Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[N:19]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1

Procedure:
40.0 g of 4-nitrobenzyl bromide are dissolved in 500 ml of methylene chloride, 51.5 ml of triethylamine are added and 18.3 ml of piperidine are carefully added dropwise. After the end of the exothermic reaction the mixture is refluxed for another 30 minutes. After cooling it is washed with water and the organic phase is dried over sodium sulphate. Finally, the organic phase is evaporated down.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[C:21]([CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)#[N:22]>>[NH2:22][C:21]1[N:12]2[N:13]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:11]2[CH:10]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:23]=1
Reactant: N#CC=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2ccc(S(=O)(=O)Nc3ccccc3)cc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 430 (M—H−, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 4-(2-cyano-vinyl)-N-phenyl-benzenesulfonamide
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>O.ClCCl>[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18](=[O:2])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Clc1cccc2c1CNCCS2
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S1CCNCc2c(Cl)cccc21
Reaction time: 19 h

Procedure:
A solution of sodium periodate (3.09 g) in water (25 ml) was added dropwise with cooling to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.88 g, prepared in a similar manner to that described in the preceding paragraph) in dichloromethane (75 ml). The stirring was continued at room temperature for 19 hours. Solvent was removed from the mixture by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 2.15 g (m.p. 125°-126° C.).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (30 mg), N,N-dimethyl-p-aminopyridine (52.6 mg), anhydrous triethylamine (34.2 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (S)-α-methoxy-α-trifluoromethylphenylacetyl chloride (50.4 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (31.6 mg) of 67.8 minutes at retention time and the subject oily substance (31.9 mg) of 71.6 minutes at retention time.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][CH:28]1[CH:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][NH:30][CH2:29]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:30]1[CH2:31][CH2:32][CH:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]([CH3:27])[CH2:29]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: CC1CNCCC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4)C(C)C3)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
7-Benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in step 4 was dissolved in DMF (2 mL), 3-methyl-4-phenylpiperidine hydrochloride (Journal of Heterocyclic Chemistry, vol. 12, page 709, 0.15 g, 0.70 mmol), 1-hydroxybenzotriazole (0.13 g, 0.70 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.10 g, 0.70 mmol) were added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added dropwise to the reaction mixture, and the precipitated solid was m collected by filtration. The obtained solid was washed with water, and dried under reduced pressure at 50° C. overnight to give the title compound (0.23 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([Cl:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[Cl:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: Nc1c(F)ccc(O)c1Cl
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1c(F)ccc(O)c1Cl)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.6 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (478 mg, 2.04 mmol, 1.1 eq) in DCM (9 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (779 mg, 6.14 mmol, 3.3 eq) dropwise. The reaction mixture was stirred at room temperature for 1.5 h, then the solvent removed in vacuo. The residue obtained was dissolved in THF (7 mL) and added dropwise to a mixture of 3-amino-2-chloro-4-fluoro-phenol (intermediate X(f)) (300 mg, 1.86 mmol, 1.0 eq) and NaHCO3 (781 mg, 9.3 mmol, 5.0 eq) in THF (7 mL) at 0° C. After addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. Water was added and the aqueous mixture was extracted with EtOAc. The organic extract was washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 3:20 to 1:4) to give the title as a yellow solid compound (180 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C(OCC)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (4 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (4.4 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, 6% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound: Rf =0.3 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:36][CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C2CCC(n3cc(-c4ccc(CC(=O)Nc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
