Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([CH2:10][OH:11])=[N:3]1.[H-].[Na+].[CH3:14]OS(OC)(=O)=O.N>C1COCC1.O>[CH3:14][O:11][CH2:10][C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1cc([N+](=O)[O-])c(CO)n1
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methyl-4-nitropyrazol-3-yl)methanol (2.0 g) was dissolved in THF (80 ml) and NaH (0.6 g, 60% in oil) added at <5° C. After 30 minutes, dimethylsulfate (1.92 g) was added and the reaction stirred overnight at room temperature. An additional 0.5 eq NaH was charged and the reaction warmed to 50° C. for 30 minutes. The reaction was cooled to room temperature, and water added dropwise (10 ml), then the mixture was poured into 5% aq. ammonia (100 ml). The organic phase was separated and the aqueous extracted with EtOAc (4×50 ml). The combined organic phases were washed with 5% aq. ammonia (2×50 ml), brine (50 ml), then dried, filtered and concentrated in vacuo to yield 3-(methoxymethyl)-1-methyl-4-nitropyrazole, 2.03 g, 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1.CCOCC.O.[Cl:27]CCl>Cl>[Cl:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[CH:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:14][CH:15]=1
Reactant: ClCCl
Reactant: COc1ccc(OC)c(C=Cc2ccc(CO)cc2)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(OC)c(C=Cc2ccc(CCl)cc2)c1
Yield: 68 %

Procedure:
2,5-Dimethoxystilbene-4'-methanol (1.18 g, 4.36 mmol) in dichloromethane (3 ml) and hydrochloric acid (10M, 100 ml) was stirred for 1 h at room temperature. Ether (100 ml) and water (100 ml) were added and the organic layer separated, washed with water (2×125 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane) to give 4'-chloromethyl-2,5-dimethoxystilbene (856 mg, 68%); δH ; (CDCl3) 3.83 (3 H, s, OCH3), 3.85 (3 H, s, OCH3), 4.59 (2 H, s, CH2Cl), 6.81 (1H, dd, J=8.8, 2.7 Hz), 6.85 (1 H, d, J=8.8 Hz), 7.10 and 7.49 (2 H, d, J=16.5 Hz, vinylic H), 7.17 (1 H, d, J=2.7 Hz), 7.37 and 7.53 (4 H, AA'BB'); δc (CDCl3) 46.1, 55.7, 56.0, 111.5, 112.2, 113.6, 123.9, 126.8, 128.4, 128.7, 136.4, 137.9, 151.4 and 153.6.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.[CH3:64][NH:65][O:66][CH3:67]>ClCCl>[CH2:1]([O:5][C:6]1[C:14]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)=[CH:13][C:9]([C:10]([N:65]([O:66][CH3:67])[CH3:64])=[O:12])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCCOc1ncc(C(=O)O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCOc1ncc(C(=O)N(C)OC)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.9 %

Procedure:
6-Butoxy-5-[3-ethyl-2-(2-methoxyethyl)-7-oxo-6,7-dihydro-2H-pyrazolo-[4,3-d]pyrimidin-5-yl]nicotinic acid (Example 3) (200 mg, 0.48 mmol) was dissolved in dichloromethane and 1-hydroxybenzotriazole hydrate (78 mg, 0.58 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (120 mg, 0.58 mmol) were added followed by diisopropylethylamine (0.34 mL, 1.95 mmol). N,O-dimethylhydroxyl-amine hydrochloride (56.3 mg, 0.58 mmol) was added and the mixture stirred at room temperature for 14 h. A further 0.29 mmol of 1-hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride were added and the reaction stirred for a further 3 h. The reaction mixture was diluted with further dichloromethane, washed with water, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution from dichloromethane to 5% methanol:dichloromethane) gave the title compound (178 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)[CH3:2].[O:11]1CC[CH2:13][CH2:12]1.C([Li])CCC.[Cl-].[NH4+]>O.CN(C)C(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:12](=[O:11])[CH3:13])[N:5]=1)[CH3:2]
Reactant: CCOc1cccc(Br)n1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOc1cccc(C(C)=O)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
16.8 g of 2-ethoxy-6-bromopyridine were introduced into 220 ml of tetrahydrofuran at -75° C. 54.4 ml of n-butyllithium (1.6-molar solution in n-hexane) were added dropwise at this temperature. Stirring was continued for two hours at -75° C., and 7.6 g of N,N-dimethylacetamide were added dropwise at this temperature. The mixture was stirred for a further hour at -75° C. and then warmed to -10° C., and first approximately 170 ml of 20 percent strength aqueous ammonium chloride solution and then 200 ml of water were added dropwise at this temperature. The mixture was extracted 3 times using methyl tert-butyl ether. The combined organic phases were washed 3 times with water and subsequently dried over sodium sulfate. After the solvent had been stripped off, the residue which remained was chromatographed on silica gel using cyclohexane/methyl tert-butyl ether 8:1. This gave 5.5 g of 2-ethoxy-6-acetylpyridine as a colorless solid (m.p.: 36-37° C).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[F:18][C:19](I)([F:21])[F:20].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:18][C:19]([F:21])([F:20])[C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
0.24 g (1.0 mmol) of cytidine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethylcytidine (19F-NMR yield: 24%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethylcytidine was obtained (0.034 g, yield: 11%) by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[F:11].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[CH:4][C:3]=1[F:11]
Reactant: CC(O)c1ccc(Br)c(F)c1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 1-(4-bromo-3-fluorophenyl)ethanol (1 g, 4.58 mmol), phenol (474 mg, 4.58 mmol), and triphenyl phosphine (2.4 g, 6.88 mmol) was stirred in dry tetrahydrofuran (40 mL) under nitrogen atmosphere. After 1 h, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (2.3 g, 6.88 mmol) was added with drop-wise method and the reaction was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether) to get 1-bromo-2-fluoro-4-(1-phenoxyethyl)benzene (900 mg, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Yield: 63.1 %

