Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([OH:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40]N(C)C=O.[H-].[Na+].CI>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]([O:34][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]([O:31][CH3:32])=[O:30])[C@@H:24]([CH3:33])[CH2:23][CH2:22]4)[CH:16]=[N:15]2)[CH:10]([O:39][CH3:40])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4O)c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4OC)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A 50-mL round-bottom flask was charged with methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 0.46 mmol,) and N,N-dimethylformamide (5 mL). Sodium hydride (78 mg, 3.25 mmol,) was added, and the mixture stirred at room temperature for 30 minutes. Methyl iodide (0.079 mL, 1.28 mmol) was added, and the resulting solution stirred for 4 h at room temperature. The reaction mixture was then poured into 20 mL of water and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:5, ethyl acetate/petroleum ether) to afford (2S)-methyl 6-(1-(1-(tert-butoxycarbonyl)-3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (80 mg, 31%) as colorless oil. MS (ESI, pos. ion) m/z 555 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:17][C:18]#[N:19]>CN(C)C=O>[N:1]1([CH2:17][C:18]#[N:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To an ice cooled solution of benzimidazole (10 g, 0.085 mol) in dry N,N-dimethylformamide (500 mL) was added potassium tert-butoxide (9.6 g, 0.085 mol) portionwise. The mixture was stirred at room temperature for 1 h then bromoacetonitrile (6 mL, 0.086 mol) was added in one portion and stirred for 3 h. The mixture was then quenched with solid carbon dioxide followed by water and the organics separated. The organics were washed further with water (100 mL×5), and brine (100 mL×1) combined and dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel column eluting with dichloromethane:ethanol (1% up to 6% ethanol) to give a yellow solid (12 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 5.08 (2H, s), 7.36-7.43 (2H, m), 7.47 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=7.2 Hz), 7.93 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=1)=[C:9](Cl)[CH2:10]2)=[O:5])[CH3:2].C(N(CC)CC)C.C(O)=O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][N:16]=1)=[CH:9][CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1C(c1cc(-c3ccccc3)on1)=C(Cl)C2
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C2CC=C(c3cc(-c4ccccc4)on3)C1CC2

Procedure:
1.3 g (3.6 mmol) 8-ethoxycarbonyl-3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene was dissolved in 30 ml ethanol. 300 mg Pd/C 5%, triethylamine (7 ml) and formic acid (3 ml) was added and the reaction mixture heated at reflux for 4 h. The mixture was concentrated in vacuo, water (50 ml) was added and the solution extracted with ethylether 3×20 ml. The organic phase was dried over magnesiumsulphate and concentrated in vacuo. The crude product was purified by column chromatography with methylenchloride/ethylacetate (9:1) as eluent. Yield 600 mg oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(Br)cc1)NCc1ccccc1
Yield: 82 %

Procedure:
Amide coupling of 4-Bromophenylacetic acid with benzylamine was done according to procedures in Step 10A for Example 3.60 to give N-Benzyl-2-(4-bromo-phenyl)-acetamide in 82% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.5 (s, 2 H) 4.3 (d, J=5.8 Hz, 2 H) 7.2 (dd, J=7.8, 5.6 Hz, 5 H) 7.3 (m, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 8.6 (t, J=5.9 Hz, 1 H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[N:22]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: S=C(NCc1cccnc1)NC1CCCCC1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NCc3cccnc3)N2C2CCCCC2)ccc1Cl
Temperature: 25 °C

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3.7 g of 1-cyclohexyl-3-(3-pyridylmethyl)-thiourea were reacted as prescribed in Example 23. The end product precipitated first as oil and crystallized after stirring for several hours at room temperature. Colorless crystals, melting point 140° C., decomposition beginning at 165° C., γC=N 1600 cm-1.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.Cl[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To a solution of 2-bromothiophene (10 mL, 103.3 mmol, 1.0 eq) in dichloromethane (200 mL) was added ethyl 2-chloro-2-oxoacetate (13.8 mL, 123.9 mmol, 1.2 eq) and aluminum trichloride (16.5 g, 123.9 mmol, 1.2 eq) at 0° C. After stirring for 10 minutes, the reaction mixture was diluted with dichloromethane and poured into ice. The combined organic phase was washed (brine), dried (MgSO4), filtered and concentrated to give a residue, the residue was purified by silica gel column chromatography to yield ethyl 2-(5-bromothiophen-2-yl)-2-oxoacetate (7.0 g, 25.8%). LC-MS (m/z): 262.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.33 (t, J=7.2 Hz, 3H), 4.33-4.39 (m, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46]CCO)=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([C:34]2[N:39]=[N:38][N:37]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:42][C:41]=3[OH:50])[C:35]=2[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCOc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1

