Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].Cl.[Cl:38][CH2:39][CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>CN(C=O)C>[Cl:38][CH2:39][CH2:40][CH2:41][NH:42][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:36])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: NCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCCl)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (206 mg, 0.4 mmol) in DMF (4 mL) was added (3-chloropropyl)amine hydrochloride (78 mg, 0.6 mmol) and triethylamine (112 uL, 0.8 mmol). The mixture was heated with microwave at 60° C. for 2 hrs. The mixture was separated by flash chromatography to afford the title compound (100 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1C

Procedure:
Using 3,4-xylidine (1.35 g, 11.0 mmol) and 4-nitrobenzoic acid (1.69 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.70 g (quantitative) of the title compound in the form of light yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:27][C:26]4[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccn(Cc3ccc(Cl)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 90 °C
Yield: 25 %

Procedure:
To a solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide (0.2 g, 0.67 mmol) in dimethyl sulfoxide (5 mL) was added with 4-chlorobenzyl bromide (0.14 g, 0.67 mmol) and potassium carbonate (0.30 g, 2.0 mmol). The reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)amide as a white solid (0.071 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.56 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.39 (s, 1H) 7.26-7.33 (m, 3H), 7.18 (d, J=4 Hz, 2H), 6.84 (d, J=4 Hz, 1H), 6.18-6.21 (m, 1H), 5.31 (s, 2H), 4.62 (d, J=4 Hz, 2H), 2.74 (s, 3H). MS (M+H)+=423.9; Rt=1.29 min; HRMS (M+H)+=424.10.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].O>C(#N)C.O.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>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)c2)c1
Reactant: CC(C)c1ccc(B(O)O)cc1
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: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2ccnc(-c3ccc(C(C)C)cc3)c2)c1
Yield: 70 %

Procedure:
Part C. A solution of ethyl 3-(2-chloro-pyridin-4-yl)-benzoate (81 mg, 0.31 mmol), sodium carbonate (99 mg, 0.93 mmol) and 4-isopropylbenzeneboronic acid (60 mg) in acetonitrile-water (2 mL/0.5 mL) is treated with a catalytic quantity of tetrakis(triphenylphosphine)palladium, and heated to reflux for 24 h. The mixture is poured into water (60 mL), and this mixture is extracted with diethyl ether (3×60 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford ethyl 3-[2-(4-isopropyl-phenyl)-pyridin-4-yl]-benzoate (75 mg, 76%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH2:33]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[CH3:26])=[O:20]
Reactant: CC1CCCCC1N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: CC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-methylcyclohexylamine (0.620 g, 5.48 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-methylcyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.373 g, 28.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[Mn]([O-])(=O)(=O)=[O:17].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([Cl:15])[C:3]=1[C:4]([OH:17])=[O:5]
Reactant: COCCOc1cc(Cl)c(C=O)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-(2-methoxyethoxy)benzaldehyde (0.5 g, 2.0 mmol) in acetone (20 mL) were cooled down in ice bath and then potassium permanganate (0.47 g, 3.0 mmol) in water (5 mL) was added slowly under vigorous stirring. The reaction mixture was warmed up slowly to room temperature and reacted over 24 h. The reaction mixture was filtered through celite and washed with acetone. The organic phase was evaporated and then re-dissolved in EtOAc to be extracted with 1N HCl aqueous solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum to afford the compound 2,6-dichloro-4-(2-methoxyethoxy)benzoic acid.
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][CH2:5][NH:6][CH:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH3:8].ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH3:2][S:3]([CH2:4][CH2:5][NH:6][CH:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:10][CH2:11][CH2:12]1)[CH3:8])=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCNC(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: ClCCl
Product: CC(NCCS(C)=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the product of Example 78 in the form of its free base (5.7 g), m-chloroperbenzoic acid (3.7 g-85% purity) and dichloromethane (300 ml) was stirred at ambient temperature for 12 hours. The reaction solution was washed with 5N aqueous sodium hydroxide solution and water and then dried. Evaporation of the solvent gave an oil from which N-[2-(methylsulphinyl)ethyl]-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was separated by high pressure liquid chromatography. The amine was dissolved in dry ether and hydrogen chloride gas passed through the solution to give a gum which was dissolved in ethyl acetate. Heating this solution to 80° C. caused the precipitation of N-[2-(methylsulphinyl)ethyl]-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 170°-171° C.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:25][CH2:26]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)CC1

