Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=1.[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:51][CH:52]=[CH:53][N:54]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:45]=1>>[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:54][CH:53]=[CH:52][N:51]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58][C:24]2[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=2)[N:45]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CN(C)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)c1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyl)}dimethylamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-dimethylamino-3-nitro pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]-ethyl}amine.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>C(OCC)(=O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH:16]=1)[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CS(=O)(=O)OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1OCCN1CCOCC1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
A flask was charged with 2-morpholinoethyl methanesulfonate (1.5 g, 6.9 mmol), 5-fluoro-2-nitrophenol (0.99 g, 6.3 mmol), cesium carbonate (4.0 g, 12 mmol) and DMA (100 mL), and the reaction mixture was heated to 90° C. for 15 hours. Ethyl acetate (200 ml) was added to the cooled reaction mixture and the mixture was extracted with water (2×100 ml), 1N sodium hydroxide (2×50 ml) and aqueous 5% lithium chloride (2×50 ml). The organic solvent was removed on a rotary evaporator under reduced pressure. Purified of the crude product by silica column chromatography using 50:50 ethyl acetate:hexanes as eluant gave 0.71 g of 4-(2-(5-fluoro-2-nitrophenoxy)ethyl)morpholine (39% yield). EI (MS): 271 (MH+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:1][CH:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][N:4]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C=O
Reactant: CN1CCNCC1
Product: CN1CCN(CC2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 88 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Molander, G. A. et al., Tetrahedron, 61:2631-2643 (2005)) (95 mg, 0.36 mmol) and 1-methylpiperazine (44 mg, 0.44 mmol) were converted to the title compound (110 mg, 88%), which was used in the subsequent step without purification. MS(ESI+) m/z 346.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:8][N:7]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.860 g (2.49 mmol) of tert-butyl 4-(5-(trifluoromethyl)(pyridin-2-ylamino)piperidine-1-carboxylate obtained in stage 6.1. is dissolved in 8.5 ml of dichloromethane. 1.91 ml of trifluoroacetic acid are added and the mixture is stirred at ambient temperature for 4 hours. The dichloromethane is evaporated and then the residue is coevaporated twice with 10 ml of 1,2-dichloroethane. The residue is taken up in a mixture of 50 ml of ethyl acetate, 10 ml of a 1N aqueous sodium hydroxide solution and 5 ml of a 33% aqueous ammonia solution. The organic phase is separated by settling. It is washed with 2 times 10 ml of water and then with 10 ml of a saturated aqueous sodium chloride solution. It is dried over sodium sulphate and evaporated to dryness to produce 0.572 g (2.33 mmol) of product in the form of an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(O)CO.C(=O)([O-])[O-].[Na+].[Na+]>O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1CCc2c(Cl)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2CCC3=O)cc1
Yield: 95.9 %

Procedure:
14.0 g (84 mmol) of 4-chloroindanone, 32.9 g (185 mmol) of 4-tert-butylphenylboronic acid, 230 ml of ethylene glycol and 38 ml of water together with 19.6 g of sodium carbonate are placed in a reaction vessel and degassed three times. A solution of 94 mg (0.42 mmol) of Pd(OAc)2 and 2.1 ml (1.26 mmol) of TPPTS in 2 ml of water is subsequently added. The resulting reaction mixture is refluxed for 5 hours. After cooling, it is extracted three times with toluene and the combined organic phases are washed with saturated NaCl solution. After drying over magnesium sulfate, the solvent is removed in an oil pump vacuum. 21.3 g (96%) of the desired product are isolated.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:23][CH:21]([S:18]([NH:17][CH2:16][CH:15]([O:14][C:13]1[CH:25]=[CH:26][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:36]([C:35]([F:41])([F:40])[F:34])(=[O:38])=[O:37])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH3:24])(=[O:20])=[O:19])[CH3:22]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 10.8 %

