Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)CC([O-])=O.[C:8](N1C(C2C=CC=CC=2B(O)O)=NN=N1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:42][C:43](=[O:92])[C@@H:44]([N:48]([C:86](=[O:91])[CH2:87][CH2:88][CH2:89][CH3:90])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[C:62]2[N:66](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:65]=[N:64][N:63]=2)=[CH:52][CH:51]=1)[CH:45]([CH3:47])[CH3:46]>>[CH3:90][CH2:89][CH2:88][CH2:87][C:86]([N:48]([C@H:44]([C:43]([OH:42])=[O:92])[CH:45]([CH2:46][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:47])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[C:57]([C:62]3[N:66]=[N:65][NH:64][N:63]=3)=[CH:58][CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:55]=1)=[O:91]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@H](C(=O)OC)C(C)C
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)CC(=O)[O-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1)[C@H](C(=O)O)C(C)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
WO 2007/005967 discloses the condensation of p-Bromobenzylbromide with valine methyl ester to give (S)-methyl-2-(4-bromobenzylamino)-3-methyl butanoate which on reaction with valeryl chloride to give (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate. (S)-methyl-2-(4-bromobenzyl)pentanamido)-3-methylbutanoate is treated with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid to give (S)-3-methyl-2-{pentanoyl-[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amino}butyric acid methyl ester and base hydrolysis to give trityl valsartan. Triltyl valsartan is treated with an acid to give valsartan.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)c1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a 15 ml round-bottomed flask was added methyl 2-(quinolin-6-yl)propanoate (1.0 g, 4.7 mmol), methanol (5.0 ml, 12 mmol) and aq. sodium hydroxide (5 M, 2.3 ml, 12 mmol). The mixture was stirred at 25° C. for 24 h. The mixture was neutralized with aq. HCl (5 M, 2.3 mL, 12 mmol). After sitting overnight a white precipitate had formed. The mixture was filtered and the filtercake was washed with water and then dried in vacuo to afford the title compound as a white solid (0.72 g, 77%). MS (ESI, pos. ion) m/z: 202 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([NH:15]C(=O)OC(C)(C)C)[CH2:12]1.[ClH:23]>CO>[ClH:23].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([NH2:15])[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccc3ccccc3n2)C1
Agent: Cl
Solvent: CO
Product: NC1CN(c2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To tert-butyl (1-(quinolin-2-yl)azetidin-3-yl)carbamate (0.8 g, 2.9 mmol) was added 4 M HCl in MeOH (20 mL). The reaction mixture was stirred at room temperature for 30 min and concentrated. The remained solid was dried under high vacuum to give 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (557 mg, 2.8 mmol, 96% yield) as a white solid. ESI-MS (M+1): 200 calc. for C12H13N3 199.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]3([CH2:14][C:15]4([O:21][C:7]=2[CH:6]=[C:5]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[S:13][CH2:12][CH2:11][S:10]3.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9]3([CH2:14][C:15]4([O:21][C:7]=2[CH:6]=[C:5]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[S:13][CH2:12][CH2:11][S:10]3
Reactant: CCOC(=O)COc1cc(OC)c2c(c1)OC1(CCCCC1)CC21SCCS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OCC(=O)O)cc2c1C1(CC3(CCCCC3)O2)SCCS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl {(5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Preparation 49) (0.5 g, 1.44 mmol), ethanedithiol (0.149 g, 1.59 mmol), dry benzene (10 ml), and p-toluenesulfonic acid (0.013 g, 0.076 mmol) is heated to reflux for 12 hours under conditions for azeotropic dehydration. The solvent is removed under reduced pressure. The residue is applied to a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:9). The eluate is applied to a Lober column and eluted with a mixture of ethyl acetate and hexane (1:2) to obtain ethyl {(5-methoxy-3,4-dihydrodispiro[2H-1-benzopyran-2,1'-cyclohexan-4,2"-[1,3]dithiolan]-7-yl)oxy}acetate as an oil (0.50 g, 82.1%). A mixture of the ester (0.49 g, 1.16 mmol), 1N sodium hydroxide (1.27 ml, 1.27 mmol), and ethanol (5 ml) is stirred at room temperature for 0.5 hours. The reaction mixture is made acid with 1N HCl and distilled under reduced pressure at room temperature to remove ethanol. The residue is extracted with diethyl ether. The extract is washed with saturated brine, dried, and the solvent is removed under reduced pressure. The residue is treated with a mixture of diethyl ether and hexane to obtain the title compound as a crystalline soild (0.43 g, 93.7%). Recrystallization from ethyl acetate gives a product having a melting point of 189°-190° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[CH:7]([N:8]=[CH:19][C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccs1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)CC(N=Cc1cccs1)C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a stirred solution of leucine t-butyl ester (10 g) in toluene (100 mL) is added thiophene-2-carboxaldehyde (5.0 mL) and the mixture is heated to 90° C. for 2 hours. The mixture was cooled, washed with water, dried over magnesium sulfate, filtered, and evaporated to an oil (14.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([SH:8])[CH:7]=1.[C:10](=S)=[S:11].C(O)(=O)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:10]([SH:11])[S:8][C:6]=2[CH:7]=1
Reactant: S=C=S
Reactant: Nc1ccc(Cl)cc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.4 %

Procedure:
4-Chloroaniline (14.3g, .112mol) was dissolved in 30 mL of glacial acetic acid and added slowly to S2Cl2 (75 mL) cooled in a CH2OH--ice bath. The reaction was stirred for 15 hours at room temperature. It was then increased to 50° C. for 4 hours and then to 78° C. for 3 hours. The reaction was cooled and 100 mL of dry benzene added. The mixture was stirred for 30 minutes and filtered. The product was washed two times with 25 mL of benzene. The green/yellow substance was added to 250 mL of crushed ice and 150mL of H2O and stirred 3 hours. The purple product was filtered and added with vigorou stirring to cooled 5% NaOH. The reaction was stirred to one hour, filtered and the pH adjusted to 7 with dilute acetic acid. The product precipitated and was isolated by vacuum filtration to yield 10.7g of 5-chloro-2-aminobenzenethiol (59.8% yield): m.p. 70° -72° C.; NMR(DMSO-d6) δ7.3-6.7(m, 3H); 5.7-4.7(s, 3H); mass spectrum, m/e 159(M calcd. 159.6) 5-Chloro-2-aminobenzenethiol(15g, 0.095mol) was dissolved in 5% NaOH and 17mL of carbon disulfide were added. The reaction was stirred 15 hours at room temperature and heated at reflux for 3 hours. The pH of the reaction was adjusted to 6 with dilute acetic acid and filtered to yield 16.9g of 6-chloro-2-mercaptobenzothiazole (89.4% yield): m.p. 243° -246° C. (decomposes); NMR(DMSO-d6) δ11.5(s, lH); 8.0-7.2(m, 3H)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[CH2:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]4)[CH:11]=3)[CH:14]=2)=[CH:25][C:26]=1[C:31]([F:32])([F:33])[F:34]
Reactant: CCN1CCNCC1
Reactant: O=C(CCc1cccc(Oc2ccnc(NC(=O)CCl)c2)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(CC(=O)Nc2cc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)ccn2)CC1

Procedure:
A mixture of 3-[3-({2-[(chloroacetyl)amino]pyridin-4-yl}oxy)phenyl]-N-[4-chloro-3-(trifluoromethyl)phenyl]-propanamide (0.050 g, 0.090 mmol), 1-ethylpiperazine (0.040 mL, 0.29 mmol), and K2CO3 (0.050 g, 0.36 mmol) was stirred at 60° C. in DMF for 1 h. The mixture was concentrated and partitioned between EtOAc and water. The organic solution was concentrated and the residue was purified by column chromatography to give A-192. 1H NMR (400 MHz, d6-DMSO) δ: 10.98 (m, 1H), 10.60 (m, 1H), 8.21 (m, 2H), 7.83 (dd, 1H), 7.63 (d, 1H), 7.60 (m, 1H), 7.41 (t, 1H), 7.21 (d, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.75 (dd, 1H), 4.85 (br, 6H), 3.84 (br, 1H), 3.39 (br, 1H), 3.22 (br, 2H), 3.13 (m, 2H), 2.95 (t, 2H), 2.70 (t, 2H), and 1.23 (t, 3H). LCMS: (FA) ES+ 590.3 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:23].[CH2:24]([O:26][C:27](=[O:50])[C@H:28](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:25].C(OCC)(=O)C.CCCCCC.Cl>C(OCC)(=O)C.O1CCCC1>[CH2:24]([O:26][C:27]([C@@H:28]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)[C:3]1=[O:23])[CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:50])[CH3:25]
Reactant: CC(C)c1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@H](CCC1CCCCC1)NC1CCc2ccccc2N(Cc2ccc(C(C)C)cc2)C1=O

Procedure:
Was prepared analogously to Example 1c) starting from 3-(R/S)-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and (R)-alpha-[[(4-nitrophenyl)sulfonyl]-oxy]-4-phenylbutyric acid ethyl ester (Helv. Chim. Acta 71 (2), 337, 1988). Flash chromatography (eluant: ethyl acetate/hexane: 1:4) yields the two pure diastereoisomeric forms which, after being dissolved in ethyl acetate/tetrahydrofuran, are each converted separately into the corresponding hydrochloride by treatment with 3 equivalents of 1N hydrochloric acid. Rf values of the free bases (eluant ethyl acetate/hexane):
Reaction SMILES: CC1N=C(N[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])SC=1C1C=CN=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[S:32][C:31]([NH2:33])=[N:30][C:29]=2[CH3:34])[CH:25]=[C:24]([CH3:35])[N:23]=1>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[S:32][C:31]([NH:33][C:14]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[O:15])=[N:30][C:29]=2[CH3:34])[CH:25]=[C:24]([CH3:35])[N:23]=1
Reactant: Cc1cc(-c2sc(N)nc2C)cc(C)n1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Product: Cc1cc(-c2sc(NC(=O)n3ccnc3)nc2C)cc(C)n1

Procedure:
The titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine with 5-(2,6-Dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]4[CH2:21][CH2:20]4)[CH2:23][CH2:24]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CN(C2CC2)CCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 31 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (8.2 g, 33 mmol) in EtOH (115 mL) was added Et3N (16.7 g, 165 mmol), followed by 1-cyclopropylpiperazine (5 g, 39.6 mmol). The mixture was heated at reflux for 12 h. Then the mixture was evaporated to remove EtOH. Water (120 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with a mixture of EtOAc/petroleum ether (1:10 with 0.1% NH4OH added) to give 3.46 g (31%) 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[O:27]1CCC[CH2:28]1>>[Cl:8][C:6]1[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:28](=[O:27])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Reactant: C1CCOC1
Product: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 65 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-4-chloro-5-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D85, 200 mg, 0.52 mmol) in tetrahydrofuran (2 ml) was treated with N,N′-carbonyldiimidazole (125 mg, 0.78 mmol) and heated at 50° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with Na2CO3 solution (5 ml) and extracted with ethyl acetate (2×10 ml). The combined extract was dried (MgSO4), concentrated under vacuum to leave the title compound as an oil (140 mg, 65%). M+−H=408.2.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.N1C=CC=CC=1.O>O1CCOCC1.C([O-])(=O)C.[Cu+]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2=[O:1])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
To a solution of 2-hydroxy-3-nitropyridine (Aldrich, 3.0 mmol, 420 mg) in 1,4-dioxane (20 mL), were added 4-fluorophenyl boronic acid (Combi-block, 6.0 mmol, 840 mg), copper(I) acetate (Aldrich, 4.5 mmol, 815 mg) and pyridine (2 mL). The reaction was heated at 80° C. for 20 h. After cooling to room temperature, 30 mL of cold water was added. The solid formed was collected by filtration, washed with ammonium hydroxide and water, and dried under vacuum to give the desired product (610 mg, 87% yield) as a solid. MS(ESI+) m/z 235.30 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
2-Hydroxy-5-aminobenzoic acid (20.0 g, 0.131 mole) was suspended in water (100 ml), and acetic anhydride (15.0 ml) was added. The reaction mixture was heated to 100° C., with stirring, for 10 minutes, cooled in an ice bath, and the product was isolated by filtration. After recrystallization from water, with activated carbon, analytically pure 2-hydroxy-5-acetamidobenzoic acid (17.0 g, 67%) was obtained, m.p. 218°-220° C. Found (Calc. for C9H9NO4) C 55.10 (55.38), H 4.61 (4.62), N 7.10 (7.18).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:11][C:3]2[C:2]([NH:1][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[Br:10])=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1cc(N)c(O)c(Br)c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Product: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step c, from 2-amino-6-bromo-4-methoxyphenol and 4-methoxy-3-trifluoromethyl benzoyl chloride. The product was obtained as an off-white solid, m.p. 205-208° C.; MS m/e 622 (M+H)+.
Reaction SMILES: [C:1](O[K])(C)(C)C.O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)O[K]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of methyltriphenylphosphonium bromide (2.15 g, 6.02 mmol) in hexane (15 mL) was added with tert-butoxypotassium (0.676 g, 6.02 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added portionwise with tert-butyl 4-oxopiperidine-1-carboxylate (1.10 g, 5.52 mmol), and the mixture was stirred overnight at room temperature. The solid was removed by filtration, the concentrated filtrate was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-methylenepiperidine-1-carboxylate (0.731 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1>CO.[Ni]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
24 g (58.4 mmol) of 2-[4-(6-bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1e) is shacked in 300 ml of MeOH-THE (1:1) under 1.1 bar of H2 in the presence of 8.35 g of Raney-Ni for 1 h. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated to dryness to give the title compound as a yellow foam. ES-MS: 381, 383 (M+H)+, Br pattern; analytical HPLC: tret=3.21 min (Grad 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.O>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A stirred solution of 9.0 grams (0.032 mole) of 2-fluoro-4-(4-chlorophenylmethoxy)nitrobenzene and 10 mL of water in 150 mL of glacial acetic acid was maintained at 50° C. while 9.0 grams of iron powder was slowly added. Upon completion of addition, the reaction mixture was cooled to 25° C. where it was stirred for about one hour. After this time the reaction mixture was filtered ,and the filtrate was poured into water. The mixture was then extracted with ethyl acetate. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.1 grams of 2-fluoro-4-(4-chlorophenylmethoxy)aniline, mp 73°-75° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.O>[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:3](=[O:4])[CH2:2][Br:1])[CH2:17][CH2:18]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a stirring solution of bromoacetyl bromide (29.8 g, 148 mmol) in THF (250 mL) at 0° C. was added via an addition funnel a solution of Boc-piperazine (25 g, 134 mmol) and triethylamine (14.9 g, 148 mmol) in THF (75 mL). After 1 h, a few grams of ice were added and the mixture was diluted with ethyl acetate and cold water. The layers were separated and the organic phase was washed with 1 M aq. citric acid, brine, satd aq. NaHCO3 and again with brine. The organic phase was then dried with MgSO4, filtered, and concentrated in vacuo to give 38.2 g (93%) of an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]CC[Si](C)(C)C)[N:3]=1.C(O[CH:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:20]1[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:19]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:30]([O:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]2[O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4](=[O:8])[N:3]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 12 (8.17 g. 35.4 mmol) in 200 mL anhydrous acetonitrile is treated with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (Pfanstiehl) at room temperature and under an atmosphere of argon. To this mixture is added TMS-triflate (6.11 mL, 35.4 mmol) and the mixture stirred at this temperature for 2 hr. Evaporation of the solvents in vacuo yielded an amber syrup which was immediately redissolved in 300 mL CH2Cl2, washed with cold, saturated NaHCO3 (2×150 mL), dried over magnesium sulfate, filtered and evaporated to a tan residue. Trituration of this residue with cold, anhydrous acetonitrile yielded analytically pure 13, 14.4 g (71%). 1H-NMR (DMSO-d6): δ 8.39 (d, 1 H, 6-H, J6,5 =11.8 Hz); 8.0-7.4 (m, 15 H, aromatic); 6.68 (d, 1 H, H-5); 6.11 (d, 1H, H-1', J1,2=2 Hz); 5.95 (m, 2 H, H-2',3'); 4.85 (m, 1 H, H-4'); 4.70 (m, 2 H, H-5',5"). Anal. Calcd for C30H23N2O8Cl: C, 62.67; H, 4.03; N, 4.87. Found: C, 62.21; H, 3.92; N, 4.80.