Procedure:
A solution of 12 ml (0.0718 mol) of diethyl azodicarboxylate (93%) in 80 ml of benzene is added dropwise to a mixture of 14.62 g (0.06791 mol) of cis-4-(N-BOC-amino)-cyclohexanol, 11.1 g (0.068 mol) of N-hydroxyphthalimide, 17.84 g (0.068 mol) of triphenylphosphine and 600 ml of benzene at 20°-30° C., while stirring. The reaction mixture is further stirred at room temperature for 15 hours and then evaporated in vacuo. The residue is purified by flash chromatography on silica gel of particle size 0.04-0.063 mm using methylene chloride. After evaporation of the product-containing fractions, the title compound is obtained as a crystalline residue, m.p. 207°-208° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[N+:39]([O-])([OH:41])=[O:40]>ClC(Cl)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[C:31]([N+:39]([O-:41])=[O:40])[CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c([N+](=O)[O-])c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of compound prepared in step I (2 g, 3.64 mmol) in dichloroethane (20 mL) was added TBAB (117 mg, 0.364 mmol), 6% aqueous nitric acid (20 mmol) at 0-5° C. and stirred at room temperature for 4 h. Organic layer was separated, washed with water and brine and concentrated to furnish crude acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester which was further purified by column chromatography (1.5 g)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](O)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCCP(=O)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:20])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 1 h

Procedure:
To a suspension of 2.58 g (9.2 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid in 50 ml DMF, 12.8 ml (92 mMol) Et3N, 490 mg (4.0 mMol) DMAP, 1.41 ml (11 mMol) 4-fluoro-3-trifluoromethyl-aniline and finally 11 ml propylphosphonic anhydride (50% in DMF; 19 mMol) are added. The mixture is stirred for 1 h and then concentrated in vacuo. The residue is diluted with water and EtOAc, the aq. phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/EtOAc 2:1→1:1→1:2) and re-crystallization from CH3CN gives the title compound: m.p.: 205° C.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][CH2:51][F:52])=[N:40]2>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:45]([C:43]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][C:39]([NH:48][CH2:49][CH2:50][CH2:51][F:52])=[N:40]3)=[C:35]([F:34])[CH:44]=2)=[O:46])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(NCCCF)nc2c1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCCCF)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-2-(3-fluoro-propylamino)-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-59) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87b.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH2:18][CH:17]=[CH2:16])[CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.52 g, 38 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 30 mmol), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 ,g 38 mmol). The mixture was stirred at 95±5° C. for one hour, cooled to room temperature, and added to water (250 mL). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 mL). The concentrated ethereal extracts were combined with the filtrated solid, taken up in 20% aqueous ethanol (100 mL), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 mL) and petroleum ethers (30°-60°, 50 mL), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 mL).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16]P([O-])([O-])=O.[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N+:12]=2[O-:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P([O-])([O-])O
Reactant: O=C(O)c1cccc(-c2ccccc2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=C(O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 60 °C
Yield: 68.2 %

