Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:20])[CH2:10][C:11]([NH:13][C:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>C(O)C.O.ClCCl>[CH3:17][CH:16]([O:15][C:14](=[O:19])[NH:13][C@H:11]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[NH:8][C@@H:9]([CH3:20])[CH2:10]1)[CH3:18]
Reactant: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)OC(=O)N[C@@H]1C[C@H](C)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methylethyl {(3S)-3-[(4-bromophenyl)amino]butanoyl}carbamate (for a preparation see Intermediate 102) (17.9 g, 52.2 mmol) was taken up in ethanol (150 mL) and cooled to below −10° C. (internal temperature) in a CO2/acetone bath. NaBH4 (1.381 g, 36.5 mmol) was added followed by magnesium chloride hexahydrate (11.35 g, 55.8 mmol) in water (25 mL) keeping the temperature below −5° C. The mixture was allowed to stir at <0° C. for 1 h then warmed to room temperature and stirred for an hour. The resulting thick suspension was poured into a mixture of citric acid (25.05 g, 130 mmol), HCl (1M in water, 205 mL, 205 mmol) and dichloromethane (DCM) (205 mL). The biphasic mixture was stirred at room temperature for 1 h. LCMS showed no remaining starting material so the layers were separated and the organic layer dried with Na2SO4, filtered and concentrated to yield the product as a light brown solid (14.1 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1.0 g, 6.2 mmol), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 minol), anhydrous Na2CO3 (0.33 g, 3.1 mmcl) and Nal (0.09~3 g, 0.6 mrnol) in dry toluene (10 ml) was stirred at 110° C. for 12 hrs. The solvent was removed at reduced pressure and residue was poured on water (20 ml). The separated residue was extracted with ethylacetate (3×20 ml), dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 0.60 g (30.0%)
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[N:9]=[CH:10][C:11]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:18]([N+:36]([O-])=O)=[CH:17][N:16]=2)=[N:12][CH:13]=1)#[N:7]>C(O)C>[NH2:36][C:18]1[C:19]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:20][C:15]([NH:14][C:11]2[CH:10]=[N:9][C:8]([C:6]#[N:7])=[CH:13][N:12]=2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Temperature: 78 °C
Yield: 89 %

Procedure:
Tin (II) chloride dihydrate (745 mg, 3.3 mmol) was added to a solution of crude tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl)piperidine-1-carboxylate (301 mg, 0.66 mmol) in ethanol. After heating at 78° C. for 2 hours the mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and water and the resulting precipitate was removed by filtration. The biphasic filtrate was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a brown solid (250 mg). A portion of the crude material was purified by preparative HPLC to give tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-yloxy)methyl) piperidine-1-carboxylate (16 mg) as a yellow powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH3:15])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].FC(F)(F)C(O)=O.N[C@H](C(N[C@H](C(OCC1C=CC=CC=1)=O)C)=O)CC(C)C.FC(F)(F)C([O-])=O.[ClH:68]>CCOCC.C(OCC)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH3:15])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[ClH:68]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)CN)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Gly-Leu-Ala-OBzl was prepared by coupling Boc-Gly-OH (5.70 g, 32.6 mmoles) to H-Leu-Ala-OBzl using the mixed anhydride procedure described in Example 2. The product (13.8 g) was obtained as an amorphous solid. Boc-Gly-Leu-Ala-OBzl was deblocked with trifluoroacetic acid by the procedure described for the preparation of H-Leu-Ala-OBzl except that the trifluoroacetate salt was soluble in ether. The preparation was dissolved in ethyl acetate and treated with anhydrous hydrogen chloride. The resulting product was precipitated by the addition of ether to yield 7.7 g of H-Gly-Leu-Ala-OBzl HCl in a first crop.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[CH:18](=[O:21])[CH2:19][CH3:20]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:18]([CH2:19][CH3:20])[OH:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: CCC=O
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
A solution of 7.0 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of dry tetrahydrofuran is cooled to -30°, using a dry ice-carbon tetrachloride bath and to the mixture is added dropwise, 35 ml of 2.2M n-butyllithium in hexane while the temperature is maintained below -20°. Following the addition, the bath is replaced with an ice-water bath and the reaction is stirred for 4 hrs at a temperature of 0°-5°. To the mixture is added dropwise solution of 3 ml of freshly distilled propionaldehyde in 5 ml of tetrahydrofuran. The bath is removed. The reaction mixture is stirred for 20 minutes and poured onto cold 10% hydrochloric acid. The mixture is extracted 3 times with ethyl ether. The combined ether extracts are washed, dried and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 5.9 g of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol, mp 145°-145.5°.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.Br[CH2:27][C:28]#[C:29][CH3:30]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)([CH2:27][C:28]#[C:29][CH3:30])[C:6]([OH:5])=[O:25])(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)C(Cc1cccnc1)S(=O)(=O)c1ccc(F)cc1
Reactant: CC#CCBr
Product: CC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 g of the product was isolated. Yield 100%; yellowish gum; MS: 419.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:18])[CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=[C:8]2[C:7]1=[O:17].N([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O>[CH3:2][N:3]([CH3:18])[CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:12]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:9][C:8]=4[NH:16][C:13]=3[CH:14]=[CH:15][C:8]=2[C:7]1=[O:17]
Reactant: CN(C)CCN1C(=O)c2ccc(N)cc2C1=O
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4c(c3c2C1=O)CCCC4
Temperature: 0 °C
Yield: 3.4 %

