Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[C:9]1[N:14]=[C:13]2[N:15]([CH2:23][CH3:24])[C:16]([C:18]([O:20]CC)=[O:19])=[CH:17][C:12]2=[C:11]2[N:25]([CH3:28])[CH:26]=[N:27][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[C:9]1[N:14]=[C:13]2[N:15]([CH2:23][CH3:24])[C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]2=[C:11]2[N:25]([CH3:28])[CH:26]=[N:27][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc2n1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C(=O)O)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To a solution of ethyl 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylate (example 1G, 5.32 g, 9.9 mmol) in ethanol (49.5 mL) was added 1 N NaOH aqueous solution (49.5 mL). The reaction mixture was heated at 60° C. 3 h and cooled to rt. Ethanol was removed by concentration in vacuo. The residue was acidified with 1 N HCl and the product was collected by vacuum filtration. 4-(tert-Butoxycarbonyl(2,4-dimethoxybenzyl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylic acid (4.3 g, 8.44 mmol, 85% yield over two steps) was isolated as a white solid after drying on the vacuum.
Reaction SMILES: CN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>CCO>[NH2:5][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: NCc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A 40% solution of methylamine (6.14 mL; 7.1 mmol) was added to 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]benzoic acid C (2 g; 7.1 mmol) and then EtOH (30 mL) was added. After 5 minutes stirring at room temperature the reaction mixture was heated at 50° C. After 2.5 h, the mixture was cooled and the solvent was evaporated under reduced pressure. The crude product was suspended in 50 mL of absolute ethanol and the suspension was stirred at room temperature for 1 h. The solid was filtered and washed with EtOH to afford 2-(aminomethyl)benzoic acid D (0.87 g; 5.8 mmol). Yield 81%.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24]COC)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([Si](CC)(CC)CC)[O:8][C:5]2=[N:6][CH:7]=1.C1C(=O)N([I:35])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][C:9]([I:35])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[OH:24]
Reactant: O=C1CCC(=O)N1I
Reactant: CC[Si](CC)(CC)c1oc2ncc(F)c(OCOC)c2c1-c1ccccc1
Solvent: CN(C)C=O
Product: Oc1c(F)cnc2oc(I)c(-c3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The mixture of 5-fluoro-4-methoxymethoxy-3-phenyl-2-(triethylsilanyl)-furo[2,3-b]pyridine (4) (0.10 g, 0.26 mmol) and NIS (0.07 g, 0.31 mmol) in DMF (1.5 mL) was stirred at 50° C. overnight. The reaction mixture was purified by preparative HPLC to give the title compound 5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH:15][S:21]([CH3:20])(=[O:23])=[O:22])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc(N)nc(N)c1-c1cc(NS(C)(=O)=O)ccc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2-chloro-5-aminophenyl)-6-methylpyrimidine from Example 54 by reaction with methanesulphonylchloride in pyridine, mp. 234°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:24]=1[CH2:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:27][O:26][CH2:25][C:24]4[C:28]([F:35])=[C:29]([F:34])[C:30]([F:33])=[C:31]([F:32])[C:23]=4[F:22])=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: NOCc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(NOCc1c(F)c(F)c(F)c(F)c1F)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-[(2,3,4,5,6-pentafluorobenzyl)oxy]amine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.69 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.33-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.56 (s, 2H), 5.09 (s, 2H). LCMS (API-ES, M+H+): 467.0. HRMS calcd for C21H13F6N4O2 (M+H) 467.0943, found 467.0942. HPLC: >80% purity.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C@@H:24]([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C@@H:24]([CH3:28])[C:25]([NH2:30])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid (115 mg, 0.28 mmol) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol), ammonium chloride (23 mg, 0.42 mmol) and triethylamine (674, 0.42 mmol) and the reaction mixture stirred at room temperature (RT) for 5 hours. Further quantities of HATU (106 mg, 0.28 mmol), ammonium chloride (15 mg, 0.28 mmol) and triethylamine (21 μL, 0.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 426 as a white solid (68 mg, 58%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H, s), 7.05 (1H, s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.9 Hz), 4.59-4.43 (4H, m), 1.47-1.37 (9H, m)
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CO>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[O:20][CH:12]=[N:11][CH:10]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1csc(-c2cnco2)c1
Yield: 36.7 %

