:31][C:32]([NH:34][NH2:35])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:27][Si:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][O:31][C:32](=[O:33])[NH:34][N:35]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=[C:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)CCOC(=O)NN
Reactant: CC(C)(C)c1ccc(C(=O)CCC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2ccc(-c3ccc(C(C)(C)C)cc3)n2NC(=O)OCC[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-bis-(4-tert-butyl-phenyl)-butane-1,4-dione (377 mg, 1.08 mmol) in toluene (3 mL) was treated with hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (212 mg, 1.18 mmol) and p-toluene sulfonic acid (11.3 mg). The resulting solution was heated to reflux under Ar for 1.5 h, then cooled to rt and concentrated in vacuo to provide crude [2,5-Bis-(4-tert-butyl-phenyl)-pyrrol-1-yl]-carbamic acid 2-trimethylsilanyl-ethyl ester. The residue was not purified, but was deprotected immediately as follows.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([O-])(=O)C.[NH4+].[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cccc(Oc3ccccc3)c2)S1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A solution of thiazolidine-2,4-dione (90%, 78 mg, 0.6 mmol) and ammonium acetate (92 mg, 1.2 mmol) in acetic acid (1 mL) was added to 3-phenoxybenzaldehyde (52 μL, 0.6 mmol) and the resulting mixture was shaken at 115° C. for 16 hours. After cooling, the mixture was concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.[C:20](O)(C(F)(F)F)=[O:21]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:8])[C:3]=1[OH:9])[CH:20]=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1c(F)cccc1F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(F)c(O)c(F)c1
Temperature: 130 °C

Procedure:
To a solution of 2,6-difluoro phenol (1 g; 7.69 mmol) in CF3COOH (10 ml) is added hexamethylene tetramine (1.08 g; 7.69 mmol) and the mixture is heated in a microwave apparatus at 130° C. for 15 min. After evaporation to dryness the residue is taken-up in CH2Cl2 and saturated K2CO3 solution. After acidification with hydrochloric acid the aqueous layer is extracted with CH2Cl2 (3×100 ml). The combined organic layer is washed with brine, dried over MgSO4 and evaporated to dryness to give 3,5-difluoro-4-hydroxy-benzaldehyde as a colourless solid (0.82 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=O)=[O:14])=[CH:8][CH:7]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:21]([C:17]1[S:18][CH:19]=[CH:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)=[O:23])[NH2:3]
Reactant: NN
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
Hydrazine monohydrate (0.825 mL, 17.1 mmol) was added to a solution of methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (3.48 g, 11.4 mmol) in ethanol (40 mL) and the resulting solution was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 1/1 to 1/9) to give N-(2-(hydrazine-carbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (1.71 g, 5.60 mmol, 49%). Retention time (min)=1.300, method [1], MS(ESI) 306.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[C:4]([F:17])[CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([B:8]3[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16]3)=[C:4]([F:17])[CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-amino-2-fluorophenyl boronic acid pinacol ester (3.0 g, 12.7 mmol) in THF (10 ml) was added sodium hydrogen carbonate (1.6 g, 19.0 mmol) followed by phenyl chloroformate (1.9 ml, 15.2 mmol) and stirred overnight at room temperature. The reaction mixture was partitioned between DCM and water, the organic phase recovered, dried over Mg2SO4 and filtered before being concentrated in-vacuo to afford a white solid (4.95 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:15]([CH3:16])[CH3:14])[CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN(C)C)c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a cooled (−10° C.) solution of methyl-3-(bromomethyl)benzoate (22.9 g, 100 mmol) in ether (250 ml) was added dimethylamine hydrochloride salt (17.9 g, 220 mmol) followed by slow addition of triethylamine (30.6 ml, 220 mmol). The mixture was then allowed to warm to r.t. over 48 h, the solids were filtered off and the filter-cake washed with ether. The yellow oil remaining after evaporation of the solvent was distilled over a Vigreux column to afford the title compound (10.7 g, 55% yield) as a colorless oil. MS: m/e=193 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].[N:20]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCOC(C)=O>O1CCOCC1>[C:9]([C:8]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=[C:6]([CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:10])[NH2:20]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C(N)=O)cc(C(=O)OCC)c1
Yield: 92.7 %

