Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]1[C:40]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH2:32])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1>C1COCC1>[F:19][C:20]1[C:40]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH:32][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10 mL of piperidinecarbonyl chloride and 13.55 mL of N,N-diisopropylethylamine are added to a solution of 10 g of 3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine in 200 mL of THF. The reaction mixture is refluxed for 3 hours and then left stirring at ambient temperature for 48 hours. After concentration of the medium vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on 1200 g of 40-63 μM silica, elution being carried out with a 90:10 mixture of dichloromethane/acetone. 10.4 g of piperidine-1-carboxylic acid [3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide are isolated. 1H NMR (300 MHz, (CD3)2S, δ in ppm): 1.50-1.79 (m: 10H); 1.91-2.04 (m: 2H); 3.00 (m: 4H); 3.50 (m: 4H); 3.66 (m: 1H); 3.77 (m: 4H); 3.96 (broad d J=11 Hz: 1H); 5.46 (dd, J=10 and 2 Hz: 1H); 7.10 (very broad s: 1H); 7.40 (very broad s: 1H); 8.13 (s: 1H); 9.96 (broad s: 1H); 13.00 (very broad s: 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)C.[N:8]1([CH2:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH:25][NH2:26])=[O:24])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CC[O:32]CC>>[CH3:1][N:3]([CH3:6])[C:4]([NH:26][NH:25][C:23]([NH:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][CH:29]=[C:15]([CH2:14][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:16]=1)=[O:24])=[O:32]
Reactant: CCOCC
Reactant: CCN(CC)CC
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: CN(C)C(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 12 h

Procedure:
0.6 ml (4 mmol) of triethylamine and 0.4 ml (4 mmol) of N,N-dimethyl-carbamide chloride are added to 1.2 g (4 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carboxamide in 20 ml of ether and the reaction mixture is stirred for 12 hours. Solid triethylammonium chloride is filtered off and the filtrate is concentrated by evaporation under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH:29]([CH3:30])[CH2:28][CH:27](OC)[O:26]1>C(O)(=O)C>[CH3:30][C:29]1[CH2:28][C:27](=[O:26])[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]3=[O:22])[CH:25]=1
Reactant: COC1CC(C)C(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Solvent: CC(=O)O
Product: CC1=CN(c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)C(=O)C1

Procedure:
To a solution of 60 mg (0.18 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 5 ml of acetic acid are added 26 mg (0.18 mmol) of 2,5-dimethoxy-3-methyl-tetrahydro-furan (prepared according to: Markwell, Roger Edward; Hadley, Michael Stewart; Blaney, Frank Edward. Azabicycloalkane derivatives and medicaments containing them. Eur. Pat. Appl. (1983) EP 95262 A1). The reaction mixture is stirred at reflux for 10 hours. Subsequently the solvents are evaporated and the crude product is purified by flash-master chromatography (cyclohexane/ethyl acetate, from 100/0 to 20/80) to yield N-[6-(4-methyl-2-oxo-2,3-dihydro-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl] methanesulfonamide. 1H-NMR ; DMSO-d6 (400 MHz, ppm):; 8.06 (s, 1H, aromatic); 7.60 (s, 1H , aromatic); 7.13 (m, 1H, N-CH═C(CH3)); 4.24 CO—CH2-C(s, 2CO—CH2-C(CH3)); 3.16 (s, 3H, S02-CH3); 1.84 (d, 3H, CH3) [M−H]-; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (72.6 mg, 0.224 mmol) in tetrahydrofuran (4.0 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (46.3 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (68 mg, 0.672 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, washed with ethyl acetate/hexane to give the title compound (64 mg, 64%) as a brown powder.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of p-toluenesulfonyl chloride (14.3 g, 75 mmol) in pyridine (60 mL) is slowly added 3-methyl-3-oxetanemethanol A3a (5.1 g, 50 mmol) over 10 min. The resulting suspension is stirred at rt for 1.5 h and poured into vigorously stirred ice water (300 mL). The slurry is stirred for 45 min. The solid is collected by filtration, washed with ice-cold H2O (100 mL), and dried under high vacuum to afford (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate A3b as a white powder. The compound is used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ=7.83 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 4.39 (d, J=6.4 Hz, 2H), 4.36 (d, J=6.4 Hz, 2H), 4.13 (s, 2H), 2.49 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH2:9]O.C1C=CC(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.CC(=O)OCC>C1(C)C=CC=CC=1>[N:25]([CH2:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[N+:26]=[N-:27]