Procedure:
11.3 ml of concentrated hydrochloric acid and 12 ml of water were added to 7.90 g of N-(2-dimethylaminoethyl)-4-aminophthalimide. The mixture was cooled to 0° C. Thereto was dropwise added a solution of 2.34 g of sodium nitrite dissolved in 5 ml of water, in 15 minutes with stirring. The mixture was added to a mixture of 21.3 g of sodium sulfite, 50 ml of water and 20 g of ice, in one portion. The resulting mixture was heated to 60° C., stirred at the same temperature for 15 minutes, cooled to room temperature, and adjusted to pH 1.5 with 6N hydrochloric acid. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of acetic acid, and the mixture was concentrated to dryness under reduced pressure. This procedure was conducted two more times to remove water. To the residue were added 130 ml of acetic acid and 6.64 g of cyclohexanone, and the mixture was refluxed for 2 hours. While the mixture was hot, the resulting insoluble material was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was mixed with 200 ml of ethyl acetate and 200 ml of water. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=1/0 to 10/1) to obtain two fractions. The first obtained fraction was concentrated to dryness under reduced pressure. The residue was recrystallized from toluene to obtain 180 mg (yield: 1.7%) of N-(2-dimethylaminoethyl)-5,6,7,8-tetrahydrocarbazole-3,4-dicarboximide as yellow needles. The later obtained fraction was concentrated to dryness under reduced pressure. The residue was recrystallized from toluene to obtain 1.60 g (yield: 15%) of N-(2-dimethylaminoethyl)-5,6,7,8-tetrahydrocarbazole-2,3-dicarboximide as light yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]=[O:34])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:35]P([O-])(O)=O.[K+].C1COCC1.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C.CC(=CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][C:33]([OH:35])=[O:34])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetaldehyde (3 mg, 5.97 μmol; mixture of stereoisomers, Example 224, Step E) in a solution of 1.25 M potassium phosphate monobasic in water (0.050 mL), t-butanol (0.050 mL) and 2.0 M 2-methylbut-2-ene in THF (0.15 mL, 0.30 mmol) was treated with sodium chlorite (2.16 mg, 0.024 mmol) at ambient temperature for 3 h. The reaction was quenched with 1 M sodium thiosulphate solution (0.03 mL). After 10 min, the mixture was acidified with 1M potassium bisulphate solution (0.03 mL) and extracted with ethyl acetate. The organic layers were washed with sat. aq. NaCl solution and dried over anhydrous sodium sulfate. Purification by reversed phase preparatory HPLC (eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) gave the title compound as the first eluting isomer.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[C:19]([C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccnc(/C=C/c2ccc(-c3ccccc3)cc2)c1

