Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:24])=[C:13]([CH2:20]C(O)=O)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([CH3:20])[C:12]=2[F:24])[CH:3]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(CC(=O)O)c2F)c1
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Yield: 87 %

Procedure:
The crude {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}acetic acid was dissolved in CH3CN (50 mL) and Cu2O (0.65 g, 4.5 mmol) was added. A condenser was attached and the heterogeneous mixture was heated to reflux for 2 h. The reaction mixture was cooled to RT, filtered through Celite and the solvent evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (6.0 g, 87%), which solidified upon standing. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.98 (dd, 1H), 7.81 (d, 1H), 7.60 (d, 2H), 7.52 (t, 1H), 2.37 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1>>[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH:26]=[C:25]([NH:27][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[CH:24]=[N:23]2)=[C:19]([CH3:28])[O:18][N:17]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: COc1ccc(OC)c(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)c1
Yield: 13 %

Procedure:
Prepared as in Example 4-8 from 2,5-dimethoxybenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 13%. MS M+H calculated 357.5. Found 357.3.
Reaction SMILES: Cl[C:2]1[C:11]2=[N:12][N:13]([CH2:16][CH2:17][CH3:18])[C:14]([CH3:15])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:19]>CO>[CH3:15][C:14]1[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:19]
Reactant: N
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1C
Solvent: CO
Product: CCCn1nc2c(N)nc3ccccc3c2c1C
Temperature: 150 °C

Procedure:
A Parr vessel was charged with 4-chloro-1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinoline (4.31 g) and a solution of ammonia in methanol (50 mL of 7 N). The reaction was heated at 150° C. for 24 hours and allowed to cool to room temperature. Most of the methanol was removed under reduced pressure, and water was added. A precipitate formed and was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 3.8 g of 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1.Br[C:16]1C(C)=CC(N)=NC=1>>[CH3:16][C:5]1[C:4]([CH:2]2[CH2:3][O:1]2)=[CH:9][N:8]=[C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:6]=1
Reactant: c1cc(-n2cnnn2)ncc1C1CO1
Reactant: Cc1cc(N)ncc1Br
Product: Cc1cc(-n2cnnn2)ncc1C1CO1

Procedure:
4-Methyl-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl) pyridine was prepared in a similar fashion to that described for the synthesis of 5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine (INTERMEDIATE 32) starting from commercially available 5-bromo-4-methylpyridin-2-amine to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC2CCCCO2)cc(C)c1Br
Yield: 98.7 %

Procedure:
Pyridinium para-toluenesulfonate (0.01 g) was added to a chloroform solution containing 4-bromo-3,5-dimethylphenol (50 g) and 3,4-dihydro-2H-pyran (35 g), followed by stirring. After confirmation of the degree of reaction progress by thin-layer chromatography (hereinafter referred to as TLC), the reaction was quenched with triethylamine. The organic phase was washed with water and saturated brine in this order. The resulting organic phase was dried over anhydrous magnesium sulfate. Subsequently, the organic phase was concentrated and purified by column chromatography to obtain 70 g (yield: 980) of 2-(4-bromo-3,5-dimethylphenoxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18]>>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([O:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])=[O:19])[CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Product: O=C(O[C@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O

Procedure:
In particular, when the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is processed with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedione is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivative.
Reaction SMILES: [CH2:1]([C:10](=O)[C:11]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[CH2:1]([C:10]1[S:33][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][C:11]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(CC(=O)C(=CC(=O)c2ccc(C)cc2)Cc2ccc(OC)cc2)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(Cc2cc(-c3ccc(C)cc3)sc2Cc2ccc(OC)cc2)cc1
Reaction time: 3.58 h

