Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>N1CCCC1>[C:11]([N:18]1[CH2:19][CH2:20][C:21]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The examples listed in Table 1 were prepared according to Schemes 1-37. The synthesis of compounds 1A-1U is outlined in Scheme 1. The 2′-hydroxyacetophenone derivatives 1.1a-1.1m were condensed with 1-Boc-4-piperidone 1.2 in neat pyrrolidine (method 1A) at room temperature or in refluxing methanol in the presence of pyrrolidine (method 1B) to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 1.3. Conversion of the ketones 1.3 to the enol triflate derivatives 1.5 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Suzuki type coupling of the enol triflate derivatives 1.5 with either 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 (commercially available from Combi-Blocks Inc.) or 2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0) (method 1C) or palladium, 10 wt. % (dry basis) on activated carbon (method 1D), lithium chloride, and an aqueous solution of sodium carbonate afforded compounds 1.8 which were converted to the final products (compounds 1A-1T) under acidic conditions (method 1E: anhydrous HCl, diethyl ether, room temperature or method 1F: neat trifluoroacetic acid, room temperature). Demethylation of compound 1G using boron tribromide provided the corresponding phenolic derivative (compound 1U). The boronate derivative 1.7 was prepared in 4 steps from 2,5-dibromopyridine 1.9. Treatment of 2,5-dibromopyridine with n-butyllithium provided the corresponding lithiated derivative, which reacted with carbon dioxide to provide 5-bromopyridine-2-carboxylic acid 1.10. Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride furnished the acyl chloride 1.11, which reacted with diethylamine 1.12 to provide 5-bromo-2-(N,N-diethylaminocarbonyl)-pyridine 1.13. Conversion of the aryl bromide 1.13 to the corresponding boron derivative 1.7 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2].
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24][Cl:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[ClH:25].[C:16]1([C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24][N:10]2[CH2:9][CH2:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([CH2:13][CH2:14][O:15][C:38](=[O:40])[CH3:39])[CH2:12][CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCC1(c2ccccc2)CCNCC1
Reactant: ClCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)OCCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Product: Cl

Procedure:
Alternatively this compound is prepared by the reaction of 4-phenyl-4-piperidineethanol with 3,3,3-triphenylpropyl chloride, also as described in Example 1. Reaction with acetic anhydride by methods set out in Example 3 provides 1-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxyethylpiperidine hydrochloride.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: Cc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-p-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[Cl-:1].[OH:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][N+:16]1[CH:17]=[CH:18][N:14]([CH3:13])[CH:15]=1
Reactant: Cn1ccnc1
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Product: Cn1cc[n+](Cc2cc([N+](=O)[O-])ccc2O)c1
Product: [Cl-]

Procedure:
Starting with 56.3 g (0.3 mol) of 2-chloromethyl-4-nitrophenol and 29.6 g (0.36 mol) of 1-methyl-1H-imidazole, 65.1 g of yellow crystals melting with decomposition at 250-260° C. (Kofler) were obtained, the elemental analysis of which, calculated for C11H12N3O3Cl, was:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To a 25 mL vial which contained a suspension of -(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (293 mg, 1 mmol) and dry Cs2CO3 (400 mg, 1.2 mmol) in anhydrous acetone (15 mL) was added 2-chloro-benzooxazole (154 mg, 1 mmol) at rt. The reaction mixture which resulted was allowed to stir at rt for 72 h. The mixture was poured onto 100 mL ice-water solution and this solution was allowed to stir at 0° C. for 1 h. The solid formed was filtered out, dried through air to provide the title product (300 mg, 75%); LCMS; 88% APCI+, Calcd: 410.50; Found m/z: 411.28 (M+1); 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.78-2.01 (m, 4H), 3.28-3.46 (m, 2H), 3.73-3.97 (m, 1H), 4.08-4.21 (m 2H), 6.93-7.02 (m, 2H), 7.18-7.33 (m, 4H), 7.41 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Ca+2].[Cl-].C(Cl)Cl>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and calcium chloride (1 g, 9 mmol) were added to 100 mL of methylene dichloride and stirred for 30 minutes. (S)-epichlorohydrin (21 g, 0.23 mol) was then added. The mixture was stirred at room temperature (30° C.) for 5 hours. Filtered, and the solvent was evaporated to provide 56 g of colorless oil in 95% yield.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h under argon. DCC (5.72 g, 27.8 mmol) was added and mixture heated to 80° C. for 45 min. After stirring the mixture was diluted with water and concentrated i.vac. The residue was diluted with ethanol and 1 M NaOH (aq). The mixture was heated to 100° C. and stirred overnight. Then ethanol was evaporated and the aq. phase was cooled, acidified with acetic acid, filtered and the solid washed with water.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCCC1>[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. 2,3,4,5-Tetrafluorobenzoyl chloride (31 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 24 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with 7M ammonia in methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. This purification was unsuccessful. The solvent was concentrated in vacuo. The residue was dissolved in water, basified with ammonium hydroxide, and extracted with methylene chloride. The organic extracts were washed with brine, glacial acetic acid (0.5 mL) was added to the organic extracts and the solution was mixed for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43.7 mg (97%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[N:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CS(C)=O>C(O)C>[N:17]1([CH:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(N3CCC(N4CCCCC4)CC3)cc2)[nH]c1=O

