Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30].C[O-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:9][CH:4]([C:1](=[O:3])[CH2:2][CH:29]([C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=2)[OH:30])[C:5](=[O:24])[N:6]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CC(O)c1cccc(F)c1)C1C=C(c2ccc(Cl)cc2)C(c2ccccc2Cl)=NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Example 4, Step A (0.5 g, 1.4 mmol) in THF (3 mL) and MeOH (1.5 mL) was added 3-fluorobenzaldehyde (0.6 mL, 2.8 mmol) and NaOMe (0.2 g, 0.56 mmol). The reaction was stirred at rt overnight, followed by heating at 50° C. for an additional day. The reaction was diluted with EtOAc and washed with saturated aq NaHCO3, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-30% EtOAc in hexane to afford the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-methylmorpholine in DMF.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[NH:9][C:8](=[O:20])[CH:7]=1.C(=O)(O)[O-].[Na+]>O.Cl>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[C:10](=[O:19])[NH:9][C:8](=[O:20])[C:7]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccncc1
Reaction time: 0.25 h

Procedure:
2.6 ml of 4N sodium nitrite was added to a solution of 2.35 g of 6-amino-1-(4-picolyl)-uracil in 25 ml of water and 4 ml of 5N HCl. After 15 minutes, 10 ml of 1N sodium bicarbonate was added. The solid was collected, washed and dried to give the title compound (2.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.C(COC)OC.[CH:32]1(/[CH:35]=[CH:36]/B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](/[CH:36]=[CH:35]/[CH:32]3[CH2:34][CH2:33]3)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CC1(C)OB(/C=C/C2CC2)OC1(C)C
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(/C=C/C3CC3)c2)N=C1N
Reaction time: 15 h
Yield: 68.5 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (150 g, 0.36 mmol), dimethoxyethane, 2-[(E)-2-cyclopropylvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg) and Na2CO3 (2 M, 2.5 mL) was degassed under argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol). The reaction mixture was stirred for 15 hour, poured into water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by ICSO (EtOAc/MeOH 10/1) gave the title product as a white solid (98 mg), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]([CH:20]([CH3:31])[C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]([CH:20]([CH3:31])[C:21]([OH:23])=[O:22])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C(C)C(=O)OCc1ccccc1)CN2C(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(C(C)C(=O)O)CN2C(=O)c1ccccc1

Procedure:
Thirty grams of benzyl 2-(1-benzoyl-5-methoxy-3-indolinyl)propionate were hydrogenated over palladium-on-carbon in ethanol to remove the benzyl ester group. 2-(1-Benzoyl-5-methoxy-3-indolinyl)propionic acid thus formed crystallized on cooling in the hydrogenation bomb and separated with the catalyst on filtration. The desired product was dissolved away from the catalyst by washing with hot ethanol. Ethanol was removed from the combined filtrate and washings by evaporation. The resulting residue was dissolved in tetrahydrofuran (THF). The THF solution was filtered and the THF removed from the filtrate in vacuo. The resulting residue was crystallized from about 500 ml. of ethanol; yield= 21.2 g. of 2-(1-benzoyl-5-methoxy-3-indolinyl)propionic acid melting at 169-70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([C:35]4[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([C:35]4[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=4)[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: CSc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(-n2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)cc1
Product: CSc1ccc(-n2ncc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23 %
Yield: 10 %

Procedure:
In a volumetric flask molecular sieves of 4 Å (1 g, previously dried for 3 h at 200° C. under vacuum), 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30 g, 0.8 mmol, obtained in example 1), (4-methylsulfanylphenyl)boronic acid (0.26 g, 1.6 mmol), copper 11 acetate (0.28 g, 1.6 mmol), pyridine (0.12 g, 1.6 mmol), triethylamine (0.16 g, 1.6 mmol) and CH2Cl2 (22 mL) were introduced under argon atmosphere. This was stirred at room temperature for 2 days. It was filtered through celite and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 40 mg of 4,6-bis(4-fluorophenyl)-2-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 10%) and 90 mg of 4,6-bis(4-fluorophenyl)-1-(4-methylsulfanylphenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 23%).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>CCOCC.O1CCCC1>[Br:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:21]
Reactant: Brc1ccsc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2sccc2Br)cc1
Reaction time: 8 h

Procedure:
A solution of phenyllithium (67 ml, 1.65M in ether/benzene) was added dropwise to a solution of 16.3 g of 3-bromothiophene in 100 ml of dry ether at room temperature under nitrogen. After the addition, the solution was stirred overnight under nitrogen. The resultant solution was then added dropwise to a solution of p-methoxybenzoyl chloride (20.5 g) in 80 ml of tetrahydrofuran at -70° C. over two hours and stirring was further continued for two hours at the same temperature. The reaction was then quenched with water, the organics were extracted into ether, and the ether phase was washed with 10% aqueous sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. Upon evaporation of the solvent, oily liquid was obtained which was chromatographed by high performance liquid chromatography with 5% ethyl acetate/hexane used as an eluent. Appropriate fractions were combined and evaporated to give crystals which were recrystallized from ether/hexane (yield 11.9 g).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[C@H:11]2[O:12][CH2:13][C@@H:14]([O:15][C:16]3[N:17](COCC[Si](C)(C)C)[C:18]4[C:19]([N:39]=3)=[N:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=3)=[C:22]([Cl:24])[CH:23]=4)[C@H:10]2[O:9][CH2:8]1)(C)(C)C.CCN(C(C)C)C(C)C.[CH:59]1([S:62](Cl)(=[O:64])=[O:63])[CH2:61][CH2:60]1.CCOC(C)=O>ClCCl>[Cl:24][C:22]1[CH:23]=[C:18]2[NH:17][C:16]([O:15][C@H:14]3[C@H:10]4[O:9][CH2:8][C@@H:7]([OH:6])[C@H:11]4[O:12][CH2:13]3)=[N:39][C:19]2=[N:20][C:21]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH:33]2[CH2:34][CH2:35][N:36]([S:62]([CH:59]3[CH2:61][CH2:60]3)(=[O:64])=[O:63])[CH2:37][CH2:38]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C#CC4CCNCC4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(C1CC1)N1CCC(C#Cc2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(((3R,3aR,6R,6aS)-6-((tertbutyldimethylsilyl)oxy)hexa-hydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridine (33 mg, 0.045 mmol) in anhydrous dichloromethane (1.00 mL) was added DIEA (0.016 mL, 0.091 mmol) and cyclopropylsulfonyl chloride (14.6 mg, 0.113 mmol). After 2 hours, the mixture was directly loaded onto a Biotage™ 10 G silica gel SNAP cartridge and employing a linear gradient: 0-50% EtOAc in 1:1 Hex/DCM over 25 column volumes. The desired product fractions were combined and concentrated under reduced pressure to afford a colorless oil. The resultant colorless oil was dissolved in formic acid (1.0 mL), then saturated aqueous KHSO4 (0.25 mL) was added and the mixture was stirred at 50° C. After 2 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (120 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated under reduced pressure to afford a white solid which was dissolved in methanol (5 mL) and then treated with aqueous sodium hydroxide (3N, 1.0 mL). After stirring for 10 minutes, the mixture was neutralized with 1N aqueous HCl (3.0 mL), and poured into saturated aqueous sodium bicarbonate (40 mL). The aqueous mixture was extracted with ethyl acetate (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant white solid was dissolved in acetonitrile/water mixture, cooled to −78° C., and then lyophilized to dryness to afford the title compound as a white solid. LC-MS: calculated for C28H29ClN4O6S 584.15, observed m/e: 585.14 (M+H)+ (Rt 1.95/4 min); 1H NMR δ (ppm) (CD3OD): 7.78 (s, 1H), 7.60 (d, J=4.3 Hz, 2H), 7.45 (d, J=4.3 Hz, 2H), 5.52 (q, J=5.5 Hz, 1H), 4.95 (t, J=5.5 Hz, 1H), 4.45 (t, J=5.0 Hz), 4.27 (m, 1H), 4.15 (dd, J=10.0, 6.0 Hz, 1H), 4.09 (dd, J=10.0, 6.0 Hz, 1H), 3.88 (dd, J=8.0, 7.0 Hz, 1H), 3.59 (m, 4H), 3.21 (m, 2H), 2.88 (m, 1H), 2.49 (m, 1H), 2.03 (m, 2H), 1.80 (m, 2H), 1.03 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC4C=CC([N+]([O-])=O)=CC=4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1.O1CCCC1.C(N(CC)C(C)C)(C)C.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([N:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1
Reactant: C1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCCC1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitrophenyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (30 mg, 0.00007 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (25.0 μL, 0.000144 mol) and piperidine (10 μL, 0.0001 mol). After stirring at rt for 16 h, the crude reaction mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 364.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 100 %

Procedure:
Sodium hydride (60% in oil, 274.1 mg, 6.853 mmol) was suspended in DMF (8.0 ml). To the resulting suspension was added methyl indole-3-carboxylate (400.2 mg, 2.284 mmol) under stirring at 0° C., followed by stirring at the same temperature for 30 minutes. To the reaction mixture was added benzyl bromide (0.41 ml, 3.427 mmol) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was added with water to terminate the reaction. The reaction mixture was then extracted with ethyl acetate. The extract was washed with 1N HCl, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (6:1, v/v) eluate fractions, methyl 1-benzylindole-3-carboxylate (100%) was obtained as a gum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1.[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][C:43]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN)COc1ccccc1-3
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCNC(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 7(R,S)-(2-aminoethyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.14 M) in DCM was treated with N-(tert-butoxycarbonyl)-β-alanine (2 eq) followed by HATU (1.3 eq) and DIPEA (2.5 eq) and the resulting mixture was stirred overnight at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with sat. aq. NaHCO3, HCl (1N) and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 604 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[C:11]([NH2:25])=[N:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[N:30][CH:29]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[C:11]2=[N:25][C:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][N:30]=3)=[CH:35][C:36](=[O:37])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN=C(N)C(N2C(=O)c3ccccc3C2=O)C1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a suspension of 33.00 g (89.97 mmol) of (+/−)-5-amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride (1:1) in 300 mL of tetrahydrofuran was added 6.47 g (161.94 mmol) of sodium hydride (60% in oil), the reaction mixture was stirred at room temperature for 1 h and 17.47 g (89.97 mmol) of ethyl 3-(pyrimidin-4-yl)-3-oxopropionate dissolved in 300 mL of toluene was added. The resulting solution was evaporated to remove tetrahydrofuran, heated under reflux and 5.00 mL of glacial acetic acid was added. The reaction mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and filtered to afford 18.60 g (45%) of the product as a brown powder. The compound was used as such in the next step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([Cl:30])[CH:32]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3cccc(Cl)c3)CN2Cc2ccccc2)CC1
Yield: 6.4 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3-chloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (4.3 mg, 6.4%) as light yellow oil. MS m/e=528.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.Cl.NCC1(O)CCCCC1>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[N:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: NCC1(O)CCCCC1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.38 mL, 60.1 mmol) was added over 10 min to a stirred mixture of 4-chloro-3-nitro-1,5-naphthyridine (6.00 g, 28.6 mmol) and 1-aminomethyl-1-cyclohexanol hydrochloride (5.00 g, 30.1 mmol) in dichloromethane (115 mL) at 0° C. The solution was allowed to warm to rt and more 1-aminomethyl-1-cyclohexanol hydrochloride (0.2 g) was added. The solution was stirred overnight and more triethylamine (0.5 mL) was added. After 30 min, the solution was partitioned between saturated aqueous sodium bicarbonate (100 mL) and chloroform (200 mL). The aqueous layer was extracted with chloroform (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (80 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol as a yellow solid (8.65 g, 100%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]#[C:24][Si](C)(C)C)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:9]=1)=[O:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:23]([C:21]1[CH:20]=[CH:19][N:18]2[C:14]([C:10]3[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:30])([F:29])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=3)=[CH:15][N:16]=[C:17]2[CH:22]=1)#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 1-(2,2,2-Trifluoro-ethyl)-3-[3-(7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-urea (25 mg, 0.06 mmol) in THF (5 ml) at 0° C. was added a 1M tetrabutylammonium fluoride solution (0.09 ml) and the reaction mixture stirred for 1 h at 0° C. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase HPLC to afford the product as an off-white solid (4.2 mg). MS: [M+H]+ 359