Procedure:
To a solution of p-toluenesulfonylmethyl isocyanide (3.0 g, 15.36 mmol) and Thiophene-2-carboxaldehyde (1.72 g, 15.36 mmol) in methanol (45 mL) under N2 is added potassium carbonate (2.12 g, 15.36 mmol). The mixture is heated to reflux for 5 hr, then cooled and concentrated in vacuum (cold water bath). The residue is partitioned between ether (100 mL) and water (100 mL). The organic layer is washed with water (100 mL), dried over magnesium sulfate and then concentrated in vacuum. The residue is purified over 35 g silica gel, eluted with ethyl acetate: heptane (1:5) to afford 5-thiophen-2-yl-oxazole (0.852 g, 37%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13](/[CH:21]=[CH:22]/[C:23](OCC)=[O:24])[CH:12]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:12]=1
Reactant: CCOC(=O)/C=C/c1cnc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC/C=C/c1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.0M, 31 ml) was added dropwise to a solution of ethyl (E)-3-(3-quinolinyl)acrylate (2.94 g) in CH2Cl2 (50 ml) at −78° C. and the mixture was stirred at −78° C. for 30 minutes. The reaction mixture was washed with saturated aqueous solution of sodium potassium tartrate and brine, dried and concentrated. The residue was crystallized from CH2Cl2-ethyl acetate to give the titled compound (1.31 g) as a colorless solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]1=[O:43].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[O:33][N:32]=4)=[CH:23][CH:24]=3)[C:7](=[O:43])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)n4COCCOC)cc3)c2s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethyl-1-[(2′-{4-[(2-methoxyethoxy)methyl]-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl}biphenyl-4-yl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15.5 g) and trifluoroacetic acid (100 mL) was stirred at 50° C. for 3 hr. To the reaction mixture was added toluene (100 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (11.7 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[O-:11].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:11][C:3]2[CH:4]=[C:5]([Cl:10])[C:6]([S:8][CH3:9])=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]([CH3:21])[N:15]=1
Reactant: Cc1cc(Cl)cc(Cl)n1
Reactant: CSc1cc(Cl)c([O-])cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(Cl)c(Oc2cc(C)nc(Cl)c2)cc1Cl

Procedure:
A solution of 25.5 gm (0.1 mol) of potassium 2,5-dichloro-4-methylmercapto-phenolate and 16.2 gm (0.1 mol) of 2,4-dichloro-6-methyl-pyridine in 100 ml of dimethylformamide was heated under reflux for 5 hours. It was then cooled and poured into 300 ml of water. The precipitate which separated out was recovered by suction filtration, washed with water, and recrystallized from isopropanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: CCOP([O-])OCC
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
1,4-Dibromobenzene (2.36 g), diethyl phosphite (1.52 g) and triethylamine (1.53 ml) were dissolved in toluene, tetrakis(triphenylphosphine)palladium(0) (578 mg) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:8]2[N:13]([C:14]=1[Br:15])[N:12]=[CH:11][N:10]=[C:9]2[NH2:16])=[O:5])[CH3:2].O.O.[Sn](Cl)Cl>CCO>[NH2:16][C:9]1[C:8]2=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([Br:15])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnn2c1Br
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(N)cc2)c2c(N)ncnn2c1Br
Yield: 78.6 %

Procedure:
Ethyl-4-amino-7-bromo-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.06 g, 5.07 mmol) was suspended in EtOH (30 mL) and treated with tin(II)chloride dihydrate (3.66 g. 16.2 mmol). The mixture was heated to reflux for 18 h. The mixture was concentrated then diluted with EtOAc and saturated NaHCO3 solution. The emulsion was filtered and the filtrate was transferred to a separatory funnel. The organic layer was washed with water and saturated NaCl solution, dried then (MgSO4) and concentrated to afford 1.5 g of the desired product as tan solid (79%). 1H-NMR (DMSO-d6) δ 8.00 (s, 1H), 7.00 (d, J=8.6, 1H), 6.62 (d, J=9.2, 3H), 5.40 (bd, 2H), 5.19 (bs, 2H), 4.05 (q, J=7.0, 2H), 1.03 (t, J=7.0, 3H); MS [M+H]+=376.0, 378.0; LCMS RT=2.02.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=1.Cl>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([C:21]([F:22])([F:24])[F:23])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 5.2 g portion of 60% sodium hydride oil dispersion was suspended in 50 ml of DMF, and 6.73 ml of benzyl alcohol was added thereto under ice-cooling. After warming up to room temperature, 12.3 g of 4-fluoro-2-trifluoromethylbenzoic acid was added thereto and stirred at room temperature for 6 hours. A 1 M hydrochloric acid aqueous solution was added to the reaction mixture, and the thus precipitated crystals were collected by filtration to obtain 16.39 g of 4-(benzyloxy)-2-(trifluoromethyl)benzoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH2:17].[Br-]>C1COCC1.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>[N+:14]([C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:3]=1[NH2:17])([O-:16])=[O:15]
Reactant: Nc1c(Br)cc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Nc1c(-c2ccccn2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 150.9 %