A mixture of cis-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.18 mmol), N1-phenyl -2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (0.81 g, 2.40 mmol), tetrakis(triphenyl-phosphine)palladium (70 mg, 0.131 mmol) and sodium carbonate monohydrate (0.65 g, 2.40 mmol) in ethylene glycol dimethyl ether (16 mL) and water (8 mL) was heated at 85° C. under an atmosphere of nitrogen for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane/methanol (9:1) as an eluent to give N1-phenyl-2-(4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-5-yl}phenyl)acetamide (0.74 g, 62%): 1H NMR (DMSO-d6, 400 MHz) 10.20(s, 1H), 8.66(s, 1H), 7.81(s, 1H), 7.62(d, 2H), 7.52(d, 2H), 7.41(d, 2H), 7.31(t, 2H), 7.04(t, 1H), 4.83(m, 1H), 3.70(s, 2H)<2.05-2.5(m, 13H), 2.17(s, 3H), 1.59-1.77(m, 4H); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-100% acetontrile over 10 min, 1 mL/min) tr 8.23 min.; MS:MH+ 543.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(=O)O[CH2:14][CH2:13][O:12]1>[Br-].C([N+](CC)(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C1OCCO1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: O=Cc1cc(Cl)ccc1OCCO

Procedure:
Prepared from 25 g of 3-chloro-6-hydroxybenzaldehyde, 14 g of ethylene carbonate and 45 g of tetraethylammonium bromide as described in Example VIIa. The compound was purified by chromatography (silica, ethyl acetate:petroleum ether 60-80/2:1).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([Cl:15])[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:22][CH:23]=1
Reactant: CC(O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
3.7 g of 1-[3-(4-bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]ethanol is dissolved in 20 ml of acetic acid and slowly treated at 15° C. with a solution of 15.6 g of (NH4)2Ce(NO3)-6 in 30 ml of water. The mixture is stirred at 10° C. for 30 minutes, then allowed to warm to RT. It is diluted with 200 ml of water and adjusted to pH=5 using NaHCO3, and the product is filtered off with suction. Chromatography once each with DIP and MTB yields 2.0 g of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([Sn](C)(C)C)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].Cl.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[C:24]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]2[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=2)=[C:34]([CH3:46])[CH:33]=1.CCN(C(C)C)C(C)C.CCOC(C)=O.CO>CN(C=O)C.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>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[C:24]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[C:34]([CH3:46])[CH:33]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1nc([Sn](C)(C)C)cs1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(I)cc34)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5csc(CNC(=O)OC(C)(C)C)n5)cc34)cc2C)cn1
Temperature: 100 °C
Yield: 29.3 %

Procedure:
(4-Trimethylstannyl- thiazol-2-ylmethyl)-carbamic acid tert-butyl ester (191 mg, 0.507 mmol) and [3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.251 g, 0.478 mmol) (from Step C, Example 3) are dissolved in anhydrous DMF under a nitrogen atmosphere. Hunig's base (0.44 ml, 2.53 mmol), and PdCl2(PPh3)2 are added to the reaction mixture at room temperature. The reaction mixture is degassed and heated at 100° C. overnight. After cooling to room temperature the reaction mixture is diluted with with water and thoroughly extracted with EtOAc and DCM. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica with EtOAc-MeOH as an eluant affords 81 mg (0.14 mmol, 28%) of clean desired product.
Reaction SMILES: CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:53][C:54]1[N:59]=[C:58]([C:60]2[N:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]3=[N:62][CH:61]=2)[CH:57]=[CH:56][N:55]=1.Br[C:70]1[CH:89]=[CH:88][C:73]([C:74]([C:76]2[CH:81]=[CH:80][C:79]([N:82]3[CH2:87][CH2:86][O:85][CH2:84][CH2:83]3)=[CH:78][CH:77]=2)=[O:75])=[CH:72][CH:71]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:85]1[CH2:84][CH2:83][N:82]([C:79]2[CH:78]=[CH:77][C:76]([C:74]([C:73]3[CH:88]=[CH:89][C:70]([NH:53][C:54]4[N:59]=[C:58]([C:60]5[N:64]6[CH:65]=[CH:66][CH:67]=[CH:68][C:63]6=[N:62][CH:61]=5)[CH:57]=[CH:56][N:55]=4)=[CH:71][CH:72]=3)=[O:75])=[CH:81][CH:80]=2)[CH2:87][CH2:86]1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(N2CCOCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of sodium tert-butoxide (31 mg, 0.32 mmol), palladium acetate (3 mg, 0.013 mmol), and (S)-BINAP (11 mg, 0.018 mmol) in toluene (2 mL) was stirred at room temperature for 0.5 h. A warm suspension of 2-amino-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine (58 mg, 0.27 mmol) in toluene (4 mL) and 4-bromo-4′-morpholinobenzophenone (79 mg, 0.23 mmol) was added, and the mixture was heated at 100° C. for 4 h. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane and water. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent affording 25 mg (23% yield) of the title compound as a yellow solid: mp (decomp.) >237° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J=6.8 Hz, 1 H), 10.1 (s, 1 H), 8.68 (s, 1 H), 8.53 (d, J=5.4 Hz, 1 H), 7.96 (d, J=8.5 Hz, 2 H), 7.80 (d, J=8.9 Hz, 1 H), 7.73 (d, J=8.6 Hz, 2 H), 7.69 (d, J=8.7 Hz, 2 H), 7.56-7.51 (m, 2 H), 7.19 (t, J=6.8 Hz, 1 H), 7.05 (d, J=8.7 Hz, 2 H), 3.76 (s, 4 H), 3.33 (s, 4 H); 13C NMR (400 MHz, DMSO-d6) δ 193.0, 159.4, 157.6, 157.3, 153.9, 148.3, 144.3, 139.3, 131.9, 131.1, 131.0, 129.7, 127.5, 127.4, 121.3, 118.2, 117.7, 114.2, 113.3, 108.4, 66.2, 47.2; MS (TSP) 7 m/z 477 (M+1).
