Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[S:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:12][C:11]([C:25]([C:31]([F:34])([F:33])[F:32])([C:27]([F:30])([F:29])[F:28])[OH:26])=[N:10]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[S:15][C:16]([C:19]3[CH2:20][CH2:21][N:22]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:12][C:11]([C:25]([C:27]([F:30])([F:28])[F:29])([C:31]([F:32])([F:34])[F:33])[OH:26])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)s2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
1-(2-Chloro-phenyl)-5-[5-(1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 417, methanesulfonyl chloride (6.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[F:21]>>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: Cc1ccc(F)c(CBr)c1
Product: Br
Product: Cc1ccc(F)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1

Procedure:
According to the method of Example 172, 2-amino-5-chloronicotinamide was reacted with 2-(bromomethyl)-1-fluoro-4-methylbenzene to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[C:26]2=[N:27][CH:28]=[CH:29][N:25]2[N:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[C:26]4=[N:27][CH:28]=[CH:29][N:25]4[N:24]=[CH:23][N:22]=3)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnn2ccnc12
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnn2ccnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Yield: 63.7 %

Procedure:
(S)-1-(6-Fluoro-1-pyrid-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.066 g, 0.26 mmol), 4-chloroimidazo[2,1-f][1,2,4]triazine (WO2010/014930) (0.040 g, 0.26 mmol) and diisopropylethylamine (0.090 mL, 0.52 mmol) in isopropanol (2 mL) was heated to 60° C. in a sealed tube for 0.5 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and washed with water (2 mL) The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 322 as a white solid, (62 mg, 63%). LCMS (Method C): RT 3.78 min [M+H]+ 375.04. 1H NMR δ (ppm) (DMSO-d): 9.13 (1H, d, J=7.61 Hz), 8.57 (1H, dd, J=4.90, 1.81 Hz), 8.01-7.98 (2H, m), 7.93 (1H, s), 7.74-7.73 (2H, m), 7.55 (1H, d, J=1.12 Hz), 7.44-7.44 (1H, m), 7.15-7.15 (2H, m), 5.92 (1H, dq, J=7.11 Hz), 1.65 (3H, d, J=6.87 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:15][C:14](=[CH2:16])[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl.N#N>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:15][C:14](=[CH2:16])[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1CC(c2ncc3c(Cl)nccn23)C1

Procedure:
N-[(3-Chloropyrazin-2-yl)methyl]-3-methylenecyclobutanecarboxamide (52.1 g, 219.2 mmol) in anhydrous MeCN (1.0 L) was treated with DMF (1.0 mL) and POCl3 (100 mL, 1.09 mol) and the mixture was stirred at 55° C. for 30 min. under a gentle stream of N2. The reaction was then concentrated in vacuo and the residue reconstituted in CH2Cl2 and treated with cold 2.0 M NH3 in IPA. This mixture was concentrated in vacuo, water added to dissolve the salts, and then extracted with CH2Cl2 (4×60 mL). The organic layers where combined and washed with sat. NaHCO3 (1×70 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by chromatography over silica gel eluting with 2:1 hexane: EtOAc to yield desired product. 1H NMR (400 MHz, CDCl3) δ ppm 3.24-3.30 (4H, m), 3.78-3.85 (1H, m), 4.89-4.94 (2H, m), 7.33 (1H, d, J=4.99 Hz), 7.53 (1H, d, J=5.09 Hz) and 7.82 (1H, s). MS (ES+): m/z 220.28 and 222.30 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>COCCOC.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>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34](=[O:36])(=[O:35])[NH2:37])[CH:29]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
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: CN(C)C=O
Solvent: COCCOC
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 20.2 %

Procedure:
The mixture of 4-amino-7-bromo-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (40 mg, 0.112 mmol), Pd(PPh3)4 (19 mg, 10 mol %), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (36.8 mg, 0.224 mmol) and 2M Na2CO3 aqueous solution (0.28 ml, 0.56 mmol) in 2 ml of DME was stirred for 14 hours at 80° C. As starting material remained, same amount of reagents described above and DMF (2 ml) were added and stirred for 5 hours at 100° C. The resultant mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH was collected, and the eluant was concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (9.8 mg) 1H NMR (400 MHz, DMSO-d6) ppm 8.12 (dd, J=1.8 Hz, 1H), 8.0 s, 1H), 7.91 (ddd, J=1.5, 1.5, 7.6 Hz, 1H), 7.85 (ddd, J=1.4, 1.4, 7.1 Hz, 1H), 7.75 (dd, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.57 (dd, J=9.0 Hz, 1H), 7.51 (ddd, J=2.2, 4.9, 8.5 Hz, 1H), 7.45 (s, 2H), 5.66 (s, 2H). MS: m/z 434 (M+H)+.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[N:38]=[CH:37][CH:36]=[N:35]1)=[O:27])[CH2:20]2.Cl[C:40]1[N:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:42][N:41]=1>>[C:46]1([C:44]2[CH:43]=[CH:42][N:41]=[C:40]([N:24]3[CH2:25][CH:19]4[CH:23]3[CH2:22][N:21]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[N:38]=[CH:37][CH:36]=[N:35]3)=[O:27])[CH2:20]4)[N:45]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(c1ccccc1-n1nccn1)N1CC2CNC2C1
Reactant: Clc1nccc(-c2ccccc2)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: O=C(c1ccccc1-n1nccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 25 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C24H21N7O, 423.48; m/z found, 424.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[I:26][C:23]1[CH:22]=[CH:21][C:20]([N:18]2[CH:19]=[C:15]([CH2:14][NH:13][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[CH:2][NH:1]4)=[CH:5][CH:6]=3)=[O:12])[N:16]=[CH:17]2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: NCc1cn(-c2ccc(I)cc2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-6-carboxylic acid (85 mg, 0.528 mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole 1-2 prepared in Example 1 (136 mg, 0.455 mmol) and TEA (0.150 mL, 1.08 mmol) in DMF (4 mL), BOP (280 mg, 0.633 mmol) was added. After the mixture was stirred at room temperature overnight, water and EtOAc were added. The organic layer was separated, washed with 5% aq. NaHCO3, dried over Na2SO4, concentrated in vacuo to give N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide as a crude sample, which was used in the next reaction without further purification. MS 443.0 (M+H).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH:11]=[CH2:12].[NH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:37])=[C:34]([O:35][CH3:36])[C:29]=4[C:28](=[O:38])[N:27]4[CH2:39][CH2:40][C@H:26]4[C:25]=23)[N:17]=1>C(Cl)Cl>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][C:33]([F:37])=[C:34]([O:35][CH3:36])[C:29]=4[C:28](=[O:38])[N:27]4[CH2:39][CH2:40][C@H:26]4[C:25]=23)[N:17]=1)[CH2:6][CH:4]=[CH2:5])[CH:11]=[CH2:12]
Reactant: COc1c(F)ccc2c1C(=O)N1CC[C@H]1c1c(-c3noc(CN)n3)ncn1-2
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2OC)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
5.1ml (29.8 mmol) of N-ethyldiisopropylamine and 1.46 ml (17.34 mmol) of allyl bromide were added to a solution of 800 mg (2.16 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 12 ml of methylene chloride. The reaction solution was stirred at room temperature for 20 hours, subsequently diluted with methylene chloride and washed three times with water. The organic phases were dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol 19:1). There were obtained 770 mg (79%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as a colourless foam, Rf=0.37 (silica gel, methylene chloride/methanol 19:1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20](=[O:32])[CH2:21][CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25](=[CH:30][CH:29]=[C:28]([Cl:31])[CH:27]=3)[CH:24]=[C:23]3[CH2:22][CH2:21][C:20](=[O:32])[C:19]=23)=[CH:14][CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C#CC(=O)CC/C=C/c2ccc(Cl)cc2)cc1
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2c3c(cc4ccc(Cl)cc24)CCC3=O)cc1
Yield: 89 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added compound 14a (0.057 g, 0.12 mmol) in 1,2-dichlorobenzene (2 mL). The reaction was irradiated with stirring at 225° C. for 60 min until complete by TLC (AcOEt/n-hexane 2:8). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2.5:8.5 to collect the pure product. The title compound was isolated as a yellow solid in an 89% yield (0.050 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.C[OH:18]>O.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C:4]2=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reactant: CO
Agent: [Pd]
Solvent: O
Product: CN1CCN(c2cccc(N)c2)C(=O)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
Pd/C (10%, 420 mg) was added to a solution of 1-methyl-4-(3-nitrophenyl)piperazine (8.4 g) in methanol (500 mL) and water (20 mL). The reaction mixture was stirred and degassed with nitrogen, and the vessel was charged with H2 gas at atmospheric pressure. The reaction was allowed to proceed overnight after which time the Pd/C was removed by filtration over celite and the methanol and water were removed in vacuo to give 1-(3-aminophenyl)-4-methyl-2-piperazinone as a yellow solid (7.08 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (1H, t, J=7.83 Hz) 6.48-6.55 (2H, m) 6.46 (1H, d, J=1.01 Hz) 6.44 (1H, s) 3.88 (4H, s) 3.54 (2H, br. s.) 2.82 (3H, s)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(O)(COS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 5 g (17.35 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 50 ml of dry pyridine was cooled to 0° C. and 8.86 g (34.70 mmol) of 4-bromo-benzenesulfonyl chloride was added in small portions. The mixture was stirred at 0° C. for 5 h, then diluted with 200 ml of dichloromethane, washed three times with 50 ml of saturated aqueous sodium hydrogencarbonate, twice with 50 ml of 10% aqueous hydrochloric acid and 50 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized from a 1:5 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:36]
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.7 %