Procedure:
2-(4-Hydroxyphenyl)-4,5-diphenylimidazole (5 g) (J. Org. Chem., 1964, 29, 1926) was reacted with 8-bromooctane (6.2 g) in a method similar to Example 9. Work-up and recrystallisation from ethanol and water gave 2-(4-octyloxyphenyl)-4,5-diphenylimidazole (4.29 g, 63%) as a white solid, m.p. 178°. Found: C, 82.31; H, 7.66; N, 6.73%; C29H32N2O requires C, 82.04; H, 7.60; N, 6.60%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:20][O:21]S(C)(=O)=O)([CH2:14][O:15]S(C)(=O)=O)[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[OH:21][CH2:20][C@:13]12[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:10]([O:15][CH2:14]1)[C@H:11]([N:26]1[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]1=[O:28])[O:12]2
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cn([C@@H]2O[C@]3(CO)CO[C@H]2[C@H]3OCc2ccccc2)c(=O)[nH]c1=O
Temperature: 80 °C
Yield: 43.7 %

Procedure:
To a solution of nucleoside 11 (329 mg, 0.54 mmol) in ethanol/water (10 cm3, 1:1, v/v) was added 6M NaOH (aq) (0.9 ml, 5.4 mmol). The mixture was refluxed at 80° C. for 43 h followed by evaporation to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2.4% methanol, v/v) as eluent to afford nucleoside 12 (85 mg, 44%). δC ((CD3)2SO) 163.8, 150.3, 138.0, 135.8, 128.3, 127.7, 127.5, 108.0, 90.2, 86.5, 86.4, 79.3, 76.5, 72.5, 71.2, 57.2, 40.2, 40.0, 39.8. 39.6, 39.4, 39.2, 39.0, 12.3.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH3:24])[CH:12]=[CH2:13]>C(O)(=O)C>[CH2:11]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=1[CH2:24][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:12]=[CH2:13]
Reactant: C=CCOc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: C=CCOc1cccc([N+](=O)[O-])c1CC(=O)C(=O)OCC

Procedure:
0.625 mol Potassium tert.-butylate, 542 ml. diethyl oxalate and 95.7 g. 2-allyloxy-6-nitrotoluene are stirred for 3 hours at 60° C., then mixed with 1 N acetic acid and extracted with diethyl ether. The oxalic acid ester remaining behind in the ether residue is removed at an elevated temperature at water-pump pressure, 171 g. ethyl 2-allyloxy-6-nitrophenylpyruvate being obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[C:3]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sc2cccc(F)c2c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To an ice-cold suspension of 3-chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride (5.46 g, 23.6 mmol) in THF (120 mL) was added lithium aluminum hydride (11.8 mL of a 1.0 M solution in THF, 11.8 mmol) dropwise. The mixture was stirred for 2 h then quenched with NaOH (0.35 N solution in H2O). The mixture was diluted with Et2O and the solution filtered. The filtrate was dried (Na2SO4) and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 8:2) gave the title compound (4.52 g, 96%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1 Hz, 1H), 7.31 (ddd, J=8.0, 8.0, 4.7 Hz, 1H), 7.06 (dd, J=11.3, 8.0 Hz, 1H), 4.97 (d, J=6.2 Hz, 2H),
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[C:17]1([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)[C@H](C)N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)[C@H](C)Nc1cccc2ccccc12
Reaction time: 48 h
Yield: 34.1 %

