Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([I:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][CH:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[S:25][C:24]([I:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one quantitatively. MS (ESI+) [M+H]+ 528.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[S:28]1[C:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=2[CH:30]=[C:29]1[C:37](Cl)=[O:38].C(N(C(C)C)C(C)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([NH:23][C:37]([C:29]4[S:28][C:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=5[CH:30]=4)=[O:38])[CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Reactant: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3nccc(-c4cccc(NC(=O)c5cc6c(s5)CCCC6)c4C)c3o2)cc1OC

Procedure:
The compound was synthesized according to the procedure L with 3-[2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridin-7-yl]-2-methylaniline (40.00 mg, 0.11 mmol) and 4,5,6,7-tetrahydro-1-benzothiophene-2-carbonyl chloride (24.5 mg, 0.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml, 0.17 mmol). The title compound was obtained as a yellow solid (32 mg, 55%). HPLC (method F): 96%, RT=4.512 min. 1H NMR (DMSO-d6) δ [ppm] 9.95 (s, 1H), 8.53 (d, 1H), 7.63 (d, 2H), 7.45-7.27 (m, 6H), 7.03 (d, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.70 (s, 2H), 2.55 (m, 2H), 2.05 (s, 3H), 1.72-1.69 (m, 4H). MS: m/z=525 [M+H]+, RT=4.50 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:38][N:39]([CH:41]=O)[CH3:40]>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([NH:24][C:18]4[CH:19]=[CH:33][C:15]([CH2:41][N:39]([CH3:38])[CH:40]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (200 mg) in THF (10 ml) were added thionyl chloride (0.064 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (107 mg) and triethylamine (0.37 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 104) (264.2 mg) as yellow crystals.
Reaction SMILES: [O:1]1[CH2:4][C:2]1([C:5]([F:8])([F:7])[F:6])[CH3:3].[C:9]([CH2:12][N:13]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:15][CH2:14]1)([OH:11])=[O:10].[OH-].[K+]>O1CCOCC1.O>[OH:1][C:2]([C:5]([F:8])([F:7])[F:6])([CH3:3])[CH2:4][N:22]1[CH2:23][CH2:24][N:13]([CH2:12][C:9]([OH:11])=[O:10])[CH2:14][CH2:15][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:17][CH2:18][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:21]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC1(C(F)(F)F)CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 24 h

Procedure:
10.29 g (86.58 mmol) of 2,3-epoxy-2-trifluoromethylpropane and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. (with exclusion of pressure). It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 11.04 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:36]([CH2:35][CH:34]([OH:38])[C:31]4[CH:32]=[CH:33][C:28]([CH2:27][OH:26])=[CH:29][CH:30]=4)[CH3:37])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(CO)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ccc(CO)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-[4-(hydroxymethyl)phenyl]-2-(methylamino)ethanol (Preparation 93) (69 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/DMF (15 mL/1 mL, dissolved with warming DMF, added with acetonitrile, and then cooled to 0° C. overnight) gave the title compound (92 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.C[OH:24]>O>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1)=[O:24]
Reactant: CO
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1SC
Solvent: O
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Yield: 70 %

Procedure:
The sulfide of Example 35, (300 mg, 0.95 mmoles), was reacted with 300 mg (1.41 mmoles) NaIO4 in 6 mL MeOH and 3 mL water at 25° C. for 24 h. The reaction mixture was partitioned between 100 mL EtOAc and 25 mL water and the EtOAc extract was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 1:1 EtOAc/hexanes as eluent to give 220 mg product, (70% yield); mp 144-146° C. Elemental analysis for C18H25N3O5 : Theory C: 65.22, H: 7.60, N: 12.68, S: 9.67. Found: C: 65.12, H: 7.63, N: 12.48, S: 9.71.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:26])([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:12]2)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:27])[C:20]([F:25])([F:26])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:12]2)([OH:4])=[O:2]
Reactant: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(F)(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1

