Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C:6]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CC(C)=O>CCCCCC>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:6]=2[CH:18]=1)[CH:26]=[CH2:25]
Reactant: Oc1ccc2c(c1)CC(CCc1ccccc1)O2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CC(CCc1ccccc1)O2
Yield: 82 %

Procedure:
A mixture 5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzoruan, E5, (50 gm; 208 mmoles), potassium carbonate (55 gm; 400 mmoles), allyl bromide (48 gm; 400 mmoles) and acetone (500 mL) was refluxed for 18 hours. The mixture was cooled, diluted with hexane (250 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue chromatographed in silica gel using 10% ethylacetate in hexane as eluent to obtain 47.8 gm (82%) of 5-allyloxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran E6 as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1>C(OC(=O)C)(=O)C.C(O)(=O)C.CO.[Pt]=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cc2ccoc2cc1N1CCCCC1

Procedure:
A solution of 2.51 g (10.0 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one in 15 ml of acetic anhydride and 15 ml of glacial acetic acid is maintained at 100° for 24 hours. The reaction mixture is subsequently poured onto ice and extracted with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The crude 3-acetoxy-5-chloro-6-(piperidin-1-yl)-benzofuran so obtained is dissolved in 15 ml of absolute methanol, 250 mg of platinum oxide are added and the whole is hydrogenated at 3 atmospheres and room temperature. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant (Rf =0.63). In that manner, 5-chloro-6-(piperidin-1-yl)-benzofuran is obtained in the form of an oil which distills at 96°-97°/1.5 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][C:12]([O-])([CH3:14])[CH3:13].[K+].[C:17]([Si:21]([CH3:24])([CH3:23])Cl)(C)(C)C>C1COCC1>[C:12]([N:6]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[Si:21]([CH3:24])([CH3:23])[CH3:17])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: Clc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c([Si](C)(C)C)cc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
4-Chloroindole (131.1 g, 0.871 mol) was dissolved in dry THF (0.5 L). The solution was chilled to 0° C. (ice bath, stirring). t-BuOK (97.6 g, 0.871 mol) was added in one portion and the stirring was continued for additional 5 minutes, Tert-butyldimethylchlorosilane (131.3 g, 0.871 mol) was added portionwise over 10 min with a good stirring. The reaction is exothermic. After 30 minutes the reaction was quenched with water (20 ml) and pH was adjusted to 8-9 and extracted with ethyl acetate (3×50 mL). The organic phases were dried (MgSO4), filtered and the volatiles were eliminate by vacuum. The residue was triturated and crystallized from heptane to yield 181 g (78%) of the title compound. 1H NMR (CDCl3) δ 7.45 (dd, J=7.9 Hz, J=0.8 Hz, 1H), 7.25 (d, J=3.0 Hz, 1H), 7.18-7.07 (m, 2H), 6.77 (d, 1H), 0.96 (s, 9H), 0.62 (s, 6H); 13C NMR (CDCl3) 141.8; 131.7; 130.3; 125.9; 122.0; 119.7; 112.5; 103.5; 26.3; 19.5; −3.9; MS (ESI) 266.1 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[OH:25][CH2:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:25][CH2:26][CH2:27][CH2:28][NH:29][C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]2[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:7])[CH:14]=2)=[CH:20][CH:19]=1)=[O:23]
Reactant: NCCCO
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCO)cc1
Yield: 83.5 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (30 mg, 0.093 mmol), 3-hydroxypropylamine (7 mg, 0.093 mmol), HATU (35.5 mg, 0.093 mmol), HOBT (12.6 mg, 0.093 mmol) and DIPEA (48 μl, 0.28 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(4′-{[(3-hydroxypropyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (29.4 mg, 83%). NMR; δH [2H6]—DMSO 9.91,(1H, s), 8.50,(1H, t), 8.35,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.97,(1H, m), 4.49,(1H, t), 3.47,(2H, q), 3.33,(2H, m), 2.19,(3H, s), 1.69,(2H, m). LCMS: retention time 2.77 min, MH+379.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:23][C:22](=[O:24])[NH:21][C:20](=[O:25])[CH2:19]3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)NC(=O)C2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
