Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([O-:7])=[CH:5][CH:4]=[C:3]([S:8]([O-:11])(=[O:10])=[O:9])[CH:2]=1.[Na+:12].[Na+].[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](Cl)=[O:17]>>[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]([O:7][C:6]1[CH:1]=[CH:2][C:3]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:5]=1)=[O:17].[Na+:12]
Reactant: CCCCCCCC(Cl)C(=O)Cl
Reactant: O=S(=O)([O-])c1ccc([O-])cc1
Agent: [Na+]
Product: CCCCCCCC(Cl)C(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Yield: 68 %

Procedure:
Anhydrous disodium p-phenolsulfonate (28.5 g; 0.130 mole) and 30.3 g (0.1436 mole) of 2-chlorononanoyl chloride were combined in a 500 ml round-bottomed flask. The flask was then immersed in an oil bath which had been preheated to 110° C. Within five minutes an exothermic reaction occurred which caused the entire mixture to congeal. After cooling, the mixture was triturated three times with 150-200 ml portions of ether and the product was vacuum dried. Elemental and nmr analyses of the resulting tan powder, 46.2 g, indicated that it was composed of 11.5% NaCl, 17.7% disodium p-phenolsulfonate, and 70.8% of sodium p-(2-chlorononanoyloxy)benzene sulfonate. This represents a 68% yield of the desired product.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>O>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
tert-Butyl (S)-1-(trans-4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (18 g, 34 mmol) was treated with 4 M nBu4NF/THF (50 mL) at 50° C. for 6 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give crude tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (9 g, 64%) that was purified by silica chromatography. 1H NMR (CDCl3, 400 MHz) δ 1.41(d, 9 H), 1.65(m, 6 H), 1.95(m, 3 H), 2.98(d, 3 H), 3.10(m, 1 H), 3.52(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[C:26]([O:32]C)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[C:26]([OH:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn(Cc2ccc(C)nc2O)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 80 °C
Yield: 102.3 %

Procedure:
A mixture of N-(3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (50 mg, 0.11 mmol) and HCl (2 mL, 4M in dioxane) was heated at 80° C. in a sealed vial for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and water (5 mL). Saturated NaHCO3 aqueous solution was added to adjust pH=7. The solution was concentrated under reduced pressure to a solid residue. The residue was dissolved in DCM/MeOH and filtered to remove inorganic impurities. The solution was concentrated under reduced pressure to give the product (48 mg).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:36]3[CH2:37][CH2:38][CH:33]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:34][CH2:35]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCCC2)CC1
Reaction time: 0.5 h

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (100 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then 4-(piperidin-1-yl)piperidine (144 mg) was added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:2 to 1:8). The solvent was evaporated under a reduced pressure to give a residue, which was then dried in vacuum to provide 4-(piperidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide as a crude product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>ClCCCl>[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([C:12]1[CH:11]=[CH:10][C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:6])=[O:19]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Aluminum chloride (2.03 g, 15.2 mmol) was added in portions to a solution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and 2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethane at 0° C. The mixture was allowed to warm to rt over 3 h then heated at reflux for 6 h. The resultant mixture was allowed to cool to rt, then poured into a mixture of ice (˜100 g) and concentrated hydrochloric acid (˜20 mL). The organic layer was separated. The aqueous solution was stirred at ambient temperature overnight, and extracted with dichloromethane. The organic layers were washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvents were evaporated in vacuo to give crude product. A portion of the product was purified by flash chromatography on silica gel, using a gradient of 1%-10% EtOAc/heptane as the eluent to give the title compound 3i (1.8 g). MS: m/z 264.9 (MH+). 1H NMR (CDCl3): δ 3.90 (s, 3H), 6.42 (d of d, 1H, J=9.0 and 2.5 Hz), 6.50 (d, 1H, J=2.5 Hz), 6.91-7.04 (m, 2H), 7.27-7.29 (m, 1H), 7.44-7.50 (m, 1H) and 12.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:21](=O)[C:22](=[O:27])[C:23]=1[O:24]CC)[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]1[C:23](=[O:24])[C:22](=[O:27])[C:21]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]2)=[O:9])[C:3]=1[OH:16])[CH3:18]
Reactant: Nc1cccc(C(=O)N2CC[C@@H](O)C2)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(=O)N3CC[C@@H](O)C3)c2O)c(=O)c1=O
Temperature: 60 °C
Yield: 66.2 %

Procedure:
A mixture of 3.63 g (16 mmol, 1 eq) of (3-amino-2-hydroxyphenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone and 3.40 g (20 mmol, 1.2 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in 70 ml of ethanol was heated at 60° C. for 16 hours. The reaction medium was filtered and the filtrate was chromatographed on silica gel (column puriFlash IR-50SI-300G, Spot II with solid deposition) eluted with dichloromethane/methanol (gradient). 3.67 g of 3-ethoxy-4-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained in the form of a beige solid. Yield=66%.
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:7][C:6]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48]CS([O-])(=O)=O>CC(C)=O>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[CH:10]=3)[N:5]([CH2:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[O:1][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH3:39])[C:6](=[O:28])[N:7]=2)=[CH:24][CH:23]=1)([CH3:26])[CH3:27]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1O
Reactant: COCCOCCOCCCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCOCCOCCOC
Temperature: 25 °C

Procedure:
To a solution of 125 mg (0.29 mmol) of 1-(2-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in acetone (5 ml) is added potassium carbonate (407 mg, 2.94 mmol) followed by 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl-methanesulfonate (as prepared in Step A, Example RT-5) (357 mg, 1.47 mmol). The reaction mixture is heated at reflux overnight. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by preparative TLC chromatography on Silica gel using dichloromethane/ether (1:1) to provide the title compound as a yellow oil. Yield: 29 mg (17%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7](=[C:12]([F:14])[F:13])[CH2:8][C:9](Cl)=[O:10]>C(OCC)(=O)C>[F:6][C:7](=[C:12]([F:14])[F:13])[CH2:8][C:9]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:10]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: c1nc[nH]n1
Solvent: CCOC(C)=O
Product: O=C(CC(F)=C(F)F)n1cncn1
Yield: 94.2 %

Procedure:
To a solution of 1,2,4-triazole (1.38 g, 20 mmol) in ethyl acetate (100 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (1.59 g, 10 mmol) at r.t. with stirring. The mixture was stirred for 30 min and filtered. The residue obtained after evaporation of the solvent was redissolved in dichloromethane (25 mL) and filtered. Evaporation of the solvent gave 1.8 g (94%) of the desired product as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C:13](=[N:16]NC3C=CC=CC=3)[C:12](=[O:24])[N:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]3[CH:31]=[CH:32][CH:33]=[CH:34][C:9]2=3)=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[NH2:16][CH:13]1[C:14](=[O:15])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=2)[C:9]2[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=2[N:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:12]1=[O:24]
Reactant: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccc3)c3ccccc32)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
To a vigorously stirred slurry of zinc dust (6.49 g) in acetic acid (50 ml) cooled to 10° C., was added a slurry of 1-(4-Methoxybenzyl)-5-phenyl-3-(phenylhydrazono)-1,5-dihydrobenzo [b] [1,4] diazepine-2,4-dione (5.75 g,12.1 mmol) in acetic acid (30 ml) over a fifteen minute period. After complete addition, the solution was warmed to room temperature and stirred three hours. The zinc was separated by filtration and washed with ethyl acetate (75 ml). The filtrate was concentrated in vacuo and partitioned between H2O (60 ml) and ethyl acetate (100 ml). The pH was adjusted to 9 with saturated aqueous sodium carbonate and the phases separated. The aqueous phase was extracted with ethyl acetate (2×75 ml), the organic layers combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil which was dried in vacuo to give the title compound (4.79 g) NMR (300 MHz, CDCl3): d 3.05 (s, 2H), 3.75 (s, 3H), 4.35 (s, 1H), 4.64 (d, J=14.7 Hz, 1H), 5.82 (d, J=14.7 Hz, 1H), 6.59-6.85 (m, 6H), 7.06-7.29 (m, 6H), 7.51 (d, J=7.4 Hz, 1H); MS (FAB): m/z=388.2 (MH+); TLC (CH2Cl2 /CH3OH (9:1)): Rf =0.50
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])=[C:4]([CH3:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:17](=[O:18])[CH:16]3[CH:11]([C:10]=2[O:20][CH3:22])[CH:12]2[O:19][CH:15]3[CH2:14][CH2:13]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(4-Bromo-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.0*2,6*]decane-3,5-dione (1.0 g, 2.86 mmol) (reported in WO 2009019005) in acetone (50 ml) is added potassium carbonate (0.59 g, 4.3 mmol) followed by iodomethane (2.0 g, 0.89 ml, 14 mmol). The mixture is stirred at room temperature for 18 hours then acetone is removed in vacuo and the residue is partitioned between water and ethyl acetate. The crude product is extracted with ethyl acetate and the combined organic fractions are washed with distilled water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (1RS,2SR,6RS,7SR)-4-(4-bromo-2,6-dimethylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]dec-4-en-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:28])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:4]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(C(=O)O)s3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [700 mg, 1.895 mmol, Example 8(b)] in acetone (20 mL) is added a solution of potassium permanganate (898 mg, 5.684 mmol) and NaH2PO4.H2O (79 mg, 0.568 mmol) in water (20 mL) followed by the addition of silica gel (4 g). The mixture is allowed to stir at ambient temperature for 6 hours, allowed to stand overnight, evaporated to remove the acetone and extracted several times with ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated. The residual crude product is dissolved in refluxing acetonitrile and the solids that formed upon cooling are collected by filtration to afford 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid [362 mg, 50%, Example 61].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl.[S:24]1[C:28]([NH2:29])=[N:27][CH:26]=[N:25]1>N1C=CC=CC=1>[S:24]1[C:28]([NH:29][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:27][CH:26]=[N:25]1
Reactant: Nc1ncns1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 13 %

