Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[S:36]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35]3=[S:36])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(CC3CCN(CCn4c(=S)[nH]c5ccccc54)CC3)nc3ccccc32)cc1
Yield: 41.5 %

Procedure:
A mixture of 6 parts of N1 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,2-benzenediamine, 2.7 parts of 1,1'-thiocarbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was stirred in acetonitrile. The product was filtered off and crystallized from ethanol. The product was filtered off and dried, yielding 2.8 parts (41.5%) of 1-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H- benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazole-2-thione; mp. 157.1° C. (493).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-ethoxycarbonyl-piperidinomethyl)-aniline in DMF.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][S:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])C>C1COCC1>[OH:18][CH2:17][C:16]1[CH:15]=[C:14]([S:13][CH2:12][CH2:11][CH2:10][OH:9])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCSc1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCSc1cccc(CO)c1
Temperature: 25 °C

Procedure:
A solution of lithium aluminum hydride (2M in THF, 2.2 mL) was added portionwise over 5 minutes to a solution of 3-(3-ethoxy-3-oxopropylthio)benzoic acid [Aromatic Intermediate 15, step a] (1.0 g) in THF (20 mL), pre-cooled in ice-water. After ½ the addition the mixture formed a thick precipitate and was diluted with more THF (15 mL) to maintain stirring. The mixture was removed from the cooling bath and stirred at room temperature for 3.5 hours. The mixture was cooled back down in ice-water and treated with more lithium aluminum hydride (2M in THF, 2.2 mL). The mixture was removed from the cooling bath and stirred at room temperature overnight. The cloudy solution was cooled in ice water and then quenched by the careful addition of methanol (5 mL), added portionwise over 30 minutes. After ˜½ of the addition, the mixture was removed from the cooling bath and allowed to warm to room temperature for 45 minutes. The mixture was poured into aqueous HCl (2M) and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give the subtitled compound as a pale yellow oil. Yield 0.55 g.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(2-methanesulfonyloxyethyl)pyrrolidine (5.35 g) in N,N-dimethylformamide (54 ml) were added imidazole (1.18 g) and potassium t-butoxide (1.78 g) with stirring under ice-cooling. The mixture was stirred at 40°-45° C. for 40 minutes. The reaction mixture was poured into water (100 ml) and extracted with dichloromethane (80 ml). The extract was washed in turn with water (50 ml) and 10% aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-methanesulfonyloxypyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=[CH:11][CH:10]=2)=[C:6]([CH:8]=1)[NH2:7].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[N:13]([CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[N:12]=[CH:11][C:10]=3[C:24](=[O:25])[NH:7][C:6]=2[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)ccc1-c1ccnn1C1CCCC1
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Br)ccc2c2c1cnn2C1CCCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 100 mg of 5-bromo-2-(1-cyclopentyl-1H-pyrazol-5-yl)aniline in 2.5 mL of N-methylpyrrolidone was added 105 mg of CDI, followed by stirring at 150° C. for 2 hours using a microwave reactor, and cooling to room temperature. The precipitated solid was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain 73 mg of 7-bromo-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(CCCC(=O)O)c[nH]c2c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
To a solution of methyl 3-(3-methoxycarbonylpropyl)indole-6-carboxylate (656 mg) in methanol (24 ml) was added 1N aqueous sodium hydroxide (2.46 ml), and the mixture was stirred at 20° C. for 2 days. The resulting mixture was evaporated in vacuo, and the residue was acidified with 1N hydrochloric acid (2.6 ml) and extracted with ethyl acetate. The organic chase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with ether to give methyl 3-(3-carboxypropyl)indole-6-carboxylate (486 mg) as solid.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:26][CH2:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NCC1CCOCC1
Product: C(#Cc1cnc(NCC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, white solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (tetrahydro-2H-pyran-4-yl)methanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[N:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[CH2:36]1COC[CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:36][CH3:37])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[CH:21][CH:20]=3)[C:9]=2[N:33]([CH3:34])[CH3:35])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C
Yield: 64.43 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.62 g, 4.66 ml 1M solution in THF, 4.67 mmol) was added drop wise to a stirred solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide (compound 34g, 0.5 g, 0.93 mmol) in anhydrous THF (30 ml) at 25° C. The reaction mixture was then heated at about 70 to 75° C. for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so obtained was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.27 g, 64.43%). The title compound was then purified by preparative HPLC (0.135 g, 32.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([NH:21][C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:12]2=[O:36])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>N1C=CC=CC=1>[C:38]([C:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([NH:21][C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])[C:12]2=[O:36])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(N)cc2)c2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(NC(=O)C(C)(C)C)cc2)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
A solution of 0.400 g of the compound obtained in EXAMPLE 13 in 3 ml of pyridine is cooled to 0° C. and 0.100 g of pivaloyl chloride is added. The mixture is stirred for 18 hours, the temperature being allowed to rise to RT, and then evaporated under vacuum. The residue is extracted with AcOEt, washed with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.180 g. M.p.=228° C.
Reaction SMILES: Br.C(O)(=O)C.C1(=O)[N:10]([CH2:11][C:12]2[N:13]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C(=O)C2=CC=CC=C12.[OH-].[Na+]>O>[NH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)oc1-c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NCc1nc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A mixture made up of 20 ml of 48% hydrobromic acid, 20 ml of glacial acetic acid and 10 g of 4-phthalimidomethyl-2,5-diphenyloxazole, was heated under reflux until a clear solution resulted (3 hrs.). The solvent was pulled off under vacuum until dryness. The residue was dissolved in 100 ml of water, made basic with 1N NaOH and extracted with ethyl acetate. The ethyl acetate solution was washed with water until neutral and dried over sodium sulfate. The solvent was pulled off under vacuum and the residue was recrystallized from ethyl acetate and hexane.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C
Yield: 65.9 %

