Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[CH2:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH:14]([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.060 g, 0.29 mmol) and isopropanol (4.5 ml) was added 1-isobutyl-piperazine (0.045 g, 0.32 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.06 ml, 0.32 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an orange solid (0.054 g, 60%); 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.57 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.39 Hz, 2H, N—CH2), 2.45 (br s, 4H, piperazine N(CH2)2), 3.05 (br s, 4H, piperazine N(CH2)2), 6.94 (s, 2H, NH2), 8.06 (s, 1H, 6-H);
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1([CH3:22])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([CH:20]=[CH2:21])[O:14]1>>[F:10][C:8]1[CH:9]=[C:2](/[CH:21]=[CH:20]/[B:15]2[O:16][C:17]([CH3:19])([CH3:18])[C:13]([CH3:22])([CH3:12])[O:14]2)[CH:3]=[C:4]([F:11])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Product: CC1(C)OB(/C=C/c2cc(F)c(C=O)c(F)c2)OC1(C)C
Yield: 75.1 %

Procedure:
According to procedure for the synthesis of example A51A, by using 4-bromo-2,6-difluorobenzaldehyde (1.10 g, 4.98 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.97 mL, 5.72 mmol) to give the title compound as a colorless oil (1.10 g, 76%). 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.05 (d, J=9.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 6.28 (d, J=18.8 Hz, 1H), 1.33 (s, 12H); MS ESI 295.1 [M+H]+, calcd for [C15H17BF2O3+H]+ 295.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C@H:32]5[CH2:37][O:36][CH2:35][CH2:34][NH:33]5)=[CH:28][CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Si]([O:45][CH2:46][CH:47]=O)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CO.C([BH3-])#N.[Na+].C1COCC1>[F:15][C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C@H:32]5[CH2:37][O:36][CH2:35][CH2:34][N:33]5[CH2:47][CH2:46][OH:45])=[CH:28][CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Fc1cc(-n2ccc3cnc(Nc4ccc([C@H]5COCCN5)cc4)nc32)cc(F)c1CN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH3-]C#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: OCCN1CCOC[C@@H]1c1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1

Procedure:
The compound is obtained by treating [7-(3,5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-((S)-4-morpholin-3-yl-phenyl)-amine (Example 511) with (tert-butyldimethylsilyloxy)-acetaldehyde in methanol and sodium cyanoborohydride at 60° C., followed by a deprotection with TBAF in THF. HPLC: tR=0.60 min (Method G); MS-ES: (M+H)+=551
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][CH:5]1[C:17](=[O:18])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:19][N:9]1[C:8]2[CH2:7][CH2:6][C:5](=[CH2:4])[C:17](=[O:18])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: Cn1c2c(c3ccccc31)C(=O)C(C[N+](C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O
Yield: 105.6 %

Procedure:
A solution of the product from Preparation 2 (5.0 g) in water (20 ml) was treated with 2N sodium carbonate (6.55 ml) and warmed at 35° for 45 mins. The resulting slurry was cooled to 0° and the solid was filtered off, washed with water and dried to give the title compound (2.8 g) m.p. 127°-129°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25]C(OC(C)(C)C)=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]2[O:50][CH2:51][CH2:52][CH:48]2[CH:47]([O:53][C:54](=[O:63])ON2C(=O)CCC2=O)[CH2:46]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25][C:54]([O:53][CH:47]1[CH:48]2[CH:49]([O:50][CH2:51][CH2:52]2)[O:45][CH2:46]1)=[O:63])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with dichloromethane. The residue was dissolved in dichloromethane (50 ml) and N,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17 (4.88 g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with dichloromethane, and sequentially washed with brine, 10% KHSO4, brine, saturated NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 ethyl acetate hexane as eluant, to give [3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: Rf 0.56 (7:3 ethyl acetate:hexane). MS 527 (MH)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([Br:10])=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[Br:10][C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9][C:8]=1[C:15](=[O:17])[CH3:16]
Reactant: Brc1csc2ccccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a mixture of 3-bromothianaphthene (Sigma-Aldrich Chemical Company, 2.000 mL, 9.39 mmol) and aluminum chloride (1.002 mL, 9.39 mmol) in DCM (50 mL) cooled with an ice bath was added acetyl chloride (0.667 mL, 9.39 mmol) via syringe, in one minute. The resulting intense orange reaction solution was stirred at rt for 1 h. The reaction was poured into ice and partitioned between water and DCM. The aqueous layer was extracted with DCM, and the combined extracts were washed with 50 mL 5% aqueous sodium hydroxide, 50 mL brine, and stirred over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1-(3-bromobenzo[b]thiophen-2-yl)ethanone as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.77 (s, 3H), 7.57-7.65 (m, 2H), 7.95 (dd, J=7.7, 1.1 Hz, 1H), 8.10 (dd, J=7.1, 1.3 Hz, 1H); LC-MS (ESI)] m/z 254.9 [M+H]+.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:21]([NH:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1)(=[O:23])[CH3:22]
Reactant: Nc1nccnc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1C(N)=O
Product: CC(=O)Nc1nccnc1C(=O)O
Yield: 76 %

Procedure:
A mixture of 3-aminopyrazine-2-carboxylic acid o-toluamide (1.0 g, 4.39 mmol) and acetic anhydride (12 mL) was refluxed 2 hours. The solvent was removed and the residue was triturated with hot ethyl acetate. The ethyl acetate slurry was cooled and the product was collected and rinsed with ether to afford 0.893 g (76%) of 3-acetamidopyrazine-2-carboxylic acid o-toluamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:34](=[NH:36])[NH2:35])[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:36]=[C:34]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CC1=CC=CC(O)(C(=N)N)C1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-3-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 16 mg (18% of theory)
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=1
Reactant: COCCOCCOCc1ncc(C(=O)OC)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOCc1ncc(C(=O)O)[nH]1

Procedure:
2-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-3H-imidazole-4-carboxylic acid methyl ester (460 mg) and lithium hydroxide monohydrate (450 mg) in THF (3 mL) and water (1 mL) were stirred at 58° C. for 10 h. After cooling the mixture was carefully neutralized by the addition of 2 N HCl and concentrated to give crude 2-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-3H-imidazole-4-carboxylic acid. Yield: 905 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16](=[O:18])[CH3:17])[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]([OH:18])[CH3:17])[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: CC(=O)c1cc2c(cc1C)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 1-{12-methyl-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (2.20 g) in MeOH (50.0 mL) was added NaBH4 (920 mg, 24.2 mmol). The mixture was stirred at room temperature for 2 hrs. Water was added to quench the reaction. The mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Removal of the solvent gave the crude product, which was purified by reverse phase Combi-flash eluting with a 25-30% gradient of CH3CN in 0.3% NH4HCO3 to afford the racemic product (800 mg, 58% yield for three steps). 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.85 (s, 1H), 6.81 (s, 1H), 5.74 (m, 1H), 5.07 (s, 1H), 4.87 (s, 1H), 4.48-4.44 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 1.46 (s, 6H), 1.33 (s, 3H). LCMS m/z [M+H]+ 368.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:23]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[O:10])=[C:4]([CH3:22])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: Cc1cc(Br)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 150 °C
Yield: 69.7 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)Cl2-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silcia gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc2cc[nH]c2cc1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1cc2c(C3=CCNCC3)c[nH]c2cc1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6-chloro-5-methoxyindole (2.0 g, 11 mmol) and 4-piperidone hydrochloride hydrate (3.4 g, 22 mmol). The product was isolated as a yellow solid. Yield 2.4 g (83%). mp 222°-224° C. FDMS m/e=264 (M+ of free base).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]COC)=[O:19].[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>N1C=CC=CC=1.Cl>[S:24]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([CH3:27])(=[O:26])=[O:25]
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(CCCCCCC(=O)O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
In pyridine (3 ml) was dissolved methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (0.3 g) followed by addition of mesyl chloride (0.218 g), and the mixture was stirred at 50° C. for 2 hours. This reaction mixture was poured in 0.5N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. The residue was treated with 1N HCl (3 ml) and tetrahydrofuran (6 ml) at the reflux temperature for 1.5 hours and, after cooling, extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness, and the residue was recrystallized from hexane-diisopropyl ether to provide 7-(1-mesylamino-2-naphthyl)heptanoic acid (0.281 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCc2ccccc2)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A cooled (0°) suspension of 60% sodium hydride/oil dispersion (7.2 g, 180 mmol) in anhydrous N,N-dimethylformamide (200 mL) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (30.24 g, 150 mmol) so as to keep the pot temperature below 20° C. After one hour at 40° C., the mixture was treated with benzyl bromide (30.8 g, 180 mmol) and heated to 100°±5° C. for one hour, then cooled to room temperature and added to water (600 mL). The aqueous solution was extracted with methylene chloride (3×250 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through a short column of alumina (eluted with methylene chloride). The filtrate was concentrated in vacuo, taken up in a mixture of 50% sodium hydroxide (50 mL), water (50 mL), and ethanol (100 mL), and refluxed for one hour. Most of the ethanol was removed in vacuo and water (400 mL) was added to dissolve all solid. The aqueous solution was extracted with ether (100 mL), then with petroleum ethers (30° C.-60° C., 100 mL), cooled (0° C.), and acidified to pH 3 with concentrated hydrochloric acid (about 90 mL). The resultant precipitate was filtered and the solid was washed with water, air dried, and recrystallized (2 crops) from ethanol to afford 25.51 g (61%) of tan crystals; mp 182°-184° C.
Reaction SMILES: [Na].[S:2]([C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([OH:5])(=[O:4])=[O:3].[Na].[Cl-].[Ba+2:22].[Cl-]>O>[Ba:22].[S:2]([C:6]1[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[C:8]([CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])([OH:5])(=[O:4])=[O:3]
Reactant: [Ba+2]
Agent: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)O)c1
Agent: [Cl-]
Agent: [Na]
Solvent: O
Product: [Ba]
Temperature: 30 °C

Procedure:
296 Grams of dimethyl 5-sulfoisophthalate sodium salt were placed together with 2000 g of ion exchanged water in a reactor equipped with a stirrer. The contents in the reactor were heated with stirring to 80° C. so that the sodium salt was dissolved in water. A solution of barium chloride dissolved in an amount of 104 g into 900 ml of ion exchanged water was then gradually added dropwise to the thus obtained solution. The resulting mixture was cooled to 30° C. and filtered to separate white precipitates. The precipitates were dispersed in 3000 g of ion exchanged water. The dispersion was heated to 80° C., maintained at that temperature for 1 hour, cooled to 30° C. and then filtered. The precipitates were washed with water. Such a procedure including dispersion, heating, filtration and washing steps was repeated once more. The thus obtained precipitates were dried at 120° C. for 5 hours to obtain 297 g of dimethyl 5-sulfoisophthalate barium salt as a white powder. The atomic absorption analysis revealed that the 5-sulfoisophthalic acid barium salt powder contained 20.1% by weight of barium and 100 ppm by weight of sodium.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9](O)(=O)[CH2:10][CH2:11][CH2:12]C.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)O
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCCCc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.5 %

Procedure:
To a stirred suspension of 3,6-dichloropyridazine (22.5 g, 0.151 mol), silver nitrate (12.7 g, 0.074 mol) and valeric acid (20.0 g, 0.195 mol) in water (250 ml) was added a solution of sulfuric acid (49.3 g, 0.50 mol) in water (250 ml) at 50 deg. A solution of ammonium persulfate (93 g, 0.40 mol) in water (200 ml) was then added over 30 minutes at 60 deg. The resulting mixture was then stirred at 80 deg for 40 minutes and then cooled to room temperature. The mixture was adjusted to pH8 with 25% aqueous ammonium hydroxide and extracted with diethyl ether (3×250 ml). The combined ether extracts were washed with water (200 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (5% ethyl acetate/hexane) to give 3,6-dichloro-4-n-butylpyridazine as a pale yellow oil (14.4 g, 47%). 1H-NMR (CDCl3) 7.30 (1H, s, 5-H), 2.65 (2H, t, Bu), 1.58 (2H, m, Bu), 1.37 (2H, m, Bu), 0.91 (3H, t, Bu).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:16][CH:15]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:13])[C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(O)c2ccccc2c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)c(C)c2ccccc2c1O
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,4-dimethylnaphthalen-1-ol (3.18 g, 18.46 mmol) in dichloromethane (180 mL) at −40° C. was added a 1M solution of titanium tetrachloride in dichloromethane (18.46 mL, 18.46 mmol) over 10 minutes. In a separate flask, ethyl glyoxalate (2.26 g, 22.16 mmol) was heated at 100° C. for 45 minutes. The colorless oil was dissolved in dichloromethane (20 mL) and added to the reaction mixture over 10 minutes. The reaction mixture was stirred at −40° C. for 1.5 hours, then warmed to −25° C. over 30 minutes. The reaction mixture was quenched with acetic acid (5.8 mL). Acetonitrile (30 mL) was added and the reaction mixture was stirred for 5 minutes. The cold bath was removed and water (59 mL) was added and stirred for 15 minutes. The mixture was diluted with water and brine and extracted with dichloromethane (3×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified twice by flash column chromatography (silica gel, 0 to 25% ethyl acetate/hexanes) to give ethyl 2-hydroxy-2-(1-hydroxy-3,4-dimethylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C16H17O4: 273.31. Found: 272.8.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[C:6]1[CH:11]=[CH:10][CH:9]=C[C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:15]=1.[CH3:39][C:40]([OH:42])=[O:41].C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:29][C:27]([F:28])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16]2[C:15]([CH2:14][S:13][C:12]3[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=3)=[C:39]([CH:19]=[CH:18][CH:17]=2)[C:40]([OH:42])=[O:41])=[CH:26][CH:25]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(C(=O)O)c1CSc1ccccc1
Yield: 77 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-{3-[1-(4-Trifluoromethyl-phenyl)-ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid 2,2,2-trichloro-ethyl ester (157 mg, 0.0.259 mmol), zinc (339 mg, 5.18 mmol), HOAc, 97% (1.48 mL, 25.9 mmol) and DCM (12 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (94 mg, 77%) as an oil; 1H NMR (400 MHz, CDCl3): δ 1.53 (s, 3H), 3.60 (dd, 2H), 4.54 (dd, 2H), 5.91 (m, 1H), 7.07-7.12 (m, 1H), 7.15-7.20 (m, 2H), 7.21-7.32 (m, 3H), 7.35-7.42 (m, 3H), 7.58 (d, 2H), 7.98 (d, 1H); Mass spectrum: M−H+ 473.