Reactant: Cc1nn(C)c(Cl)c1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(Cl)c1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2 (538 mg, 3.36 mmol) in toluene (10 mL) was added DPPA (1.1 mL, 5.04 mmol) and DBU (0.6 mL, 6.72 mmol) at 0° C. After stirring for 1 hr, the reaction mixture was warmed to room temperature and stirred for 24 hr. EA (20 mL) was added and the mixture was washed with water, brine, concentrated to give a yellow solid which was used without further purification. LCMS (ESI) m/z=186 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH3:15])=[CH:20][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(COC(=O)C(C)c2ccc(CC(C)C)cc2)cc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a mixture of 2.24 g of 2-(p-isobutylphenyl)propionic acid chloride and 2.10 g of p-methoxybenzyl alcohol in 20 ml of tetrahydrofuran was added 1.50 g of triethylamine under cooling and the whole was stirred for 2 hours. After the reaction was complete, an insoluble matter produced was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue thus obtained was added water and the resulting mixture was extracted with ether. The ether layer separated was washed with successive, 5% sodium carbonate solution, 5% hydrochloric acid solution and water, and then dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.81 g of 2-(p-isobutylphenyl)propionic acid-p-methoxybenzyl ester as a colorless oil, boiling at 149°-151° C./0.1 mmHg. Analysis-Calculated for C21H26O3 : C, 77.27; H, 8.03. Found: C, 77.11; H, 8.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[NH2:12])=[CH:5][CH:4]=1.CN(C)C=O.[C:20](OC)(=[O:23])[C:21]#[CH:22]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:22]=[CH:21][C:20](=[O:23])[NH:12][C:11]=2[CH3:13])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C=C(C)N)cc1
Reactant: C#CC(=O)OC
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 93 g of 3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenamine and 200 ml of dimethylformamide was added 46 ml of methyl propiolate over a 30 minute period and the reaction mixture was stirred at ambient temperature for 3 hours and then gently refluxed for 24 hours. The reaction mixture was allowed to cool, treated with 200 ml of isopropyl alcohol and the solid filtered. The solid was washed with isopropyl alcohol and dried at 90°-95° C. to yield, as white shiny crystals, 75.8 g of 5-(4-methoxybenzoyl)-6-methyl-2(1H)-pyridinone, m.p. 228°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][Mg]Br.CCOCC.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[CH:23]([OH:24])[CH3:25])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=CC1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C1CCCC(c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of the product of step 1 (232 mg; 0.64 mmol) in THF (6 mL) at 0° C. was added methyl magnesium bromide solution 3 N in Et2O (0.27 mL; 0.83 mmol) and the reaction was allowed to warm to room temperature for 1 h. The mixture was poured into saturated ammonium chloride, extracted with DCM, and dried over Na2SO4. After concentration of the solvents, the residue was purified by chromatography over silica gel (eluting Hexanes/EtOAc 8:2) to give 240 mg (100%) of 1-[1-(4-chloro-benzenesulfonyl)-6-phenyl-piperidin-2-yl]-ethanol as a ca 4.5:1 mixture of diastereoisomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: OC1CCC1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(OC3CCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-Cyclobutoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 325 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36](S(C)(=O)=O)[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2.CS(C)=O.O(C(N)C)C>C1COCC1>[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: COCCN
Agent: COC(C)N
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COCCNc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
2-Methoxyethanamine (8.70 μL, 0.10 mmol) was added o a solution of (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169, 50 mg, 0.09 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 3 hours, DMSO (1 ml) was added followed by the addition of 2 more equivalence of methoxylethanamine, the mixture was stirred at room temperature for over night. The crude was concentrated and purified by reverse phase silica gel column chromatography (20-70% MeCN in water gradient, 0.1% TFA) to give 37 mg of product.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[CH2:38]([NH2:40])[CH3:39].[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:38]([NH:40][CH2:1][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:24][CH2:25]2)=[CH:5][CH:4]=1)[CH3:39]
Reactant: CCN
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)c3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.04 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added ethyl amine (0.13 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4(10.5 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (11 mg, 52%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu].N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[S:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cc(OCc2ccccc2)cs1