Procedure:
A mixture of 10.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile [J. Med. Chem. 14, 342 (1971)] and 16.8 g. of 4-piperidinopiperidine in 140 ml. of dimethyl sulfoxide is stirred and heated at 95°-100° for 50 hours. The mixture is cooled and diluted with 450 ml. of 95% ethanol. The resulting precipitate of 6-[p-(4-piperidinopiperidino)phenyl]-1,2-dihydro-2-oxonicotinonitrile is collected by filtration, washed with 95% ethanol and dried; m.p. 288°-293° (dec.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO.O.O[Li].O>C1COCC1>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:19][CH2:20]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3ncsc3c2)c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3ncsc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.1 g, 0.218 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (45 mg, 1.090 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[d]thiazol-6-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (39 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 9.05 (s, 1H), 8.2 (m, 2H), 7.73 (m, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.63 (t, 1H), 3.40 (d, 2H), 1.99 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 0.93 (m, 7H), 0.38 (d, 2H), −0.5 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:25]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[C:16]([OH:15])[CH:24]=4)=[O:26])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CC#N
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography using Kiesel gel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent. Mp.: 180-182° C. (toluene).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([O:1][C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:28]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CC(=O)Nc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 374(MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:3]1.[Cl:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.O1CCOCC1>CN1CCCC1=O.CCOC(C)=O>[ClH:18].[CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:19]3[O:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:13][CH:12]=2)=[CH:3]1
Reactant: Clc1nc2ccccc2o1
Reactant: Cn1cc(-c2ccc(N)cc2)c2ncccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2ncccc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)aniline (70 mg) and 2-chlorobenzo[d]oxazole (57 mg) in 1-methylpyrrolidinone (2 mL) was stirred at 120° C. for 30 min. After this time, the reaction was cooled to room temperature, diluted with AcOEt (50 mL), washed with saturated NaHCO3 aqueous solution (50 mL), water (2×50 mL) then brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (CH2Cl2 to 1:19 MeOH/CH2Cl2), dissolved in 1,4-dioxane (2 ml), treated with 4 M HCl in 1,4-dioxane (0.500 mL, 2.00 mmol) and concentrated under reduced pressure. The residue obtained was triturated with boiling is CH3CN to give the title compound (60 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:42]([OH:45])[C:43]#[CH:44].CCN(CC)CC>CN(C=O)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:44]#[C:43][CH2:42][OH:45])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C#CCO
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Temperature: 90 °C
Yield: 51.9 %

Procedure:
A mixture of compound 34C (0.38 g, 0.564 mmol), prop-2-yn-1-ol (0.047 g, 0.846 mmol), CuI (0.011 g, 0.056 mmol), Et3N (1.57 mL, 11 mmol) and Pd(PPh3)2Cl2 (0.02 g, 0.028 mmol) in DMF (2 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with CH2Cl2. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with 3:2/hexanes:EtOAc to provide 0.19 g of the desired product 36B as a mixture of two inseparable isomers: MS (ESI(+)): m/z 649 (M+H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[F:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[C:23]([F:25])[CH:24]=1.CCOCC>C1COCC1>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([F:25])[CH:24]=1)[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)=[O:5]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.19 g (4.87 mmol) of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate in 15 mL of THF was added to a solution of 14.6 mL (7.31 mmol) of 3,5-difluorophenylmagnesium bromide (0.5M in THF). The reaction mixture was stirred for 2 h at 0° C., then poured into 100 mL of ether and washed with 10 mL of water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound. 1NMR(CDCl3) δ 1.48 (s, 9H), 4.08 (m, 1H), 4.24 (m, 4H), 7.36 (m, 1H), 7.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[CH:23].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:23][C:22]#[CH:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: C#CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide is alkylated using 3-bromo-propyne and K2CO3. After aqueous work-up the crude material (5.11 g) is de-acetylated in MeOH (180 ml) using DBU (1,3 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-prop-2-ynyl-1,3-dihydro-indol-2-one (4.32 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(Br)cc2)nn1
Yield: 42.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (60 mg, 0.17 mmol); 1-azido-4-bromobenzene (51 mg, 0.26 mmol); CuSO4 (4.4 mg, 0.03 mmol); NaAsc (22 mg, 0.11 mmol); TBTA (20.0 mg, 0.04 mmol); in t-BuOH/EtOH/H2O (2:2:1); afforded the 44 as a white solid (40 mg, 42.6%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.66 Hz); 8.74-8.71 (t, 1H); 8.63-8.61 (d, 1H, J=8.22 Hz); 8.54 (s, 1H); 7.60-7.56 (d, 2H, J=14.85 Hz); 7.345-7.341 (d, 1H, J=1.63 Hz); 7.11-7.07 (d, 2H, J=14.85 Hz); 4.69-4.66 (q, 1H); 4.40-4.38 (d, 2H, J=5.59 Hz); 4.20-4.13 (m, 2H); 3.66-3.66 (d, 1H, J=1.73 Hz); 3.52-3.51 (d, 1H, J=1.73 Hz); 3.33-3.12 (m, 2H); 1.23-1.20 (t, 3H). 13C NMR (100 MHz, DMSO-d6): 170.57, 167.51, 165.36, 154.07, 153.27, 146.56, 139.39, 136.25, 122.30, 121.54, 117.51, 116.23, 61.97, 53.46, 52.99, 51.76, 34.75, 33.50, 14.32.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17]CC)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (6 g, 18.75 mmol) in aqueous sodium hydroxide (206 mL, 0.2N) was refluxed for 135 minutes. The mixture was cooled to room temperature and glacial acetic acid (30 mL) was added. The insoluble material was filtered and dried to give the title compound as a yellow solid (5.1 g, 94%, m.p. >400° C. dec.).