Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+].Cl>C1COCC1.O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Yield: 101.1 %

Procedure:
Methyl 2-(4-bromophenyl)-2-methylpropanoate (3.75 g, 14.6 mmol, prepared according to J. Org. Chem., 59:2620-2622(1994)) in 150 mL of THF was allowed to react with potassium trimethylsilanolate (2.62 g, 20.4 mmol) at ambient temperature, for 60 hours, with continuous stirring. The reaction was then diluted with water and DCM. The pH of the aqueous phase was then adjusted to ca. 4, using 1M HCl. The aqueous layer was then extracted three times with additional DCM. The organic layers were pooled, dried over sodium sulfate, filtered and then concentrated to obtain 3.59 g of 2-(4-bromophenyl)-2-methylpropanoic acid, as a white solid, which gave LC/MS and proton NMR spectra consistent with theory.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].O.[H][H].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20]#[N:21])=[CH:11][CH:10]=1>[Ni].C(OC(=O)C)(=O)C>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: COc1ccc2cccc(CC#N)c2c1
Reactant: CCO
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 1 h
Yield: 89 %

Procedure:
There are introduced into an 8 litre reactor 136 g of Raney nickel, 2.06 litres of ethanol and 0.23 litre of water. Whilst stirring at 70° C. and under 30 bars of hydrogen, the compound obtained in Step B (0.8 kg), dissolved in acetic anhydride (2.4 litres), is added slowly. At the end of the addition, the reaction mixture is stirred for 1 hour under hydrogen at 30 bars; the reactor is then subjected to decompression and the liquors are filtered. After concentrating the mixture, the residue is crystallised from an ethanol/water 35/65 mixture to yield the title product in a yield of 89% and with a chemical purity of more than 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:33][C:34](Br)=[O:35].[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:33][C:34]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: COc1ccc(CC2NCCc3cc(OCc4ccccc4)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Product: COc1ccc(CC2c3cc(OC)c(OCc4ccccc4)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH3:14][C:4]1[N:3]=[C:2]([NH:20][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CC(C)(C)CN
Reactant: CSc1ncc2cc(C)nc(Cl)c2n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(C)nc(NCC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 24.2 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine (Preparation 52, 128 mg, 0.567 mmol) in NMP (6 mL) was added neopentylamine (0.66 mL, 5.67 mmol). The reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (30 mL) and water (30 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to give the title compound (38 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:14][CH3:15])=[N:9][C:10]=2[CH2:12][CH3:13])[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:30]=[N:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=3)=[CH:19][CH:18]=2)[C:4](=[O:53])[CH:3]=1.CS(C)=[O:56].[OH-].[Na+].C(O)(=O)C>O>[ClH:1].[CH2:12]([C:10]1[N:9]=[C:8]([CH2:14][CH3:15])[CH:7]=[C:6]2[C:11]=1[C:2]([OH:56])=[CH:3][C:4](=[O:53])[N:5]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[NH:30][N:31]=[N:32][N:33]=2)=[CH:19][CH:18]=1)[CH3:13]
Reactant: CS(C)=O
Reactant: CCc1cc2c(c(Cl)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc2c(c(O)cc(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Product: Cl

Procedure:
A mixture of 4-chloro-5,7-diethyl-1-[(2'-(2-triphenylmethyl2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (1.0 g), water (10 ml), DMSO (20 ml) and sodium hydroxide (1 g) was stirred and heated at reflux for one hour. The resulting mixture was diluted with water (50 ml), acidified with acetic acid and then extracted twice with ethyl acetate. The combined extracts were washed with water, saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation to give a solid, which was washed with ether and collected by filtration. A mixture of the solid (0.2 g), methanol (4 ml) and concentrated hydrochloric acid (1 ml) was stirred for one hour and then volatile material was removed by evaporation. The residue was purified by repeated precipitation from a methanolic solution with ether to give 5,7-diethyl-4-hydroxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one hydrochloride (0.11 g); m.p. 222°-225° C.; NMR (d6 -DMSO): 1.21(t, 3H), 1.31(t, 3H), 2.93(q, 2H), 3.47(q, 2H), 5.51(s, 2H), 6.21(s, 1H), 7.06(d, 2H), 7.18(d, 2H), 7.4-7.75(complex m, 5H); mass spectrum (+ve FAB, methanol/NBA): 453 (M+H)+ ; microanalysis, found: C, 62.0; H, 5.2; N, 16.7%; C26H24N6O2.HCl.H2O requires: C, 61.6; H, 5.3; N, 16.6%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:34][CH2:33][CH:31]1[O:30][N:29]=[C:28]([C:26]2[S:27][C:23]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]5)[O:10][C:9]4=[O:20])=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH2:32]1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(Br)cn3)C(=O)O2)nn1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)s4)cn3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 28.3 %

Procedure:
(5R)-3-(5-Bromopyrid-2-yl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (195 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)-dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (72 mg).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:3][CH2:4][NH2:5])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: NCCCl
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(SCCN)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirring mixture of 4.36 g (38.0 mmol) of 2-chloroethylamine hydrochloride and 12.00 g (87.0 mmol) of K2CO3 in 30 mL of CHCl3 was added 4.82 g (29.0 mmol) of 4-t-butylbenzenethiol. The mixture was stirred at 50° C. in a sealed vial overnight. The mixture was washed three times with distilled water, dried with MgSO4 and filtered. Volatiles were removed in vacuo leaving 4.50 g (74%) of clear oil. 1H NMR (300 MHz, CDCl3): δ=7.32, m, 4H; 2.93, m, 4H; 1.42, broad singlet, 2H; 1.30, s, 9H.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](=[O:25])[CH2:2][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CC(=O)c2ccncc2)CC1

Procedure:
Condensation of 4-acetylpyridine with 4-carboxymethylpiperidine-1-carboxylic acid tert-butyl ester, utilising the protocol described in Preparation 22, afforded the title compound: m/z (ES+)=247.2 [M-Boc+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.Cl[CH:10]([CH3:14])[C:11](=O)[CH3:12].[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16]>>[C:15]([NH:18][CH2:19][CH2:20][N:21]1[C:11]([CH3:12])=[C:10]([CH3:14])[C:2]([C:1]([O:7][CH3:8])=[O:6])=[C:3]1[CH3:5])(=[O:17])[CH3:16]
Reactant: CC(=O)NCCN
Reactant: CC(=O)C(C)Cl
Reactant: COC(=O)CC(C)=O
Product: COC(=O)c1c(C)c(C)n(CCNC(C)=O)c1C

Procedure:
By reaction of methyl acetoacetate with 3-chloro-2-butanone and 2-acetylaminoethylamine analogously to Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[NH3:28]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:28])[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (63 gm 160 mmol) was dissolved in tetrahydrofuran (300 mL) and to this was added 0.880 ammonia solution (100 mL) to give two phases. This was transferred to a pressure vessel, sealed and heated to 80° C. with stirring for 2 hours. The tetrahydrofuran was evaporated and the residue was partitioned between saturated brine and diethyl ether. The organic extracts were dried over sodium sulphate, filtered and evaporated to give a thick yellow slurry (65 gm) of crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][C:28]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:25][CH:24]=[C:23]3[CH3:37])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C(OC)OC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][C:28]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:25][CH:24]=[C:23]3[CH3:37])=[O:19])=[CH:9][N:11]([CH3:16])[CH3:12])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2cc(OCc3ccccc3)c(C(=O)CN3CCN(C(=O)OCc4ccccc4)CC3)cc12
Agent: COC(OC)N(C)C
Product: Cc1c[nH]c2cc(OCc3ccccc3)c(C(=O)C(=CN(C)C)N3CCN(C(=O)OCc4ccccc4)CC3)cc12
Yield: 43 %

Procedure:
A solution of 4-[2-(6-benzyloxy-3-methyl-1H-indol-5-yl)-2-oxo-ethyl]-piperazine-1-carboxylic acid benzyl ester (0.661 g, 1.33 mmol) in DMFDMA (5 ml) was heated at 100° C. overnight. The solvent was removed in vacuo and the crude product purified by column chromatography in hexane/EtOAc (1:1) to afford the product (0.158 g, 22%). LC/MS: RT=5.33 min. 553 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[CH3:15][Mg]Cl>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[CH:4][C:3]=1[F:14]
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of crude 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (3, 1106 g, 4.2 mol) in anhydrous tetrahydrofuran (THF, 11 L) was slowly added a 3.0 M solution of methylmagnesium chloride (MeMgCl, 2.5 L, 7.5 mol, 1.7 equiv) in THF at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h and then quenched very carefully with saturated aqueous ammonium chloride (NH4Cl, 1.5 L). The resulting solution was concentrated under reduced pressure to remove most of THF. The residue was then diluted with ethyl acetate (EtOAc, 5 L) and the resulting solution was washed with water (2 L). The aqueous phase was extracted with ethyl acetate (EtOAc, 2×2 L). The combined organic phases were washed with water (2 L), brine (2 L) and dried over anhydrous sodium sulfate (Na2SO4). The filtered solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to afford 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 911.6 g theoretical, 97.7% yield) as a solid which was used in the subsequent reaction without further purification. For 4: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89-7.84 (m, 2H), 7.71 (dd, 1H, J=8.30, 1.87 Hz), 2.57 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20](COC)[C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[CH3:12])(=[O:10])=[O:9].Br[CH2:31][C:32]([OH:34])=[O:33].[H-].[Na+].Cl>O1CCCC1.O>[CH3:12][N:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=[CH:18]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][O:1][CH2:31][C:32]([OH:34])=[O:33])(=[O:10])=[O:9]
Reactant: COCn1c(-c2nccs2)cc2cccc(N(C)S(=O)(=O)c3ccsc3CO)c21
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1COCC(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-3-sulfonamide (480 mg) and bromoacetic acid (178 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 95 mg), and the mixture was stirred at 80° C. for 12 hr. Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was stirred at 80° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (98 mg, yield 22%) as pale-yellow crystals. melting point 189° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[C:12]([I:14])[C:11]([OH:15])=[C:10]([I:16])[CH:9]=1)[NH2:6].[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][CH:27]([C:29](O)=[O:30])[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25].N[C@H](C(O)=O)C>>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:9]=[C:10]([I:16])[C:11]([OH:15])=[C:12]([I:14])[CH:13]=1)[NH:6][C:29](=[O:30])[CH:27]([CH3:28])[NH:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(O)c(I)c1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using 3,5-diiodo-L-tyrosine methyl ester hydrochloride (Bachem) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tic (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:17][S:14]([N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(N)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (1.0 g, 5.0 mmol, Astratech, Inc.) and diisopropylethylamine (4 mL) in tetrahydrofuran (40 mL) was stirred at +5° C. To this was added methanesulfonyl chloride (1.0 g, 8.8 mmol) in a bolus. The reaction was brought to room temperature for 1 hour, poured into water and extracted into methylene chloride (2×50 mL). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by trituration with ether/hexane to give (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a white solid. Mass spectrum (ES) H+: 278 B) A suspension of (1-methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester (1.14 g, 4.1 mmol, from Example 162, Step A) in methylene chloride (15 mL) was treated at room temperature with trifluoroacetic acid (5.3 mL). After stirring for 2 hours, all solvent was removed and the residue was triturated with ether. This was filtered, washed with ether and dried in vacuum to give 1.20 g of 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid (100% yield). HRMS, observed: 177.0692; Calcd for M+: 177.0698
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.O.[Cu]Br>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccc2c(ccn2-c2cccnc2)c1
Yield: 86.4 %

Procedure:
A mixture of 5-nitroindole (0.49 g, 3 mmol), 3-bromopyridine (0.95 g, 6 mmol), copper (I) bromide (60 mg, 0.42 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in pyridine (2 mL) and nitrobenzene (0.6 mL) was heated under reflux for 4 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated. The residue was chromatographed on silica gel eluted with ethyl acetate to give the tide compound (0.62 g, 86.5%), mp. 164-5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3C(=O)C(F)(F)F)=[C:7]3[C:14]4=[C:15]([CH2:23][CH:24]5[CH2:28][CH2:27][CH2:26][N:25]5C(=O)C(F)(F)F)[C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=5[N:13]4[CH2:12][CH2:11][N:8]32)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[C:7]3[C:14]4=[C:15]([CH2:23][CH:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=5[N:13]4[CH2:12][CH2:11][N:8]32)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(F)(F)F)c2ccc(F)cc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Fc1ccc2c(CC3CCCN3)c3n(c2c1)CCn1c-3c(CC2CCCN2)c2ccc(F)cc21
Temperature: 60 °C

Procedure:
A mixture containing 28 (1.94 g, 2.97 mmol) and K2CO3 (2.05 g, 14.8 mmol) in MeOH (60 mL) was heated at 60° C. for 1.5 h. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.57 g (quant.) of 29 as a yellow solid which was used without further purification. TLC analysis, 1:1 hexane/EtOAc, Rf(28)=0.9; Rf(29)=0.01. 1H NMR (CDCl3, 300 MHz) δ7.65 (m, 1H), 6.98 (app d, J=8.2 Hz, 1H), 6.90 (app t, J=8.3 Hz, 1H), 4.31 (s, 2H), 3.97 (br s, 3H), 3.54 (m, 1H), 3.31 (m, 1H), 3.14 (m, 1H), 2.97 (m, 1H), 1.83 (m, 1H), 1.68 (m, 2H), 1.42 (m, 1H) ppm. 13C NMR (CDCl3, 75 MHz) δ160.6 (d, JC-F=238.7 Hz), 136.2 (d, JC-F=12.0 Hz), 127.1, 125.4, 120.8 (d, JC-F=10.2 Hz), 109.8, 108.9 (d, JC-F=24.6 Hz), 95.3 (d, JC-F=26.3 Hz), 59.6, 45.6, 41.6, 31.0, 30.7, 24.5 ppm.
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:17][CH2:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)(=O)=O)=CC=1.CS(O)(=O)=O.C1(SC)C=CC=CC=1.N>FC(F)(F)C(O)=O>[NH:11]1[CH2:17][CH2:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2
Reactant: CCOC(=O)C1=Cc2ccccc2N(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: CS(=O)(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCOC(=O)C1=Cc2ccccc2NCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 86.6 %

Procedure:
The ethyl 1-(4-methylphenylsulfonyl)-2,3-dihydro-1H-benz[b]azepine-4-carboxylate (0.63 g, 1.70 mmol) synthesized in Reference Example 4 was added to a mixture of trifluoroacetic acid (10 ml), methanesulfonic acid (0.30 g) and thioanisole (1.0 ml) which had been cooled to 0° C., and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into cooled aqueous ammonia and extracted twice with ethyl acetate, and the extract solution was washed twice with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:95) to obtain 0.32 g of ethyl 2,3-dihydro-1H-benz [b]azepine-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[C:3]=1[Br:14].[NH:15]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[NH2:16].Cl>CCO.CC(O)C>[Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=[N:16][NH:15][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])[C:4]=2[C:3]=1[Br:14]
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1NCCC(=O)c2c1[nH]c(Br)c2Br
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: O=C(O)c1ccccc1NN=C1CCNC(=O)c2[nH]c(Br)c(Br)c21

Procedure:
To a solution of 2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (32.2 mg, 0.10 mmol) in EtOH (5 mL) is added 2-hydrazinobenzoic acid (22.6 mg, 0.12 mmol) and HCl in i-PrOH (6N, 0.3 mL). The mixture is refluxed for 2 hours and then concentrated under reduced pressure. The residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 2-[N′-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-c]azepin-4-ylidene)-hydrazino]-benzoic acid; 1H NMR (DMSO-d6) δ 2.80-2.86 (m, 2H), 3.30-3.34 (m, 2H), 6.82 (t, 1H, J=8.0 Hz), 7.51 (d, 1H, J=7.2 Hz), 7.83-7.88 (m, 2H), 8.13 (t, 1H, J=6.0 Hz), 11.03 (s, 1H), 12.95 (s, 1H), 13.13 (s, 1H); m/z [M++1] 456.9.