Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[CH:13]=1.[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1>>[CH3:14][O:15][C:16](=[O:32])[CH:17]([CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:10]([C:8]1[S:7][C:6]2[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH:9]=1)=[O:12])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1cc2ccc(Cl)cc2s1
Yield: 78.1 %

Procedure:
6-Chlorobenzo[b]thiophene-2-carboxylic acid (0.24 g, 1.14 mmol) is coupled to 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.295 g, 1.14 mmol) as described in EXAMPLE 1B to give 3-(3-cyanophenyl)-2-[1-(6-chlorobenzo[b]thiophene-2-carbonyl)-pyrrolidin-2-yl]-propionic acid methyl ester (0.40 g, 0.89 mmol). This material is treated and purified as described in EXAMPLE 1C to obtain the title compound (0.27 g, 0.46 mmol). NMR (DMSO-d6, 300 MHz) 9.31-9.15(m, 4H), 8.13(s, 1H), 7.95-7.85(m, 2H), 7.62-7.40(m, 5H), 4.53, 4.38(two m, 1H), 3.95-3.55(m, 2H), 3.60-3.53(m, 1H), 3.52-3.49(two s, 3H), 3.14-2.95(m, 1H), 2.94-2.80(m, 1H), 2.18-1.55(m, 4H): MS m/z: [M+H]+=470. Elemental analysis calculated with 1.0 mole of H2O: C=51.87, H=4.52, N=6.98; found C=51.93, H=4.23, N=6.75.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1)#N.C(O)(=[O:28])C.N1C=CC=CC=1>[Ni].O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1)=[O:28]
Reactant: CC(=O)O
Reactant: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc(NS(C)(=O)=O)cc21
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)n1cc(-c2ccc(C=O)cc2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Method Z-1 Place N-[3-(4-Cyano-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (500 mg, 1.41 mmol), sodium hyposulfite hydrate (311 mg, 3.53 mmol) and Raney nickel (50% soln in water, 700 μL, 2.96 mmol) in a round bottom flask then add water (6 mL), glacial acetic acid (12 mL) and pyridine (12 mL). Warm to 50° C., and stir for 1.5 hours. Cool to ambient temperature; dilute with water (10 mL); and extract with ethyl acetate (10 mL×3). Combine organic layers, and wash with saturated sodium bicarbonate, water (×3) and brine. Dry over sodium sulfate, and concentrate in vacuo. Purify residue by flash chromatography on silica (2-50% ethyl acetate in hexanes) to give N-[3-(4-formyl-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (413.1 mg, 82%). LRMS (API ES−)=355.0 (M−H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19]1>C(O)CO.C(OCC)(=O)C>[CH:18]1([CH2:21][CH2:22][NH:23][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[C:4]([NH2:17])[N:3]=2)[CH2:20][CH2:19]1
Reactant: NCCC1CC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: Nc1nc(NCCC2CC2)nc2c1ncn2C1CCCCO1
Temperature: 120 °C
Yield: 100.2 %

Procedure:
To a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (3.49 g) in ethylene glycol (17 ml) at room temperature was added cyclopropylethylamine (4.69 g). The reaction mixture was heated to 120° C. with reflux condenser overnight, resulting in a yellow/brown solution. The reaction was allowed to cool, taken up in ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark brown gum (4.17 g)
Reaction SMILES: [CH2:1]([Hg:6][CH2:7][CH2:8][CH2:9][CH:10]=C)[CH2:2][CH2:3][CH:4]=C.C([Mg]Br)CCC=C.BrCCCC=C.[Mg]>O1CCCC1.O>[CH2:1]([Hg:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC[Hg]CCCC=C
Agent: C=CCCCBr
Agent: C=CCCC[Mg]Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[Hg]CCC=C
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Preparation of bis(4-pentenyl)mercury : To a solution of 4-pentenyl magnesium bromide, prepared from 25 g of 1-bromo-4-pentene (169 mmole) and 5 g of magnesium (208 mmole) in 40 mL of tetrahydrofuran, was added dropwise at 50° C. with stirring a solution of 25.2 g of mercuric chloride (93 mmole) in 50 mL of tetrahydrofuran. After stirring for 2 hours at 60° C., the reaction mixture was hydrolyzed with water at 0°-5° C. The organic layer was separated from aqueous layer; the product was distilled to give bis-3-butenyl mercury in 67% yield. The identity of the compound was confirmed by gas chromatography and 1H NMR.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH:17]=1
Reactant: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2nc3cccnc3[nH]2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
The title compound was prepared by condensing 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 222–224° C., 60% yield. 1H-NMR (DMSO-d6) δ 8.75 (s, 1H), 8.38–8.40 (m, 1H), 8.18 (d, J=9 Hz, 2H), 7.99–8.08 (m, 4H), 7.83 (d, J=15 Hz, 1H), 7.28–7.33 (m, 1H), 6.91 (s, 1H), 4.11 (s, 3H), 4.04 (s, 3H). MS m/z=430 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Cl:16][S:17](O)(=[O:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[P+]=O>C(Cl)Cl>[C:13]([NH:12][C:4]1[S:5][C:6]([C:7]2[S:8][C:9]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1)(=[O:15])[CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2cccs2)s1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-[4-methyl-5-(2-thienyl)-1,3-thiazol-2-yl]acetamide, prepared in Step I (500 mg; 2.10 mmol; 1 eq.) is dissolved in DCM (30 ml). The reaction mixture is cooled down to 0° C. and chlorosulfonic acid (0.70 ml; 10.49 mmol; 5 eq.) dissolved in DCM (30 ml) is added dropwise over 15 min. The solution becomes pink. It is stirred 15 minutes at 0° C. Phosphorus pentachloride (873.7 mg; 4.20 mmol; 2 eq.) and phosphorus oxide chloride (0.78 ml; 8.39 mmol; 4 eq.) are added successively. The reaction mixture is stirred for 2 additional hours at room temperature. It is poured on ice and the desired product is extracted with 2 portions of EtOAc, dried over MgSO4, and evaporated, affording 5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride as yellow solid (650 mg; 92%). M″(ESI): 335.08; M+ (ESI): 337.08.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][CH2:35][N:36]3[C:39](=[O:41])[CH3:40])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([N:29]([CH:26]3[CH2:25][CH2:24][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:28][CH2:27]3)[C:9](=[O:11])[C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:38]=2)[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCc2ccc(N(C(=O)C#Cc3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of phenyl-propynoic acid (220 mg, 1.5 mmol) and thionyl chloride (3.0 mL) in toluene (3.0 mL) was heated at reflux for 4 h. The reaction mixture was cooled to rt and the excess thionyl chloride and toluene were removed under reduced pressure. The resulting crude acid chloride was dissolved in CH2Cl2 (5 mL) and treated with 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (349 mg, 1.0 mmol) and TEA (0.28 mL, 2.0 mmol) at rt for 20 h. The reaction mixture was concentrated, and the residue was purified on silica gel (60-70% EtOAc/hexanes) to afford the title compound (402 mg, 84%). 1H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 7.28-7.18 (m, 9H), 7.09 (d, J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 4.65-4.59 (m, 1H), 4.13 (t, J=8.5 Hz, 2H) 3.44 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 2.89 (d, J=10.7 Hz, 2H), 2.22 (s, 3H), 2.10 (t, J=10.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.63-1.58 (m, 2H). MS: exact mass calculated for C31H31N3O2, 477.24; m/z found, 478.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:45]=[C:46]([N+:48]([O-])=O)[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:43])([F:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:48][C:46]1[CH:45]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:42])([F:43])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 83.1 %

Procedure:
5.95 g (8.38 mmol) of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)-prop-2-enoyl)oxy]-hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 54 mL of N,N-di-methylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate is added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 4.53 g of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenyl]-methoxy}-phenyl)-prop-2-enoyl)oxy]hexyl 3,5-diaminobenzoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([OH:11])[CH:10]=1.C(N(CC)CC)C.[Cl:27][C:28]1[C:29]([O:38][C:39]2[CH:50]=[CH:49][C:42]([O:43][CH:44]([CH3:48])[C:45](Cl)=[O:46])=[CH:41][CH:40]=2)=[N:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>O1CCCC1>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([O:11][C:45](=[O:46])[CH:44]([O:43][C:42]2[CH:41]=[CH:40][C:39]([O:38][C:29]3[C:28]([Cl:27])=[CH:33][C:32]([C:34]([F:35])([F:36])[F:37])=[CH:31][N:30]=3)=[CH:50][CH:49]=2)[CH3:48])[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1O
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Yield: 66.4 %

Procedure:
5-(2,4-Dichlorophenoxy)-2-nitrophenol (0.8 g) and triethylamine (0.6 ml) were dissolved in dry tetrahydrofuran (10 ml), and the solution was stirred at room temperature for 2 hours, with an addition of a solution of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride (0.8 g), in dry tetrahydrofuran (10 ml). After completing the reaction, the solvent was distilled off under a reduced pressure and the residue was dissolved in methylene chloride (20 ml), followed by washing with 1 N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution. The resultant reaction mixture was dried over anhydrous magnesium sulfate, ether was evaporated under a reduced pressure, and the resultant residue was subjected to silica gel medium pressure column chromatography for purification. Thus, the title compound (0.9 g) was obtained in the form of a colorless oily product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:23][C@H:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:23][CH:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:9]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Product: CC(C)CC(CO)NC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinic acid and rac-leucinol as starting materials, MS (ISP) 476.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][C:2]1[C:3]([CH3:15])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(C(=O)OC)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc(C(=O)OC)c(OC)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl 4-hydroxy-3-methyl-2,5-thiophene dicarboxylate (4.26 g) in acetone (100 ml) containing anhydrous potassium carbonate (2.34 g) was stirred for 1 hour at room temperature. Dimethyl sulphate (1.62 ml) was added and the solution refluxed for 2 hours. The solvent was then removed under vacuum and, after treating the residue with water-ethyl acetate, was extracted several times with ethyl acetate; the organic extracts were collected, washed with water, dried over anhydrous magnesium sulphate, filtered and the solvent evaporated to give a solid, m.p. 61°-64° ex methanol.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:31][CH:30]=1>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[CH:33][CH:34]=3)[N:21]=2)=[CH:18][CH:19]=1)([CH3:13])[CH3:12])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(-n4ccnc4)cc3)ncc2Cl)cc1
Yield: 23.4 %

Procedure:
Sodium hydride (330 mg, 8.25 mmol) was added to a solution of 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.0 g, 2.62 mmol) and 1-(4-aminophenyl)-1H-imidazole (438 mg, 2.75 mmol) in dry THF (40 ml) under N2 and the mixture heated to reflux for 3 h. The reaction was quenched with H2O (5 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×150 ml). The ethyl acetate extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography (silica; 2% ethyl acetate in CH2Cl2) to give 4-[4-(1-tert-butoxy carbonylamino-1-methylethyl)phenyl]-5-chloro-N-[4-(1-imidazolyl)-phenyl]pyrimidine-2-amine as a yellow solid (310 mg) m.p. 218-220°. This intermediate was stirrd at room temperature in trifluoroacetic acid (4 ml) for 3 h before concentrating the reaction in vacuo. The residue was diluted with 2M NaOH (aq) (50 ml) and extracted with CH2Cl2-ethanol (20:1) (3×50 ml), the extracts dried (MgSO4) and concentrated in vacuo. Trituration of the resultant solid with diethylether-ethyl acetate (4:1) gave the title compound as a pale yellow solid (175 mg) m.p. 199-201°. δH (d6DMSO) 10.05 (1H, bs), 8.62 (1H, s),8.15 (1H, s), 7.88 (2H, d, J 7.9 Hz), 7.78 (2H, d, J 8.5 Hz), 7.69 (2H, d, J 8.5 Hz), 7.65 (1H, s), 7.55 (2H, d, J 8.8 Hz), 1.42 (6H, s). MS (ESI) 405 (MH+, 100%).
Reaction SMILES: C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:9]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1)C=CCCC.[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(OCC)(=O)C>CN(C)C1C=CC=CC=1>[N:26]1[N:22]([C:9]2[CH:10]=[C:11]([C:14]([CH3:20])([CH3:21])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:12]=[C:13]([CH:33]([CH2:34][CH2:35][CH3:36])[CH:32]=[CH2:31])[C:8]=2[OH:7])[N:23]=[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=12
Reactant: CCCC=CCOc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1
Reactant: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: C=CC(CCC)c1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 22 h
Yield: 84 %

Procedure:
5.6 g (13.8 mmol) of 2-(2-hex-2-enyloxy-5-(1,1,3,3-tetramethylbutyl)-phenyl)-2H-benzotriazole, prepared as described above, in 100 ml of N,N-dimethylaniline were heated to reflux. The reaction was traced by tlc. (hexane:ethyl acetate=7:3). After 22 hours the reaction was complete. N,N-dimethylaniline was distilled off and the product freed from residual amine in a high vacuum to yield 4.7 g (84%) of 2-(benzotriazole-2-yl)-4-(1,1,3,3-tetramethylbutyl)-6-(1-hexen-3-yl)-phenol as an orange liquid.
Reaction SMILES: C(OC1C=[CH:13][C:12]([NH:15][C:16]2[N:21]=CN=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[CH2:31][C:32](NC4C=CC(F)=CC=4)=O)=[CH:25][C:24]=3[F:43])[CH:17]=2)=CC=1)C1C=CC=CC=1.CCO[C:47]([CH3:49])=O.C([O-])(O)=O.[Na+]>ClCCCl>[NH2:21][C:16]1[CH:17]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:42])[C:31]3[CH:32]=[CH:12][N:15]=[C:16]([NH:21][C:47]4[CH:49]=[CH:25][C:24]([F:43])=[CH:23][CH:28]=4)[CH:17]=3)=[CH:25][C:24]=2[F:43])[CH:13]=[CH:12][N:15]=1
Reactant: CCOC(C)=O
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1cc(Oc2ccc(NC(=O)c3ccnc(Nc4ccc(F)cc4)c3)cc2F)ccn1
Reaction time: 8 h
Yield: 6.3 %

Procedure:
A solution of 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 450 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL) was added slowly to a solution of acylchloride obtained above in 1,2-dichloroethane (10 mL) at ice bath temperature with stirring. The reaction mixture was allowed to stand at rt overnight. To the reaction mixture were added EtOAc (150 mL) and saturated aq. NaHCO3 solution (50 mL). The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to obtain the title compound (69 mg, 6.3%) as a yellow solid (bis-TFA salt). 1H NMR (DMSO-d6) δ 10.90 (s, 1H), 9.32 (s, 1H), 8.27 (d, 1H, J=5.5 Hz), 7.92-7.07 (m, 11H), 6.68 (dd, 1H, J=7.1, 2.2 Hz), 6.10 (d, 1H, J=2.2 Hz); MS (ESI+) m/z 217.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-methoxynicotinate (Avacado), 0.1 g (0.6 mmol) in 5 mL of tetrahydrofuran was added a solution of 1.2 mL of 5 N sodium hydroxide in 5 mL of water. The mixture was stirred for four hours at ambient temperature, acidified to pH=3 with 5 N HCl and concentrated to dryness to yield the crude desired compound. MS (ion spray) 154.0 (M+1). The crude product was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:18]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccc(Cl)c(Cl)c1

Procedure:
2-Amino-4-chloro-5-nitrophenol (34.0g, 0. 18 mole) was slurried in ethyl acetate (250 ml). 3,4-Dichlorobenzoyl chloride (38.g, 0.18 mole) was added and the reaction mixture refluxed for 2 h. After cooling, the beige precipitate was filtered then slurried in hot ethyl acetate (200 ml). Filtration gave the product as a beige solid, 50.5 g, (77%), mp.263-265° C.
Reaction SMILES: C(O[C:4]([C:6]12[CH2:12][N:9]([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])C.Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C>Cl.S(Cl)(Cl)=O>[N:9]12[CH2:12][C:6]([C:4]([N:15]([O:16][CH3:17])[CH3:14])=[O:5])([CH2:7][CH2:8]1)[CH2:11][CH2:10]2
Reactant: CNOC
Reactant: CCOC(=O)C12CCN(CC1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)C12CCN(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Ethyl-1-azabicyclo[2.2.1]hept-4-ylcarboxylate (D20, 1.75 g, 0.01 mole) in concentrated hydrochloric acid (50 ml) was heated under reflux for 1.5 h. The reaction was then concentrated in vacuo to give a solid which was dissolved in thionyl chloride (30 ml) and heated under reflux for 1.5 h. The mixture was then evaporated to dryness, and freed from residual thionyl chloride by co-evaporation which toluene. The residue was then dissolved in dry acetonitrile (50 ml) and treated with N,O-dimethylhydroxylamine hydrochloride (0.73 g, 0.0075 mole) and triethylamine (4.5 ml, 0.032 mole). The mixture was stirred overnight at room temperature and then filtered to remove most of the triethylamine hydrochloride. The filtrate was evaporated to dryness and saturated potassium carbonate solution was added. The product was then extracted into chloroform (3×100 ml) and the combined extracts were dried (Na2SO4), filtered and evaporated to dryness to give the title compound (D21) as a white solid (0.79 g, 41%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>C(OCC)C>[CH2:20]=[C:21]([C:26]([O:8][C:7]1[C:6]([F:9])=[C:5]([F:10])[C:4]([F:11])=[C:3]([F:12])[C:2]=1[F:1])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C(F)(F)F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (7.5 g, 0.040 mole) and triethylamine (4.5 g, 0.044 mole) in dry ethyl ether (7 ml) are added gradually to CH2═C(CF3)CF2OSO2F (11 g, 0.045 mole) in ethyl ether (14 ml) at 20° C. The reaction mixture is agitated at 20° C. for 30 minutes and washed in turn with water, dilute aqueous HCl, water, sodium bicarbonate solution, and water and the resulting ether solution is dried over MgSO4. Distillation of the dried mixture gives CH2═C(CF3)CF2OC6F5 (9.8 g, 73% yield, b.pt. 86-88° C. at 20 mm Hg).