Procedure:
(1S,2S,3R,5S)-(E)-7-(4-Methoxycarbonylbutylidene)-2-[4,4-difluoro-3(RS)-hydroxy-(E )-1-octenyl]-3-tetrayhydropyranyloxybicyclo[3.3.0]octane (18) (0.175 g) was dissolved into methanol. To the solution, 1N aqueous solution of sodium hydroxide was added, and the mixture was stirred until it became completely clear. After a usual work-up a crude product, (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4,4-difluoro-3(R S)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (19), was obtained. Yield: 0.172 g
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To 15 ml of a dichloromethane solution of 922.6 mg (3.06 mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)-pyrrolidine (isomer B) was added 0.874 ml (6.12 mmol) of benzyl chloroformate at room temperature, followed by stirring at the same temperature overnight. To the reaction mixture was further added 0.502 ml (3.52 mmol) of benzyl chloroformate, followed by stirring for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 685.5 mg (64.8%) of the title compound as a colorless oily substance.
Reaction SMILES: [O:1]1[C:13]([CH3:15])([CH3:14])[C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9](=O)[CH3:10].C(C(CC)(P(O)(O)=O)[C:20]#[N:21])C.[Na].[CH2:29](O)C>>[O:1]1[C:13]([CH3:15])([CH3:14])[C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([CH3:29])=[CH:10][C:20]#[N:21]
Reactant: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Reactant: CCO
Reactant: CCC(C#N)(CC)P(=O)(O)O
Agent: [Na]
Product: CC(=CC#N)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution containing 9.85 g. of 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one and 7.3 g. of diethyl phosphono acetonitrile in 50 ml. of ethyl alcohol, there was added dropwise a solution containing 1.1 g. of sodium in 25 ml. of ethyl alcohol. After the addition, the reaction mixture was allowed to stand 2 hours at room temperature. After this period, the reaction mixture was dried under vacuum and poured onto ice water. After this, the reaction mixture was exhaustively extracted with diethyl ether. The combined ether extracts were washed with an aqueous saturated sodium chloride solution, dried under sodium sulfate and evaporated. By chromatography on Kieselgel with hexane-ethyl acetate (1:1 parts by volume) was obtained pure 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadiene nitrile, b.p. 108°-111°C./0.005 mmHg; nD20 = 1.4861.
Reaction SMILES: [CH2:1]([C:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)=[O:50]>>[CH2:21]([C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)=[O:50])[CH:13]=1)=[O:11])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC(=CC(=O)c1c[nH]c2ccccc12)CCCCCCC
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Product: CCCCCCCC(=CC(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)CCCCCCC

Procedure:
The procedure of Ex. 1 was repeated except that 3-(3-heptyl-2-decenoyl)indole obtained in Pre. Ex. 26 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate was used in place of 4-bromobutyrate to give 4-methoxybenzyl 4-[3-(3-heptyl-2-decenoyl)-1-indolyl]butyrate as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([C:20](=[O:26])[C:21]([O:23]CC)=[O:22])=[C:9]2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[O:28]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1.[CH3:41][C:42]([NH2:46])([C:44]#[CH:45])[CH3:43]>>[NH2:46][C:42]([CH3:43])([CH3:41])[C:44]#[C:45][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([CH:20]([O:26][C:5]([CH3:10])([CH3:6])[CH3:4])[C:21]([OH:23])=[O:22])=[C:9]2[C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[O:28][CH2:29][CH2:30][CH2:31]3)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)N
Reactant: OB(O)c1ccc2c(c1)CCCO2
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Product: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(chroman-6-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87) was prepared by the method of Example 67 from ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate using chroman-6-ylboronic acid. The remainder of the sequence follows the method of Example 67 using 2-methylbut-3-yn-2-amine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.77 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.48 (s, 1H), 7.45 (m, 1H), 7.23 (m, 1H), 6.90 (m, 2H), 5.31 (s, 1H), 4.28 (t, J=5 Hz, 1H), 2.87 (m, 2H), 2.58 (s, 3H), 2.08 (m, 2H), 1.68 (s, 6H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C31H33O4: 469.2; found: 469.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.COS(OC)(=O)=O.[O:15]=[C:16]1[C:25]2[NH:26][CH:27]=[CH:28][C:24]=2[C:23]2[CH:22]=[C:21]([S:29](=[O:38])(=[O:37])[NH:30][CH:31]3CCNCC3)[CH:20]=[CH:19][C:18]=2[NH:17]1.[CH:39]1([C:44]([O-:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1.N>CN(C)C=O.O>[CH3:1][N:3]1[CH2:6][CH2:7][CH:31]([NH:30][S:29]([C:21]2[CH:20]=[CH:19][C:18]3[NH:17][C:16](=[O:15])[C:25]4[NH:26][CH:27]=[CH:28][C:24]=4[C:23]=3[CH:22]=2)(=[O:37])=[O:38])[CH2:5][CH2:4]1.[CH:39]1([C:44]([O-:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CCN(CC)CC
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CCNCC3)cc2c2cc[nH]c12
Agent: N
Agent: O=C([O-])C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CCC(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
83 μL (0.6 mmol) of triethylamine and 22 μL (0.24 mmol) of dimethylsulfate are added to a solution of 55 mg (0.12 mmol) of 4-oxo-8-(piperidin-4-ylsulfamoyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate dissolved in 5 mL of anhydrous dimethylformamide. The solution is stirred at room temperature for 3 hours before adding 2 mL of ammonia. After stirring for a further 10 minutes, water is added and the product is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (eluent chloroform/methanol/ammonia 300/24/4) to give 22 mg (39%) of 8-(1-methyl-piperidin-4-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(F)(F)F)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][CH:32]([C:29]3[S:30][CH:31]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[N:28]=3)[CH2:37][CH2:36]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(F)(F)F)cn1
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCC(c3nc(-c4ccc(F)cc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trifluoroethyl [6-(acetylamino)pyridin-3-yl]carbamate (274 mg, 0.839 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (193 mg, 57.6%) as a solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:14]1[C:15]([Cl:32])=[CH:16][C:17]([F:31])=[C:18]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[CH:19]=1.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][CH:2]([CH2:3][C:14]1[CH:19]=[C:18]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:17]([F:31])=[CH:16][C:15]=1[Cl:32])[C:1]([OH:5])=[O:4]
Reactant: Cl
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reactant: C=CC(=O)O
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl

Procedure:
In 200 ml of acetonitrile were dissolved 36.0 g of acrylic acid and 7.73 g of t-butyl nitrite, and 8.07 g of copper (II) chloride was added. Under stirring, 14.5 g of N-(5-amino-4-chloro-2-fluorophenyl)phthalimide was added thereto in small portions, followed by stirring at room temperature for 1.5 hours. 3N Hydrochloric acid was added to the reaction mixture. After stirring, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:1) to give 14.0 g of the title compound (No. 3 of Table 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([N:21](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2.Cl.C(O)CO.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: C1COCCO1
Product: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
A stirred solution of 3-(6-fluoroquinolin-3-yl)-5-[1-(tetrahydro-2H-pyran-4-ylamino)ethyl]-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[1,5-a]pyrimidin-7-amine (890 mg, 1.33 mmol) in dioxane (4 mL) was treated with 4 M HCl in dioxane (4 mL) followed by 1,2-ethanediol (4 mL), and the resulting amber mixture was stirred at room temperature for 15 min and then at 50° C. for 5 h at which point the reaction was near completion. The mixture was cooled to room temperature, added carefully in portions to saturated aqueous NaHCO3 (200 mL) with stirring, and extracted with DCM (3×100 mL). The combined organic phase was washed with water (100 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The solid residue was taken up in 10% MeOH/DCM (˜7-8 mL), diluted with diethyl ether (˜40 mL) and the small amount of precipitate that formed was removed by filtration through a fine frit. The filtrate was concentrated under reduced pressure to give 3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)pyrazolo[1,5-a]pyrimidin-7-amine (510 mg, 80% yield @ 85% purity) as a tan amorphous solid. MS (ESI+) for C22H23FN6O m/z 407 (MAI); HPLC, 2.43 min (Method B).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>O>[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:41][CH:40]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(N(C)C)cc4)cc23)CC1
Yield: 6.1 %

Procedure:
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.097 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (40 mg, 0.289 mmol) in water (1.2 mL). To this mixture was added [4-(dimethylamino)phenyl]boronic acid (65 mg, 0.386 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol). The vial was capped and the reaction was reacted in a CEM microwave for 10 min at 160° C. The reaction was concentrated under a stream of nitrogen at 80° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified through a 1 g silica SPE cartridge eluting with dimethyl sulfoxide (4 mL). The dimethyl sulfoxide was concentrated in a Genevac at 65° C. for 3 h, and the residue was reconstituted in dimethyl sulfoxide (1 mL) and filtered through an acrodisc. The solution of crude product was then purified on the Agilent MDAP (UV 214 selection). The purified product was passed through a polymer-bound carbonate SPE cartridge to afford 2.7 mg of the title compound (6.2%).