Procedure:
(E)-2-(4-Phenylphenyl)ethenylpyridine-4-carboxylic acid (3.60 g) and a mixture of concentrated sulfuric acid/ethanol (9:1) were refluxed under heating for 2 hr, and neutralized under ice-cooling. The reaction mixture was partitioned between dichloromethane and water, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-4/1) to give the objective compound (3.14 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22](O)=[C:19]([O:20][CH3:21])[CH:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:8][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH:16]=[O:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1nn(-c2ccccn2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Reaction time: 15 h
Yield: 77.5 %

Procedure:
To a mixture of (3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methanol (1.07 g), vanillin (0.85 g), tributylphosphine (1.70 g) and tetrahydrofuran (100 mL) as added 1,1′-(azodicarbonyl)dipiperidine (2.12 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.40 g, yield 77%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O-])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]([N:43]2[CH2:42][CH2:41][CH2:40][CH2:38]2)=[O:18])[CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)[O-])ccc4c3c2)cc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCC5)ccc4c3c2)cc1F
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
8-Carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylic acid (16 mg, 0.042 mmol, Example 395), HATU (24.12 mg, 0.063 mmol) and DIPEA (0.022 mL, 0.127 mmol) were dissolved in DMF (1 mL) and stirred for 10 minutes. Pyrrolidine (9.2 mg, 0.13 mmol) was added and the mixture shaken over night. Purification by prep HPLC gave 9.4 mg 3-(3-fluoro-4-methoxyphenyl)-7-(pyrrolidine-1-carbonyl)-9H-carbazole-1-carboxamide. HPLC retention time 4.36 min. (Ascentis 4.6×50 mm 5 um C18, 2 ml/min, 0 to 100% B in 8 minutes, then 100% B for 1 minute. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc). MS (ESI) m/e+=432 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:25]4[S:26][C:27]([C:36]5[N:40]=[CH:39][N:38](C6CCCCO6)[N:37]=5)=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=4)=[C:22]([CH3:24])[N:23]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:24][C:22]1[N:23]=[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:20][N:19]2[C:21]=1[C:25]1[S:26][C:27]([C:36]2[N:40]=[CH:39][NH:38][N:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1
Reactant: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCNCC3)cn2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Yield: 47.7 %