Procedure:
In a 1-liter stainless steel autoclave equipped with stirrer were placed 40.6 g (0.105 mole) of 1,2-di-p-anisyl-4-p-tolylbutene-1,4-dione, 100 ml of xylene and 25 g (0.056 mole) of phosphorus pentasulfide. The vessel was chilled with a Dry Ice-acetone bath and charged with 130 g (3.81 moles) of hydrogen sulfide. The autoclave was then heated with stirring for 215 minutes at 158°-165° C. (1250-1360 psig). After cooling the vessel, the hydrogen sulfide was allowed to vent into a sodium hydroxide solution. The residue was treated with 150 ml of absolute ethanol to destroy unreacted phosphorus pentasulfide. After removal of the ethanol there remained 70.5 g of crude product. Recrystallization from ethanol-dioxane (70:30) gave 20 g (49.3%) of pure 2,3-di-p-anisyl-5-p-tolythiophene, m.p. 99°-102° C. and a second crop of 6.5 g (16.0%) m.p. 92°-96° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]C(C)C)(C)C.[Cl-].CN([CH:21]=[O:22])C>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:21]=[O:22])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1cnc(Cl)nc1Cl
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 454 mg, 2 mmol) in THF at −78° C., diisopropyl magnesium chloride (2M solution in THF, 2.1 mmol, 1.05 mL) was added and the mixture was stirred for 30 minutes at −35° C. Next, the solution was cooled to −78° C. and 1 mL of dry DMF was added. The mixture was stirred for 120 minutes at −78° C. and the reaction was quenched with 1 N HCl. The mixture was extracted with EtOAc and dried with sodium sulfate. The solvent was removed and the residue was chromatographed to give a brown solid. 102 mg, 28%. H1NMR (CDCl3), δ (ppm), 9.0 (s, 1 H), 10.4 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Reactant: COCCN
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 61.6 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), 2-methoxyethylamine (72 μL, 62 mg, 0.83 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 40 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(2-methoxyethylamino)methyl]phenoxy}benzonitrile fumarate (208 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:21])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH3:1][C:2]1([CH3:27])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:26])[C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:21][C:36]4=[O:38])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)COc2cccc(Oc3ncc(NC(=O)[C@H](N)C(C)(C)C)cn3)c21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2cccc(Oc3ncc(N4C(=O)N[C@H](C(C)(C)C)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N1-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-3-methyl-D-valinamide (Intermediate 78, 9.9 mg) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (22.35 μl, 0.160 mmol) was added. The reaction mixture was cooled down at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (0.015 mmol) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. Some water (2 ml) was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 60/40. This afforded the title compound (7.7 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:7]=1.[Si:19]([O:36][CH2:37][CH2:38][C@@H:39](O)[CH2:40][CH3:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Si:19]([O:36][CH2:37][CH2:38][C@H:39]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][CH:5]=1)[CH2:40][CH3:41])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ncc(-c2ccccc2O)cc1F
Reactant: CC[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)OC)c(F)c1

Procedure:
In accordance with the method of Example 5-2, the compound of Example 38-2 was used instead of the compound of Example 1-3, and (3S)-1-{[tert-butyl(diphenyl)silyl]oxy}pentane-3-ol (Tetrahedron Letters, 2006, 47(7), 1213-1215) was used instead of the compound of Example 5-1 to afford methyl 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-ethylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][C:16](OCC)=[O:17]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][C:16](=[O:17])[NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Nc1cccc(I)c1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cccc(I)c2)C(=O)N1
Reaction time: 5 h

Procedure:
A solution of 3-iodophenylurea (2.1 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion; 640 mg), followed by ethyl chloroacetate (0.93 ml) and the mixture was stirred for 5 h. The mixture was partitioned between EtOAc and 2M HCl and the organic solution was washed with NaHCO3, brine, dried and evaporated to dryness to give the title compound (2.08 g) ES+ve 303(MH)+.
Reaction SMILES: S1CCS[CH:2]1[C:6]1[NH:20][C:19]2[C:21]3[C:7]=1[CH2:8][C@@H:9]1[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][C@H:12]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:11][N:10]1[CH3:30].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:2]([C:6]1[NH:20][C:19]2[C:21]3[C:7]=1[CH2:8][C@@H:9]1[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][C@H:12]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:11][N:10]1[CH3:30])=[O:33]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
Under argon, 1.10 g (2.5 mmol) of 3-[9,10-didehydro-2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]-1,1-diethylurea is dissolved in 25 ml of chloroform and combined with 1.9 g of silica gel of a particle size of 0.063-0.2 mm. Under vigorous agitation, 2 ml of distilled water is added dropwise. Subsequently, within a time period of 15 minutes, a solution of 0.5 ml (0.6 mmol) of sulfuryl chloride in 13 ml of chloroform is added dropwise and the mixture is stirred for 2 hours at room temperature. For working-up purposes, 3 g of potassium carbonate is added and the mixture is vigorously agitated for 20 minutes. The precipitate is filtered off and washed with methylene chloride. The precipitate is moistened with ethanol and made into a slurry with 250 ml of saturated sodium chloride solution. This mixture is repeatedly extracted with methylene chloride. The extracts are dried together with the methylene chloride filtrate over magnesium sulfate and concentrated. The crude product is chromatographed under pressure on silica gel with a chloroform/methanol mixture and the main fraction of 448 mg is recrystallized from diisopropyl ether, thus obtaining 225 mg of 3-(9,10-didehydro-2-formyl-6-methyl-8α-ergolinyl)-1,1-diethylurea (25% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:8]=1[NH:15][C:16](=[O:32])[CH2:17][CH:18]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:25][C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.O>C(Cl)Cl>[S:34]([O:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:8]=1[NH:15][C:16](=[O:32])[CH2:17][CH:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[O:25][C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:33])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1cccc(COCCCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cccc(COCCCOS(C)(=O)=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 1 h

