Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11]([O:13]CC)=O)[C:9]#[N:10].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[CH:8]([C:11](=[O:13])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: CCOC(=O)C(C#N)C(=O)c1cccn1C
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 1.1 g of aniline and 60 ml of xylene, is refluxed for 41/2 hours. After standing and cooling to room temperature overnight, the solution is filtered, evaporated and the residue recrystallized from methanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 173°-174°; it is identical with that obtained according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41]Cl)[CH3:38].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:37]([N:39]([CH2:43][CH2:44][O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:40][CH3:41])[CH3:38]
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.8 %

Procedure:
To a mixture of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol), 2-diethylaminoethyl chloride hydrochloride (487 mg, 2.75 mmol) and potassium carbonate (380 mg, 2.7 mmol) was added ethyl acetate (3 mL) and water (3 mL) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into a mixture of water (30 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product, which was purified by silica gel chromatography using a Biotage (40s) column afforded 122 mg (71% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C30H32Cl2F3N3O4 (M+H) 626.1796, found 626.1802.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:18])=[N:4][N:3]=1.[C:19]([NH:23][S:24]([C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C([O-])=O.[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[C:19]([NH:23][S:24]([C:27]1[CH:28]=[N:29][CH:30]=[C:31]([C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:18])=[N:4][N:3]=2)[CH:32]=1)(=[O:26])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)cccc12
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Temperature: 95 °C
Yield: 76.1 %

Procedure:
To a solution of 1,4-dichloro-5-phenylphthalazine (0.400 g, 1.45 mmol) and N-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.742 g, 2.18 mmol) (Johnson et al., WO 2011/28741) in 1,4-dioxane (15 mL) and water (3 mL) was added K3PO4 (0.617 g, 2.91 mmol) and the contents purged with nitrogen for 10 min. Tricyclohexylphosphine (10.2 mg, 0.0360 mmol) was added followed by Pd2(dba)3 (0.0130 g, 0.0150 mmol) and heated at 95° C. for 12 h. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with HCOONH4 buffer (pH˜5) solution and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 12 g, 30% EtOAc/hexanes) to obtain N-(tert-butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.500 g, 76.0%) as a pale yellow solid. LCMS (Condition 11): retention time 1.04 min, [M+1]=453.2. 1H NMR (400 MHz, DMSO-d6) δ 1.20 (s, 9 H), 7.43-7.46 (m, 2 H), 7.50-7.54 (m, 3 H), 7.98 (s, 1 H), 7.99 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 8.03 (dd, J=1.2 Hz, J=7.2 Hz, 1 H), 8.15 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.58 (t, J=2.0 Hz, 1 H), 9.17 (d, J=2.0 Hz, 1 H), 9.23 (d, J=2.0 Hz, 1 H).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[N-][Si](C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[C:43]([O:47][C:48](=[O:50])[CH3:49])([CH3:46])([CH3:45])[CH3:44].[Cl:51][C:52]1[C:61](OS(C(F)(F)F)(=O)=O)=[C:60]2[C:55]([CH:56]=[CH:57][C:58]([CH3:70])=[N:59]2)=[CH:54][CH:53]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:43]([O:47][C:48](=[O:50])[CH2:49][C:61]1[C:52]([Cl:51])=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([CH3:70])[CH:57]=[CH:56]2)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1ccc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2n1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(Cl)c(CC(=O)OC(C)(C)C)c2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
n-Butyl lithium (1.6 M in hexane, 5.3 ml, 8.52 mmol, 1.5 equiv) was added at −78° C. under an atmosphere of argon to a degassed solution of hexamethyl disilazide (1.38 g, 8.52 mmol, 1.5 equiv) in toluene (16 ml). After stirring at −78° C. for 15 minutes and at room temperature for 15 minutes, Pd2(dba)3 (156 mg, 0.17 mmol, 0.03 equiv) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (141 mg, 0.36 mmol, 0.063 equiv) were added. After stirring at room temperature for 10 minutes, the reaction mixture was cooled to −10° C. and treated dropwise with acetic acid tert-butyl ester (858 mg, 7.38 mmol, 1.3 equiv). After stirring for 10 minutes at −10° C., trifluoro-methanesulfonic acid 7-chloro-2-methyl-quinolin-8-yl ester (1.85 g, 5.68 mmol) was added in one portion, and the cooling bath was removed. The temperature of the reaction mixture rose to 29° C. within the next 30 minutes. After 40 minutes, TLC analysis indicated formation of unwanted side products (e.g. 4-(7-chloro-2-methyl-quinolin-8-yl)-3-oxo-butyric acid tert-butyl ester). The reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of toluene/EtOAc 100:0 to 95:5) to afford the title compound (662 mg, 40%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.98 (d, J=12.8 Hz, 1H), 7.63 (d, J=12.8 Hz, 1H), 7.47 (d, J=12.8 Hz, 1H), 7.26 (d, J=12.8 Hz, 1H), 4.43 (s, 2H), 2.72 (s, 3H), 1.47 (s, 9H). MS (ES+): 292.2 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)CO.[OH-].[K+]>O>[CH:1]1([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(OC2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)c1ccc(OC2CCCC2)cc1