Procedure:
The final title compound (23 mg, 11%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (150 mg, 0.430 mmol, prepared in example 32) methylene chloride 2.5 mL, anhydrous) triethylamine (0.07 mL, 0.471 mmol) and trifluoromethylsulfonyl chloride (9.06 mL, 0.565 mmol), in a manner analogous to Example 29.
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)=[CH:12][N:11]=[CH:10]1)([CH3:8])[CH3:7].CN([CH:30]=[O:31])C>C1COCC1>[NH:20]([C:16]1[N:15]=[C:14]([C:13]2[N:9]([CH:6]([CH3:8])[CH3:7])[C:10]([CH:30]=[O:31])=[N:11][CH:12]=2)[CH:19]=[CH:18][N:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=O
Reactant: CC(C)n1cncc1-c1ccnc(Nc2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
n-Butyllithium (7.2 ml of 1.6 M solution in hexane, 11.2 mmol) was added to a solution of 4-(1-isopropylimidazol-5-yl)-2-anilinopyrimidine (Method 5; 1.25 g, 4.48 mmol) in anhydrous THF (50 ml) cooled to −70° C., and the reaction mixture was then stirred at −70° C. for 30 minutes. Anhydrous DMF (0.7 ml, 9.0 mmol) was added and the mixture was stirred for 18 hour at ambient temperature. The mixture was quenched with water (50 ml), and was extracted with EtOAc (4×75 ml). The organic extracts were combined, washed with brine (2×50 ml), dried and evaporated. The residue was purified by chromatography eluting with EtOAc/Hexane (1:1) to give the title compound (930 mg, 68%) as a pale yellow crystalline solid. NMR (CDCl3): 1.6 (d, 6H), 5.60-5.75 (m, 1H), 6.98 (d, 1H), 7.12 (t, 1H) , 7.30-7.40 (m, 3H), 7.55-7.65 (m, 3H), 8.50(d, 1H), 9.90 (s, 1H); m/z 308.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:23])([F:22])[F:21])[O:11][N:10]=1.O.[CH:32](O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:32]=[O:33])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=1
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: O=CO
Solvent: O
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-amine (example IB-36) (40 mg, 0.1 mmol) was dissolved in formic acid (3 mL). The mixture was stirred at room temperature overnight. To the reaction mixture was added water. The resulting precipitate was collected, washed with water and dried under vacuum. The product was purified by pTLC (EE/PE 2:1) to give 32 mg of the desired product (example IB-48) (yield 75%). Result of LC/MS MH+: 484.82; 1H NMR (CDCl3): 6.63 (t, 1H), 7.22 (m, 1H), 7.38-7.59 (m, 6H), 8.02 (s, 1H) 8.22 (s, 1H)
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CC#CCOc1ncnc(F)c1F
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CCCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
0.2 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine and 0.12 g of piperidine were added to 0.3 ml of toluene, then the mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.25 g of 4-(2-butynyloxy)-5-fluoro-6-piperidinopyrimidine (referred as the present compound (2) hereinafter).
Reaction SMILES: [I-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:7][C:8]1[C:9]2[CH:25]=[C:24]([O:26]C)[C:23]([O:28]C)=[CH:22][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)=[O:14].Cl.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:7][C:8]1[C:9]2[CH:25]=[C:24]([OH:26])[C:23]([OH:28])=[CH:22][C:10]=2[S:11][C:12]=1[C:13]([N:15]1[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]1)=[O:14]
Reactant: COc1cc2sc(C(=O)N3CCC(O)CC3)c(Cl)c2cc1OC
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: CC#N
Product: O=C(c1sc2cc(O)c(O)cc2c1Cl)N1CCC(O)CC1
Temperature: 50 °C

Procedure:
Sodium iodide (1.62 g) was added to a solution of aluminum chloride (2.52 g) in acetonitrile (7 ml). After 30 minutes stirring (3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-(4-hydroxy-piperidin-1-yl)-methanone (0.96 g) was added and the mixture was heated at 50° C. for 12 hours. To the mixture 2 N HCl (4 ml), Na2SO3 (0.68 g) and water were added and the mixture was heated at 60° C. for 30 minutes and then cooled to room temperature. The precipitate was filtered.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2c(Cl)cccc12
Yield: 62.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 7-chloro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 6) (30 mg, 0.10 mmol) and 3-amino-benzoic acid (29 mg, 0.21 mmol) to afford 24 mg (63%) of the title compound. MS (ESI+) calcd for C16H12ClNO4S2 380.989627, found 380.989977.
Reaction SMILES: Br[C:2]1[S:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC(C)C)(C)C.C(OCC)(=O)C>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.[Pd]>[C:19]1([C:2]2[S:16][C:5]3[O:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[NH:9][C:10](=[O:11])[C:4]=3[CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccccc2Oc2sc(Br)cc21
Reactant: [O-]B([O-])Oc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: O=C1Nc2ccccc2Oc2sc(-c3ccccc3)cc21
Temperature: 25 °C
Yield: 83.8 %

