Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].F[C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a 5-liter, 4-necked flask fitted with a stirrer, thermometer, addition funnel, reflux condenser and drying tube is added dimethyl sulfoxide (200 ml), 2-chloro-4-trifluoromethylphenol) (715 g, 3.64 mole), and anhydrous potassium carbonate (520 g, 3.72 moles). The reaction mixture is stirred at room temperature overnight under a nitrogen atmosphere. Then methyl 5-fluoro-2-nitrobenzoate (724 g, 3.64 moles) is added over a 1 hour period (slight exotherm to 31° C.). After stirring overnight at room temperature, the inorganic solids are removed by filtration and 1700 ml of dimethyl sulfoxide removed under vacuum (1 mm, pot temp. of 85° C., vapor temp. of -40° C.). The residue is diluted with a large volume of carbon tetrachloride and water washed. The organic layer is dried with anhydrous magnesium sulfate and the solvent removed under vacuum to afford 1142 g of methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (84% yield). Anal. Calcd. for C15H9ClF3NO5 : C, 47.90; H, 2.42; Cl, 9.45; F, 15.20; N, 3.73. Found: C, 47.83; H, 2.47; Cl, 9.15; F, 14.84; N, 3.69.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:26]2[S:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)sc1C(=O)OC(C)(C)C
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc3ccccc3s2)sc1C(=O)OC(C)(C)C
Yield: 55.6 %

Procedure:
Suzuki coupling of 5-Bromo-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (43 mg, 0.1 mmol) and benzothiophene-2-boronic acid (53.4 mg, 0.3 mmol) was carried out using Pd(PPh3)4 and Na2CO3 (as described in example 2) resulted in 5-Benzo[b]thiophen-2-yl-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (27 mg, 55% yield). 1H NMR (CDCl3, 400 MHz) 9.92 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.45-7.24 (m, 7H), 2.7 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:12])[CH2:11][O:10][CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:12])[CH2:9][O:10][CH2:11]1
Reactant: Nc1ccc(C2(O)COC2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a stirred solution of 3-(4-amino-2-fluorophenyl)oxetan-3-ol (0.93 g, 5.08 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.82 mL, 10.16 mmol, 2.0 eq) and phenyl chloroformate (0.7 mL, 5.59 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvents was evaporated and the crude product was extracted with EtOAC (25 mL), diluted with water (15 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The resulting residue was washed with diethyl ether (25 mL) to get phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (0.892 g, 59%) as a off white solid (TLC system: 100% EtOAc, Rf: 0.55).
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]1)([OH:38])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2-c2ccccc2Cl)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1-c1ccccc1Cl)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A 250-mL three-necked flask was charged with magnesium turning (2.88 g, 0.12 mol) and a small crystal of iodine. The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (60 mL) was added dropwise to the above mixture. After heating under reflux for 2 h most of magnesium had been consumed and the Grignard solution was cooled to rt. A 250-mL three-necked flask was charged with (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 11 mmol) and THF (50 ml), evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. The mixture was quenched with sat'd aq NH4Cl (100 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was purified by flash column chromatography to afford pure (3R)-tert-butyl 3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (2.5 g, 47%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](N3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([N:1]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(CC(=O)O)c1ccc2c(c1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(CC(=O)O)c1ccc2c(c1)CCCN2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A suspension of (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid (2.6 g) and sodium bicarbonate (2.2 g) in acetone (40 ml) and water (40 ml) was treated with 2,5-dioxo-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.0 g) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated to low bulk. The residue was treated with dilute hydrochloric acid and the resulting gummy precipitate was extracted into a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. This solution was washed with brine, then dried and then evaporated to give the title compound (5.8 g) as a light brown oil, which solidified on standing. MS (ES+) 464 (MNa+), MS (ES−) 440 (M−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19](=[N:21][OH:22])[NH2:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:30](Cl)(=O)[O:31]C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[NH:20][C:30](=[O:31])[O:22][N:21]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: NC(Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12)=NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1
Reaction time: 1 h

Procedure:
A solution of 2-(6-fluoro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl)-N′-hydroxyacetimidamide (0.040 g, 0.13 mmol) and triethylamine (0.025 mL, 0.198 mmol) in CHCl3 (1 mL) was treated with phenyl carbonochloridate (0.018 mL, 0.19 mmol) and stirred for 1 h. The reaction mixture was washed with water (30 mL) and dichloromethane (30 mL). The organic solution was dried with Na2SO4, evaporated under vacuum. The crude product was purified by HPLC to provide the title product. M/e+ 329 for C16H11F2N4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.0, 2.2 Hz, 1H), 7.77 (dd, J=9.9, 4.7 Hz, 1H), 7.69 (m, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CCCO)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(CCCBr)c1C
Yield: 83.8 %

Procedure:
Compound 49-2 (1.83 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.25 g) and N-bromosuccinimide (2.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.12 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C(CCl)NC(=O)Nc1ccccc1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(=O)Nc2ccccc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with N-chloroacetyl-N'-phenylurea according to the method of Example 1; m.p. 159°-161°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][C:11](C)=[O:12]>CS(C)=O.O1CCCC1>[C:4]1([C:1](=[O:3])[CH2:2][C:11](=[O:12])[CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccc1

Procedure:
The procedure of Example 1 is repeated, using in place of acetophenone 17.4 g of acetone and increasing the amount of solvent from 100 g to 150 g of dimethyl sulfoxide/tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:17]#[N:18].C(N(CC)CC)C>C(N(CC)CC)C.C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[CH:8]=2)[CH2:24][CH2:23]1)[C:17]#[N:18]
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.140 g), 3-chloro-4-(piperazin-1-yl)benzonitrile (0.155 g), triethylamine (0.078 g), and THF (2.5 mL) is heated at reflux for 5.5 h and then stirred overnight at room temperature. A few drops of triethylamine are then added and the mixture is stirred an additional 4 h at reflux. After cooling, the mixture is concentrated and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel using methanol/dichloromethane (4/96) gives 0.238 g of the title compound. A portion of the material is recrystallized from ethyl acetate/ethyl ether/hexane; mp 137-138° C.; MS m/z 385, 387; IR (mineral oil) 1501, 2225, 1130, 1342, 1490 cm-1. 1H NMR (CDCl3) δ2.77, 3.21, 3.79, 7.03, 7.14, 7.47-7.54, 7.61, 8.14.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1.[IH:18].C([O-])(O)=O.[Na+]>CCO>[I:18][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=1
Reactant: I
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(I)cc(C(=O)OCC)n1

Procedure:
A mixture of diethyl 4-bromopyridine-2,6-dicarboxylate (8.36 g, 27.7 mmol), 57% (w/w) aqueous hydriodic acid (31.05 g, 138.4 mmol) and EtOH (67 mL) was stirred at 50° C. for 1 h and neutralized with saturated NaHCO3 solution. The product was extracted from the aqueous phase with CH2Cl2 (2×300 mL). The combined organic fractions were dried with Na2SO4 and evaporated to dryness. Yield was 5.24 g (54%). ESI-TOF-MS [M+H]+: calc. for C11H13INO4+ 349.99. found 349.99.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:13][N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Reactant: C1CCNC1
Product: CCc1cc(-c2ccc(C(=O)N3CCCC3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]([OH:11])[C:9](=[CH:12]N(C)C)[C:8]([OH:16])=[C:7](Br)[C:3]=1[C:4]([OH:6])=[O:5]>[OH-].[Na+].[Ni]>[OH:11][C:10]1[CH:2]=[C:3]([CH:7]=[C:8]([OH:16])[C:9]=1[CH3:12])[C:4]([OH:6])=[O:5]
Reactant: CN(C)C=C1C(O)=C(Br)C(C(=O)O)=C(Br)C1O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(O)cc(C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a stirred solution of 2,6-Dibromo-3,5-dihydroxy-4[(dimethylamino) methylene]-benzoic Acid (1 mmol) in 2.5 mL of 3 N NaOH under nitrogen was added 0.345 g of Raney nickel in portions over a period of 1 h. The mixture was then stirred at 25° C. for about 12 h and filtered. The filter cake was washed with water (2×5 mL), and the combined filtrates were acidified to a pH of 1 with concentrated HCl to give a pale yellow or light purple solution. The solution was extracted with ethyl acetate, and the combined organic extracts were washed with saturated NaCl solution (2×0.2 mL), dried over sodium sulphate and evaporated by a rotatory evaporator to give 3,5-Dihydroxy-4-methylbenzoic Acid (70%) as a white solid: 1H NMR (DMSO-d6) δ 6.90 (s, 2H), 1.95 (s, 3H).
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[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:11].F[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)=[O:11])=[C:13]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

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)(4,5-difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 492 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.55 (m, 9H), 4.85-2.75 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH:15]=1)([O-])=O.C([O-])=O.[NH4+]>O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]1
Reactant: CC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)N1CCC(c2ccccc2N)CC1
Yield: 76.3 %

Procedure:
1-[4-(2-Nitro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone (0.43 g, 1.8 mmol) was dissolved in a solution of ammonium formate (1.13 g, 18 mmol) in IMS (20 mL) and water (20 mL). Palladium on carbon (10% w/w, 0.2 g) was then added and the mixture heated at reflux for 1 hour. The solution was filtered and then the solvent removed by evaporation under vacuum. The residue was dissolved in ethyl acetate (50 mL) and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a pale pink oil (0.3 g). LCMS m/z 219.38 [M+H]+. R.T.=2.29 min (Analytical Method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)(=O)=O)[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([S:21][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(S(=O)(=O)c4ccc(OC)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: COc1ccc(SC2CCN(C[C@H]3CN(c4ccc(OC)cc4)C(=O)O3)CC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-methoxyphenylsulfonylpiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 254°-256°; [αD =-31.6° (DMSO);
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[S:47]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Temperature: 0 °C

Procedure:
Into a 500-mL 3 neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-(1-hydroxy-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (25.2 g, 56.88 mmol, 1.00 equiv) in dichloromethane (300 mL), triethylamine (17.2 g, 170.30 mmol, 3.00 equiv). This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (16.3 g, 85.34 mmol, 1.50 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (5:1-1:1). This resulted in 31 g (91%) of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as a brown oil.
Reaction SMILES: [SnH3][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=CC=C[CH:12]=1.[Li+].[Cl-].BrC(C)=C>CN(C=O)C.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:11]=[CH2:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [SnH3]c1cc2ccccc2[nH]1
Agent: [Cu]I
Agent: [Pd]
Agent: C=C(C)Br
Solvent: CN(C)C=O
Product: C=CCc1cc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
The 2-stannylindole 23-1 (1.280 g, 2.34 mmol; prepared using methods described in WO 03/010141), triphenylphosphine (0.065 g, 0.25 mmol), CuI (0.045 g, 0.24 mmol), LiCl (0.200 g, 4.72 mmol) and 2-bromopropene (0.444 mL, 5.00 mmol) were dissolved in DMF (6 mL) and the suspension degassed by bubbling Ar for 20 min. Pd2(dba)3 (0.035 g, 0.034 mmol) was added and after degassing for an additional 10 min, the reaction mixture was heated to 100° C. overnight. The suspension was then diluted with TBME (100 mL) and washed with brine (2×25 mL). The extract was dried (MgSO4) and concentrated under reduced pressure to give a residue that was purified by flash chromatography using 5-10% EtOAc in hexane as eluent. The desired 2-(2-propenyl)indole 23-2 was obtained as beige solid (0.57 g, 81% yield): MS-ES m/z 298.1 (MH+). The methyl ester 23-2 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 23-3 in 96% yield: MS-ESm/z 284.1 (MH+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[N:8][CH:7]=1)=[O:5].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:2]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=2)=[N:8][CH:7]=1)[CH3:1]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Ethyl 6-chloro nicotinate (5.00 g, 26.9 mmol), 4-(trifluoromethoxy)phenol (5.28 g, 29.6 mmol), potassium carbonate (4.84 g, 35.0 mmol) and N,N-dimethylformamide (50 ml) were mixed and stirred at 100 to 110° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to afford the title compound as a colorless oil (7.48 g, 85%).