Procedure:
To 50 g of methyl p-hydroxybenzoate were added 82 g of cyclopentyl bromide. The mixture was cooled to 0° C. and 24 g of sodium hydride (in a 50% mineral oil suspension) were added in small portions. Ice bath cooling was continued until the resulting effervescence terminated. The reaction mixture then was heated to 75° C. for four hours, cooled, and 25 mL of ethanol was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of water and ether. The ether layer was separated and washed with cold 5% aqueous sodium hydroxide and then with water. The ether layer then was dried over magnesium sulfate and evaporated to dryness to give about 72 g of crude methyl p-cyclopentyloxybenzoate. The crude ester was added to 400 mL of ethylene glycol containing 100 g of potassium hydroxide. The mixture was refluxed for several hours and then was transferred to a 4 L beaker. A mixture of ice and water was added. The resulting mixture then was placed in a separatory funnel and was washed with ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 44.1 g of p-cyclopentyloxybenzoic acid. A solution of 8.7 g (0.024 mole) of p-cyclopentyloxybenzoic acid in 250 mL of anhydrous ether was prepared. The solution was cooled to 5° C.-10° C. and 8.85 g of thionyl chloride followed by two drops of pyridine were added. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture then was evaporated to dryness, and the oily residue of p-cyclopentyloxybenzoyl chloride was dissolved in 150 mL of 1,2-dichloroethane for use as described in Example 10 below.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([NH2:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)NC2CC2)ccc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(S(=O)(=O)NC2CC2)ccc1F
Yield: 95.5 %

Procedure:
The mixture of N-cyclopropyl-4-fluoro-3-nitrobenzenesulfonamide (520 mg, 2 mmol) and Pd/C (10%, 100 mg) in EtOH was hydrogenated (1 atm) overnight. The mixture was filtered through a short pad of celite and concentrated in vacuo to afford N-cyclopropyl-4-fluoro-3-aminobenzenesulfonamide (440 mg, 95% ) as an ivory solid. LC/MS; (M+H)+=231.
Reaction SMILES: [C:1]([N:5]([C:29](=O)[CH2:30][CH3:31])[C:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[N:11]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[N:9]=[C:8]([CH3:28])[CH:7]=1)(=O)[CH2:2][CH3:3]>C1COCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH3:3])[C:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[N:9]=[C:8]([CH3:28])[CH:7]=1)[CH2:30][CH3:31]
Reactant: CCC(=O)N(C(=O)CC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)C=CCC1
Solvent: C1CCOC1
Product: CCCN(CCC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)CCCC1

Procedure:
N,N-Dipropionyl-2-methyl-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine 1c (312 mg) is refluxed in 8 mL THF with borane-methylsulfide complex (10 M, 1.2 mL) for 10 hours. After cooling the solution, it is carefully quenched with 5 mL of methanol. The resulting solution is refluxed for another 2 hours and then concentrated. The dialkylamine product is purified on silica gel using 20% ethyl acetate in hexanes as eluant to afford N,N-Dipropyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine (Compound 1) as a white solid, m.p.: 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C.CCCCCC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]3[C:23]([CH:22]=2)=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(C#N)ccc21
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C#N)ccc21
Yield: 42.9 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (68.4 mg, 0.230 mmol) was dissolved in acetonitrile (1.4 mL), and the solution was treated with 1-(tert-butoxycarbonyl)-5-cyanoindole-2-boronic acid (100 mg, 0.350 mmol) synthesized in a similar manner to the method described in Journal of Organic Chemistry, 2002, vol. 67, p. 7551, palladium acetate (4.1 mg, 0.018 mmol) and triethylamine (0.321 mL, 2.30 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-cyanoindol-2-yl]isoindolinone (40.2 mg).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16](=[O:29])[CH2:17][N:18]3[C:22]([CH3:23])=[C:21]([Cl:24])[C:20]([C:25]([F:28])([F:27])[F:26])=[N:19]3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:24][C:21]1[C:20]([C:25]([F:28])([F:26])[F:27])=[N:19][N:18]([CH2:17][C:16]([N:12]2[CH2:13][CH:14]3[CH:10]([CH2:9][NH:8][CH2:15]3)[CH2:11]2)=[O:29])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of compound 6 (146 mg) and trifluoroacetic acid (2 mL) was stirred at room temperature for 30 min and concentrated in vacuo to provide the title compound 7 as a pale yellow oil (111 mg, 99%). LCMS: Rf: 0.612 min, M+H+: 303.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:9]([N:6]1[CH2:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCc1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
A solution of 4-ethylpyridine (3.0 g, 28 mmol) in anhydrous dimethylformamide (10 ml) was treated with benzyl bromide (3.7 ml, 31 mmol) and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with absolute ethanol (60 ml), treated with sodium borohydride (1.3 g, 35 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to give the title compound (1.92 g, 34% over two steps) as a colourless oil; δH (CDCl3) 1.00 (3H, t, J 7.5 Hz, CH2CH3), 1.94-2.12 (4H, m, CH2CH3 and tetrahydropyridinyl CH2), 2.55 (2H, t, J 6.3 Hz, tetrahydropyridinyl CH2), 2.90-3.00 (2H, m, tetrahydropyridinyl CH2), 3.58 (2H, s, PhCH2N), 5.32-5.40 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.40 (5H, m, ArH); m/z (CI+, NH3) 202 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][CH3:19])[N:11]=1)[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([C:15]1[C:10]([NH:9][C@H:5]2[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:8][N:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]2)=[N:11][C:12]([CH2:18][CH3:19])=[CH:13][N:14]=1)[CH3:17]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (4.50 g, 17 mmole) in CH2Cl2 (0.1 M, 170 mL) under N2 at 0° C. was added triethyl amine (7.09 mL, 3.0 eq.). Methyl chloroformate (1.44 mL, 1.1 eq.) was added drop-wise over 15 min. After 1 hour, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with CH2Cl2 (1×200 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-50% ethyl acetate in heptane gradient) provided 5.35g (98%) of methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2972, 2937, 2877, 2338, 1937, 1708, 1581, 1546, 1499, 1453, 1392, 1189, 1174, 1135, 1103 (s) cm−1 HRMS (ESI) calcd for C16H26N4O3+H1 323.2083. found 323.2089. Anal. Calcd for C16 H26 N4O3: C, 59.61; H, 8.13; N, 17.38. Found: C, 59.23; H, 8.35; N, 17.33.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[BH4-].[Na+].I(O)(=O)(=O)=O.Br[CH2:35]C(OC(C)(C)C)=O.FC(F)(F)C([O-])=O>[Zn]>[CH3:1][CH2:2][C@:3]1([OH:26])[C:4]2[CH:25]=[C:24]3[N:12]([C:10](=[O:11])[C:5]=2[CH2:6][O:7][C:8](=[O:9])[CH2:35]1)[CH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[N:22][C:23]3=1)[CH:20]=[CH:19][CH:18]=[CH:17]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=C([O-])C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1