Procedure:
2-Bromothieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.0 g) was dissolved in 2M sodium carbonate (8 ml)-toluene (8 ml)-ethanol (8 ml) and phenyl borate (620 mg) and tetrakstriphenylphosphine palladium (390 mg) were added. The mixture was stirred under reflux with heating for 80 minutes. The reaction system was cooled to room temperature and diisopropyl ether and ethyl acetate were added. The precipitated crystals were collected by filtration and the obtained crystals were washed with ethyl acetate and water to give phenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (830 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[N:25][CH:26]=1>>[F:27][C:24]1[N:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:22][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(OCCBr)cn1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(F)nc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[(2-bromoethyl)oxy]-2-fluoropyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=8.5 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.03 (dd, J=9.0 and 3.4 Hz, 1H), 6.54 (s, 1H), 4.69 (t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 2.56 (s, 3H); MS (ES) m/z 364 (M+1).
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.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>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([C:37]4[N:33]([CH:28]5[CH2:29][CH2:30][CH2:31][CH2:32][O:27]5)[N:34]=[CH:35][CH:36]=4)[O:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(Br)n1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2ccnn2C2CCCCO2)n1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide (153 mg, 0.352 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (490 mg, 1.760 mmol), tetrakis(triphenylphosphine)palladium (4.07 mg, 3.52 umol), THF and 2 M Na2CO3 solution were added in a microwave flask and heated at 100° C. for 1 h. The reaction mixture was diluted with DCM and washed twice with NaHCO3 solution. Organic phase was dried and evaporated to dryness. The product was purified twice by Flash-chromatography. Yield 31.4%. m/z [506.0+1].
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2C=C[C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[O:18][CH:15]=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.52 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (−78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 ml of THF). PMR (CDCl3): δ 1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 2.35 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 6.41 (1H, t, J=5.0 Hz), 6.50 (2H, s), 7.36 (1H, d, J=8.0 Hz), 7.45 (1H, dd, J=1.7, 8.0 Hz), 7.49 (1H, s), 7.57 (2H, d, J=8.2 Hz), 7.63 (1H, d, J=1.7 Hz), 8.02 (2H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1.[N+](=[CH2:33])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:20]([O:22][CH3:33])=[O:21])[CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:6]=2[CH:30]=1
Reactant: CN(C)CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CCN(C)C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[[1-carboxy-3-(dimethylamino)propylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-3-(dimethylamino)propylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>>[ClH:21].[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[N:12]1[CH2:11][CH:10]2[CH:14]([CH2:15][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nccs3)CC2C1
Agent: Cl
Product: c1csc(N2CC3CNCC3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
400 mg (1.36 mmol) 5-thiazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl-ester was dissolved in an ethereal HCl soln. After stirring for 1 h at RT, the resulting precipitate was filtered off and subsequently washed with ether. 130 mg (0.56 mmol, 41%) 2-thiazol-2-yl-octahydro-pyrrolo[3,4-c]pyrrole hydrochloride was thus obtained.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:24][C:25]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:29]([C:25]([CH2:24][C:8]1[N:7]([CH2:6][C:5]2[CH:33]=[CH:34][C:2]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=1)([CH2:31][CH3:32])[C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1)C(=O)O
Reactant: C1CCNCC1
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(N2CCCCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from 2-({1-(4-Bromobenzyl)-6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1H-benzimidazol-2-yl}methyl)-2-ethylbutanoic acid using piperidine in the conditions for Example 152. MS (ESI): mass calcd. for C31H39N5O3, 529.31; m/z found, 530.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.70 (d, J=9.0, 1H), 7.55 (d, J=2.2, 1H), 7.35-7.27 (m, 5H), 7.25 (dd, J=9.0, 2.3, 1H), 6.31 (d, J=2.3, 1H), 5.75 (s, 2H), 5.05 (s, 2H), 3.86 (s, 3H), 3.45-3.33 (m, 6H), 1.91-1.64 (m, 10H), 0.87 (t, J=7.5, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:31](=[O:33])[CH3:32])[CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[CH3:26])=[O:8]
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)c(C(=O)NCc1ccc(F)c(F)c1)c(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.9 %

Procedure:
To a solution of 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 46, 50 mg, 0.12 mmol) in pyridine (3 ml) was added acetic anhydride (120 μl, 1.23 mmol). The reaction was stirred at room temperature for 72 h, diluted with EtOAc, washed successively with 1M HCl, H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was crystallized from CH2Cl2-Et2O to yield 5-acetamido-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 47) as a white solid (37 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])[OH:6]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:17])=[O:6]
Reactant: COCOc1ccc[n+]([O-])c1C(O)c1cccc(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COCOc1ccc[n+]([O-])c1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A suspension of 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine 1-oxide (4.58 g) and activated manganese dioxide (13.1 g) in ethyl acetate (150 mL) was stirred overnight at room temperature. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-methoxymethoxy pyridine 1-oxide (4.29 g). Physical properties and spectrum data of the product are shown below: