Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:5].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[NH2:1][C:2]1[N:25]=[C:24]([NH:30][CH:27]2[CH2:29][CH2:28]2)[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: NC1CC1
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc(NC2CC2)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Temperature: 140 °C
Yield: 14 %

Procedure:
2-Amino-6-chloro-N-(4-benzyloxy-benzyl)-nicotinamide described in Example A-27 (80 mg, 0.22 mmol) was dissolved in tetrahydrofuran (3 mL), cyclopropylamine (0.3 mL, 4.3 mmol) was added thereto, and the solution was heated in a sealed tube for 16 hours (oil bath temperature: 140° C.). The reaction solution was allowed to room temperature, the solution was concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=2:1), and the title compound (12 mg, 0.031 mmol, 14%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].O1CCOCC1.[CH3:26][NH:27][CH3:28]>CO>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:27]([CH3:28])[CH3:26])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: CNC
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.4 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine was suspended in 14 ml. of a mixture of dioxan and methanol (1:1), 6.7 ml. 30% methanolic dimethylamine solution were added thereto, the reaction mixture was stirred for 1 hour at 60° C., then cooled in an ice bath, the product was filtered off with suction, washed with a mixture of dioxan and methanol (1:1) and then with ether and the product thus obtained (0.66 g.) recrystallized from 15 ml. dioxan-dimethylformamide (9:1), with the addition of charcoal, 0.35 g. of intense yellow crystals of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]pyridazine thereby being obtained. It has a melting point of 233° - 236° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH2:3][CH3:4].[C:23]([O:27][C:28](=[O:36])[NH:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH:32]=O)([CH3:26])([CH3:25])[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:23]([O:27][C:28](=[O:36])[NH:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH2:32][NH:1][CH:2]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7](=[O:15])[C:8]2[C:13]([CH3:14])=[N:12][S:11][C:9]=2[N:10]=1)[CH2:3][CH3:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCC(N)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCC(C)(C)NC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of 36 (136 mg, 0.433 mmol) in MeOH (5 ml) was added (1,1-dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester(105 mg, 0.522 mmol) followed by NaBH(OAc)3 (138 mg, 0.65 mmol). The reaction mixture was stirred at room temperature overnight, quenched with water. Solvent was removed in vacuo, the residue was purified by preparative HPLC to give 37 (86 mg) at the yield of 41% for the two steps. 1H-NMR (500 MHz, CDCl3): δ 7.23–7.39 (m, 5H), 5.89 (d, J=16.0 Hz, 1H), 5.01 (d, J=16.0 Hz, 1H), 4.66 (t, J=5.77 Hz, 1H), 4.43 (brs, 1H), 2.86 (s, 3H), 2.45 (m, 2H), 2.11 (m, 1H), 1.96 (m, 2H), 1.74 (m, 1H), 1.30 (s, 9H), 1.13 (s, 3H), 1.01 (s, 3H), 0.88 (t, J=7.42 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([C@@H:55]([NH2:59])[CH2:56][O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([NH:59][C@H:55]([C:53]1[NH:52][C:51]2[CH:60]=[CH:61][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][O:57][CH3:58])=[O:7]
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCCCC2=O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)c1ccc(N2CCCCC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in DMF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5->90:10).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[O:6][CH2:5]1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:14][C:12]1[CH:11]=[CH:10][C:8]2[O:9][CH:4]([CH2:3][N:2]([CH3:1])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[CH2:5][O:6][C:7]=2[CH:13]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: CNCC1COc2cc(O)ccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2cc(O)ccc2O1
Temperature: 96 °C
Yield: 24.9 %

Procedure:
N-Methyl-2,3-dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (3.68 g, 17.3 mmole), 7-(3-chloropropoxy)coumarin (4.15 g, 17.4 mmole), diisopropylethylamine (4.4 ml, 25.3 mmole) and sodium iodide (2.59 g, 17.3 mmole) were combined in 75 ml of DMF and heated at 96° C. for 26 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was column chromatographed on silica gel using first 1% methanol/dichloromethane, then 2% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from isopropanol with addition of 4N HCl/isopropanol and diethyl ether to give 1.71 g of white solid, monohydrochloride, quarter hydrate, m.p. 186°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([S:18][CH3:19])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([S:18]([CH3:19])=[O:28])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc(SC)nn2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cnc(S(C)=O)nn2)cc1F

Procedure:
To a cooled (0° C.) solution of methyl 2-fluoro-4-[3-(methylthio)-1,2,4-triazin-6-yl]benzoate (0.180 g, 0.000644 mol) in methylene chloride (10 mL) was added m-chloroperbenzoic acid (0.32 g, 0.0014 mol) in DCM (3 ml) with stirring. The mixture was stirred at 0° C. for 1.5 h, and diluted with DCM. The resulting solution was quenched with saturated Na2S2O3 solution. After separation the organic layer was washed with saturated NaHCO3 solution, brine; and dried over Na2SO4. After filtration the filtrate was concentrated to yield nearly quantitative product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=296.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:26]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOc1cccc(NC(=N)c2ccc(C)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of 1.1 g (4.0 mmol) of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 5 to 40% ethyl acetate in hexanes gradient then 40% ethyl acetate in hexanes) gave the title compound as a yellow oil. LC/MS 351.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(O)C.[OH-].[Li+]>O>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Yield: 52.3 %

Procedure:
A flask is charged successively with 5 g (22.62 mmol) of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Azasynth), 50 mL of 95% ethanol, 50 mL of water and 1.63 g (67.92 mmol) of lithium hydroxide. The reaction mixture is refluxed for 30 minutes and then left to return to room temperature. The solution is concentrated under reduced pressure and then diluted in 200 mL of water. The aqueous phase is extracted with 3×60 mL of ethyl acetate, then acidified with 32% hydrochloric acid until the pH is between 2 and 3. The precipitate formed is filtered, rinsed with 50 mL of ethyl acetate and then dried under vacuum for 6 h. 2.45 g of a white solid is obtained (52%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1.O>CO>[CH3:1][O:2][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
19 ml of a 28% methanolic solution of sodium methoxide were added dropwise to a solution of 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) in 120 ml of methanol at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 5.34 g of the title compound, melting at 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[N:32]1[CH:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([N:38]2[CH2:39][CH2:40][N:35]3[CH:34]=[CH:33][N:32]=[C:36]3[CH2:37]2)[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (5)), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 73 mg, triethylamine 0.083 ml and N,N-dimethylacetamide 4 ml is stirred at 110° C. for 4 hours. After cooling the reaction mixture is diluted with a 10% aqueous citric acid solution and washed with ethyl acetate. The organic layer is extracted with a 10% aqueous citric acid solution. The water layer is made basic with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:methanol=100:1→50:1), and then crystallized from a mixture of ethyl acetate, methanol and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 20 mg.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CN(C)C(=O)CBr
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC(=O)N(C)C)cc3)cc12

Procedure:
2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)-N,N-dimethylacetamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) and following the procedure described for Example 139, but using 2-bromo-N,N-dimethylacetamide. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.28 (d, 1H), 7.40 (s, 1H), 7.18 (t, 3H), 6.87 (d, 2H), 6.56 (br, 2H), 4.72 (s, 2H), 3.20 (t, 2H), 3.07 (s, 3H), 3.05 (t, 2H), 2.87 (s, 3H), 2.45 (s, 3H). LRMS [M+H]=415.2
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: Brc1nsc2ncccc12
Reactant: NCCCN
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCCNc1nsc2ncccc12
Temperature: 64 °C

Procedure:
A mixture of 3-bromoisothiazolo[5,4-b]pyridine (1.9 g, 8.8 mmol), and 1,3-diaminopropane (6.7 g, 90 mmol) in methanol (10 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water mixture yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.53 (d, 1H), 7.73 (br s, 1H), 7.40 (dd, 1H), 3.46 (dd, 2H), 2.85 (t, 2H), 1.75 (t, 2H), 1.45 ppm (t, 2H). MW=208 confirmed by LC-MS, tr=5.55 min (Method Y) MH+=209.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:14]CC3C=CC=CC=3)[C:8]=2[CH2:7][C@@H:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:5]1>CO.[Pd].C(OCC)(=O)C>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:22][CH3:23])=[C:13]([OH:14])[C:8]=2[CH2:7][C@@H:6]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:5]1
Reactant: COc1ccc2c(c1OCc1ccccc1)C[C@@H](c1ccccc1)O[C@H]2CN
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1O)C[C@@H](c1ccccc1)O[C@H]2CN
Yield: 66.5 %

Procedure:
A solution of 940 mg (2.28 mmol) of [1R,3S] 1-aminomethyl-5-benzyloxy-3,4-dihydro--6-methoxy-3-phenyl-1H-2-benzopyran hydrochloride, from Step 9, in 500 mL of methanol was treated with 500 mg of 10% palladium on carbon and the resultant mixture was shaken under a hydrogen atmosphere for 24 h. The reaction mixture was diluted with ethyl acetate and filtered through Celite filter aid. The filtrate was concentrated in vacuo to give an off-white solid which was crystallized from methanol/methylene chloride/ether to give 488 mg (66% yield) of the title compound, m.p. 234° C.; MS DCl-NH3M/Z: 286 (M+H)+. Analysis calculated for C17H20ClNO3 +0.25 CH2Cl2 : C, 60.40; H, 6.02; N, 4.08. Found: C, 60.07; H, 5.97; N, 4.03.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Clc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Reaction time: 3.33 h
Yield: 134.7 %

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 76.9 g (0.220 mole) of 1,2-diphenyl4-p-chlorophenylbutane-1,4-dione, 100 ml of xylene and 45 g (0.101 mole) of phosphorus pentasulfide. The autoclave was cooled with a Dry Ice-acetone bath and charged with 120 g (3.52 moles) of hydrogen sulfide. The autoclave was heated with stirring for 200 minutes at 155°-178° C. (1000-2000 psig). The autoclave was cooled and the hydrogen sulfide allowed to escape into a sodium hydroxide solution. The residue was stirred with 150 ml of absolute ethanol. Filtration and drying gave a crude product of 61.2 g (80.2%) m.p. 115°-117°. Recrystallization from 190 ml of toluene and 625 ml of ethanol gave 47.2 g (61.9%) of pure 2,3-diphenyl-5-p-chlorophenylthiophene, m.p. 121°-122° C.
Reaction SMILES: CS(O[CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+].CN(C)C=O>O>[N:57]([CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(COCCCCCCCCCCCCCCCCCCCCCC)COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN=[N+]=[N-])COCCCCCCCCCCCCCCCCCCCCCC
Temperature: 110 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
After a mixture of 2,2-bis(docosyloxymethyl)propyl methanesulfonate (22.7 g; 27.8 mmol), sodium azide (0.27 g; 83.5 mmol), and dimethylformamide (150 ml) was stirred at 110° C. for 20 h, the reaction mixture was poured into water. Precipitates thus obtained were collected by suction, washed successively with water and acetone, and dried to obtain the title compound (20.8 g; 98%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[C:18]1([S:24]([C:27]([CH3:39])([CH3:38])[CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][C:35](Br)=[CH:34][CH2:33][CH2:32]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[C:18]1([S:24]([C:27]([CH3:39])([CH3:38])[CH2:28][CH2:29][CH2:30][N:31]2[CH2:32][C:33]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)=[CH:34][CH2:35][CH2:36]2)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(CCCN1CCC=C(Br)C1)S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C2=CCCN(CCCC(C)(C)S(=O)(=O)c3ccccc3)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
2M Potassium carbonate solution (containing tetra-n-butylammonium hydroxide) (0.25 ml) followed by 4-methoxybenzeneboronic acid (0.056 g; 0.37 mmol) was added to a solution of Example 229 (0.095 g; 0.25 mmol) in 1,4-dioxane (6 ml). The solution was deoxygenated with nitrogen at room temperature for 5 minutes. Tetrakistriphenylphosphine palladium(0) (catalytic) was added and the solution stirred for 30 minutes at 80° C. After cooling to room temperature, ethyl acetate was added and the organic phase separated then washed twice with water. The organic layer was dried (MgSO4) and evaporated in vacuo. Purification using an SCX cartridge eluting with 1/9 NH3/MeOH afforded the title compound as a yellow oil (90 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.[CH:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([NH:37][S:34]([CH:31]4[CH2:33][CH2:32]4)(=[O:36])=[O:35])=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)O)c3)c3ccc(Cl)cc32)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)NS(=O)(=O)C4CC4)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in the synthesis of Example 117 using the following starting materials: {3-[6-Chloro-1-(1-propyl-1H-pyrazol-4-yl)-2-methyl-1H-indol-3-ylsulfanyl]-phenyl}-acetic acid and cyclopropanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: COc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1cccc(O)c1)c1cc2ccccc2o1
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide (315 mg, 0.69 mmol) in CH2Cl2 (5 ml) at room temperature was added BBr3 (1M solution in CH2Cl2, 2.1 ml, 2.1 mmol) and the reaction was stirred for 2 h, diluted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (25% ethyl acetate in hexane) to give the title compound (196 mg, 64%).
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].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[N:36]O)[NH2:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]2[N:35]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])[CH2:12]3)[O:25][N:36]=2)=[CH:31][CH:32]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(Cl)cc4)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 41 mg (0.22 mmol, 1.1 eq.) of 2-(4-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 62 mg (63% of theory)