Procedure:
NH4HCO3 (0.15 g, 1.89 mmol, 1.26 eq) was added to a stirred solution of 3,5-bis(ethoxycarbonyl)benzoic acid (0.42 g, 1.5 mmol, 1 eq), pyridine (0.24 mL, 0.237 g, 3.0 mmol, 2 eq), and (Boc)2O (0.45 mL, 0.43 g, 1.95 mmol, 1.3 eq) in 2 mL anh. dioxane under Ar. The reaction was stirred over the weekend to form a white solid. EtOAc was added, but the solid did not dissolve. The mixture was washed with 0.1 N HCl (×2) and water (×4). The solid stayed suspended in the organic layer, but did dissolve. The solvent was removed in vacuo yielding 0.369 g (1.39 mmol, 93% yield) of diethyl 5-carbamoylisophthalate as an insoluble white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]=[CH:20][NH:21][C:22](=O)[C:23]=4[N:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1P(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.CCN(C(C)C)C(C)C.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]=[CH:20][N:21]=[C:22]([NH2:26])[C:23]=4[N:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1[nH]cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 16.2 %

Procedure:
6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4 (3H)-one (100 mg, 0.28 mmol), phosphonitrilic chloride (100 mg, 0.28 mmol) and as stir bar were transferred to a vial, capped and placed under nitrogen atmosphere. Dry acetonitrile (3 mL) was transferred and allowed the contents to stir at room temperature. i-Pr2NEt was added for 2 min to the heterogeneous slurry. Upon stirring the red homogeneous slurry for 2 h, nitrogen balloon was replaced with NH3 balloon and stirred. After stirring the contents for 6 h, the reaction mixture was concentrated and the crude residue was partitioned between chloroform/water. Organic layer was removed and re-extracted the aqueous layer with chloroform. Usual workup and purification by preparative HPLC provided 6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (16 mg) as a white solid.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:21])=[C:14]([NH:16][C:17]([NH:19][CH3:20])=[S:18])[CH:15]=1>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:21])=[C:14]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH3:20])[C:17]2=[S:18])[CH:15]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CNC(=S)Nc1cc(Cl)ccc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1C(=O)C(=O)N(C)C1=S
Yield: 72.2 %

Procedure:
Ethyl chlorooxoacetate (16.3 g; 0.128 mol) was added dropwise to the solution N-(5-chloro-2-methylphenyl)-N′-methylthiourea (10.7 g; 0.05 mol) in chloroform (200 mL). The mixture was heated at reflux for 4 hours then evaporated to dryness. The residue was treated with ether (200 mL). The precipitated solid was collected by filtration and dried to give 9.7 g of 1-(5-chloro-2-methylphenyl)-3-methyl-2-thioxo-4,5-imidazolidinedione, m.p. 171–173° C. Mass spectrum; (El, M.+) m/z268/270. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50–7.47 (m, 1H), 7.42–7.40 (m, 2H), 3.31 (s, 3H), and 2.15 ppm (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[OH-].[Na+].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[C:4]([CH2:3][NH:2][S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15])#[N:5]
Reactant: N#CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCNS(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 27.8 g (0.3 moles) aminoacetonitrile hydrochloride and 24.0 g (0.3 moles) 50% aqueous sodium hydroxide in 200 ml water, 17.7 g (0.1 mole) benzenesulfonyl chloride were dropped in over about 25 minutes. During the addition, the temperatures of the reaction mixture was kept under 20° C. using an ice bath. After the addition was complete, the ice bath was removed; stirring of the reaction mixture continued for about 30 minutes. The solids which formed were isolated by filtration and were washed with 200 ml water. The resulting beige solids were dissolved in 150 ml methylene chloride, dried over magnesium sulfate and stripped. The resulting white solids were washed with hexane, filtered and air-dried to give 13.9 g of the above-identified product, melting point 81°-83° C.