Procedure:
A one-liter flask fitted with a thermocouple, addition tunnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C3H7) (120.0 g; 0.352 mole), and sodium carbonate (39.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (62.0 g; 0.371 mole) was slowly added over a period of 4 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (23.8 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (95-121° C.; 4.0 mm Hg) to yield C4F9SO2N(C3H7)CH2CO2C2H5 (132.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C3H7)CH2CO2C2H5 (116.0 g; 0.27 mole) KOH (20.0 g; 0.303 mole) water (60 mL) and isopropanol (60.0 g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (31.0 g; concentrated) the temperature increased to 78° C. and two phases appeared. The bottom phase was separated and distilled (136-142° C.; 4.0-5.4 mm Hg) to yield a white solid, C4F9SO2N(C3H7)CH2CO2H (71.0 g).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1cccc(Br)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of 3-bromo-phenyl -carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.218 g., ½ mmol) and 5% Pd—C (0.02 g.) in absolute ethanol (25 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed with dichloromethane (2×3 ml) to give 2c; yield: 0.16 g. (92.4%), m.p.: 198° C., C16H15BrN2O2, 1H NMR δ ppm (CDCl3+DMSO-d6): 1.73-1.81 (m, 2H), 2.55 (t, 2H), 3.06 (t, 2H), 6.67-6.98 (m, 4H), 6.90-7.20 (m, 2H), 7.36 (bs, 1H), 9.39 (bs, 1H), IR vmax (KBr) (cm−1): 509, 694, 758, 815, 886, 1012, 1084, 1149, 1216, 1319, 1352, 1442, 1504, 1549, 1600, 1710, 2365, 2479, 2727, 2827, 2927, 3420, 3780.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:20][CH2:19]2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (63 mg, 0.125 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.188 mmol) to afford the crude product (75 mg) as a yellow-green solid: ESI MS m/z 568 [C31H35ClFN3O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5].CN(P(N(C)C)(N(C)C)=O)C.C([Li])CCC.CON(C)[C:38](=O)[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40]>C1COCC1>[NH2:41][C@H:39]([C:40]1[N:6]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:4](=[O:5])[C:3]2[C:14]([CH:18]=1)=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[CH3:38]
Reactant: Cc1cccc(Cl)c1C(=O)NCCN1CCCC1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide I-31 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) in THF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M in hexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping the temperature below −60° C. The resulting mixture was stirred between −70° C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol, 1.2 eq) was added quickly. The resulting mixture was allowed to slowly warm to RT (over 1 h) and then stirred at RT for an additional 2 h. The reaction mixture was cooled to 0° C., quenched with water (5.0 mL), and then acidified with aqueous HCl (5 M) to adjust the pH to 5-6. The mixture was concentrated in vacuo. The residue was suspended in a mixture of MeOH (20 mL) and H2O (5.0 mL), concentrated HCl (10.0 mL) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to −5° C. and basified with saturated aqueous NH4OH to adjust the pH to 8-9. The precipitate was filtered off and the filtrate was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one I-32.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1Br.[F:28][CH:29]([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1[C:32]1[CH:33]=[N:34][CH:35]=[C:30]([CH:29]([F:39])[F:28])[CH:31]=1
Reactant: OB(O)c1cncc(C(F)F)c1
Reactant: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc(CNc3ncnc(N)c3-c3cncc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 2-(((6-amino-5-bromopyrimidin-4-yl)amino)methyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.12 mmol) were added (5-(difluoromethyl)pyridin-3-yl)boronic acid (31 mg, 0.18 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) and 117 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 33 mg (59% yield) as a white solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18](O)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:26])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2=O
Reactant: N
Solvent: C1CCOC1
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(N)=O)c(Cl)c1Cl)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[(5,6-Dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid (3.82 g, 10 mMole) is dissolved in tetrahydrofuran (30 ml) and 1,1-carbonyldiimidazole (1.78 g, 11 mMole) and the mixture stirred at ambient temperature for 30 minutes. The solution is saturated with ammonia gas and then stirred at ambient temperature for 24 hours and at 50° for 16 hours. Evaporation of the solvent and addition of water yields [(5,6-dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetamide which is separated by filtration, washed with water, and dried.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[Si:20]([O:27][C@H:28]([C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:43])[NH:37]2)[CH2:29][NH:30][CH3:31])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:20]([O:27][C@H:28]([C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36](=[O:43])[NH:37]2)[CH2:29][N:30]([CH3:31])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Reactant: CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C

Procedure:
A mixture of Intermediate 40 (0.30 g, 0.90 mmol) and Intermediate 4 (375 mg, 1.1 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) and catalytic tetra-n-butylammonium iodide (100 mg). The mixture was heated for 3 days in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Silicycle SiliSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound. ES/MS calcd. for C31H39F3N3O4Si+ 602.3. Found m/z=602.4 (M+H)+.