Procedure:
A mixture of 2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 eq), 2-pyridylznic bromide (6 eq) and tetrakis(triphenylphosphine)palladium (0.1 eq) in THF (10 mL) was heated at 100° C. for 18 hours. The reaction was quenched with water (2 mL). The product was extracted with EtOAc (20×3). The combined organic layer was then concentrated in vacuo and the residue was purified by chromatography (Silica Gel, EtOAC) to afford the title compound (75 mg) as a yellow solid. (M+1) 293.
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([NH:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)[CH2:8][CH2:9][N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:12]2[CH2:11][N:10]([CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:36])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:6][OH:5])[CH2:13]2)=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)N[C@@H](CCN2CC(Oc3ccc(F)cc3)C2)COC(C)(C)C)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@H](CO)CCN2CC(Oc3ccc(F)cc3)C2)cc(OC)c1OC
Reaction time: 20 h

Procedure:
A solution of N-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide (Example 1, 0.066 g, 0.130 mmol) in dichloromethane (2 ml) is treated with trifluoroacetic acid (0.11 ml, 0.65 mmol) and the reaction mixture stirred for 20 hours. The solvent is evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution 100% ethylacetate then 5:95 methanol/dichloromethane) to afford N-{(S)-3-[3-(4-fluorophenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3,4,5-trimethoxy-benzamide [MH]+ 449.1.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].Cl.[NH2:14][OH:15]>C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[N:14][OH:15])[NH2:12])=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: NO
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(=NO)c1ccc(C(=O)O)cn1

Procedure:
Sodium (18 mmol) is added to a flask containing 20 ml of ethanol. After the sodium has dissolved, 3.8 mmol of 5-carboxy-2-cyanopyridine and 18 mmol of hydroxylamine hydrochloride are added, and the solution is refluxed for 5 h. After cooling, the resulting precipitate is filtered off and recrystallized from water; m.p.>300°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[O:12][C:13](=[O:26])[O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([F:24])=[CH:17][C:16]=1[Cl:25].[H][H]>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13](=[O:26])[O:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([F:24])=[CH:17][C:16]=1[Cl:25]
Reactant: [H][H]
Reactant: O=C(Oc1cc([N+](=O)[O-])c(F)cc1Cl)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1cc(OC(=O)Oc2cc(N)c(F)cc2Cl)c(Cl)cc1F
Yield: 99.7 %

Procedure:
Bis(2-chloro-4-fluoro-5-nitrophenyl)carbonate (1.2 kg, 2.9 mol), toluene (7 liters) as a solvent, and 5 % Pd/C (200 g) as a catalyst were put in a 10-liter three-neck flask as equipped with a stirrer, and hydrogen gas was introduced thereinto with vigorously stirring. With progress of the reaction, the reaction system became exothermic. By introduction of hydrogen gas into the reaction system at such a rate that no hydrogen gas leaked out from the system, the reaction temperature was maintained to fall within the range of from 60° to 70° C. After reaction, the reaction mixture was heated (60° to 70° C.) and the used catalyst was taken out therefrom by filtration. The organic layer of the resulting filtrate was separated and was dried with anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed by distillation under reduced pressure to obtain bis(2-chloro-4-fluoro-5-aminophenyl)carbonate (1.01 kg, 2.89 mol) as a white solid. Yield: 99.6 %. Melting point, 1H NMR spectral data and IR spectral data of the product were same as those in Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[CH2:19]([O:18][C:4]1[CH:3]=[C:2]([NH:1][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=3)=[CH:38][CH:37]=2)[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Product: O=C(OCc1ccccc1)c1ccc(NCc2ccc(-c3ccc(Br)cc3)cc2)cc1OCc1ccccc1
Yield: 70 %

Procedure:
Primary aniline 1 was coupled to 4′-bromo-[1,1′-biphenyl]-4-carbaldehyde on a 3.7 mmol scale via General Procedure A to furnish 5 (1.52 g, 70%): δH (400 MHz, CDCl3) 4.39 (s, 2H, CH2), 4.59 (br s, 1H, NH), 5.10 (s, 2H, CH2), 5.31 (s, 2H, CH2), 6.20 (d, J=2.0 Hz, 1H, CH), 6.24 (d of d, J=8.6 and 2.0 Hz, 1H, CH), 7.25-7.36 (m, 6H, CH), 7.37-7.49 (m, 8H, CH), 7.53 (d, J=8.4 Hz, 2H, CH), 7.57 (d, J=8.4 Hz, 2H, CH) 7.85 (d, J=8.6 Hz, 1H, CH); δC (100 MHz, CDCl3) 47.3, 65.7, 70.3, 97.4, 104.9, 108.7, 121.5, 126.8, 127.1, 127.5, 127.6, 127.8, 127.9, 128.3, 128.3, 128.5, 131.8, 134.3, 136.6, 136.7, 137.6, 139.1, 139.4, 152.6, 160.8, 165.6.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 60 mg (0.56 mmol, 1.5 eq.) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 104 mg (59% of theory)
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (89 mg, 4.61 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-fluorobenzene (0.416 mL, 3.38 mmol; Aldrich) was added dropwise. After 30 minutes the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL), extracted with dichloromethane (2×10 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 218 (M+H−NH3)+.