Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]4[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=[C:13]4[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:10]1[N:9]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]3[C:17]([C:20]([F:22])([F:21])[F:23])=[N:18][N:19]=[C:13]3[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)c1nnc2n1CCC(c1ncc3c(Cl)nccn13)C2
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCC(c1nc(Br)c3c(Cl)nccn13)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To a solution of 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (335 mg, 0.978 mmol) in DMF (4.9 mL) was added NBS (226.19 mg, 1.271 mmol) at ice water, the resulting solution was stirred at this temperature for 10 minutes. The reaction was quenched with water, then extracted with EA and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to give 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine (0.41 g, yield 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH3:18][NH:19]C=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][N:19]=[C:7]([OH:8])[C:6]1[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[C:10]([OH:9])=[O:11]
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Reactant: CNC=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Yield: 77.8 %

Procedure:
238.11 g (1 mol) of 3,5-dinitrophthalic anhydride are dissolved under reflux in 1 liter of xylene. 62.02 g (1.05 mols) of N-methylformamide are added dropwise under reflux in the course of 30 minutes. After 18 hours under reflux, the water formed and the formic acid, together with some xylene (total 140 ml), are distilled off, the boiling point rising to 137° C. The solution is filtered hot. After slow cooling and concentration of the mother liquor, 209.42 g (83% of theory) of 3,5-dinitrophthalic acid N-methylimide are obtained; melting point: 174°-6° C.
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.[CH:21]([NH2:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+]>C(Cl)CCl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:4](=[O:20])[N:24]([CH:21]([CH3:23])[CH3:22])[CH:12]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)N1C(=O)c2ccc(Br)cc2C1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Benzoyl-4-bromo-benzoic acid ethyl ester (50 mg; 0.15 mmol) is dissolved in ethylene dichloride (1 ml) and treated with 1 mol/l Titanium(IV)chloride solution (150 μl; 0.15 mmol) and cooled down to 0° C. Isopropylamine (13 μl; 0.15 mmol) is added and stirred for 2 hours at ambient temperature and 16 hours at 80° C. A 6.5 mol/l solution of sodium cyano borohydride in methanol (140 μl; 0.90 mmol) is added and stirred for 3 days followed by another portion of sodium cyano borohydride in methanol and 16 hours at 50° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[O:23]([CH2:30][CH2:31][NH2:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:23]([CH2:30][CH2:31][NH:32][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCOc1ccccc1
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound D (150 mg, 483 μmol), 2-phenoxyethylamine (127 μl) and sodium hydrogencarbonate (400 mg) were added to DMSO (3 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile (82 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:22])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
To a slurry of sodium 4-(4-fluorobenzyloxy)benzenesulfonate (0.5 grams, 1.64 mmole), in methylene chloride (5 mL) was added phosphorus pentachloride (275 mg, 1.31 mmole). The resulting mixture was heated at reflux for 7 hours. After cooling in an ice bath and quenching with water (15 mL), the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to afford 4-(4-fluorobenzyloxy)benzenesulfonyl chloride a white solid (130 mg, 26%).
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=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (65 mg, 82%), MS (ISP) m/z=318.4 [(M+H)+], mp 278.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)[CH2:33][CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=3)[CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
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: COC(=O)c1ccc(CCc2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 56.3 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (88 mg, 0.27 mmol) and methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)benzoate (100 mg, 0.27 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (100 mg, 0.94 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoate (80 mg, 56%) as a yellow sold. LC-MS: 527 [M+H]+, tR=1.87 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:28][C:29]([OH:31])=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[C:16]([N+:25]([O-:27])=[O:26])=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.[CH3:32][CH2:33]O>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][C:15]1[C:16]([N+:25]([O-:27])=[O:26])=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2ncccc2c1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Oc2ccc3ncccc3c2[N+](=O)[O-])c(OC)c1