Procedure:
9.11 g of acetic anhydride, 18.1 g of triethylamine and 0.73 g of dimethylaminopyridine in 400 ml of anhydrous dichloromethane are added to the product from Example A9. The reaction mixture is heated to boiling. When the reaction is complete (monitoring by TLC), the solvent is removed in vac. and the residue is taken up in dichloromethane. The organic phase is washed with water and dried with magnesium sulfate. After removal of the solvent, the residue is chromatographed on silica gel, yielding the product having the following NMR data:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH3:27])(=O)C>O1CCOCC1.COC1C(N)=CC=CC=1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:11][C:10]1[CH:9]=[CH:1][CH:2]=[CH:27][C:26]=1[O:25][CH3:22])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Reactant: CCOC(C)=O
Solvent: COc1ccccc1N
Solvent: C1COCCO1
Product: COc1ccccc1Nc1c(C(=O)c2ccccc2)cnc2c(OC)cccc12
Yield: 61 %

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (2.8 g, 0.0094 mol) was heated under reflux in a mixture of 1,4-dioxan (50 ml) and o-anisidine (7 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, and washed with dilute hydrochloric acid sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to give an oil which afforded yellow crystals of 3-benzoyl-4-(2-methoxyphenylamino)-8-methoxyquinoline (2.2 g, 61%) from ethyl acetate, m.p. 200°-202°.
Reaction SMILES: [CH2:1]=[O:2].[OH-].[K+].[C:5]1([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[OH:2][CH2:1][C:11]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Paraformaldehyde (720 mg) was suspended in diethyl phenylmalonate (4.73 g), and potassium hydroxide (catalytic amount) was added thereto at 60° C. After stirring for 1.5 hours, the reaction solution was purified by chromatograophy on silica gel (ethyl acetate:hexane=1:5 to 1:2) to give the title compound (4.96 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([NH:20][CH:21](O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:24].[Na+]>C(Cl)Cl>[CH2:13]([N:20]([CH2:21][CH2:22][OH:24])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)c(F)c1F)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,3,4-Trifluorobenzoylchloride (195 mg, 1 mmol) in DCM (1 mL) was added to a stirred solution of N-benzylaminoethanol (166 mg, 1.1 mmol) in a mixture of DCM (1 mL) and 10% sodium hydroxide solution (1 mL) at 0° C. After the addition of the acid chloride was complete, the mixture was warmed to RT and stirred for approximately 4 hours. The two layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to give a colourless oil (190 mg). 1H NMR δ (CDCl3): 3.74 (t, 2H), 3.82 (t, 2H), 4.5 (s, 2H), 4.85 (s, 1H), 7.06 (td, 1H), 7.15 (m, 1H), 7.28-7.37 (m, 1H). m/z 310 (M+H)+
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([NH2:24])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1/[CH:36]=[CH:37]/[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:38](=[O:39])/[CH:37]=[CH:36]/[C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:26]=2[Cl:25])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
0.29 mL (2.10 mmol) of triethylamine was added to a solution of 0.28 g (1.00 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-hydrochloride (intermediate product Z1b), 0.25 g (1.00 mmol) of (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 0.34 g (1.05 mmol) of TBTU in 10 mL abs. THF and the mixture was stirred for 1 hour at RT. The reaction mixture was evaporated down i. vac. and the residue was combined with dichloromethane and water. The org. phase was separated off, washed with sat. aqueous sodium bicarbonate solution and water and evaporated down i. vac. The residue was purified by column chromatography (silica gel, gradient dichloromethane/10% conc. aqueous ammonia in MeOH 100:0→5:95).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:19]/[C:15]1[NH:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COC(=O)c1cc2c(s1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 18.2 %

Procedure:
Methyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (37 mg, 0.39 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of methyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate as a yellow solid. MS(ES): m/e 275 [M+H].
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH2:52]>CN(C=O)C.CCOC(C)=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH:52][C:3](=[O:5])[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH3:6]
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)C(C)(C)c2ccccc2)cc1OC
Yield: 94.9 %

Procedure:
A solution of 2-methyl-2-phenylpropionic acid (3.28 g, 20 mmol) in DMF (50 ml) was treated sequentially with N,N-diisopropylethylamine (8.09 g, 80 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (7.60 g, 20 mmol) then 3,4-dimethoxybenzylamine (3.34 g, 20 mmol) and then stirred at room temperature, under argon for 24 h. The reaction mixture was diluted with EtOAc then washed with water (3×) then brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether/pentane to afford the title compound as a beige solid (5.95 g, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>CCO>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:11][CH:8]1[CH2:10][CH2:9]1)[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Solvent: CCO
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Bromoacetic acid ethyl ester (14.2 g, 9.37 ml, 84.8 mmol) was added dropwise to a soln. of cyclopropylamine (19.4 g; 23.5 ml, 0.34 mol) in EtOH (100 ml), while cooling with ice. The reaction mixture was stirred at RT for 18 h and then concentrated i. vac. Water was added to the residue and the mixture was extracted with CHCl3 (5×100 ml). The combined organic phases were washed with half-saturated sodium chloride soln., dried with Na2SO4 and concentrated i. vac. The crude product was distilled at approx. 85° C. under 24 mbar. Yield: 12.03 g (99%)
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:10]2[CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: C1CCC2NCCCC2C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1csc(Br)n1)N1CCCC2CCCCC21
Yield: 86 %

