Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[C:39]([F:49])[CH:38]=2)[CH2:33][CH2:32]1)=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37]6[CH:42]=[CH:41][C:40]([C:43]7[N:44]=[CH:45][CH:46]=[CH:47][N:48]=7)=[C:39]([F:49])[CH:38]=6)[CH2:33][CH2:32]5)=[O:30])[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCNC1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (12AB) (40 mg, 0.09 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (37 mg, 0.11 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (23 mg, 32 uL, 0.18 mmol, 2 equiv). The reaction content was stirred at room temperature overnight.
Reaction SMILES: [N:1]1([C:6](=[O:34])[CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=4)=[N:17][CH:18]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:36]1[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C1CCCCC1>O.C(Cl)Cl>[CH3:41][N:40]1[C:36]([C:21]2[CH:20]=[C:19]([C:16]3[N:15]=[CH:14][C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:34])[CH:12]=4)=[CH:18][N:17]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:37][N:38]=[CH:39]1
Reactant: Cn1cncc1Br
Reactant: CC1(C)OB(c2cccc(-c3ncc(-c4cnn(CC(=O)N5CCCC5)c4)cn3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: Cn1cncc1-c1cccc(-c2ncc(-c3cnn(CC(=O)N4CCCC4)c3)cn2)c1
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of 1-Pyrrolidin-1-yl-2-(4-{2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-ethanone (4 mL of the solution obtained in step 1), 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 eq.), Pd(Ph3)4 (13 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (90 mg; 0.65 mmol; 3.0 eq.) in water (0.73 mL) was heated at 120° C. in MW for 30 min. Addition of 5-bromo-1-methyl-1H-imidazole (35 mg; 0.22 mmol; 1.0 eq.) and heating at 120° C. for 30 min had to be repeated twice to complete the reaction. The reaction mixture was then diluted with water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 80:20) gave a black gum which was redissolved in DCM. Addition of cyclohexane afforded a brown precipitate which was filtered and dried under vacuum to give the title compound as a beige solid (40 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.47-8.46 (m, 1H), 8.41-8.37 (m, 2H), 8.14 (d, J=0.6 Hz, 1H), 7.76 (s, 1H), 7.68-7.60 (m, 2H), 7.15 (s, 1H), 5.12 (s, 2H), 3.74 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 3.32 (t, J=6.8 Hz, 2H), 1.93 (quint., J=6.8 Hz, 2H), 1.80 (quint., J=6.8 Hz, 2H). HPLC (Condition A): Rt 2.21 min (purity 96.2%). MS (ESI+): 414.4.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:33][CH2:32][C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1.[OH-].[K+]>CN1C(=O)CCC1.O>[CH3:5][N:6]1[CH2:33][CH2:32][C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: CNC(=O)c1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)c1ccc(C(C)=Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
Thionyl chloride (1.5 mL, 20.67 mmol) was added to a solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-N-methyl-benzamide (130 mg, 0.33 mmol) and the reaction mixture stirred at RT for 30 min. The solvent was removed under vacuum to obtain the crude as a foamy solid, which was dissolved in NMP (3 mL). The reaction mixture was stirred for 5 min. Powdered KOH (186 mg, 3.32 mmol) was added and the contents heated at 80° C. for 20 min. After completion of reaction, the reaction mixture was poured in water and the desired compound extracted with EtOAc (3×40 mL). The organic layer was washed with water, concentrated under vacuum to obtain the crude product (100 mg) which was purified by reverse phase HPLC to yield 6.0 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1methyl-vinyl]-N-methyl-benzamide as the free base. 1H NMR (CDCl3, free base) δ (ppm): 7.78 (d, 2H), 7.58 (d, 2H), 7.22 (s, 1H), 7.05 (m, 2H), 6.96 (s, 1H), 6.20 (bs, 1H), 4.0 (s, 2H), 3.16 (m, 2H), 3.05 (d, 3H), 2.90 (m, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+].O.C(OCC)(=O)C>CN(C=O)C>[N:17]([CH2:2][C:3]([C:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1cn2c3c(cccc13)CCC2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1cn2c3c(cccc13)CCC2
Yield: 90.6 %

Procedure:
A solution of 2-chloro-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone (5.04 g, 21.6 mmol) and sodium azide (1.47 g, 22.7 mmol) in DMF (20 mL) was shaken for 16 h at room temperature. Water (200 mL) and ethyl acetate (200 mL) were added. The ethyl acetate layer was separated and washed twice with water (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, neat DCM), to yield 2-azido-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone as an off-white solid (4.70 g, 90%). M.p.=92-93° C.; 1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.23 (m, 1H), 7.04 (d, J=7.6 Hz, 1H), 4.35 (s, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.27 (m, 2H). LCMS: m/e 241.07 [M+H].
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#N)=[CH:5][CH:4]=1.CC(C[Al]CC(C)C)C.CO.[OH:22]S(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:22])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: CNc1ccc(C#N)cn1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CNc1ccc(C=O)cn1
Temperature: -78 °C

Procedure:
To 6-(methylamino)-3-pyridinecarbonitrile (D94) (0.1 g, 0.752 mmol) in toluene (10 mL) cooled to −78 C under argon was added Dibal-H (1.88 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at −78° C. and then allowed to warm to room temperature overnight. MeOH (0.47 mL) and 2 M H2SO4 (1.42 mL) were added and mixture was stirred for 1.5 h then concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried and concentrated to give the title compound (0.067 g). δH (CDCl3, 400 MHz) 9.78 (1H, s), 8.52 (1H, d), 7.92 (1H, dd), 6.45 (1H, d), 5.38 (1H, br.s), 3.04 (3H, d). MS (ES): MH+ 137.1.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=4)[N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C.O>[Cl:19][C:18]1[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][C:6]3([CH2:5][CH2:4][N:3]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:2][CH2:1]3)[CH2:7][CH2:8]2)=[N:14][C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=2)=[N:16][CH:17]=1
Reactant: N#CCC(=O)O
Reactant: OCCn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To a solution of 2-[4-[[4-(3-azaspiro[5.5]undecan-9-ylamino)-5-chloropyrimidin-2-yl]amino]-1H-pyrazol-1-yl]ethanol (200.5 mg, 0.4940 mmol) in a mixture of dichloromethane (40 mL) and DMF (10 mL) were added 2-cyanoacetic acid (46.5 mg, 0.547 mmol), HATU (375.2 mg, 0.9868 mmol) and TEA (100.5 mg, 0.9932 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL), and extracted with DCM/MeOH (10/1, 50 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the product as a yellow solid (105 mg, 44.94%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1.[C-:16]#[N:17].[K+].Cl>O.CO>[CH3:1][N:2]([CH:14]([CH:11]1[CH2:10][CH2:9][C:8]2([O:4][CH2:5][CH2:6][O:7]2)[CH2:13][CH2:12]1)[C:16]#[N:17])[CH3:3]
Reactant: [C-]#N
Reactant: CNC
Reactant: O=CC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
40% aqueous dimethylamine solution (85 ml, 0.67 mol), 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde 2 (240 g, 0.141 mol) and potassium cyanide (22.05 g, 0.338 mol) were added, while cooling with ice, to a mixture of 4N hydrochloric acid (37 ml) and methanol (22 ml). The mixture was stirred for 4 d at room temperature and then, after addition of water (80 ml), extracted with diethyl ether (4×100 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, and the product was obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42]>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH2:31][N:32]1[C:36](=[O:37])[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:42])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CCOC(=O)Cc1c(F)cnc2ccc(OC)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CN1C(=O)c2ccccc2C1=O)c1c(F)cnc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of (3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-acetic acid ethyl ester (6.78 g; prepared in analogy to the corresponding methyl ester described in WO 2007/122258) in THF (30 mL) was added dropwise at −78° C. to a solution of LiHMDS (31 mL; 1M in THF) diluted in THF (20 mL). After stirring for 1 h at −78° C. a solution of N-(bromomethyl)phthalimide (7.40 g) in THF (30 mL) was added dropwise and the mixture was stirred for an additional 1 h at −78° C. and then overnight at rt. The yellow solution was quenched with 1N HCl (280 mL) and extracted with DCM. The combined org. layers were washed with H2O, dried over MgSO4, concentrated and purified by CC (Hept/EA 1:1), affording a light yellow foam (5.49 g; 51% yield).