Procedure:
Prepared using general procedure 15, method A. Under an N2 atmosphere, a mixture of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (13.0 g, 36.5 mmol), 1,2,4-thiadiazol-5-amine hydrochloride (5.0 g, 36.5 mmol), and pyridine (10 mL) was stirred at RT for 19 h. The crude product was purified via silica gel chromatography using 5% MeOH in CH2Cl2 giving N-(1,2,4-thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide as a clear oil (2.0 g). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=421.1; tR=2.85 min.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[CH:7]=[C:8]([O:16][CH3:17])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:16][CH3:17])=[CH:7][C:6]=2[C:4]2[C:3](=[O:18])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[CH:11]=[CH:12]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cc(OC)cc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c(ccn2C)c1
Temperature: 50 °C
Yield: 56.5 %

Procedure:
To a mixture of (1-methyl-5-methoxy-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.27 g, 1.1 mmol) and 2-(1H-indol-3-yl-acetamide (0.17 g, 1 mmol) in DMF (5 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 4 mL, 4 mmol) at room temperature. The reaction mixture was heated at 50° C. for 7 h, cooled to room temperature, quenched with water, and the mixture extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3(1-methyl-5-methoxy-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (210 mg, 56.5%). 1H NMR (d6-DMSO, 400 MHz) 3.52 (s, 3H), 3.56 (s, 3H), 6.35˜6.46 (m, 1H), 6.28 (d, J=2.93 Hz, 1H), 6.41 (t, J=2.44 Hz, 1H), 6.88 (t, J=6.84 Hz, 1H), 7.02 (d, J=2.44 Hz, 1H), 7.10 (d, J=3.42 Hz, 1H), 7.24 (d, J=7.82, 1H), 7.80 (d, J=2.93, 1H), 11.03 (s, 1H), 11.76 (m, 1H); MS (ES, m/z): C22H17N3O3: 372.2 (M++1); 370.3 (M+−1).
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Br)(Br)(Br)(Br)[Br:24]>>[Br:24][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: BrP(Br)(Br)(Br)Br
Product: CCOC(=O)C(Br)CCc1ccc(-c2ccccc2Cl)cc1

Procedure:
To 15.4 g. (0.0476 moles) of ethyl α-hydroxy-γ-(2'-chloro-4-biphenylyl)butyrate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:33]=1)[C:18](=[O:32])[C:19]([CH2:30][CH3:31])=[C:20](/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:21]=2)=[O:12]>CN(C)C=O>[C:24]1(/[CH:23]=[CH:22]/[C:20]2[N:21]=[C:16]3[CH:15]=[CH:14][C:13]4([CH2:2][CH:33]4[N:17]3[C:18](=[O:32])[C:19]=2[CH2:30][CH3:31])[C:11]([O:10][CH3:9])=[O:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1c(/C=C/c2ccccc2)nc2ccc(C(=O)OC)cn2c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)OC)C=C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyl-sulphoxonium iodide (0.7 g) was reacted with 50% sodium hydride (0.15 g) in dimethylformamide (30 ml) under stirring at room temperature for 1 hour, then a solution of 2-trans-(2-phenyl-ethenyl)-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 214°-216° C., (0.82 g) in dimethyl-formamide (20 ml) was added. The mixture was allowed to react under stirring at room temperature for 3 hours, then it was diluted with ice water and filtered. Crystallization from acetone gave 2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 194°-195° C. (0.58 g), which was reacted with 1% KOH in 95% ethanol solution (11 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was acidified with acetic acid, concentrated in vacuo and diluted with ice water: the precipitate was filtered and washed with water until neutral. Crystallization from acetone gave 0.34 g of 2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2]pyrimidine-7-carboxylic acid, m.p. 215°-216° C., NMR (CF3COOD) δ: 1.22(m) and 2.93(m)(6,7-CH2 protons), 1.36(t) (CH2CH3), 2.93(m)(CH2 --CH3), 5.51(d.d)(C-6proton), 7.01(d) (C-9 proton), 7.31(d)(Hβ vinyl proton), 7.63(b.s)(phenyl protons), 7.76(d)(Hα vinyl proton), 8.26(d)(C-8 proton). By proceeding analogously the following compounds were prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol)(Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.18 g, 75.3%).
Reaction SMILES: C([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:6])(=O)C.[ClH:20]>>[ClH:20].[NH2:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:6]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c([N+](=O)[O-])c1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Methyl (R)-4-(1-acetamidoethyl)-3-nitrobenzoate (650 mg) was dissolved in 2N hydrochloric acid, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was evaporated under reduced pressure, and further boiled with toluene, which was followed by drying to give 620 mg of (R)-4-(1-aminoethyl)-3-nitrobenzoic acid hydrochloride.