Procedure:
is prepared according to the procedure of Bigg et al. (Bioorg. Med. Chem. Lett. 1997, 17, 2235-2238) by the reduction of camptothecin with sodium borohydride. This furnishes the hydroxylactol which converts to formyloxy-mappicin ketone using periodic acid. The reaction of this ketone with zinc and t-butyl bromoacetate followed treatment with trifluoroacetate affords homocamptothecin. To then derivitize homocamptothecin at the 12-position, a suspension of homocamptothecin (3.12 g, 8.6 mmol) in a mixture of chloroacetaldehyde (18 ml) and H2O (75 ml) is prepared. 75% H2SO4 (75 ml) is added dropwise, and then FeSO47H2O (2.40 g, 8.6 mmol) was added. To the ice-cold mixture, 30% H2O2 (15 ml, 6.6 mmol) is added dropwise for 2 h with stirring. The mixture is stirred at room temperature for 14 h and then diluted with H2O, extracted with chloroform (3×200 ml), and the organic layer washed with brine and dried over MgSO4. Evaporation of the solvent renders a brown oil which upon purification using column chromatography (eluent: chloroform: methanol 98:2) yields the yellow solid product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([F:22])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[C:4]([F:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Br)cc1F
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a stirred solution of (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (15.5 g) and triethylamine (9.85 ml) in THF (120 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (3.35 ml). The reaction mixture was then stirred at room temperature for 1 hour to afford a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (20 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (36.2 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 20 min and then poured into EtOAc and washed sequentially with 1 M aq. HCl, water and saturated brine. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-tert-butyl 2-(4-bromo-2-fluorophenyl)morpholine-4-carboxylate (6.46 g, 44%) as a yellow oil. MS (EI): 305 ([{81Br}M-C4H8]+), 303 ([{79Br}M-C4H8]+), 260 ([{∥Br}M-C4H8—CO2H]+), 258 ([{79Br}M-C4H8—CO2H]+).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:15]=[C:9]2[N:10]=[CH:11][C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:14][C:12]1[CH:11]=[N:10][C:9]2=[CH:15][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:13]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (223 mg described in Example 157) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (145 mg, 38%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, CHLOROFORM-d): 1.95 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.84-7.90 (m, 2H), 8.11 (s, 1H), 8.22 (dd, J=2.0, 1.0 Hz, 1H), 8.42 (d, J=0.8 Hz, 1H) and 8.64 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-])(=[O:14])=[O:13].[Na+]>CS(C)=O.CCOC(C)=O.[Cu]I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)[O-]
Reactant: CCC(=O)c1cnc(Br)s1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methanesulfonate (41 mg, 0.34 mmol) followed by copper (I) iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 hour. The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to afford 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1>C(N)CC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([NH:8][CH2:7][CH2:6][CH3:5])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Solvent: CCCN
Product: CCCNN1C=Cc2ccc(Br)cc2C1

Procedure:
A solution of 7-bromo-1-chloroisoquinoline in propylamine (15.0 mL) was heated at 70° C. in a sealed tube overnight. The reaction mixture was concentrated under reduced pressure, then dissolved in chloroform and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 7-bromo-2-(N-propylamino)isoquinoline (820 mg): ESI MS m/z 266 [M+H]+