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH:6]([C@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.O.[CH2:27]1COCC1>CCCCCC>[CH3:5][C:4]([CH3:27])=[CH:3][CH:2]=[CH:6][C@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2C=O)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1ccc(CCN2C(=O)CC[C@@H]2C=CC=C(C)C)cc1
Reaction time: 0.33 h

Procedure:
To a suspension of intermediate 5.1 (580 mg, 1.41 mmol) in anhydrous THF (20 mL) at −5° C. was added n-BuLi (0.97 mL, 1.6 M, 1.55 mmol) in hexane dropwise under Ar. The mixture was stirred for 20 min after addition was complete. To the reaction mixture was then added a solution of methyl 4-{2-[(2R)-2-formyl-5-oxopyrrolidin-1-yl]ethyl}benzoate (intermediate 1.4) (388 mg, 1.41 mmol) in anhydrous THF (4 mL) dropwise. The stirring was continued for 1 hr. Water was added to quench the reaction and the mixture was concentrated in vacuo to remove most of the THF. Extraction with ethyl acetate, washing organic phase with brined, drying and concentration afforded the crude product mixture containing cis and trans compounds as a pale oil, which was used directly for step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])([F:43])[F:42])=O>>[F:27][C:25]([F:28])([F:26])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:14]([C:11]3[CH2:10][CH2:9][N:8]([C:13]4[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:13][CH:12]=3)[NH:15][C:16]=2[C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccc(C(F)(F)F)cc3)c(-c3ccc(C(F)(F)F)cc3)[nH]2)CC1
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-[4,5-Bis-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from step (a) above was treated with TFA under the condition of Example 22(c) to give the title compound, which was used directly in the next step without additional purification. MS (ESI, positive ion) m/z: 438 (M+1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10]C1C=CC=CC=1>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:9])[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 9.5 h

Procedure:
To a solution of phenyl isocyanate(1.0 equiv.) in dimethyl formamide (1 ml) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at 80° C. until complete (3-16 hrs.), then removed solvent under vacuum. The purification, yields and spectral characteristics for each individual compound are listed below. Additional synthetic methods are provided for in PCT US96/02260 filed Feb. 16, 1996 whose disclosure is incorporated herein by reference.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:54])[C@@H:20]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:21][CH2:22][NH2:23])[CH2:15][CH2:14]1)=[O:12])[CH3:9].N1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:54])[C@@H:20]([NH:24][C:25]([C:27]2[CH:31]=[C:30]([O:32][CH2:33][C:34]([N:36]3[CH2:40][CH2:39][CH2:38][C@H:37]3[C:41](=[O:47])[NH:42][CH:43]3[CH2:46][CH2:45][CH2:44]3)=[O:35])[N:29]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:28]=2)=[O:26])[CH2:21][CH2:22][NH:23][C:3](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(C)=O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 302 mg 4-[(S)-4-amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 5 ml dichloromethane were added 96 μl pyridine, 5 mg DMAP and 48 μl Ac2O at 0° C. After 1 h stirring at this temperature the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 27 mg MS (ES+): m/e=695.
Reaction SMILES: ClCl.C(Cl)(Cl)(Cl)Cl.[CH3:8][O:9][C:10]([C:12]1[CH:13]([O:17][CH3:18])[CH2:14][S:15][CH:16]=1)=[O:11]>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:13]([O:17][CH3:18])=[CH:14][S:15][CH:16]=1)=[O:11]
Reactant: COC(=O)C1=CSCC1OC
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cscc1OC
Reaction time: 1 h
Yield: 93 %

Procedure:
15 parts by volume of a Cl2 /CCl4 solution (7.1 parts of chlorine in 100 parts of CCl4) are added in the course of 10 minutes to a solution, cooled to 0° C., of 1.74 parts of 3-methoxy-dihydrothiophene-4-carboxylic acid methyl ester in 15 parts by volume of CCl4. The mixture is kept at 0° C. for one hour. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.6 parts (93% of theory) of 3-methoxythiophene-4-carboxylic acid methyl ester of melting point 66°-67° C. are obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C.C(OCC)(=O)C>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 45 h

Procedure:
A dispersion of Lindlar catalyst (0.150 g) in ethanol (10 ml) was hydrogenated at atmospheric pressure for 15 min. Then, a solution of the product of step c) (0.187 g, 0.38 mmol) in ethyl acetate (3 mL) was added with a syringe, and the resulting mixture stirred vigorously for 45 h. The solution was filtered through Celite® (a silica gel) and the solvents evaporated. Chromatography on silica (ethyl acetate/methanol/ammonium hydroxide; 80/20/2; v/v) furnished 20.1 mg of 3-[1-(3-aminomethylbenzyl)-indol-3-yl]-4-(1-methyl-indol-3-yl)-pyrrole-2,5-dione which was dissolved in ethanolic HCl (1.5 M), evaporated, dissolved in methanol, evaporated to dryness, dissolved in water and freeze dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
Using procedure 4, 4-chlorobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 137-140° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([OH:52])[CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:53]1([CH3:62])[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH:59](O)[CH3:60]>C1COCC1>[CH2:34]([O:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH:59]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH3:62])[CH3:60])[CH:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: Cc1ccccc1C(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC(C)c1ccccc1C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
A solution of triphenylphosphine(5.48 g) in dry THF (35 mL) is treated with diisopropyl azodicarboxylate (4.23 g) at 0-5° C. and stirred for 15 minutes. The suspension is treated dropwise with a solution of methyl 4-benzyloxy-2-hydroxybenzoate (2.7 g) and 1-o-tolylethanol (1.42 g) in dry THF (35 mL) during 25 minutes at 0-5° C. and then stirred at 0-5° C. for 1 hour and at 25° C. for 24 hours. The mixture is evaporated and the residual gum purified by flash chromatography on silica, eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated to yield methyl 4-benzyloxy-2-(1-o-tolyiethoxy)benzoate as a colourless oil (2.83 g, 72%). 1H NMR (CDCl3) 1.6(3H,d), 2.4(3H,s), 3.9(3H,s), 4.9(2H,s), 5.5(1H,q), 6.3(1H,s), 6.5(1H,d), 7.1-7.6(9H,m), 7.8(1H,d).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was added butyryl chloride (0.25 mL, 2.4 mmol) and N,N-diisopropyl ethylamine (0.65 mL, 3.9 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-butyramide as a light yellow solid (270 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.18 min (98.6%); mp, 250-252° C.; 1HNMR (DMSO-d6) 0.88 (t, J=7 Hz, 3H, CH3), 1.56 (m, J=7 Hz, 2H, CH2CH2CH3), 2.15-2.20 (m, 3H, CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.77-4.85 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.30-7.76 (m, 3H, Ar), 8.18 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.65, 18.67, 20.77, 23.27, 30.58, 37.32, 41.39, 56.47, 117.63, 124.28, 125.38, 133.83, 141.23, 148.44, 154.76, 160.95, 169.51, 172.14, 172.60. LCMS MH=371; Anal Calcd For C19H22N4O4: C, 61.61; H[5.99; N, 15.13. Found: C, 61.49; H, 5.76; N, 15.00.