Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])=[CH:15][C:14]=2[Br:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])=[CH:15][C:14]=2[Br:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[O:34][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2Br)ccc(C(C)=O)c1O
Solvent: c1ccncc1
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reaction time: 18 h

Procedure:
In a mixture of pyridine (5 ml) and acetic anhydride (5 ml) was dissolved 3-(N,N-dimethylamino)propyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate (1 g). The solution was stirred at 110° to 120° C. for about 18 hours, followed by concentration. The residue was chromatographed on a column of silica gel. The elution was conducted with ethyl acetate, and the eluate was evaporated. The resulting oily substance was dissolved in ether, to which was added an ether solution of anhydrous oxalic acid. The resultant crystals were collected by filtration, which were washed with ethanol and then with isopropyl ether, followed by drying to give 866 mg of 3-(N,N-dimethyl-amino)propyl 4-[3-(4-acetyl-3-acetoxy-2-propylphenoxy)propoxy]-3-bromobenzoate.mono-oxalate, m.p. 141°-142° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=O)C.[CH2:34]([NH2:36])[CH3:35]>C(O)C>[CH2:34]([NH:36][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:8][N:7]=1)=[O:3])[CH3:35]
Reactant: CCOC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CCO
Product: CCNC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C

Procedure:
5-(2,4-bis-benzyloxy-5-bromo-phenyl)-isoxazole-3-carboxylic acid ethyl ester was suspended in ethanol and ethylamine (2M in methanol, 3 eq), the resulting yellow suspension was heated to reflux (80° C.) under nitrogen, at which point the reagents went into solution. This was heated for 14 hours, then left to cool to ambient temperature. A white precipitate formed, which was filtered off and washed with further ethanol before being dried in vacuo.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([Br:22])=[C:18]([CH:21]=1)[CH2:19]O>>[Br:22][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:21][C:18]=1[CH2:19][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Br)c(CO)c1
Reactant: Oc1cccc2ccccc12
Product: COc1ccc(Br)c(COc2cccc3ccccc23)c1

Procedure:
The title compound was prepared by reacting 1-naphthol (5.7 g, 39.6 mmol) with 5-methoxy-2-bromobenzyl alcohol as described for intermediate 5 to yield 5.94 g (44%) of a white solid: mp 74-75° C.; 1H NMR (CDCl3): δ 3.78 (3H, s), 5.28 (2H, s), 6.77 (1H, dd, J=2.93 Hz, J=8.79 Hz), 6.88 (1H, d, J=7.69 Hz), 7.27 (1H, d, J=3.30 Hz), 7.36-7.39 (1H, m), 7.47-7.53 (4H, m), 7.81-7.83 (1H, m), 8.37-8.39 (1H, m); MS (ESI) m/z 343/345 ([M+H]+);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:14]=[O:16])=[C:6]([CH3:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N=C=O)c(C)c1

Procedure:
In analogy to the procedure described in example 9.1, 4-amino-3-methyl-benzoic acid methyl ester ([18595-14-7]) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 14 h to give the title compound as brown solid. MS: m/e=191.1 [M+].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10](S(C2SC(Cl)=CC=2)(=O)=O)[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:25][CH:24]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])=[CH:27][CH:28]=3)[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(OCCN(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(OCCN(C)C)cc1
Temperature: 70 °C
Yield: 64 %

Procedure:
A solution of 5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-N-[1-[(4-{[2-(dimethylamino)ethyl]oxy}phenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 18) (91 mg, 0.13 mmol) in MeOH (5 mL) was treated with a 2M aq. NaOH solution (1 mL) and the mixture was heated to 70° C. for 2 h, and then allowed to stand at RT over the weekend. The solvents evaporated by this time and the white solid residue was diluted with water and 2M HCl solution (1 mL) and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO4) and evaporated to dryness (72 mg). The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP on Xbridge column using acetonitrile-water with an ammonium carbonate modifier. The solvent was evaporated in vacuo to give the title compound (43 mg, 64%) as a colourless gum. LCMS (System C) RT=2.20 min, ES+ve m/z 521/523 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(F)c1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2F)O3)nc1

Procedure:
2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.88 g of 2-(2,3-difluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1, 3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, 9.1 Hz), 7.03 (d, 1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.92 (d, 1H, 8.8 Hz), 5.42 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(OC)C=CC=CC=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[CH:8]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCS
Product: C1=Cc2ccccc2C1

Procedure:
Treatment of p-methoxydeoxybenzoic (32) (FIG. 4) with PCl5 in refluxing benzene provided p-methoxy-α'-chlorostilbene 33 (Nagano, 1955), which underwent Friedel-Crafts conditions with anisole to furnish the triarylethylene 34. The carbonyl group in deoxybenzoic 32 was converted to a gem-dichloride intermediate, using phosphorus pentachloride, and with the subsequent elimination of HCl, the vinyl chloride 33 was obtained. Compound 32 was prepared using Friedel-Crafts conditions involving phenylacetyl chloride and anisole in carbon disulfide and aluminum chloride (BUCK, J. S. and IDE, W. S. (1932), "The isomeric desoxybenzanisoins", Journal of the American Chemical Society, 54, 3012). Demethylation of 35 was accomplished with EtSH/AlCl3, and 36 was isolated by column chromatography. Drying of phenol 36 at a high temperature resulted in the formation of an indene, which was observed previously (MAGARIAN, R. A., MELTON, S. AND NATARELLI, G. (1972), "2-Chloro-1-phenylindene from 1,1-dichloro-trans-2,3-diphenylcyclopropane", Journal of Pharmaceutical Sciences, 61, 1216). Compound 36 was isolated as the diacetate (37) using column chromatography.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: Cc1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4C)nc3)C3CC3)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg, Intermediate 20), 2-chloro-5-methylpyrazine (15 mg) and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1.0 mL) is heated in a microwave oven for 30 min at 200° C. After removal of the solvent the residue is purified by HPLC(H2O/MeOH/TFA) to give the title compound. LC (method 3): tR=0.92 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][CH3:11])[NH:7][CH:8]=1.CN(C)C=O.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[N:19]=1>O>[CH3:28][O:27][C:20]1[N:19]=[C:18]([N:7]2[CH:8]=[C:4]([CH3:3])[N:5]=[C:6]2[CH2:9][CH2:10][CH3:11])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: CCCc1nc(C)c[nH]1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)cn1-c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension prepared of 20.0 g KOH (solid), 25.8 g 4-methyl-2-propyl imidazole and 130 ml dimethyl formamide were added 38.0 g 2-chloro-6-methoxy-3-nitro pyridine in small amounts at a reaction temperature of 5° C. The reaction mixture was stirred for 75 minutes at room temperature. Then the reaction mixture was poured in 600 ml water. The mixture was further stirred for 1 hr. The desired product precipitated during this time. The resulting solid was collected by filtration, washed with 100 ml water for 3 times and dried in a dry box with vacuum (40° C.).
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]([CH2:22][CH2:23][C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:31]1CCCC1.ClC1C=CC=C(C(OO)=O)C=1>O>[N:1]1([C:10]2[O:11][C:12]([CH2:22][CH2:23][C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27]3)=[O:25])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCS(=O)C1
Yield: 28 %

Procedure:
To a mixture of 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine (25 mg) and tetrahydrofuran (10 mL) was added m-chloroperbenzoic acid (14.4 mg) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried (MgSO4) and concentrated. The residue was introduced into preparative HPLC and purified to give 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine-1-oxide (7.3 mg, yield 28%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CN(C)CCN
Reactant: CCOC(=O)CN1CCCC1=O
Product: CN(C)CCNC(=O)CN1CCCC1=O

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 8.8 g. of 2-(dimethylamino)ethylamine, following the procedure of Example 1, there is obtained N-[2-(dimethylamino)ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 146°-147° C./0.1 mm.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH3:18].C(O)C>C(OCC)(=O)C>[NH2:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Twent-six grams (0.096m) of crude 4-chloro-3,5-dinitrobenzotrifluoride, 150 ml. of liquid ammonia and 150 ml. of 2B ethanol were heated in a sealed autoclave at 100° C. for about 4 hours. After cooling and venting, the reaction mixture was taken up in ethyl acetate. The ethyl acetate phase was washed with water. The ethyl acetate solution was dried and evaporated in vacuo to yield crude 4-amino-3,5-dinitrobenzotrifluoride.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:14]>>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([CH3:10])=[C:3]([CH3:11])[C:2]([C:21]2[CH:22]=[C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])[CH:18]=[CH:19][CH:20]=2)=[CH:7]1
Reactant: Cc1c(Br)cn(C)c(=O)c1C
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: Cc1c(-c2cccc(NS(C)(=O)=O)c2)cn(C)c(=O)c1C

Procedure:
5-Bromo-1,3,4-trimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.42 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 7.05 (d, J=7.6 Hz, 1H), 3.59 (s, 3H), 3.06 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H). LCMS (M+H)+ 307.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
300 g (1.49 mol) of 4-chloro-3-nitrobenzoic acid were suspended in 769 g of a 25-30% aqueous solution of methylamine. After heating to reflux temperature, a clear solution was obtained. The solution was kept at reflux temperature for 2 hours and total consumption of 4-chloro-3-nitrobenzoic acid was checked by TLC. The solution was cooled to room temperature, and pH was adjusted to about 1 by addition of 2M aqueous sulphuric acid. Precipitation of a yellow solid was observed, which was isolated by filtration. The filtered cake was washed with water and subsequently with methanol to obtain 331 g of wet 4-(methylamino)-3-nitrobenzoic acid as a yellow powder. Purity (HPLC, method 2): 99.1%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-[3,3′-bipyridin]-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:17][C:11]2=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].C(OC(=O)C)(=[O:21])C>O>[S:5]([C:8]1[S:17][C:11]2[NH:12][C:13](=[O:21])[CH:14]=[CH:15][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: CN(C)C=NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cc2ccc(=O)[nH]c2s1
Yield: 60 %

Procedure:
A mixture of the product from Step A (10.75 g, 0.038 mol) and 50 ml of acetic anhydride was heated at reflux for 16 hours. After removal of the acetic anhydride in vacuo, the residue was heated in 6 N hydrochloric acid (50 ml) for 3 hours. The cooled reaction mixture was diluted with water (400 ml), chilled and the resulting solid was filtered, washed with water and dried, 5.25 g (60% yield). Recrystallization from water gave 2-sulfamoylthieno[2,3-b]pyridin-6(7H)-one; m.p. 306°-308° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:24]([OH:26])=[O:25])[CH2:7]2)[CH3:2].Cl.CC(O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH2:10][NH:9][C@H:8]([C:24]([OH:26])=[O:25])[CH2:7]2)[CH3:2]
Reactant: CCOc1cc2c(cc1OCC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1OCC)C[C@@H](C(=O)O)NC2
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (S)-1,2,3,4-tetrahydro-6,7-diethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid (example 4) (18.3 g, 0.05 mol), 20% HCl/IPA solution (18.3 g, 0.1 mol) in ethyl acetate (100 mL) was stirred at 40° C. for 3 hrs. The resulting suspension was cooled to room temperature, filtered, and rinsed with ethyl acetate (2×30 mL). The solids were dried under vacuum to give 12.1 g of (S)-1,2,3,4-tetrahydro-6,7-diethoxy-3-isoquinolinecarboxylic acid. Yield 81%. 1H NMR (DMSO-d6) δ: 1.32 (t, J=6.9 Hz, 6H, CH2CH3), 3.03 (dd, J=16.7, 10.9 Hz, 1H, CHHCHCOOH), 3.21 (dd, J=16.7, 4.9 Hz, 1H, CHHCHCOOH), 3.9-4.06 (m, 2H, CH2CH3), 4.2 (br s, 2H, CH2N), 4.33 (dd, J=10.9, 4.9 Hz, 1H, CHCOOH), 6.84, 6.85 (s, 2H, PhH), 9.96 (br s, 2H, NHHCl).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: CC1(C)CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (1.0 eq), and CeCl3-7H2O (1.2 eq) in MeOH (0.2 M) was added NaBH4 (1.0 eq) at 0° C. The solution was stirred for 1 hour, and then quenched by 5 mL of water. The volatiles were removed in vacuum and the residue was partitioned between EtOAc and H2O. The organic layer was separated and washed with brine. The combined aqueous was back extracted with EtOAc and the organic was washed with brine. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (74%). LC/MS (m/z): MH+=249.2, Rt=0.76 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: Nc1c(F)c(N2CCC(c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 84 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.04 g, 3.5 mmol) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.26 g, 84%) as a yellow solid, mp 250°-252° C.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([O:7]C2CCCCO2)[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:23])[CH:17]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C(O)(=O)C>O>[OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([CH:14]=[CH:15][CH:16]([OH:23])[CH:17]([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCCCC(C)C(O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(C)C(O)C=CC1CC(O)C(O)C1CCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 5.2 %

Procedure:
A mixture of 7-[2-hydroxy-5-(3-hydroxy-4-methyloct-1-enyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (1.06 g.), glacial acetic acid (40 ml.) and water (20 ml.) was stirred at 40° C. for 4 hours. The mixture was then treated with water (50 ml.) and extracted with diethyl ether (2 × 50 ml.). The combined ethereal extracts were washed once with water, dried over magnesium sulphate, and concentrated in vacuo to low volume. Repeatedly, small portions of benzene were then added, concentrating in vacuo in order to remove last traces of acetic acid, and then the mixture was evaporated to dryness. The residue (0.5 g.) was subjected to preparative thin-layer chromatography on silica gel, using a mixture of ethyl acetate, cyclohexane and formic acid (40:40:1 by volume) as the eluent, to give 7-[2,3-dihydroxy-5-(3-hydroxy-4-methyloct-1-enyl)cyclopentyl]heptanoic acid (0.045 g.), νmax 1705 cm-1, 980 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>C(#N)C.C(OCC)(=O)C>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: O=C1CCc2ccccc2C12CCNCC2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C12CCN(CCCOc1cccc3[nH]ccc13)CC2

Procedure:
A solution of 1-chloro-3-(1H-indole-4-oxy)propane, 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4′-piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 37% overall yield. FDMS m/e=388 (M+ of free base).