Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C(F)(F)F)c4)c3O2)cc1
Yield: 90.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 3-(trifluoromethyl)phenylboronic acid (3.72 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 5.28 g (90%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 90-93° C.; Anal. calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18](Cl)=[C:19]([CH3:21])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=C>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([CH:23]=[CH2:24])=[C:19]([CH3:21])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Solvent: Cc1ccccc1
Product: C=Cc1ncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C
Yield: 55 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-6-chloro-5-methylpyridine (830 mg, 2.57 mmol) in toluene (10 mL) was added [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(U) (83 mg) and allyltributyltin (1.3 mL, 5.1 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 3:2) to afford an oil (450 mg, 57%): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.62 (m, 1H), 1.86 (m, 1H), 2.00-2.10 (m, 2H), 2.34 (s, 3H), 3.30-3.46 (m, 2H), 3.90 (m, 1H), 4.04-4.20 (m, 2H), 5.37 (d, 1H, J=11.0 Hz), 6.20 (d, 1H, J=17.0 Hz), 6.94 (dd, 1H, J=11.0, 17.0 Hz), 7.02 (br s, 1H), 8.14 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/z 319 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccncc1
Yield: 76.1 %

Procedure:
4-Pyridinecarboxaldehyde (18.96 g, 0.177 mol) and malonic acid (55.3 g, 0.53 mol) were placed in 200 ml of pyridine. Piperidine (5.25 ml, 0.053 mol) was added and the reaction was refluxed for 6 hours. The reaction mixture was cooled in an ice bath and then the white solid was filtered off and rinsed with ether and dried to afford 20.1 g of the subtitle compound. Concentration of the filtrate and then filtration and rinsing with ether resulted in recovery of another 2.2 g of product (84% total yield).
Reaction SMILES: [OH-].[Na+].C1COCC1.[C:8]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:10][CH:9]=1>CO>[C:8]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:9]=[CH:10][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.1 mL, 0.30 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(2-(([1,1′-biphenyl]-4-ylamino)methyl)phenyl)picolinamido)propanoate (73 mg, 0.15 mmol) and the homogeneous mixture was stirred at room temperature. After 3 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:4][C:5]2[S:10][CH:9]=[C:8]([Cl:11])[C:6]=2[N:7]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:1].[Cl:11][C:8]1[C:6]2[N:7]=[C:3]([CH2:2][P+:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:4][C:5]=2[S:10][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1csc2sc(CBr)nc12
Solvent: CC#N
Product: Clc1csc2sc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Product: [Br-]
Yield: 68.5 %

Procedure:
A solution of 300 mg (1.1 mmol) of 2-(bromomethyl)-6-chlorothieno[3.2-d1]thiazole (from Step 3) and 650 mg (2.4 mmol) of triphenylphosphine in 5 ml of acetonitrile was stirred at r.t. for 4 h. The product was precipitated from the solution with Et2O, filtered and swished with Et2O to give 400 mg (70%) of the title product. 1H NMR (DMSO-d6) 7.95-7.73(m, 16H), 5.91(d, J=14 Hz, 2H).
Reaction SMILES: [N+](C1NC=NC=1)([O-])=O.[N+:9]([C:12]1[N:16]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH:15]=[N:14][CH:13]=1)([O-])=O.[C:27](Cl)(Cl)=[O:28].[CH:31]1([NH2:34])[CH2:33][CH2:32]1>[Pd]>[CH:31]1([NH:34][C:27]([NH:9][C:12]2[N:16]([CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)[CH:15]=[N:14][CH:13]=2)=[O:28])[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cncn1C1CCCc2ccccc21
Agent: [Pd]
Agent: O=[N+]([O-])c1cnc[nH]1
Product: O=C(Nc1cncn1C1CCCc2ccccc21)NC1CC1

Procedure:
In the first step a modified Mitsunobu reaction employing 5-nitro-1H-imidazole (CAS #3034-38-6) can be preformed as described in Example 1. The resulting 5-nitro-1(1,2,3,4-tetrahydro-naphthalen-1-yl)-1H-imidazole, can then be reduced via the employment of palladium on carbon under a hydrogen atmosphere. The resulting amine can undergo treatment with phosgene followed by the addition of cyclopropylamine to afford 1-cyclopropyl-3-[3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazol-4-yl]-urea; MS: (ESI) m/z 297.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46-0.57 (m, 2 H), 0.68-0.77 (m, 2 H), 1.78-2.29 (m, 4 H), 2.49-2.60 (m, 1 H), 2.79-3.01 (m, 2 H), 5.17-5.31 (m, 1 H), 5.34-5.43 (m, 1 H), 6.33-6.43 (m, 1 H), 6.85 (d, J=7.6 Hz, 1 H), 7.01 (s, 1 H), 7.13 (t, J=7.5 Hz, 1 H), 7.17-7.26 (m, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:16])=[O:4].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:16])=[O:4]
Reactant: COC(=O)c1cc2c(cc1C)[C@@H](N)CCS2
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1cc2c(cc1C)[C@@H](NC(=O)OCc1ccccc1)CCS2

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-amino-6-methylthiochromane-7-carboxylic acid methyl ester (1.20 g) and benzyloxycarbonyl chloride (0.87 ml), the objective (S)-4-(benzyloxycarbonylamino)-6-methylthiochromane-7-carboxylic acid methyl ester (1.74 g) was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C(O)(=O)/C=C\C(O)=O.[BrH:18].C(O)(=O)C>>[Br:18][CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: Br
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(=O)O
Product: COC(=O)C(Br)CC(=O)O
Temperature: -2 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methyl hydrogen (2Z)-2-butendioate (also known as the monomethyl ester of maleic acid) (50 g, 0.385 mol) was added dropwise to a solution of hydrogen bromide in acetic acid (141.43 g, 33%, 0.577 mol) at 0° C. over 1 h. The reaction mixture was stored at about 5° C. overnight. The solvent was then removed under reduced pressure. Toluene (100 mL) was added, and the mixture was evaporated under reduced pressure. The process was repeated three times using more toluene (3×100 mL). Then toluene (50 mL) was added, and the mixture was cooled to −2° C. Hexanes (50 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred about 30 minutes while the product crystallized. The product was then isolated by filtration and dried in vacuo to provide the title compound as a white solid (63.37 g, 81.8% yield). A sample recrystallized from toluene/hexanes melted at 38-40° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.C(OC1C=CC(S(C2(C(O)=O)CCN(CC3C=CC=CC=3)CC2)(=O)=O)=CC=1)C1C=CC=CC=1.[OH:69][NH:70]C(C1CCN(CC2C=CC=CC=2)C(S(C2C=CC(OCC3C=CC=CC=3)=CC=2)(=O)=O)C1)=O>CO.C1COCC1>[OH:69][NH:70][C:4]([C:6]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)=[O:3]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reactant: O=C(NO)C1CCN(Cc2ccccc2)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Agent: O=C(O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1, 200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. HCl by dissolving it in water (200 mL). After the neutralization reaction mixture was concentrated to dryness. Ice cold water (100 mL) was added to the solid and filtered. The product 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid was dried at 50° C. and taken to next step with out any purification. Colorless solid. MP: 66-68; Yield: 4.3 g, 91% ; MS: 466 (M+H) Starting from 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure outlined in example 83, 1.1 g of 4-(4-Benzyloxy-benzenesulfonyl-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colurless solid. Yield 21%; mp 89° C.; MS: 481.1 1H NMR (300 MHz, DMSO-d6): δ2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH:25]([OH:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCN1CCSc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(O)Cc1ccc(OCCN2CCSc3ccccc32)cc1
Yield: 16.3 %

Procedure:
The title compound (1.9 g, 17%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g, 30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][CH:28]([CH3:29])[CH3:30])#[N:24]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reactant: CC(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (0.6 g), 5-amino-2-isobutoxybenzonitrile (0.5 g), triethylamine (0.8 g) and diethyl cyanophosphate (0.7 g) were added to dimethylformamide (8 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (0.2 g), melting point: 179–180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc2nc[nH]c2c(OCc2ccccc2)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc2cc(Cl)nc(OCc3ccccc3)c21
Reaction time: 2 h

Procedure:
A mixture of 4-(benzyloxy)-6-chloro-3H-imidazo[4,5-c]pyridine 2.24 (1.00 g, 3.85 mmol) and K2CO3 (1.06 g, 7.70 mmol) were suspended in DMF and iodomethane (0.312 mL. 5.01 mmol) was added dropwise. The reaction was stirred for 2 hours and judged to be complete by LC and TLC. The reaction was concentrated, diluted with NaHCO3 (30 mL) and EtOAc (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3×50 mL), dried, filtered, and concentrated under reduced pressure to afford a mixture of regioisomers. Purification via flash chromatography (2→5% THF in CH2Cl2) afforded 4-(benzyloxy)-6-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.25 as the first eluting isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1.[NH:19]1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)C1>>[CH3:3][C:2]1[N:19]=[N:4][C:5]([N:8]2[CH2:9][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)C1CNC1
Product: Cc1ccc(N2CC(C(=O)OC(C)(C)C)C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-chloro-6-methylpyridazine for 3-bromopyridine and tert-butyl azetidine-3-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[CH:7]=[C:6]([N:8]=[N+:27]=[N-:28])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N′-(2-iodophenyl)urea (77 mg, 0.21 mmol) was added to HCl/H2O (0.21 mL/0.42 mL), and cooled to 0° C. Sodium nitrate (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (20 mg, 24%). EI-MS m/z 396 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1S(Cl)(=O)=O.CN1C=CN=C1.[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([OH:38])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:49])[C@H:25]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C@H:26]([O:38][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@H](O)COCc1ccc(OC)cc1
Agent: Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON=C[C@@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](COCc1ccc(OC)cc1)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 79.1 %

Procedure:
2.03 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.772 mL of 1-methylimidazole were added to a solution of 1.02 g of the (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 20 mL of acetonitrile at room temperature, and the obtained mixture was stirred at room temperature for 1.75 hours, and then at 40° C. for 1.25 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and a solid was removed by filtration. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 1.15 g of (2R,3R,4R)-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)-4-(2,4,5-trichlorophenoxy)pentan al O-methyloxime in the form of a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C(O)C.[CH:21](Br)([CH3:23])[CH3:22]>[OH-].[K+]>[CH:21]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(OC(C)C)c1
Reaction time: 1 h

Procedure:
A 22.7 g (0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 100 ml of 1N-potassium hydroxide solution. To this solution 150 ml of ethanol was added and the mixture was stirred for one hour, which was followed by the addition of 12.3 g (0.1 mol) of isopropylbromide. After the addition of the iso-propylbromide, the reaction mixture was warmed and stirred under reflux for 4 hours. After distillation of most of the ethanol, the oily material remaining was extracted with benzene and the residue was distilled to obtain 20.9 g (77.9%) of a red, viscous oil having a boiling point of 186°C/0.08 mm Hg. The product was recrystallized from a mixture of benzene and n-hexane (1:1 ) as white prismatic crystals having a melting point of 92°C. IR cm-1 (KBr-tablet) νNH 3250(S), νCH 2980(S), νCO 1660(S), 1610(S).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[Cl:25])C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[C:17]([O:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([OH:8])=[C:10]([Cl:25])[CH:11]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(OC(=O)c2ccccc2)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.9 %

Procedure:
A reaction vessel was charged with 35 g of 4-benzyloxy-3-chloro-5-methyl-1-benzoyloxybenzene and 200 ml of ethyl acetate, and the air in the vessel was replaced with nitrogen. Then, 2 g of 10% palladium carbon was added, and the nitrogen in the vessel was replaced with hydrogen, followed by vigorous stirring at room temperature for 10 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered, and the filtrate was concentrated. The residue was silica gel chromatography was subjected to silica gel chromatography, which afforded 25 g of 4-benzoyloxy-2-chloro-6-methylphenol (96% yield).
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:23]([O:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([CH:8]=[C:7]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:18]=1)=[O:21])[CH3:24]
Reactant: CC[n+]1ccc(C)c2ccccc21
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(C=C2C=CN(CC)c3ccccc32)c([N+](=O)[O-])c1

Procedure:
1-Ethyllepidinium iodide (5.8 g., 19.4 mmole) and ethyl 4-chloro-3-nitrobenzoate (4.6 g., 20 mmole) are stirred together in acetonitrile (50 ml.). Diisopropylethylamine (5.2 g., 40 mmole) is added and the mixture refluxed on a steam bath for 6 hours. The mixture is dissolved in 500 ml. ether and extracted five times with 200 ml. portions of water. The ether extract is dried over anhydrous magnesium sulfate. The dried ether solution is evaporated to dryness and then taken up on 25 ml. ether and chilled overnight. The precipitated dye is filtered off, washed with ether and petroleum ether, and dried. The yield is 2.8 g. (40%) with a m.p. of about 100° C.