119 mg of (S)-4-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazine-2,6-dione, 34 mg of 2-aminopyrazine, 19 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 139 mg of tripotassium phosphate and 17 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added to 2.5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 26 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:14][NH2:15]>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:14][NH2:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: NN
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(Cl)c(C(=O)NN)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carboxylic acid (4.0 g, 19.6 mmol) and 1,1-carbonyl diimidazole (6.35 g, 39.2 mmol) were dissolved in 80 mL THF and stirred at room temperature. After 3 h, the solution was cooled with an ice bath and hydrazine hydrate (1.90 mL, 39.2 mmol) was added in one quick portion. The solution was allowed to stir for 5 h, gradually warming to room temperature. The reaction mixture was diluted with excess H2O and extracted with EtOAc several times. These organics were combined and washed with 2 N HCl. The combined aqueous layers were then basified carefully with 5 N NaOH, and extracted once again with EtOAc. This second set of organic layers were combined, dried over magnesium sulfate and concentrated under vacuum to give 2.46 g (58% yield) of product as a white solid. MS (M+H)+ 219.
Reaction SMILES: [N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.S(=Cl)=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.P(Br)(Br)Br>>[N:1]#[N:2].[C:3]1([S:13]([NH:16][C@H:17]([C:25]([NH2:1])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)O
Agent: BrP(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(N)=O

Procedure:
An N2 -naphthalenesulfonyl-L-argininamide is prepared by reaction of a corresponding N2 -naphthalenesulfonyl-L-arginyl halide and an amine. The N2 -naphthalenesulfonyl-L-arginyl halide is prepared by reacting a corresponding N2 -naphthalenesulfonyl-L-arginine with a halogenating agent such as thionyl chlorine, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, etc.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: ClCCCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(OCCCCl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Compound b2 may be prepared according to reported methods (see, e.g., Gumbley, P.; Koylu, D.; Thomas, S. W. Macromolecules 2011, 44, 7956). 1-Bromo-3-chloropropane (0.650 mL, 0.00658 moles) was added to a solution of 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 0.00598 moles), and potassium carbonate (1.66 g, 0.0120 moles) in anhydrous DMF (6 mL). The solution was stirred at 40° C. for 24 hours. The reaction was diluted with ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution (75 mL), water (75 mL), and brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was removed by filtration. The filtrate was concentrated, and the resulting residue was subject to silica gel chromatography using a gradient of 100% hexanes to 50% ethyl acetate in hexanes. The fractions containing the product were collected, and volatiles were removed by rotary evaporation. The resulting residue was dried overnight to yield 5-(3-chloropropoxy)-2-nitrobenzaldehyde as a bright-green yellow solid (yield 87%*). 1H NMR (400 MHz, CD2Cl2) δ 10.42 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 7.32 (d, J=2.9 Hz, 1H), 7.18 (dd, J=9.0, 2.9 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.3 Hz, 2H), 2.35-2.24 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 189.05, 163.84, 135.04, 127.84, 119.16, 114.57, 66.28, 41.74, 32.35 HRMS m/z: calculated for C10H10ClNO4 [M+H]+, 244.0371. found, 244.0366.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].CCN(CC)CC.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.2 mL (30.0 mmol) of Et3N and 9 mL (90.0 mmol) of piperidine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 4.6 g (89%) of the desired product as a tan oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=1[O:28][CH2:29][CH3:30])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl.O>[CH2:29]([O:28][C:17]1[C:18]([CH:25]([CH3:27])[CH3:26])=[CH:19][C:20]([CH:22]([CH3:23])[CH3:24])=[CH:21][C:16]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:31])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[CH3:30]
Reactant: CCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 59.9 %

Procedure:
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (77 mg, 0.14 mmol) was dissolved in methanol (1 mL)/dioxane (1 mL) and treated with 1N NaOH (1 mL) at 55° C. for 5 h. Diluted with 1N HCl (3 mL)/water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with brine (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 68 mg. The material was purified by radial chromatography using a hexane/ethyl acetate gradient to provide 34 mg (62%) of a yellow foam. 1H NMR (250 MHz, CDCl3): δ 8.33 (bs, 1H), 8.04 (s, 1H), 7.58 (d, 1H, J=2.4), 7.44 (s, 1H), 7.29 (d, 1H, J=2.2), 7.09 (d, 1H, J=2.2), 6.27 (s, 1H), 3.56-3.38 (m, 3H), 2.95 (sep, 1H, J=6.9), 2.70 (s, 3H), 1.32 (s, 12H, J=6.9), 1.08 (t, 3H, J=7.0). MS [EI−] 404 (M−H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
1-(tert-Butoxycarbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (17) (6.30 g; 13.2 mmol) is dissolved in methylene chloride (60 mL) at ambient temperature. Trifluoroacetic acid (40 mL) is added in a slow stream, and the solution is stirred for 1 hour at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (300 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×100 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (5.34 g) as a white solid. ESMS: MH+ 379.0
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:60][CH3:61])[C:44]([NH:49][C@@H:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][C@@H:51]2[OH:59])=[N:45][C:46]=1[CH2:47][CH3:48].Br[CH2:63][CH2:64][F:65]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:60][CH3:61])[C:44]([NH:49][C@@H:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][C@@H:51]2[O:59][CH2:63][CH2:64][F:65])=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: FCCBr
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a pale yellow semi-solid. IR (diffuse reflectance) 2970, 1604, 1564, 1481, 1439, 1391, 1286, 1228, 1204, 1182, 1123, 1109, 1044, 876, 750 cm−1; OAMS supporting ions at: ESI+ 470.1; MS (EI) m/z 469 (M+); HRMS (FAB) calcd for C26H29CLFN3O2+H1 470.2010, found 470.2013. [α]25D=−82 (c 0.39, methylene chloride); Anal. Calcd for C26H29ClFN3O2: C, 66.45; H, 6.22; N, 8.94. Found: C, 66.41; H, 6.37; N, 8.84.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[Cl:13][C:14]1[S:41][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[C:25]3=[O:40])=[O:22])=[CH:20][C:16]=2[CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[S:41][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][CH:35]4[CH2:38][O:39][C:1](=[O:2])[O:37][CH2:36]4)[C:25]3=[O:40])=[O:22])=[CH:20][C:16]=2[CH:15]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(CO)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ccncc1
Product: O=C1OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)CO1
Temperature: 50 °C
Yield: 69 %

Procedure:
Carbonyl diimidazole (143 mg, 0.88 mmol) was added to 2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 22; 250 mg, 0.58 mmol) followed by DMAP (2 mg) and the reaction was heated at 50° C. for 4 hours. The reaction was quenched by addition of EtOAc (50 mL) and H2O (10 mL) and the organic layer was separated and washed further with saturated aqueous NaHCO3, 1M HCl (aq.) and brine. The organic layer was then dried (MgSO4), filtered and evaporated. Trituration with hot Et2O (15 mL), cooling and filtration afforded the title compound (182 mg, 0.40 mmol, 68%) as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1.[CH2:24](I)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34].O>C1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH:13]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24])[C:12](=[O:23])[C:11]2=1.[CH3:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][C:21]=1[CH3:22])[CH:18]=[CH:17][C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:23])[C:11]2=1
Reactant: C=CCCCCCCCCCI
Agent: CC(C)(C)[O-]
Agent: Cc1cc2ccc3c(c2cc1C)C(=O)CCC3
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCCCCCCCCCC1CCc2ccc3cc(C)c(C)cc3c2C1=O
Temperature: 60 °C
Yield: 39 %

Procedure:
t-BuOK (3.6 g, 0.032 mole) was dissolved in 250 ml of dry benzene at 40°-50° C. To the stirred solution was added 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (3.6 g, 0.016 mole) in 50 ml of dry benzene and then, 10-undecenyl iodide (4.58 g, 0.016 mole) at 30° C. under N2. The mixture was heated to 60° C. for 2.5 hr under N2. After cooling the reaction mixture to room temperature, water was added. The whole mixture was extracted twice with diethylether. The combined diethylether solution was dried over anhydrous MgSO4 and then concentrated. Flash column chromatography of the residue on silica gel afforded 6,7-Dimethyl-4-oxo-3-(10-undecenyl)-1,2,3,4-tetrahydrophenanthrene as a sticky brown solid (2.36 g, 0.0063 mole, 39% yield) as a desired product, and unreacted 6,7-Dimethyl-4-oxo-1,2,3,4-tetrahydrophenanthrene (1.70 g, 47% recovered). 1H NMR (CDCl3)δ 1.29-1.62 (m,14H), 1.86-2.08 (m,4H), 2.21-2.35 (m,2H), 2.40 (s,3H), 2.46 (s,3H), 2.52-2.63 (m,1H), 3.07-3.13 (m,2H), 4.90-5.04 (m,2H), 5.75-5.89 (m,1H), 7.17 (d, J=8.2 Hz,1H), 7.53 (s,1H), 7.77 (d, J=8.2 Hz,1H), 9.10 (s,1H), IR (KBr) cm-1 2920, 2850, 1669, 1600, exact (EI) mass. calcd. for C27H36O: 376.2766, Found: 376.2766.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2.[Cl:19][C:20]1[C:25]([NH2:26])=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[Cl:19][C:20]1[C:25]([NH:26][C:9]2[C:8]3[C:13](=[CH:14][C:15]([F:17])=[CH:16][C:7]=3[F:6])[N:12]=[CH:11][N:10]=2)=[C:24]2[O:27][CH2:28][O:29][C:23]2=[CH:22][CH:21]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Solvent: Clc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Phosphoryl chloride (4.96 ml) was added over a period of 40 minutes to a stirred mixture of 5,7-difluoro-3,4-dihydroquinazolin-4-one (6.5 g), chlorobenzene (64.9 ml), 6-chloro-2,3-methylenedioxyaniline (7.08 g) and diisopropylethylamine (7.47 ml) that had been heated to 95° C. under an atmosphere of nitrogen gas. The resultant reaction mixture was heated at 95° C. for 5 hours. The reaction mixture was cooled to 18° C. and stirred for 30 minutes. Stirring was stopped and the reaction mixture was allowed to stand for 30 minutes. The mixture was filtered and the isolated solid was washed with chlorobenzene (2×23 ml) and dried in vacuo at 45° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline as a mono-hydrochloride salt (8.9 g, 96.5% HPLC purity using Method A, retention time 4.46 minutes); m.p. 234-237° C.; NMR Spectrum: (DMSOd6) 5.5-6.0 (br s, 1H), 6.15 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.7 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])(=O)=O.CS(C1C=CC(N2C=NN=N2)=CC=1)=O.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:17][CH2:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccc(-n2cnnn2)cc1
Agent: CS(=O)c1ccc(-n2cnnn2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: ClCSc1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4.8 g. of 1-[p-(methylthio)phenyl]-1H-tetrazole in 80 ml. of methylene chloride was treated with 2.2 ml. of sulfuryl chloride in 10 ml. of methylene chloride. The solution was stirred at room temperature for 1 hour, evaporated to dryness on a steam bath, washed with hexane and recrystallized from methylene chloride to give white crystals, m.p. 115°-117° C. This product was also obtained by a similar reaction of 0.5 g. of 1-[p-(methylsulfinyl)phenyl]-1H-tetrazole and 0.18 ml. of thionyl chloride in methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15]Br)[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Product: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
16.0 g (45.8 mmol) of 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 50.3 ml (183.3 mmol) of triisopropyl phosphite (90%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2). 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellow oil.