Procedure:
To a solution of 0.12 g (0.29 mmol) of 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step (A) of Example 28) in 5 mL of CH2Cl2, 0.061 g (0.348 mmol) of 2-chlorobenzoyl chloride and 0.065 g (0.638 mmol) of triethylamine were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 72% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 28% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.043 g (26%) of the title compound of this Example as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[NH2:11].C(O)(=O)C>CCO.C1COCC1>[NH2:6][C:5]1[N:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:19][CH:20]=2)[N:11]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Yield: 98.6 %

Procedure:
A mixture of 4,4-dimethyl-3-oxo-pentanenitrile (4.52 g, 36.15 mmol), 4-hydrazinobenzoic acid (5.00 g, 32.86 mmol), and acetic acid (2 mL) in EtOH/THF (1:1) was refluxed for 16 h. After cooling, the solvent was concentrated at reduced pressure, and the crude was re-dissolved in EtOAc. The organic layer was washed with aqueous saturated Na2CO3 solution and brine, dried over MgSO4, filtered, and concentrated to half its volume. The resulting residue was filtered, and the solids were washed with cold EtOAc and dried under high vacuum to afford the title compound as a white solid (8.4 g, 99%). 1H-NMR (DMSO-d6) δ 12.91 (s, 1H), 7.99 (d, J=6.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 5.42 (s, 1H), 5.39 (s, 2H), 1.21 (s, 9H); MS LC-MS [M+H]+=260, RT=1.83 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8][C:7]=2[CH:14]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH:10]1[CH2:9][CH2:8][C:7]2[CH:14]=[C:3]([O:2][CH3:1])[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCC(=O)CC2
Reactant: COCCN
Product: COCCNC1CCc2cc(OC)c([N+](=O)[O-])cc2CC1

Procedure:
(2-Methoxyethyl)-(2-methoxy-3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)amine was prepared from 2-methoxy-3-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 2-methoxyethylamine in a analogous manner to Example 881a. Product was isolated as a brown film. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.53 (t, 1H, J=14 Hz), 3.37 (s, 6H), 2.83-2.92 (m, 5H), 2.71 (m, 2H), 2.12 (m, 2H), 1.39 (m, 2H).
Reaction SMILES: P(O[C:18]([CH3:49])=[C:19]([N:33]1[C:39](=[O:40])[CH:38]2[CH:34]1[S:35][C:36]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[N:37]2)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.O>C(OCC)(=O)C>[O:42]([CH2:41][C:36]1[S:35][CH:34]2[CH:38]([C:39](=[O:40])[N:33]2[C:19](=[C:18]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH3:49])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[N:37]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: C1COCCN1
Reactant: CC(OP(=O)(Oc1ccccc1)Oc1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diphenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (7.02 g) in ethyl acetate (70 ml) at 0°-5° C. was added morpholine (1.83 ml) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (30 ml) was added and the organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. TLC (silica) Rf 0.57 (ethyl acetate). The product was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond. NMRδCDCl3 1.93 (s), +2.43 (s) (3H), 3.17-3.93 (m, 8H), 4.90 (s, 2H), 5.25 (s, 2H), 5.68-6.13 (m, 2H) and 6.87-7.7+8.1-8.4 (m, 9H).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Cl:28])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 66 mg of 19d in 1 ml of DMF was added at 0° C. 27 mg of N-chlorosuccinimide. The mixture was stirred for 2 h. Then, 5 ml of water was added and 1 drop of a sat. Na2S2O3 solution. Stirring was continued for 5 min and the product was extracted into ethyl acetate. The extract was washed with water, dried, concentrated and the residue was treated with cold pentane, to provide 65 mg of 19e as a white crystalline material; Mp 203-205° C. MS-ESI: [M+1] 464.12, 465.10, 466.09, 467.08, 468.08 and 469.07.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[OH:12].[C:13](=[O:16])([O-])O.[Na+]>C(Cl)Cl.O1C=CCCC1.O1CCOCC1>[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[O:12][CH:5]1[CH2:4][CH2:3][CH2:11][CH2:13][O:16]1
Reactant: O=C([O-])O
Reactant: O[C@H]1CCc2c(Br)cccc21
Agent: C1=COCCC1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (15 g).