Procedure:
A mixture of 6-phenylpicolinic acid (150 mg, 0.75 mmol), K2HPO4 (600 mg) m-CPBA (300 mg, max 70% from Aldrich) in dichloroethane (8.0 mL) was heated at 60° C. for 1.5 h. Additional m-CPBA (2×300 mg) was added and the mixture was heated at 60° C. for 40 min. The reaction mixture was purified by preparative HPLC to afford the desired product (110 mg, 68%) as a white solid. 1H NMR (DMF-d7) δ 8.57 (s, 1H), 8.43 (d, 1H, J=2.2 Hz), 8.10-7.88 (m, 5H), 7.59-7.57 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:54][NH:55][O:56][CH3:57].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([N:55]([CH3:54])[O:56][CH3:57])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)OC
Reaction time: 0.05 h

Procedure:
To 400 μL CH2Cl2 was added 47.4 mg (200 μmole) of EtOCO-Phe, 34.8 mL (200 μmole) DIEA, and 88.4 mg (200 μmole) BOP. After 3 min, 19.4 mg (200 μmole) N,O-dimethyl-hydroxylamine.HCl and 34.8 mL (200 μmole) DIEA were added. The reaction was monitored by TLC, and after 45 min it was diluted with CH2Cl2, washed 2× with dilute HCl and 2× with saturated NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated by rotary evaporation to give the title compound. NMR (300 MHz, CDCl3): δ 7.20 (m, Ph, 5H), 4.82 (br m, Phe-α, 1H), 4.00 (q, CH3 CH2OCO, 2H), 3.62 (s, N(CH3)OCH3, 3H), 3.11 (s, N(CH3)OCH3, 3H), 3.00 (dd, Phe-b, 1H), 2.85 (dd, Phe-b, 1H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:30])[CH2:23][NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[C].[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:30])[CH2:23][NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
100 mg of palladium carbon (10% w/v) was added to 105 mg (0.261 mmol) of ethyl 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethylcarbamate in 3 ml of ethanol, and they were stirred at 3.6 MPa in hydrogen gas atmosphere overnight. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[CH3:9]I>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: CI
Reactant: Oc1cc(Cl)ccn1
Product: COc1cc(Cl)ccn1
Yield: 58.3 %

Procedure:
4-Chloro-2-hydroxy-pyridine (247 mg, 1.91 mmol), Ag2CO3 (1.58 g, 5.74 mmol) and MeI (0.13 ml, 2.11 mmol) were heated in a sealed tube at 50° C. for 16 hours and then filtered through celite and concentrated at reduced pressure. The residue was purified by FCC (Pentane/Diethyl ether with gradient, 99:1 to 95:5) to provide the title compound as colourless oil (160 mg, 58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][Mg]Br>C1COCC1.CN1C(=O)CCC1>[Cl:16][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:2]([CH3:17])[N:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 0.25 h

Procedure:
tert-butyl (2,6-dichloropyridin-4-yl)carbamate (460 mg, 1.75 mmol) from Step 1 of this example, ferric acetylacetonate (309 mg, 0.87 mmol) was added in THF:NMP (1:1, 17.4 mL), methyl magnesium bromide (3 mL [3M], 8.9 mmol) was added drop-wise and stirred for 15 min. The reaction was quenched with ice-cold ammonia chloride saturated solution (100 mL), extracted with ethyl acetate (100 mL), second wash with brine (50 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel (1 inch deep), concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compounds as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:12][N:13]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:27][C:28](OC(C)=O)=[O:29]>>[C:28]([N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:12][N:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=2)[NH:9]1)(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Solvent: CCN(CC)CC
Product: CC(=O)N1NC(c2ccc(N)cn2)=NN=C1c1ccccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A dry round-bottom flask was charged with 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,2,4,5-tetrazine (0.020 g, 0.08 mmol) and cooled to 0° C. Et3N (0.012 mL, 0.12 mmol) was added followed by Ac2O (0.6 mL), which was added dropwise via syringe. The reaction mixture was allowed to stir at room temperature for 3 h and then concentrated under reduced pressure. The crude residue was chromatographed on silica gel using a gradient (0-100%) of acetone in hexanes as the eluent to give 13 mg (0.04 mmol, 56%) of the title compound as a reddish pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: COc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: COCCOC
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide.