Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:26])[C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:9]([CH3:17])[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C@H:4]([C:27](=[O:44])[NH:28][C@:29]2([C:34](=[O:43])[NH:35][S:36]([C:39]3([CH3:42])[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:31][C@H:30]2C=C)[CH2:3]1>ClCCCl.Cl[Ru](Cl)=CC1C=CC=CC=1OC(C)C>[OH:1][C@H:2]1[CH2:6][N:5]2[C:7](=[O:26])[C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C@H:9]([CH3:17])[CH2:10][CH:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH:15][C@@H:30]3[CH2:31][C@@:29]3([C:34](=[O:43])[NH:35][S:36]([C:39]3([CH3:42])[CH2:40][CH2:41]3)(=[O:37])=[O:38])[NH:28][C:27](=[O:44])[C@@H:4]2[CH2:3]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: CC(C)Oc1ccccc1C=[Ru](Cl)Cl
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 80 °C

Procedure:
A solution of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (8.40 g, 13.2 mmol) in 1,2-dichloroethane (1500 ml) was sparged with nitrogen for 30 min. and then 1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (“Hoveyda-Grubbs Catalyst 2nd Generation”, 0.413 g, 0.657 mmol) was added. The reaction solution was heated to 80° C. for 2 h. The reaction solution was cooled to room temperature and then was concentrated in vacuo. The resulting residue was subjected to silica gel chromatography (hexane:acetone 80:20 to 40:60) to afford tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate as a brown solid (5.6 g, 70% yield). MS: MS m/z 611.3 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:4]=1[CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:8]2[C:9]([NH:11][C:12](=[O:13])[C:7]=12)=[O:10].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(OCC)C>[Br:22][CH2:21][C:17]1[C:4]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[C:8]3[C:9]([NH:11][C:12](=[O:13])[C:7]=23)=[O:10])=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C)c1Cc1cccc2c1C(=O)NC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: COc1cccc(CBr)c1Cc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0.286 g, 1.02 mmol) in CC4 (25 mL) was added recrystallized N-bromosuccinimide (0.177 g, 0.99 mmol) followed by benzoyl peroxide (28 mg, 0.11 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (25 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (3:1 hexanes-EtOAc) provided 0.31 g (86%) of (6-(bromomethyl)-2-methoxybenzyl)phthalimide as a white solid. 1H NMR (CDCl3) δ 3.78 (s, 3H), 4.90 (s, 2H), 5.00 (s, 2H), 6.83 (d, 1H, J=8.4 Hz), 6.98 (d, 1H, J=7.2 Hz), 7.25 (dd, 1H, J=7.2, 8.4 Hz), 7.67–7.69 (m, 2H), 7.78–7.81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:41])[NH:6]2.Cl>O1CCOCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:41])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Yield: 96 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl 4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline-7-yloxy)propyl]piperazine-1-carboxylate was reacted with hydrogen chloride in dioxane. The crude product was absorbed onto an Isolute SCX column, washing with methanol and eluting with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (96%) as a pale orange foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=O)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@H:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: COCC(Nc1ccccc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Solvent: CO
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 10 mL Schlenk flask were charged [Rh(cod)2]OTf (2.6 mg) [mw. 468.34, 5.5 μmol, s/c 25] and (2S,4S)-skewphos (2.9 mg) [mw. 440.50, 6.6 μmol], and the system was substituted with argon. Deaeration-treated dehydrated methanol (1 mL) was added by argon pressure supply. Under an argon atmosphere, the mixture was stirred at room temperature for 1 hr. Separately, into a 120 mL stainless autoclave was charged benzyl 3-(2-methoxy-1-(phenylamino)ethylidene)-2-oxopyrrolidine-1-carboxylate (50.0 mg) [mw. 366.41, 136 μmol], and the system was substituted with argon. The catalyst in the Schlenk flask was added into the autoclave by argon pressure supply. Furthermore, the inside of the Schlenk flask was washed with dehydrated methanol (4 mL), and the washing was added into the autoclave by argon pressure supply. Hydrogen was filled therein to 5 MPa, and the mixture was stirred at a reaction temperature of 50° C. for 16 hr. The reaction mixture was allowed to cool to room temperature and depressurized. The area percentage of the resultant product, (3aR,4R,9bR)-benzyl 4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, was determined by high performance liquid chromatography to find production at a ratio of 49%. The optical purity was 60% ee.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(OP([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(OCC)=O)C.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (900 mg) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (20 ml), sodium hydride (60%, oily, 200 mg) was added at 0, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (740 mg) was obtained. After the mother liquor was concentrated, the residue was subjected to silica gel column chromatography, and 150 mg of crystals were additionally obtained from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The total was 890 mg (yield: 87%). This was recrystallized from ethyl acetate-isopropyl ether. Melting point: 98–99° C.
Reaction SMILES: [C:1]([C:9](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:1](=[O:8])[CH:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of ethyl 2-benzoyl-3-(4-hydroxyphenyl)propenoate (0.50 g, 1.7 mmol) in CH2Cl2 (15 ml) at 0° C. under an argon atmosphere was added titanium tetrachloride (0.93 ml, 8.3 mmol). The resulting mixture was allowed to stir at room temperature overnight. The reaction was slowly quenched with 3M HCl, then partitioned between EtOAc (50 ml) and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl, and dried (Na2SO4). The solvent was removed in vacuo, and the solid residue was recrystallized from EtOAc/hexanes to afford the title compound (410 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13]2/[CH2:14][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:16][CH2:17]/2)=[C:9]([O:23][CH3:24])[C:8]([CH3:25])=[C:7]2[C:3]=1[C:4](=[O:26])[O:5][CH2:6]2>CCCCCC.ClCCl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13]2/[CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]/2)=[C:9]([O:23][CH3:24])[C:8]([CH3:25])=[C:7]2[C:3]=1[C:4](=[O:26])[O:5][CH2:6]2
Reactant: CCOC(=O)C1CC/C(=C\Cc2c(O)c3c(c(C)c2OC)COC3=O)C1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C1\CCC(C(=O)O)C1)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate with ethyl (E)-3-[2-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopentane -1-carboxylate (prepared e.g, as described with reference to Reaction Scheme ZD-A, Steps 1 through 4) there is obtained (E)-3-[2-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopentane -1-carboxylic acid, m.p. 128°-130° C. (hexane-dichloromethane).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:11][C:10]=1[C@@H:27]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:34]([N:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][C@@H:27]([C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH:13]=[CH:14][C:9]=1[OH:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/CCOCCCCCC#N)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOCCCCCC#N)ccc1O)C(C)C
Temperature: 25 °C

Procedure:
6-{[(3E)-4-{4-(Benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}but-3-en-1-yl]oxy}hexanenitrile (Preparation 24, 935 mg, 1.65 mmol) was dissolved in ethanol (20 ml) and ammonium formate (1.90 g, 30.0 mmol) and 10% palladium hydroxide on carbon (190 mg) added. The reaction was heated under reflux for 1 hour, cooled to room temperature and the reaction filtered through Arbocel™, the filtrate solvent was removed in vacuo to furnish the title compound as a colourless oil, 783 mg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCC1
Yield: 59.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclopentylamine (0.09 ml, 0.92 mmol), and acetic acid (0.1 ml) were used to give 75 mg (0.24 mmol, 59.7% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23](OC1C=CC=CC=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)N1CCCCC1
Yield: 66.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.1 of Example 1, followed by treating, under the same conditions as those of step 1.2 of Example 1, 1 g of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine with 10 ml de piperidine, 0.68 g of 1,4-dibenzyl-2-(1′-piperidinocarbonyloxymethyl)piperazine is obtained in the form of a viscous product. Yield: 66.5%. Rf=0.09 (70/30 v/v ether/petroleum ether).
Reaction SMILES: C(N1C=NN=C1C1C=CN=CC=1)C.C(N1C(C2C=CN=CC=2)=NN=C1[CH2:27][OH:28])C.C(N1C(C2C=CN=CC=2)=NN=C1C=O)C.[F:44][C:45]1[CH:46]=[C:47]([C:52]2[N:53]([CH3:58])[C:54](=S)[NH:55][N:56]=2)[CH:48]=[C:49]([F:51])[CH:50]=1>>[F:44][C:45]1[CH:46]=[C:47]([C:52]2[N:53]([CH3:58])[C:54]([CH:27]=[O:28])=[N:55][N:56]=2)[CH:48]=[C:49]([F:51])[CH:50]=1
Reactant: CCn1c(CO)nnc1-c1ccncc1
Reactant: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Agent: CCn1c(C=O)nnc1-c1ccncc1
Agent: CCn1cnnc1-c1ccncc1
Product: Cn1c(C=O)nnc1-c1cc(F)cc(F)c1

Procedure:
The title compound is prepared analogously to the sequence described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example 21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (example 22), and 4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example 23a) by using 5-(3,5-Difluoro-phenyl)-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione as starting material.
Reaction SMILES: [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](=[CH:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:19][N:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccnc(C=C2c3ccccc3CCc3ccccc32)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccnc(C=C2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
Mix 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-4-ylamine (176 mg, 0.590 mmol), triethylamine (600 μL, 4.13 mmol), N,N-dimethylaminopyridine (7 mg, 0.059 mmol), and methanesulfonyl chloride (137 μL, 1.769 mmol) in CH2Cl2 (10 mL). Stir at room temperature for 3 h and dilute with H2O (15 mL). Extract into CH2Cl2, dry (MgSO4) and concentrate organics. Dissolve crude product in THF (10 mL), add 1.0M tetrabutylammonium fluoride (0.89 mL), and heat to reflux for 4 h. Cool to room temperature and dilute with H2O. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (10 g), eluting with 80% →90% ethyl acetate/hexanes to afford 150 mg (68%) of the title compound as a yellow foam. MS (ES) 377 (M+H), 375 (M−H); BPLC shows 96% purity.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1N
Yield: 95 %

Procedure:
To a stirred solution of 2-amino-3-hydroxybenzoic acid (1.22 g, 8.0 mmol) in MeOH (80 mL) was added SOCl2 (9.52 g, 80.0 mmol) dropwise at 0° C. The mixture was then heated at reflux overnight. Most of the methanol was removed and the residue was partitioned between DCM and saturated aqueous NaHCO3. The organic phase was washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give methyl 2-amino-3-hydroxybenzoate (1.27 g, 95%). LC-MS (ES-API); rt 8.09 min; m/z calculated for C8H9NO3 [M+H]+ 168.1, found 168.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: CCOC(=O)c1nn(CC2CC2)cc1[N+](=O)[O-]
Yield: 46 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and bromomethyl-cyclopropane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 88 mg (23%) of the desired regioisomer and 179 mg (46%) of 1-cyclopropylmethyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1C=CC=CC=1C(=O)CC(=O)CC(C1C=CC=CN=1)=O.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30](=O)[CH2:31][C:32](=[O:45])[CH2:33][C:34]([C:36]2[CH:41]=[C:40]([O:42][CH2:43][CH3:44])[CH:39]=[CH:38][N:37]=2)=O)[CH:25]=1)[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[NH:1][C:34]([C:36]3[CH:41]=[C:40]([O:42][CH2:43][CH3:44])[CH:39]=[CH:38][N:37]=3)=[CH:33][C:32](=[O:45])[CH:31]=2)[CH:25]=1)[CH3:22]
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Reactant: CCOc1ccnc(C(=O)CC(=O)CC(=O)c2cc(OCC)ccn2)c1
Product: CCOc1ccnc(-c2cc(=O)cc(-c3cc(OCC)ccn3)[nH]2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 2 for 1,5-di-pyridin-2-yl-pentane-1,3,5-trione, but instead the ethoxy-substituted triketone from Example 20 is used. Pure 4,4″-diethoxy-1′H-[2,2′;6′,2″]terpyridin-4′-one can be obtained by chromatography on silica gel (chloroform/methanol 9:1, 0.1% NH4OH) in the form of a white crystalline powder. 1H-NMR (360 MHz, CDCl3): 1.37 (t, 6H, 7.2 Hz); 4.05 (q, 4H, 7.2 Hz); 6.77 (dd, 2H, J=5.9, 2.3 Hz), 6.99 (br s, 2H), 7.30 (br s, 2H); 8.42 (d, 2H, J=5.9 Hz). MS (EI pos., 70 eV), m/z=337 (75, [M+]); 322 (90); 309 (100); 281 (75); 28 (85).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[O:6][C:5]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[CH2:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4][C:3]1=[O:26].ClC1C(=O)CC(C2CCCC2)(CCC#CC2C=CC=C(O)C=2)OC1=O.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[N:56]2[N:60]=[C:61]([SH:63])[N:62]=[C:55]2[N:54]=1>>[CH:9]1([C:5]2([CH2:14][CH2:15][NH:16][C:17](=[O:25])[CH2:18][CH2:19][C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[CH2:4][C:3]([OH:26])=[C:2]([S:63][C:61]3[N:62]=[C:55]4[N:54]=[C:53]([CH3:52])[CH:58]=[C:57]([CH3:59])[N:56]4[N:60]=3)[C:7](=[O:8])[O:6]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(CCc1ccco1)NCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCNC(=O)CCc4ccco4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The desired product was prepared analogously to example F(7), substituting N-[2-(5-chloro-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-3-furan-2-yl-propionamide from Step 3 below in place of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione and 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol in place of 2-mercaptothiazole. Yield: 11 mg, 8%. MS (ESI): 524 (M−H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:6]([C:24]([O:26]C)=[O:25])[CH:5]=1.Cl>O1CCCC1>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:7]2[CH:22]=[CH:23][C:4]([Cl:3])=[CH:5][C:6]=2[C:24]([OH:26])=[O:25])[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cc(Cl)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C(=O)O)CC1
Reaction time: 3 h
Yield: 95.8 %

Procedure:
An aqueous solution of 2N sodium hydroxide (20 ml) was added to a solution of tert-butyl 4-[4-chloro-2-(methoxycarbonyl) phenoxy]piperidine-1-carboxylate (8.1 g, 22.0 mmol) in tetrahydrofuran (70 ml) at 45° C. The mixture was stirred vigorously for 3 h then adjusted to pH 2 with 2N hydrochloric acid. The product was extracted with ethyl acetate and the organic layer washed repeatedly with water until the washings were pH 6. The organic layer was dried over magnesium sulfate and evaporated. The residue was azeotroped with toluene to give the title compound as a colourless solid (7.5 g).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][C@@:2]([NH2:1])([C:3]([OH:5])=[O:4])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(C)(N)C(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
tert-Butyl 2-amino-3-(4-methoxyphenyl)-2-methylpropanoate (0.30 g, 1.13 mmol) was dissolved in CH2Cl2 (3 mL) and BBr3 (0.85 g, 3.39 mmol, 3 equiv) was added at room temperature. The reaction mixture was stirred for 1.5 h and treated with a NaHCO3 solution to a basic pH. The aqueous phase was isolated. Solid started to precipitate in the aqueous phase in 30 min. Solid was filtered in 16 h and was washed on a filter with CH2Cl2 (2 mL) and water (2 mL). The solid was air-dried to afford metyrosine [0.10 g; 45.4%] as a white solid [HPLC 80.7% (Metyrosine; AUC; tR=2.32 & 2.57]. 1H NMR (500 MHz, TFA-d): δ 8.60 (d, J=8.7 Hz, 2H, Ar), 8.39 (d, J=8.7 Hz, 2H, Ar), 4.91 (d, J=15.0 Hz, 1H, CH2), 4.67 (d, J=15.0 Hz, 1H, CH2), 3.30 (s, 3H, CH3). Optical rotation (α30D, c=1.080, 1=10 mm, NaOAc/CuSO4/H2O/AcOH)+148.1.