Procedure:
To a dry round bottom flask equipped with a stir bar was added L-alanine methyl ester hydrochloride (500 mg, 3.58 mmol), 1-Naphthalene boronic acid (1000 mg, 5.81 mmol), dry Cu(OAc)2 (715 mg, 3.93 mmol), 4 A° molecular sieves (1.34 g). The flask was sealed with septum, evacuated and back filled with O2 atmosphere. Triethyl amine (0.92 mL), and dry DCM (30 mL) were added at room temperature, stirred for 48 h. The reaction mixture was quenched with 13 mL 2M NH3 in methanol. The volatiles were removed in vacuo and the resulting crude oil was purified by silica gel flash chromatography ethyl acetate/n-hexane (10:90) to give 280 mg of the title compound as brown viscous oil (34% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccccc2)c(=O)[nH]c1=O
Yield: 72.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (285 mg, yield: 72.5%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:42]3[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=3)(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)cc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3,5-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (78 mg, 42%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=4[Cl:33])=[CH:18][CH:17]=3)=[O:23])[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
As described for Example 136, a mixture of 0.349 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.131 g of triethylamine and 0.272 g of 2,4-dichlorobenzoyl chloride in 13 ml of dichloromethane is stirred at room temperature for 3 hours. Work-up gives a solid which is crystallized from dichloromethane-hexane to give 0.43 g of crystals, m.p. 199°-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[F:17][C:16]1([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)[CH:3]=1)[O:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncnc1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 22 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with pyrimidin-5-ylboronic acid yielded the title compound (22% yield) as a white solid. MS (ISP): m/z=409.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O.O>ClCCl>[NH2:24][C:25]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 46A (5.74 g, 20.0 mmol) in dichloromethane (40 mL) at 0° C. was treated with chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) and the mixture was stirred at 0° C. for 2 hours. Water (40 mL) was added to the cold reaction and the mixture was warmed to 25° C. and stirred for 2 hours. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](O)=[CH:5][CH:6]=[N:7]2.S(Cl)([Cl:16])=O.C(N(CC)C=O)C>CN(C)C=O>[Cl:16][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccnc2cc(Cl)cc(Cl)c12
Agent: CCN(C=O)CC
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2c(Cl)ccnc2c1

Procedure:
reacting 5,7-dichloro-4-hydoxyquinoline with thionyl chloride in the presence of N,N-dimethylformamide or N,N-diethylformamide to obtain 4,5,7-trichloroquinoline,
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCOCC1
Yield: 34.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with 4-(chloroacetyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.34 g (35% yield) of the title compound (3) as a white solid after purification by mass-guided preparative HPLC and lyophilization. M.p.: 124 to 126° C.; 1H NMR (CDCl3, 400 MHz): δ 6.97-6.91 (m, 2H), 4.84 (s, 2H), 3.82 (s, 3H), 3.72-3.70 (m, 4H), 3.64-3.62 (m, 2H), 3.46-3.41 (m, 2H). MS (ESI): m/z 258.04 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[CH2:19]([O:21][C:22]([C:24]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([N:34]=CC2SC=CC=2)[S:26][C:25]=1[N:41]=[CH:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)=[O:23])[CH3:20]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:32]([O:31][C:29]([C:28]1[C:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])=[C:25]([N:41]=[CH:42][C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)[S:26][C:27]=1[N:34]=[CH:9][C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:30])[CH3:33]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CCOC(=O)c1c(N=Cc2cccs2)sc(N=Cc2cccs2)c1C(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N=Cc2cccs2)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC

Procedure:
5-Nitrothiophene-2-carbaldehyde (9 mg) was mixed in toluene under nitrogen at 0° C. with DABCO (7 mg), TiCl4 in solution in toluene (59 μL) and 2,5-bis-[(thiophen-2-ylmethylene)-amino]-thiophene-3,4-dicarboxylic acid diethyl ester (12 mg). The mixture was refluxed for six hours, concentrated and the product isolated as a red powder after purification by flash chromatography. M.p.: 220°-222° C. 1H-NMR (300 MHz, [D] acetone): δ=8.81 (s, 1H), 8.79 (s, 1H), 8.10 (d, 1H, 3.2 Hz), 7.91 (d, 1H, 3J=4.1 Hz), 7.81 (d, 1H, 2.9 Hz), 7.78 (d, 1H, 3J=4.6 Hz), 7.29 (dd, 1H, 2.7 Hz and 3.8 Hz), 4.38 (q, 2H, 3J=5.3 Hz), 4.32 (q, 2H, 3J=5.3 Hz), 1.41 (t, 3H, 3J=5.3 Hz), 1.36 (t, 3H, 3J=5.3 Hz). 13C-NMR (300 MHz, [D] acetone): δ=176.9, 174.2, 169.1, 166.5, 155.1, 151.7, 146.6, 142.2, 140.9, 136.1, 135.9, 134.0, 132.7, 130.0, 129.0, 127.5, 61.5, 61.3, 14.2, 14.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([O:29]C)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1.[Li+].[OH-].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([OH:29])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 40 °C
Yield: 51.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.159 mmol), LiOH (19.87 mg, 0.8 mmol), H2O (2 mL) and methanol (3 mL) was heated at 40° C. for 4 h. Then methanol was removed under reduced pressure. The aqueous solution was acidified to “pH” 1-2 by addition of concentrated hydrochloride acid. The precipitate was collected by filtration and purified by Prep-HPLC to give the title compound as a white solid (50 mg).