Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:24](=[O:26])C>O1CCCC1.CCCCCC>[CH:13]1([CH:19]([CH2:24][OH:26])[C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)CC1CCCCC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (0.85 ml, 6.10 mmol) in 30 ml tetrahydrofuran at -78° under argon was added n-butyllithium (2.5 ml of a 2.5M solution in hexane). After 0.5 hour, methyl cyclohexylacetate (1 ml, 6.10 mmol) was added dropwise in 10 ml tetrahydrofuran. The solution was stirred for 45 minutes, after which was added acetaldehyde (1 ml) in 10 ml tetrahydrofuran. This solution was stirred for two hours at -78°, warmed to room temperature and stirred an additional 12 hours, quenched with water and acidified with 10% hydrochloric acid. The mixture was extracted twice with ethyl ether, and the combined organic portions were then washed once with 10% hydrochloric acid, twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the alcohol as an orange oil (b.p. 85°-92°, 0.5 mm).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH2:18][C:19]([CH3:24])([OH:23])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:27]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:34]#[C:33][C@:31]([C:28]4[N:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:15]=3)[C:10]([CH2:18][C:19]([OH:23])([CH3:24])[CH:20]([F:22])[F:21])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: CC(O)(Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12)C(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CC(C)(O)C(F)F)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 65 °C

Procedure:
To a solution of 3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol (75 mg, 0.19 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for 1.5 hr under an atmosphere of nitrogen. After cooling to RT, the reaction mixture was re-treated with additional tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for a further 3 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, eluent 9:1 DCM/MeOH) furnished a partially purified product. Further purification by reverse phase preparative HPLC gave the title compound as a brown solid: 1H NMR (500 MHz, DMSO) delta 1.17 (3H, s), 1.90 (3H, s), 2.63 (3H, s), 3.09 (1H, d, J 14.2), 3.21 (1H, d, J 14.2), 5.50 (1H, s), 5.92 (1H, t, J 56.1), 6.78 (1H, s), 7.01 (2H, s), 7.08 (1H, d, J 5.5), 7.36 (1H, dd, J 8.3, 1.2), 7.94 (1H, d, J 8.3), 8.29 (1H, d, J 5.5), 8.89 (1H, s); LC-MS: m/z=+470.05 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH:7](O)[N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15]
Reactant: COCOc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COCOc1ccc(I)c2c1CN(C(C)(C)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (1.15 g, 2.54 mmol) was dissolved in nitromethane (58 mL), and the solution was added with trifluoroacetic acid (1.20 mL, 7.62 mmol) and triethylsilane (0.587 mL, 7.62 mmol), followed by stirring at room temperature for 30 minutes. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (chloroform/methanol=100/0, 99/1, hexane/ethyl acetate=80/20, 60/40) to obtain 4-methoxymethoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (935 mg, yield 84%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[CH3:14]OC(OC)OC.Cl>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([C:11]([O:13][CH3:14])=[O:12])[NH:2]1
Reactant: COC(OC)OC
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2ccccc2CN1

Procedure:
A mixture of 1 eq. of (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (Aldrich Chemical Co., Milwaukee, Wis.), 5 eq. of trimethylorthoformate, methanol and catalytic HCl were allowed to heat at reflux for 5 h. Concentration in vacuo provided methyl (S)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:16]=[C:15]1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH3:6].CN(C)C=O.[C:34]([C:36]([C:42]#[N:43])=[C:37](C#N)[C:38]#[N:39])#[N:35]>O>[CH3:1][CH2:2][CH2:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([C:19]2[S:20][C:21]([C:37]([C:38]#[N:39])=[C:36]([C:42]#[N:43])[C:34]#[N:35])=[CH:22][CH:23]=2)=[CH:17][CH:16]=[C:15]1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH3:6]
Reactant: CCCC(CC)Oc1ccccc1-n1c(-c2cccs2)ccc1-c1cccs1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC)Oc1ccccc1-n1c(-c2cccs2)ccc1-c1ccc(C(C#N)=C(C#N)C#N)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
After dissolving 1-[(4-n-hexyloxy)phenyl]-2,5-bis(2-thienyl)pyrrole (205 mg) into N,N-dimetylformamide (30 ml), tetracyanoethylene (126 mg) was added thereto, and then they were stirred for 24 hours at room temperature. After addition of water thereinto, extraction by toluene was conducted. The obtained organic layer is dried over anhydrous sodium sulfate, and then condensation thereof under vacuum was conducted. Subsequently, the condensed substance is separated by silica gel column chromatography using toluene as eluent to obtain 1-[(4-n-hexyloxy)phenyl]-2-(2-thienyl)-5-(5-tricyanoethenyl-2-thienyl)pyrrole (212 mg, yield 83%). After recrystallization from a chloroform-hexane mixture solvent, crystals having a bronzy metallic luster were obtained. FIG. 1 is a photograph showing the appearance of the crystals. Further, physical properties thereabout are shown bellow.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CN1CCOCC1.O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:5]([CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)nc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Br)ccc2CO)C1
Temperature: 130 °C
Yield: 80.1 %

Procedure:
A mixture of (6-bromo-2-fluoro-3-pyridyl)methanol (1.766 mmol; 363.8 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (2.649 mmol; 530.5 mg), and N-Methylmorpholine (5.298 mmol; 541 mg; 0.588 mL) in 1-methyl-2-pyrrolidinone (10 mL) in a sealed pressure vial was heated at 130° C. for 4 hours. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-2-pyridyl]-3-piperidyl]carbamate (546.3 mg, 80%).
Reaction SMILES: ClC1C=C(N)C(N[C@H]2CCS(=O)(=O)C2)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH:25]2[CH2:29][N:28]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:27](=[O:39])[CH2:26]2)=[C:20]([N+:40]([O-])=O)[CH:19]=1>>[NH2:40][C:20]1[CH:19]=[C:18]([Cl:17])[CH:23]=[CH:22][C:21]=1[NH:24][CH:25]1[CH2:29][N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:27](=[O:39])[CH2:26]1
Reactant: COc1ccc(CN2CC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2=O)cc1
Agent: Nc1cc(Cl)ccc1N[C@H]1CCS(=O)(=O)C1
Product: COc1ccc(CN2CC(Nc3ccc(Cl)cc3N)CC2=O)cc1

Procedure:
4-[(2-Amino-4-chlorophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one was prepared in analogy to 4-chloro-N—((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-benzene-1,2-diamine in Example 2-1 by using 4-[(4-chloro-2-nitrophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one instead of (4-chloro-2-nitro-phenyl)-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amine.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:13]=[N:14][C:15](Cl)([CH3:17])[CH3:16])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+].[Cl-].[K+]>O>[C:9]([N:13]=[N:14][C:15]([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:17])[CH3:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N=NC(C)(C)OOC(C)(C)C
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of 72.5 grams (1.1 moles) of 85% potassium hydroxide in 175 ml. of water, cooled to 15° C in a 2 liter jacketed reactor was added 140 grams (1.4 moles) of 90% t-butylhydroperoxide slowly and with rapid stirring. The temperature was held at 20°-25° C by the rate of addition and by circulating 15° C water through the reactor jacket. After the addition was complete, the reaction was stirred for 15 minutes at 15° C and then 165 grams (1.015 moles) of 2-t-butylazo-2-chloropropane was added dropwise over a 30 minute period holding the reaction temperature at 18°-20° C. After the addition was complete the reaction was stirred for 15 minutes at 18° C. It was then cooled to 0°-5° C and stirred for 90 minutes. A 0.3 mole (24 grams) portion of 50% NaOH was then added and the reaction stirred for 15 minutes. Ice water was then added until the potassium chloride dissolved. The mixture was extracted with 300 ml. of pentane, the pentane extract washed with ice cold water, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure at 10° C to leave 187 grams (86% yield) of crude 2-t-butylazo-2-(t-butylperoxy)-propane. A pure sample of the azo-peroxide was obtained by low temperature recrystallization from reagent grade pentane. The recrystallization was repeated two more times and the purified material was used as an analytical standard. The crude azo-peroxide assayed 77.1% when compared with the analytical standard using an infrared analysis technique. The crude azo-peroxide was then diluted to 50% in cold odorless mineral spirits for safety reasons. The pure azo-peroxide is very shock sensitive and is also sensitive to acids and metal ions. The compound decomposes thermally at room temperature and must be stored at least at 0° C and for any prolonged storage at -20° C or below.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)[C:10]=1[CH3:11])=O)C.[OH-].[K+]>O.CO>[CH3:19][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CCOC(=O)c1[nH]c(C)c(C2=CCN(C)CC2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c[nH]c(C)c1C1=CCN(C)CC1
Yield: 51.2 %

Procedure:
A mixture of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.02 g, 3.9 mmol), KOH (0.287 g, 5.1 mmol) in water (5 mL) and methanol (10 mL) was heated to reflux under nitrogen for 3 days. The cooled reaction was extracted with ethyl acetate (3×), dried and concentrated to give 380 mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine. The aqueous layer was adjusted to pH 7, the resulted precipitate was collected by filtration, washed with water to give 380 mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine and 480 mg of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14]>CCOC(C)=O.O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.C1(C2[C-](C3C=CC=CC=3)C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.[Fe+2].[Zn]>[C:13]([O:17][C:18](=[O:21])[CH2:19][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1cc(Cl)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Under an atmosphere of dry argon, a mixture of palladium dibenzylideneacetone (Pd2(dba)3, 22 mg, 0.02 mmol), di-tert-butylphosphino pentaphenylferrocene (17 mg, 0.02 mmol), 2-chloro-4-iodo-5-trifluoromethyl-pyridine (1.50 g, 4.88 mmol) and the Reformatzky reagent prepared from bromo-acetic acid tert-butyl ester and activated zinc metal (1.40 g, 5.37 mmol) is suspended in dry and degassed THF (20 ml). The mixture is heated to 60° C. After 45 minutes and after 90 minutes, additional batches of palladium dibenzylideneacetone (Pd2(dba)3, 22 mg, 0.02 mmol), di-tert-butylphosphino pentaphenylferrocene (17 mg, 0.02 mmol), and of the Reformatzky reagent (1.40 g, 5.37 mmol) are added. After a total of 2.5 h at 60° C., TLC analysis indicated complete conversion of starting materials. Upon cooling to RT, the reaction mixture is diluted with equal amounts of EtOAc and H2O, and filtered through a tight plug of cotton. The organic layer is separated, washed with brine twice, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (hexanes/EtOAc, gradient from 100:0 to 97:3) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 3.71 (s, 2H), 7.39 (s, 1H), 8.63 (s, 1H). ES+−MS: 294.1, 296.2 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O.[NH3:42]>CO>[NH2:42][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: N
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CN)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 41 %

Procedure:
400 mg (0.687 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 50 mL of an about 6N solution of ammonia in methanol and the solution was stirred at room temperature for 9 hours. Water was added to the reaction solution and the mixture was extracted twice with chloroform. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 142 mg of 7-aminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 41%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:41])=[CH:17][C:18]([O:39][CH3:40])=[CH:19][C:20]=3[C:21]2([NH:27][C:28]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:29])[CH2:24][CH2:25]O)=[CH:12][CH:11]=1>C(Cl)Cl>[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:41])=[CH:17][C:18]([O:39][CH3:40])=[CH:19][C:20]=3[C:21]32[CH2:24][CH2:25][S:29][C:28]([NH:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27]3)=[CH:12][CH:11]=1
Reactant: COc1cc(F)c2c(c1)C(CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)ccc1O2
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COc1cc(F)c2c(c1)C1(CCSC(NC(=O)c3ccccc3)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (2.012 ml, 15.05 mmol) was added to a solution of N-((7-bromo-4-fluoro-9-(2-hydroxyethyl)-2-methoxy-9H-xanthen-9-yl)carbamothioyl)-benzamide (8 g, 15.05 mmol) in DCM (3 ml). The reaction mixture was stirred at RT for 8 hours. The reaction mixture was quenched with aqueous, saturated sodium carbonate solution and stirred for 10 minutes. The organic layer was separated and concentrated under reduced pressure to afford crude N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)-benzamide (7.7 g, 15.00 mmol, 100% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([OH:17])=O)=[C:7]([CH3:9])[N:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:44]1[CH2:49][CH2:48][CH:47]([C:50]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=2)[CH2:46][CH2:45]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([N:44]2[CH2:49][CH2:48][CH:47]([C:50]3[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][CH:51]=3)[CH2:46][CH2:45]2)=[O:17])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
A mixture of 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 2.3, 140 mg, 0.51 mmol), EDC.HCl (150 mg, 0.78 mmol), 4-dimethylaminopyridine (190 mg, 1.56 mmol), and HOBT (80 mg, 0.59 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred at room temperature, then after 15 min, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 100 mg, 0.45 mmol) was added. The resulting solution was stirred for 15 h at room temperature, then quenched with 20 mL of H2O. The aqueous was extracted with ethyl acetate (40 mL) and the combined organics was washed with brine (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (23% CH3CN up to 38% in 7 min, up to 100% in 2 min, down to 23% in 1 min); Detector, Waters 2489, 254 &220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (70.4 mg, 35%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:15]([CH3:26])[NH:14][C:13]=1[CH:27]=O>N1CCCC1.C(O)C>[CH3:11][C:12]1[C:16]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[C:15]([CH3:26])[NH:14][C:13]=1[CH:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: CCO
Solvent: C1CCNC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCCN1CCOCC1
Temperature: 90 °C
Yield: 84.5 %

Procedure:
A mixture of 1,3-dihydroindol-2-one (133 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carboxaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 308.9 mg (85%) of 3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a yellow solid:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[N:22]1([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(N2CCNCC2)c(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A 4M solution of HCl in dioxane (20 mL) was added to a solution of 4-(2-Pyrrolidin-1-ylmethyl-phenyl)-piperazine-1-carboxylic acid t-butyl ester (2.01 gm, 5.82 mmol). The solution was stirred at r.t. overnight under a nitrogen and then concentrated to remove dioxane. Diethyl ether was added and the solution was concentrated (2×). Diethyl ether was added and the product was isolated by suction filtration and then washed with diethyl ether. Vacuum drying at 50° C. overnight gave 1-(2-Pyrrolidin-1-ylmethyl-phenyl)-piperazine 2HCl (1.62 g, 87.6%). MS (m/z, ES+): 246.1.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=O.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[O:23].[OH-].[Na+]>C1COCC1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]1[C:3](=[O:5])[CH:2]2[CH2:6][CH2:7][CH2:8][CH2:9][N:1]2[C:22]1=[O:23]
Reactant: O=C(O)C1CCCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1N1C(=O)C2CCCCN2C1=O
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of pipecolinic acid (500 mg; 3.87 mmol), 2-methoxy-4-nitrophenylisocyanate (902 mg; 4.65 mmol) and 9:1 THF:2 M NaOH were reacted in a microwave vessel at 160° C. for 10 min. The reaction mixture was then cooled to rt and purified by column chromatography (1:1, EtOAc:hexanes) to afford 736 mg of 2-(2-methoxy-4-nitrophenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione, 1.1.1, (62%).