Reaction SMILES: COC(=O)NC(C(N1C(C2NC(C3C=CC4C(=CC=C(C5C=CC(C6NC(C7C8CC(CC8)N7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC=5)C=4)C=3)=CN=2)CC2(CC2)C1)=O)C(C)C.[CH3:63][O:64][C:65](=[O:104])[NH:66][CH:67]([C:71]([N:73]1[CH:78]([C:79]2[NH:80][C:81]([C:84]3[CH:93]=[CH:92][C:91]4[C:86](=[CH:87][CH:88]=[C:89](B5OC(C)(C)C(C)(C)O5)[CH:90]=4)[CH:85]=3)=[CH:82][N:83]=2)[CH:77]2[CH2:103][CH:74]1[CH2:75][CH2:76]2)=[O:72])[CH:68]([CH3:70])[CH3:69].[C:105]([O:109][C:110]([N:112]1[CH:118]([C:119]2[NH:120][C:121]([C:124]3[CH:129]=[CH:128][C:127](Br)=[CH:126][CH:125]=3)=[CH:122][N:123]=2)[CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:107])[CH3:106].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:105]([O:109][C:110]([N:112]1[CH:118]([C:119]2[NH:120][C:121]([C:124]3[CH:129]=[CH:128][C:127]([C:89]4[CH:88]=[CH:87][C:86]5[C:91](=[CH:92][CH:93]=[C:84]([C:81]6[NH:80][C:79]([CH:78]7[CH:77]8[CH2:103][CH:74]([CH2:75][CH2:76]8)[N:73]7[C:71](=[O:72])[CH:67]([NH:66][C:65]([O:64][CH3:63])=[O:104])[CH:68]([CH3:70])[CH3:69])=[N:83][CH:82]=6)[CH:85]=5)[CH:90]=4)=[CH:126][CH:125]=3)=[CH:122][N:123]=2)[CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:107])[CH3:106]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 59.5 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example EZ) using [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (2.25 mmol), 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (2.39 mmol), and potassium carbonate (2M, 4.3 mL, 8.55 mmol). The reaction was performed under an argon atmosphere. The crude reaction was diluted in ethyl acetate, washed with water and purified by normal phase silica chromatography (50-100% Hexanes:EthylAcetate+10% Methanol). 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.05 g, 60%) was obtained as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH2:23])=[O:18])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
192 g (0.715 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 900 ml of dimethylformamide, treated at room temperature with 116 g (0.715 mol) of carbonyldiimidazole and stirred at 50° for 1/2 hr. Then, 173 ml of 25% ammonia were added dropwise at 25°-30° within 1/2 hr. After stirring for 1/2 hr the reaction mixture was concentrated and the residue was dissolved in 500 ml of alcohol. After the addition of 250 ml of ether the solution was cooled to 0° and the suspension was suction filtered. There were obtained 133.6 g (69%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamide; m.p. 228°-230°.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][N:13](CC3C=CC(OC)=CC=3OC)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:31]([O:33]CC)=O)[O:9][N:8]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:31]([OH:33])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(Br)o2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 6.4 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)isoxazole-5-carboxylate (1.53 g, 2.78 mmol) was dissolved in 30 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (5.6 mL, 5.55 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 5 mL of 1M HCl and 100 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 1.32 g of crude oil. The crude intermediate was dissolved in 15 mL of CH2Cl2. Thionyl chloride (0.29 mL, 3.92 mmol) was added and the reaction mixture was stirred for 4 h. The mixture was filtered through a medium porosity funnel. The solid was rinsed three times with cold CH2Cl2 and dried under vacuum to give 63 mg of the title compound. The filtrate was concentrated and the residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (0-40% EtOAc/hexanes) to give additional 443 mg of the title compound. δ=11.4 (s, 1H), 8.98 (s, 1H), 7.20-7.24 (m, 1H), 6.58-6.65 (m, 1H), 4.61 (q, 2H, J=7.0 Hz), 1.55 (t, 3H, J=7.0 Hz).