Procedure:
212 mg (0.48 mmol) of N-[2-(3-hydroxypropoxy)methyl-6-methylthiophenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 4) were suspended in 15 ml of methylene chloride. The suspension was cooled on an ice bath, and then 102 mg (0.89 mmol) of methanesulfonyl chloride were added, followed by 94 mg (0.90 mmol) of triethylamine. The temperature of the reaction mixture was allowed to rise to room temperature, after which the mixture was stirred for an additional 1 hour. At the end of this time, the reaction was stopped by the addition of water. The mixture was then diluted with methylene chloride, after which the organic layer was washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure, to obtain 251 mg (a quantitative yield) of the title compound as crystals. These crystals were used for the next step without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:15]2[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5][C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[CH:35]([C:32]1[CH:31]=[CH:30][C:29]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH:10]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:27][CH:28]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:8][C:3]=2[CH2:1][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)([CH3:36])[CH3:37]
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(C=O)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(CN2CCOCC2)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid (240 mg, 0.48 mmol) and Morpholine (84 mg, 0.96 mmol) in dichloromethane (20 ml) is added NaBH(OAc)3 (143 mg, 0.67 mmol) and acetic acid (58 mg, 0.96 mmol). The resulting mixture is stirred overnight, diluted with ethyl actate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography to afford 80 mg of the titled compound as a white solid. MS (ES): 573.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1
Yield: 89.5 %

Procedure:
Following a similar procedure to that described in Example (1b), 1.10 g of N-[1-(3,5-difluorophenyl)ethyl]-N-[(3-nitrophenyl)-(4-propoxyphenyl)methyl]amine [prepared as described in step (a) above], 1.41 g of nickel chloride hexahydrate and 411 mg of sodium borohydride were reacted, to obtain 915 mg of the title compound as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])[CH:10]=[N:9]1)#[N:2].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>C(Cl)Cl>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][C:23]([N:18]1[C:19]2[C:14](=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:56]=[N:55][N:54]=4)[CH:12]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)=[O:36]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(CC(=O)NCCC#N)c4)cccc32)c1C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5nnnn5CCC#N)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of N-(2-cyanoethyl)-2-(4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetamide (20 mg, 0.04 mmol) and pyridine (19 μL, 0.24 mmol) in DCM (0.4 mL) under argon was added PCl5 (13 mg, 0.06 mmol) in one portion, and the resulting mixture was heated to reflux for 3 h. The reaction was cooled to room temperature and trimethylsilyl azide (18 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature overnight and carefully quenched with saturated aqueous NaHCO3. The resulting mixture was stirred vigorously for 15 min. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (17 mg, 81% yield) as white foam. LCMS, [M+H]+=525.2. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.47 (s, 1H), 7.30-7.16 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.2 Hz, 1H), 5.74 (s, 2H), 4.95 (t, J=6.9 Hz, 2H), 3.93 (s, 2H), 3.78 (t, J=6.8 Hz, 2H), 3.06 (t, J=6.9 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.52 (s, 2H), 2.24-2.11 (m, 5H), 1.96-1.78 (m, 5H).
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=1)O.[Cl-:33].[NH4+]>ClCCl>[Cl:33][C:15]1([C:23]2[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: COc1ncc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ncc(C2(Cl)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.28 ml) and thionyl chloride (0.18 ml) were added successively to an ice-cold solution of the intermediate from Step A (0.64 g, 2.0 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:28]([N:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].OP(O)(O)=O>C(Cl)Cl.CN(C)C=O>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][CH:38]([O:41][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CN(C)c1ccccn1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 72 h
Yield: 77.8 %

Procedure:
To a solution of p-toluenesulfonylchloride (6.42 g, 33.69 mmol) in CH2Cl2 (45 mL) and N,N-dimethylformamide (5 mL), chilled to 0° C., was added triethylamine (7.2 mL, 51.66 mmol), dimethylaminopyridine (275 mg, 2.25 mmol) and then dropwise addition of N-Boc-4-hydroxypiperidine (4.52 g, 22.46 mmol) in CH2Cl2 (45 mL). Stirred the resulting mixture for 3 days and then added 1M H3PO4 (40 mL), separated the layers and extracted with CH2Cl2 (50 mL). Combined the organics, washed with NaHCO3 (aq) (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated to provide a crude solid which was purified by flash column chromatography (7 to 60% EtOAc/Heptane) to provide 6.21 g (78% yield) of the title compound as a solid.