Procedure:
tert-Butyl-4-[(2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridin-6-yl)methyl]piperazine-1-carboxylate (0.025 g, 0.039 mmol) was treated with Trifluoroacetic Acid (2.0 mL, 26 mmol) in Methylene chloride (2.0 mL, 31 mmol) at r.t. for 18 hours. The mixture was rotavaped. The residue was triturated with hexane (3×5 mL). The solid residue was suspended in water and neutralized with saturated aqueous NaHCO3 to pH ˜9, extracted with 10% MeOH in DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered, rotavaped and dried in hi-vac to give a solid product (0.0085 g, 45% yield). LCMS: (FA) ES+ 457, ES− 455. 1H NMR (400 MHz, d-chroloform & d4-methanol) δ 9.82 (s, 1H), 8.14 (s, 1H), 7.80-7.82 (m, 2H), 7.55-7.58 (m, 1H), 7.37-7.46 (m, 4H), 3.54 (s, 2H), 2.84 (m, 2H), 2.76 (s, 3H), 2.47 (s, br, 2H), 2.32 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH3:21])[C:10](=[O:22])[CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:22]
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCNCC2=O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (5 g), 1-bromo-2,4-dimethylbenzene (3.4 mL), potassium carbonate (10.6 g) and copper (I) iodide (952 mg) were added toluene (25 mL) and N,N′-dimethylethylenediamine (1.1 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester. The obtained 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give 1-(2,4-dimethylphenyl)piperazin-2-one hydrochloride (3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:12]([CH3:30])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35]Br)[CH3:32].Br.CC(C)([O-])C.[Na+]>C1COCC1.C(Cl)Cl.CO>[CH:24]1([C:16]2[C:17]([C:22]#[N:23])=[C:18]([S:20][CH3:21])[S:19][C:15]=2[C:13]2[C:12]([CH3:30])=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:32][CH2:31][N:33]([CH2:37][CH3:38])[CH2:34][CH3:35])[CH:3]=3)[N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CSc1sc(-c2nc(Nc3cccc(N)c3)ncc2C)c(C2CCCCC2)c1C#N
Reactant: CCN(CC)CCBr
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)CCNc1cccc(Nc2ncc(C)c(-c3sc(SC)c(C#N)c3C3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 5-[2-(3-aminophenylamino)-5-methyl-pyrimidin-4-yl]-4-cyclohexyl-2-methylsulfanyl-thiophene-3-carbonitrile (20 mg, 45.91 micromol) and N,N-diethyl-2-aminobromoethane.HBr (12 mg, 45.91 micromol) in THF was added sodium t-butoxide (9 mg, 91.82 micromol) and the reaction was stirred at ambient temperature overnight. TLC indicated conversion to product (10% MeOH:CH2Cl2). The reaction was partitioned between EtOAc and water, the organics were dried over sodium sulfate then concentrated in vacuo. The crude product was purified by chromatography (silica gel, 5% MeOH:CH2Cl2) to afford VI-26 in 33% yield. δ 0.95 (bs, 6H), 1.0–1.8 (m, 10H), 2.0 (s, 3H), 2.6 (s, 3H), 2.75 (bs, 2H), 3.4 (s, 1H), 3.6 (bs, 2H), 4.0 (bs, 2H), 5.2 (s, 1H), 6.5 (d, 1H), 6.55 (s, 1H), 6.6 (d, 1H), 7.0 (t, 1H), 8.1 (s, 1H).
Reaction SMILES: C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:10][C:11]1[C:12](Br)=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2.[CH2:22](B(CC)CC)[CH3:23]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:10][C:11]1[C:12]([CH2:22][CH3:23])=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CCB(CC)CC
Reactant: Nc1ccc2ncccc2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(N)ccc2ncccc12
Temperature: 50 °C
Yield: 65.8 %

Procedure:
To a mixture of 183 mg (0.22 mmol) of Pd(dppf)Cl2.CH2Cl2 and 4.38 g (13.44 mmol) of Cs2CO3 in 13 mL of DMF under Argon atmosphere was added a solution of 500 mg (2.24 mmol) of 6-amino-5-bromoquinoline (commercially available from ACES Pharma Product List). Triethylborane in hexanes (2.91 mL of 1.0 M solution) was added, and the reaction was heated to 50° C. for 22 hours, then poured into 50 mL of water, and extracted with diethyl ether. The combined ether layers were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography, eluting with 0 to 50% EtOAc/hexanes to give 386 mg (65.8%) of 6-amino-5-ethylquinoline as e a colorless oil. MS (ESI): m/z 173.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][C:12]1([CH3:19])[CH2:17][C:16](=[O:18])[O:15][C:13]1=[O:14]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:18])[CH2:17][C:12]([CH3:19])([CH3:11])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CC(C)(CC(=O)Nc1cccc([N+](=O)[O-])c1)C(=O)O
Yield: 94.4 %

Procedure:
3-Nitroaniline (27.6 grams (g)) was dissolved by stirring in 200 milliliters (ml) tetrahydrofuran. 2,2-Dimethyl succinic anhydride (25.6 g) in some tetrahydrofuran was added dropwise with stirring. The reaction was stirred at room temperature for four hours. The reaction product was recovered by addition of 500 ml ethyl acetate, followed by three washings with 3% hydrochloric acid and one with distilled water. The solution was dried with sodium sulfate and rotary evaporated to yield 50.2 g of N-(3-nitrophenyl)-2,2-dimethylsuccinamic acid.