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A mixture of 5F (14.5 g) and quinoline (50 ml) was treated with copper powder (4.57 g) and heated to 150° C. The reaction mixture is heated for 25 minutes at 150° C. and cooled to room temperature. The mixture was filtered and washed with water. Aqueous quinoline was acidified with 6N HCI (pH=2) and extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue was chromatographed to yield a yellow liquid (8.74 g, 71 %).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1([S:17]([NH:20]C(=O)OC(C)(C)C)(=[O:19])=[O:18])[CH2:16][CH2:15]1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH2:16][CH2:15]1
Reactant: COCCOCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
TFA (5 ml) was added to the solution of the product of Step 1 (0.63 g) in dichloromethane (5 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred for 1.5 hour. The solvent was removed under reduced pressure to give the desired product (0.426 g) as a light brown oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.80-6.21 (m, 2H), 3.75 (s, 2H), 3.66-3.64 (m, 2H), 3.56-3.53 (m, 2H), 3.36 (s, 3H), 1.42-1.39 (m, 2H), 0.91-0.89 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[CH2:21]([O:23][C:24]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]([NH2:31])[CH:25]=1)[CH3:22]>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25]2[C:24]([O:23][CH2:21][CH3:22])=[N:29][C:28]([NH2:30])=[N:27][C:26]=2[NH:31][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CCOc1cc(N)nc(N)n1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CCOc1nc(N)nc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
270 mg (1 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 170 mg (1.1 mmol) of 6-ethoxypyrimidine-2,4-diamine are dissolved in 5 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is then concentrated and the residue is purified by preparative HPLC. 230 mg (56% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].O>ClCCl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CCCN3CCOCC3)cc2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(N2CCNCC2)ccc1CCCN1CCOCC1
Reaction time: 2 h

Procedure:
A solution of Example 5B (671 mg, 1.725 mmol) in dichloromethane (2 mL) at room temperature was treated with TFA (1.8 mL) and water (0.2 mL) allowed to stand for 2 hours The solution was concentrated to provide the desired product.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[N:53]2[CH2:54][CH2:55][N:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=3)[CH2:51][CH2:52]2)=[CH:9][CH:8]=1
Reactant: C1CCC(N2CCNCC2)NC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-(4-(2-pyridyl)piperazinyl)ethyl}(tert-butoxy)carboxamide was prepared according to the procedure for Preparation XIX using Boc-p-Cl-D-Phe-OH (550 mg, 1.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 g, 3.80 mmol), HOAT (260 mg, 1.9 mmol), DMF (15 mL), and 1-(2-piperidyl)piperazine (280 μl, 1.8 mmol) (Aldrich). The crude material was concentrated in vacuo to yield 810 mg. MS (ESI, pos. ion) m/z: 445 (M+H), (ESI, neg. ion) m/z: 443 (M−H). Calc'd for C23H29ClN4O3: 444.95.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCN3CCOCC3)ccc21
Yield: 107.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (37.6 mg, 0.0915 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-(2-aminoethyl)morpholine (0.048 mL, 0.37 mmol), acetic acid (0.105 mL, 1.83 mmol) and sodium triacetoxyborohydride (97 mg, 0.46 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-morpholinoethyl)aminomethyl]indol-2-yl)isoindolinone (51.7 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13](=[O:15])[CH2:12][S:11](=[O:17])(=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.[NH2:28]/[C:29](/[CH3:45])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:32]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2([OH:15])[NH:28][C:29]([CH3:45])=[C:30]([C:31]([O:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH3:37])=[O:32])[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:19]=3[Cl:18])[CH:12]2[S:11](=[O:16])(=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(=O)C1
Solvent: CCO
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2cccc(Cl)c2Cl)C2C(O)(CN(C(=O)OC(C)(C)C)CCS2(=O)=O)N1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of 4-N-(t-butyloxycarbonyl)-1,1-dioxo-2,3,4,5,6,7-hexahydro-1,4-thiazepin-6-one (8.39 g, 31.9 mmole) from Example 6, 2,3-dichlorobenzaldehyde (5.58 g, 31.9 mmole) and 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate (7.91 31.9 mmole) were heated to reflux in 40 mL of ethanol for 17 hours. The reaction was cooled to room temperature, filtered, and the solid washed with 50 mL of ether to obtain the title compound (10.72 g, 50% yield) D.C.I.M.S. (M+H) 668.