Procedure:
Concentrated sulfuric acid (0.32 mL, 11.3 mmol) was added to 24.2 (4 g, 11.3 mmol) in EtOH. The mixture was heated to reflux for 15 h. After cooling, EtOH was evaporated under vacuum, and the residue was treated with EtOAc (100 mL). Saturated NaHCO3 was added to neutralize the acid. The organic layer was separated, dried with MgSO4 and concentrated to give 24.3. MS ESI (pos.) m/z: 383.1 (M+H). 1H NMR (DMSO-d6) δ 8.99 (dd, 1H); 8.24 (m, 2H); 7.77 (dd, 1H); 7.29 (d, 1H); 7.21 (d, 1H); 7.18 (d, 1H); 6.96 (dd, 1H); 4.13 (q, 2H); 3.73 (s, 5H); 1.23 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH:3](OS(C)(=O)=O)[CH3:4].[Cl:21][C:22]1[CH:23]=[C:24]([C:28]#[N:29])[NH:25][C:26]=1[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]#[N:29])[N:25]([CH2:4][CH2:3][CH:2]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH3:1])[C:26]=1[CH3:27]
Reactant: Cc1[nH]c(C#N)cc1Cl
Reactant: CC(OS(C)(=O)=O)C(C)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C#N)n1CCC(C)N1C(=O)c2ccccc2C1=O
Yield: 65.9 %

Procedure:
A solution of 4.23 g (14.2 mmol) of 2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione, 2.05 g (14.2 mmol) of 4-chloro-5-methyl-1H-pyrrole-2-carbonitrile and 2.35 g (14.2 mmol) of K2CO3 in 60 mL DMF was heated at 60° C. overnight. The mixture was diluted with ether and washed 4 times with water. Drying (MgSO4) and removal of solvent gave an oil which was chromatographed on silica gel (15% ethyl acetate in hexanes) to give 3.2 g of 4-chloro-1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]-5-methyl-1H-pyrrole-2-carbonitrile as a solid, 1NMR (CDCl3) δ1.5 (d, 3H), 2.2 (s, 3H and m, 1H), 2.7 (m, 1H), 3.9 (m, 1H), 4.05 (m, 1H), 4.4 (m, 1H), 6.6 (s, 1H), 7.85 (m, 2H), 7.9 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[N:7][N:8]([CH3:14])[C:9]=2[CH:10]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N)cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Bromo-1H-indazol-4-amine (available from Sinova, 300 mg, 1.42 mmol) was dissolved in THF (7.5 ml) and the mixture cooled to 0° C. Sodium hydride (60% in mineral oil) (62 mg) was then slowly added. The mixture was stirred for 15 min, then methyl iodide (221 mg) was added and stirring continued at 0° C. for 3 h. The reaction mixture was quenched by careful addition of methanol (2 ml), then water (10 ml), then extracted into ethyl acetate and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient of 0-50% ethyl acetate in cyclohexane. Fractions containing desired product were combined and concentrated in vacuo to afford the title compound, 48 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>CC#N>[F:24][C:25]([F:31])([F:30])[S:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:4]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNS(=O)(=O)C(F)(F)F)c3)n2)s1

Procedure:
By treatment of (3-aminomethyl-phenyl)-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl]-amine with trifluoro-methanesulfonyl chloride. Yellow solid. Anal. RP-HPLC: tR=11.6 min (0-60% MeCN, purity ˜90%). 1H-NMR (CD3OD) δ: 2.53 (s, 3H, CH3), 2.97 (s, 3H, CH3), 4.39 (s, 2H, CH2), 6.94 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.01 (d, 1H, J=7.5 Hz, Ph-H), 7.31 (d, 1H, J=8.0 Hz, Ph-H), 7.60 (d, 1H, J=7.5 Hz, Ph-H), 7.67 (s, 1H, Ph-H), 8.28 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 459.33 [M+H]+ (C17H17F3N6O2S requires 458.48).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:23]1[CH:27]=[C:26]([CH2:28][OH:29])[O:25][N:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>ClCCl>[CH2:11]([C:23]1[CH:27]=[C:26]([CH:28]=[O:29])[O:25][N:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCc1cc(CO)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCCCCCc1cc(C=O)on1
Temperature: -60 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution of oxalyl chloride (28.8 ml) in dry dichloromethane (100 ml) was cooled to -60° C. and a solution of dimethylsulfoxide (8.9 ml) in dichloromethane (30 ml) was added, followed by a slurry of 3-(1-dodecyl)-5-isoxazolemethanol (14.0 g) in dry dichloromethane (200 ml). The mixture was stirred at -60° C. for 1 hr, quenched with triethylamine (87 ml) and allowed to warm to room temperature. The solution was poured into water (300 ml) and extracted with dichloromethane. The organic phases were washed with dilute citric acid solution, dried, filtered, and the filtrate was evaporated. The residue was passed through a short pad of silica gel using dichloromethane as the eluent. The solution was evaporated and the residue was recrystallized from ether-hexane to give 11.5 g (78%) of product, mp 53°-54° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[C:13]([CH2:14][NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH2:14][N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:30](=[O:32])[CH3:31])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CC(=O)Cl
Reactant: COC(OC)c1nc2c(cc1CNCCN(C)C)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(CCN(C)C)C(C)=O)CCCN2
Reaction time: 0.17 h

Procedure:
To a solution of N1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N2,N2-dimethylethane-1,2-diamine (intermediate 199, 300 mg, 0.973 mmol) and NEt3 (0.270 mL, 1.937 mmol) in DCM (10 ml) was added acetyl chloride (0.075 mL, 1.055 mmol) at room temperature and the reaction mixture was stirred for approximately 10 min. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined, dried using Na2SO4, filtered and concentrated to yield the title compound, which was directly used in the next step without further purification. (UPLC-MS 3) tR 0.30 min, ESI-MS 351.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.5:0.5) δ 6.94 (s, 0.5H), 6.92 (s, 0.5H), 6.52-6.48 (m, 0.5H), 6.48-6.43 (m, 0.5H), 4.98 (s, 0.5H), 4.96 (s, 0.5H), 4.53 (s, 2H), 3.32 (s, 3H), 3.31 (s, 3H), 3.28-3.22 (m, 3H), 3.19 (t, 1H), 2.65 (t, 1H), 2.61 (t, 1H), 2.31 (t, 1H), 2.26 (t, 1H), 2.15-2.06 (m, 7.5H), 1.97 (s, 1.5H), 1.79-1.71 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=O)=[N:2]1.[NH2:19][CH2:20][CH:21]([OH:32])[CH2:22][N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([NH:19][CH2:20][CH:21]([OH:32])[CH2:22][N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:12])=[N:2]1
Reactant: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Reactant: NCC(O)CN1Cc2ccccc2C1
Solvent: CCO
Product: O=C(COc1ccccc1-c1cc[nH]n1)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 8 %

Procedure:
Ethyl 2-(2-(1H-pyrazol-3-yl)phenoxy)acetate (129 mg, 0.52 mmol) and 1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (16.2 mg, yield 8%) MS (ESI+) e/z: 393.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.70 (d, J=7.53 Hz, 2H), 7.39-7.32 (m, 1H), 7.26-7.14 (m, 4H), 7.14-7.05 (m, 2H), 6.74 (d, J=1.76 Hz, 1H), 4.70 (br. s., 2H), 3.97 (s, 5H), 3.54 (dd, J=13.55, 4.77 Hz, 1H), 3.38 (d, J=8.53 Hz, 1H), 2.81 (d, J=4.27 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: CC(=O)c1ccc2c(ccn2C)c1
Yield: 51.5 %

Procedure:
Ex-28A: To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y. et al, Heterocycles, 1992, 34(6), 1169–1175; 0.45 g, 2.8 mmol) were added iodomethane (3 mL) and cesium carbonate (2.3 g, 7.1 mmol). The reaction mixture was allowed to stir at 55° C. for 1.5 day during which additional iodomethane (11 mL) was added. The reaction was quenched with water. The aqueous solution was extracted with ether. The solution of ether was washed with saturated solution sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 1-(1-methyl-1H-indol-5-yl)-ethanone (0.25 g, 51%). 1H NMR (CDCl3) δ 8.30 (s, 1H), 7.91 (dd, J=1.2, 8.1 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.61 (d, J=3.0, 1H), 3.82 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Cc1cccc(C(=O)O)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(C)c1F
Yield: 74.9 %

Procedure:
Prepared according to Method A step A from 2-fluoro-3-methylbenzoic acid (5.0 g, 32.5 mmol), N,O-dimethylhydroxylamine hydrochloride (8.4 g, 87 mmol), oxalyl chloride (2.83 mL, 32.5 mmol) and 8 mL of pyridine to give the title compound (4.8 g) as an oil. Used as is in the next prep
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[CH:7][N:8]=[C:9]3[C:14]=2[C:13](=O)[CH2:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]3[CH3:1])[CH:13]=[CH:12][CH:11]=[CH:10]2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cccc2cnc3c(c12)C(=O)CC=C3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2c(Cl)nc3ccccc3c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
The above compound, 10-methyl-phenanthridinone (4.0 grams, 19 mmole) was added to a reaction flask containing phosphorus pentachloride (6.0 grams, 0.29 mole) and phosphoryl chloride (50 mL). The reaction mixture was refluxed for 4 hours, cooled to room temperature and diluted with toluene. The excess phosphoryl chloride and toluene were removed by a rotary evaporator. The residue was dissolved into ethyl acetate and washed with distilled water followed by brine. The solvent layer was dried over magnesium sulfate, filtered and concentrated to give 6-chloro-10-methylphenanthridine (4.1 grams, 95%) as an off-white solid. The product was confirmed by Mass Spec and NMR and not purified further but used directly in the next step.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:23]=[C:13]1[N:12]([CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 85 °C

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid methyl ester (15 g, 51.7 mmol) in a mixture of THF (240 mL) and H2O (60 mL), LiOH was added and the reaction was heated at 85° C. for 16 hours. The mixture was allowed to cool down to room temperature and the solvent removed under reduced pressure. The residue was dissolved in 100 mL of H2O and the solution acidified to pH 3. The precipitate formed was filtered and washed with 100 mL of CH3CN. The titled compound (11.9 g, 79%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:4](=[O:13])[CH:5](Br)[C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].[NH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[NH2:18][C:16]1[O:17][C:5]([C:4](=[O:13])[C:2]([CH3:14])([CH3:3])[CH3:1])=[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:15]=1
Reactant: CC(C)(C)C(=O)C(Br)C(=O)C(C)(C)C
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1oc(N)nc1C(C)(C)C
Temperature: 0 °C
Yield: 42.7 %

Procedure:
A mixture of 2,2,6,6-tetramethyl-4-bromo-3,5-heptanedione (70 g) and urea (77 g) in DMF (500 mL) is heated at 110°-120° C. overnight. The reaction mixture is cooled and poured into ice water (1500 mL) and the resulting precipitate is collected by filtration and air dried. The solid is rinsed with hexane (1000 mL) and then with isopropyl ether (200 mL) and dried under vacuum overnight to give 1-[2-amino-4-(1,1-dimethylethyl)-5-oxazolyl]-2,2-dimethyl-1-propanone (25.5 g, 42%); mp 248°-250° C.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[N-:8]=[N+:9]=[N-:10].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:8]([CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1)=[N+:9]=[N-:10]
Reactant: CC1(CCl)COC1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(CN=[N+]=[N-])COC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 3-chloromethyl-3-methyloxetane (10.1 g, 83.5 mmol), tetra-n-butylammonium bromide (0.308 g, 0.96 mmol), sodium azide (6.5 g, 100 mmol) and water (27 mL) was heated at about 96° C. to about 103° C. for 4.5 h, after which time gas chromatographic analysis of the mixture indicated that the reaction had reached completion. The mixture was cooled to ambient temperature, and extracted with methylene chloride (25 mL). The organic extract was passed through a column containing aluminum oxide (10 g), and the column was rinsed with additional methylene chloride. The solvent was evaporated to give 9.84 g (93% yield) of 3-azidomethyl-3methyloxetane (>99.5% purity by glc and NMR analysis). NMR: 1H NMR: δ1.32 (s, 3H), 3.52 (s, 2H), 4.25 & 4.35 (AB, J=6.0 Hz, 4H); 13C NMR: δ21.44, 58.33, 40.03, 79.76; glc Rt= 3.19 min.