Procedure:
A solution of 2-bromo-thiazole-4-carboxylic acid (Intermediate 3; 21.2 mmol), decahydroquinoline (3.54 g, 25.4 mmol), DIPEA (7.4 mL, 42.4 mmol), and PyBrop (11.9 g, 25.4 mmol) in dry DCM (70 mL) was stirred overnight at room temperature. The mixture was extracted with DCM and water three times. The combined DCM extracts were evaporated, and the residue was chromatographed on silica, eluting with EtOAc/Hexane (0-10% gradient) to give (2-bromo-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone (6.0 g, 86%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.C(N(C(C)C)CC)(C)C.Cl.N1C=CC([C:36]([NH2:38])=[NH:37])=N1.C(OCC)C>CN(C=O)C>[O:20]=[C:17]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[O:13][C:14]4[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:36]([NH2:38])=[NH:37])=[CH:4][C:5]=4[C:6]([C:7]=23)=[N:19][NH:18]1
Reactant: N=C(N)c1cc[nH]n1
Reactant: NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N=C(N)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To the solution of 49 (0.10 g, 0.38 mmol) in DMF (5 mL) was added diisopropyl ethylamine (0.83 mmol) and 1H-pyrazole carboxamidine hydrochloride (0.12 g, 0.81 mmol). The reaction mixture was stirred at room temperature overnight. Diethyl ether was added to form a white precipitate. The precipitate was collected and recrystallized in EtOAc to afford a white solid 50 (0.11 g, 83%, HCl salt). MS (ES−): 306; 1H-NMR (DMSO-d6, 400 MHz): 12.62 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.92-7.84 (m, 2H), 7.71 (dd, J=7.5 and 2.0 Hz, 1H), 7.50 (dd, J=8.5 and 2.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 4.47 (s, 2H); Anal. Calcd. for C16H13N5O2.1ClH: C, 55.58; H, 4.27; N, 19.76; Cl, 10.38. Found: C, 55.94; H, 4.17; N, 19.32; Cl, 10.12.
Reaction SMILES: [C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O.CO.[Zn]>[C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C1CCCC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
2-Cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-nitrophenyl methyl carbonate (800 mg, 2.31 mmol) was dissolved in a mixture of glacial acetic acid (10 mL) and water (2.5 mL). Zn dust (1511 mg, 23.10 mmol) was added at room temperature. The solution was stirred for 10 min then diluted with methanol (5 mL) and filtered. The solution was concentrated and redissolved in ethyl acetate. The ethyl acetate solution was washed with 50% saturated NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and dried down to a light orange solid. Purification by silica gel chromatography (5-15% methanol/dichloromethane) provided 5-amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate as a light orange oil (420 mg, 57% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.07 (s, 1H), 6.47 (s, 1H), 5.31 (s, 2H), 3.83 (d, J=5.7 Hz, 3H), 3.48 (d, J=4.6 Hz, 2H), 2.86-2.81 (m, 1H), 2.23 (s, 6H), 1.87-1.80 (m, 2H), 1.74-1.66 (m, 2H), 1.62-1.55 (m, 2H), 1.45-1.38 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=1>>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Nc1ccc2ccn(CCCCCCC(=O)NS(=O)(=O)c3ccccc3)c2c1
Reactant: O=C(Cl)OC1CCCC1
Product: O=C(CCCCCCn1ccc2ccc(NC(=O)OC3CCCC3)cc21)NS(=O)(=O)c1ccccc1
Yield: 51 %

Procedure:
Using a similar procedure to that described in Example 157, but using cyclopentyl chloroformate and N-(7-[6-aminoindol-1-yl]heptanoyl)benzenesulphonamide, N-(7-[6-(cyclopentyloxycarbonyl)aminoindol-1-yl]heptanoyl)benzenesulphonamide was obtained in 51% yield as a solid, m.p. 74°-76° C.; microanalysis, found, C,62.74; H,6.54; N,7.84%; C27H33N3O5S, 1/4H2O requies: C, 62.83; H,6.54; N,8.14%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(2-morpholinoethoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).