Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:33]([O:34][CH3:35])=[CH:32][C:12]2[C:13](=[O:31])[N:14]3[CH2:30][CH2:29][CH2:28][C@H:15]3[C@H:16]([OH:27])[N:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[C:11]=2[C:10]=1[O:36][CH3:37])C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[C:33]([O:34][CH3:35])=[CH:32][C:12]2[C:13](=[O:31])[N:14]3[CH2:30][CH2:29][CH2:28][C@H:15]3[C@H:16]([OH:27])[N:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:24])[CH3:25])=[O:19])[C:11]=2[C:10]=1[O:36][CH3:37]
Reactant: COc1cc2c(c(OC)c1OCc1ccccc1)N(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@@H]1CCCN1C2=O
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(c(OC)c1O)N(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@@H]1CCCN1C2=O
Yield: 90.5 %

Procedure:
10% Pd/C catalyst (0.22 g) was added to a solution of the substrate 128 (0.95 g, 2.1 mmol) in absolute EtOH (200 mL). The reaction mixture was hydrogenated under pressure using a Parr hydrogenator at 55 psi H2 for 18 h. The reaction mixture was filtered through celite, and the celite washed with hot EtOH, taking care not to allow the filtration pad to dry out. Removal of excess solvent afforded the product as a colourless glass (0.84 g, 1.9 mmol, 92%); 1H NMR (270 MHz, CDCl3) δ 0.07 (s, 9H), 0.91-0.97 (m, 2H), 2.07-2.20 (m, 4H), 3.52-3.75 (m, 2H), 3.98-4.26 (m, 9H), 5.65 (d, 1H, J=9.71 Hz), 6.26 (br s, 1H), 7.14 (s, 1H); 13C NMR (CDCl3) δ 167.0, 157.3, 146.8, 143.4, 141.3, 124.9, 123.5, 105.5, 105.2, 85.8, 64.8, 64.6, 64.5, 61.2, 60.0, 56.4, 46.4, 28.9, 28.7, 23.1, 23.0, 17.3, −1.3, −1.5, −1.7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([CH3:12])[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([CH3:12])[CH2:10][Cl:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CO)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(CCl)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of an optically-active compound of [benzyl-(2-hydroxy-1-methylethyl)-amino]acetic acid tert-butyl ester (160.0 g) in chloroform (640 ml) cooled to 0° C. was added dropwise thionyl chloride (50.0 ml), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 0° C. Then, thereto were added saturated aqueous sodium bicarbonate solution (1000 ml) and chloroform (100 ml), and the mixture was stirred. The separated organic layer was washed with saturated aqueous sodium chloride solution (500 ml), and the aqueous layer was extracted with chloroform (450 ml) again. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (172.9 g).
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][O:18][C:19]4[CH:23]=[CH:22][O:21][N:20]=4)[O:14][C:13]3=[O:24])=[CH:8][C:7]=2[F:25])[CH2:3]1.FC1C=C(N2C[C@H](CO)OC2=O)C=C[C:32]=1[N:33]1C=CN=C1C>>[F:25][C:7]1[CH:8]=[C:9]([N:12]2[CH2:16][C@H:15]([CH2:17][O:18][C:19]3[CH:23]=[CH:22][O:21][N:20]=3)[O:14][C:13]2=[O:24])[CH:10]=[CH:11][C:6]=1[N:4]1[CH:3]=[CH:32][N:33]=[C:5]1[CH3:2]
Reactant: Cc1nccn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC(O)C2)c(F)c1
Product: Cc1nccn1-c1ccc(N2C[C@H](COc3ccon3)OC2=O)cc1F

Procedure:
Using essentially the same procedure as for the intermediate of Example 65, but starting with 3-(3-fluoro-4-(2-methyl-imidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (202 mg, 0.69 mmol), and purifying by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane, the title compound was prepared (137 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:14]2=[CH:15][CH:16]=[N:17][CH:18]=[C:13]2[C:5]2[C:6]([OH:12])=[CH:7][C:8]([CH2:10][CH3:11])=[CH:9][C:4]=2[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:12][C:6]1[C:5]2[C:13]3[C:14]([C:2]([CH3:1])([CH3:19])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=1)=[CH:15][CH:16]=[N:17][CH:18]=3)(=[O:22])[CH3:21]
Reactant: CCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-ethyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-ethyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(I)cc1
Reactant: C#CCCCO
Product: COc1ccc(C#CCCCO)cc1

Procedure:
5-(4'-methoxyphenyl)-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 4-iodoanisole using the same method as in Example 15 to give 1.55 g (70% of theory) of product.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]CO)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([CH:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:7][O:6][C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH2:8][CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: OCCC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
3.0 g (23.1 mg) of methyl 3-oxopentanoate and 4.9 g (23.1 mg) of 3,3-diphenylpropanol were stirred in 60 ml of toluene under heating at 100° C. overnight. Toluene was distilled out under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
88.9 g (196 mmol) 2-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-isoindol-1,3-dione are suspended in 1000 ml ethanol and added to 22.0 g (440 mmol) hydrazine hydrate and heated to boiling for four hours. After cooling, the mixture is filtered and the solvent is removed under vacuum. The solid residue is dispersed in the heat together with the filter residue between 300 ml 10% sodium hydroxide solution and 300 ml acetic acid ethyl ester. The aqueous phase is extracted once with 150 ml warm acetic acid ethyl ester. The combined organic phases are extracted twice, each with 300 ml 10% hydrochloric acid. The combined aqueous phases are made basic with 10% sodium hydroxide solution and extracted twice, each with 400 ml acetic acid ethyl ester. The combined organic phases are washed with 100 ml water and dried over sodium sulfate. The solvent is removed under vacuum, the residue is dried under high-vacuum and processed further without additional purification. Yield of a gradually hardening resin: 63 g (99%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O-:13])=O)=[CH:2]1.[K+].[C:16]([N:24]1[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([N:24]1[CH2:29][CH2:28][N:27]([C:11](=[O:13])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][N:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[C@H:26]([CH3:30])[CH2:25]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2cnccc12
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2cnccc12

Procedure:
Precursor 5h, 1-benzoyl-3-(R)-methyl-4-[(6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (6-azaindol-3-yl)oxoacetate, Precursor 4b, and 1-benzoyl-3-(R)— methylpiperazine. MS m/z: (M+H)+ Calc'd for C21H21N4O3: 377.16; Found 377.10. HPLC retention time: 0.88 minutes (column A).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=2[OH:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(O)c2cccc(C)c2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2cccc(C)c2O)cc1
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of (2-benzyloxy-3-methylphenyl)-(4-methoxyphenyl)-methanol (2.76 g, 8.25 mmol) in methanol (30 ml), a 20% palladium hydroxide catalyst (276 mg) was added and furthermore concentrated hydrochloric acid (0.27 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 18 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.75 g, 93%).
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>O.O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Oc2cccc(Cl)c2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(Oc2cccc(Cl)c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.16 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 1.0 mL of methanol and 1.0 mL of tetrahydrofuran containing 0.10 g of methyl 2-(benzamido)-4-(3-chlorophenoxy)benzoate while ice-cooled and stirred at room temperature for 5 hours. The reaction mixture was added to water and 1.0 mol/L hydrochloric acid while ice-cooled, and a solid substance was separated by filtration to obtain 92 mg of 2-(benzamido)-4-(3-chlorophenoxy)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:16]([C:4]1[N:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:17])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)c(OCC(F)(F)C(F)F)nn1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(F)(F)C(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (1.14 g, yellow oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone (1.22 g, 4.61 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (839 mg, 6.92 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[C@@H:7]([CH3:11])[CH2:8][C:9](=[O:10])[C@@H:4]2[O:3]1.CC(C[AlH]CC(C)C)C.CO.O>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[C@@H:7]([CH3:11])[CH2:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1
Reactant: C[C@H]1CC(=O)[C@@H]2OC(C)(C)O[C@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1C[C@H](O)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: -78 °C
Reaction time: 4 h

Procedure:
(3aR,6S,6aR)-2,2,6-trimethyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (6-1) (490 mg, 2.7 mmol, 1 equiv) was dissolved in dry DCM (55 mL) and 3A molecular sieves were added. The mixture was cooled to −78° C. and DIBAL (4.1 mL, 4.1 mmol, 1.5 equiv, 1.0M in heptane) was added dropwise. The resulting mixture stirred at the same temperature for 4 hours. Upon disappearance of the starting material, MeOH (6 mL) was added to quench the reaction. Water (10 mL) was added and the mixture was filtered through celite washing with DCM (2×30 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to afford (3aS,4S,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6-2) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 4.50 (t, J=6.0 Hz, 1H); 4.27 (d, J=5.5 Hz, 1H); 4.12 (quin, J=6.0 Hz, 1H); 2.46 (d, J=8.5 Hz, 1H); 2.15 (quirt, J=4.5 Hz, 1H); 1.85 (m, 1H); 1.64 (dq, J=12.5, 3.0 Hz, 1H); 1.49 (s, 3H); 1.34 (s, 3H); 0.93 (d, J=8.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.CC(O)=O.C(OCC)(=O)C>Cl.O>[Cl:13][C:10]1[S:9][C:8]([C:6]2[N:7]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)s1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Nc2nc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
An 18-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30 mg, 0.11 mmol, 1.1 eq.), 2-(4-aminophenyl)acetic acid (15 mg, 0.1 mmol, 1 eq.), and AcOH (1 ml). To the mixture was added HCl (4 N in dioxane, 5 drops) The resulting mixture was stirred at 100° C. for 2 hr. After cooling to rt, the reaction mixture was diluted with addition of water. The precipitate was collected by filtration and washed with water followed by dichloromethane, The product thus obtained (30 mg, 78% yield) was further treated with ethyl acetate to afford 2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetic acid (7.2 mg). MW=385.87. 1H NMR (DMSO-D6, 360 MHz) δ 9.22 (brs, 1H), 7.76 (d, J=3.9 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.21 (d, J=3.9 Hz, 1H), 3.55 (s, 2H), 2.87 (m, 4H), 2.09 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:16]([OH:17])[CH2:18][NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
This compound was synthesized from the commercially available (1-oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (1), which was reacted with isobutylamine thereby forming the amino alcohol 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[O:12][N:11](CC3C=CC(OC)=CC=3OC)[C:10]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[O:12][NH:11][C:10]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN2OC(c3cc(Cl)ccc3F)=CC2(C)c2ccccc2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)ON1
Reaction time: 7 h

Procedure:
To a solution of 5-(5-chloro-2-fluorophenyl)-2-(2,4-dimethoxybenzyl)-3-methyl-3-phenyl-2,3-dihydroisoxazole (2-3, 0.88 g, 1.99 mmol) in anhydrous CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL) and the resulting purple colored reaction sat for 7 h. 2M Na2CO3 was added until the color changed from purple to peach, and the reaction was immediately extracted with CH2Cl2, dried with MgSO4, filtered and concentrated to provide crude 5-(5-chloro-2-fluorophenyl)-3-methyl-3-phenyl-2,3-dihydroisoxazole (2-4). This crude material was suitable for further transformations. 1H NMR (300 MHz, CDCl3) δ 7.56 (m, 3H), 7.36 (m, 3H), 7.25 (m, 1H), 7.05 (app t, J=9.6 Hz), 6.20 (br s, 1H), 6.03 (d, J=3.4 Hz, 1H), 1.78 (s, 3H). LRMS see table.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2c(Cl)c(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)c(F)ccc2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4,8-trichloro-7-fluoro-3-methylquinoline (0.6 g, 2.27 mmol), 2-(tributylstannyl)pyridine (0.877 g, 2.38 mmol), palladium tetrakistriphenylphosphine (0.26 g, 0.23 mmol) in toluene (2 mL) to give 4,8-dichloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=307.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:4][CH:3]=1.[OH-].[Ca+2].[OH-].Cl[C:23]1[O:24][C:25]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=2[N:27]=1.O>CS(C)=O>[Cl:32][C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:23]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])=[O:9])=[CH:17][CH:18]=3)[O:24][C:25]=2[CH:31]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OC[Si](C)(C)C
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)OC[Si](C)(C)C
Temperature: 40 °C

Procedure:
A mixture of 6.7 g (0.025 mole) of the R-enantiomer of trimethylsilyl-methyl 2-(4-hydroxy-phenoxy)-propionate, 0.9 g of calcium hydroxide and 10 ml of dimethylsulphoxide is heated at 40° C. A solution of 4.7 g (0.025 mole) of 2,6-dichlorobenzoxazole in 15 ml of dimethylsulphoxide is slowly added dropwise at this temperature, with stirring. The reaction mixture is subsequently stirred at 40° C. for 2 hours and at room temperature for 16 hours. Working up is then carried out by pouring the reaction mixture into water, extracting the resulting oily product with cyclohexane, washing the organic phase successively with dilute aqueous sodium hydroxide solution and water, rendering it weakly acidic with glacial acetic acid and then drying it and concentrating it under reduced pressure. 9.3 g (88.6% of theory) of the R-enantiomer of trimethylsilyl-methyl 2-{4-[(6-chloro-2-benzoxazolyl)-oxy]-phenoxy}-propionate are obtained in this manner in the form of crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][O:12][CH2:13][CH:14]=2)=[CH:5][C:4]=1[N+:15]([O-])=O>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15]
Reactant: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a stirred solution of 3.30 g (14.0 mmol) 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (VIII) in 70 ml methanol and 70 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 20 minutes at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo to afford 2.75 g (95%) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine (IX) as an off-white crystalline solid ES-MS m/e (%): 208 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17](Br)=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C[O:28][CH2:27]C1>>[CH2:1]([O:8][C:9]1[C:17]([CH:27]=[O:28])=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c(OCc2ccccc2)c2c1CCC2
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: Cc1cc(C=O)c(OCc2ccccc2)c2c1CCC2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-benzyloxy-5-bromo-7-methylindan (5.87 g, 19.4 mmol) in THF (75 mL) at −78° C. is added dropwise n-BuLi (1.6 M in hexane, 13.3 mL, 21.3 mmol) and it is stirred at −78° C. for 1.5 h. DMF (freshly distilled from CaH2, 29 mL, 0.38 mol) is added dropwise and it is stirred at −78° C. for 4 h before slowly warmed to ambient temperature and stirred for 18 h. EtOAc is added and it is washed with 1N HCl and brine, dried and concentrated. The residue is purified by flash chromatography to give the title compound as a light yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[NH:25]1[C:21]([C:17]2[CH:16]=[C:15]([NH:14][S:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)(=[O:12])=[O:11])[CH:20]=[CH:19][CH:18]=2)=[N:22][N:23]=[N:24]1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc2ccccc2o1
Yield: 45.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 1-benzofuran-2-sulfonyl chloride (11.9 mg, 0.055 mmol) and 5-(3-amino-phenyl)-tetrazole (8 mg, 0.05 mmol) affording 7.8 mg (46%) of the title compound. MS (ESI+) calcd for C15H11N5O3S 341.058260, found 341.058160.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1)=[O:5])C.C(=O)([O-])[O-].[Cs+].[Cs+].IC.[OH-].[Na+]>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([NH:11][C:9]1[N:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)=[O:17]
Reactant: CCOC(=O)c1cc(NC(=O)C(C)(C)C)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
250 mg (0.8 mmol) of 5-(2,2-Dimethyl-propionylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 10 ml of acetone, 1.0 g (3.2 mmol, 4 eq) of caesiumcarbonate and 225 mg (1.6 mmol, 2 eq) of iodomethane are added and the resulting mixture is stirred overnight at RT. The mixture is filtrated, the solvent removed in vacuo and the crude product dissolved in 10 ml of ethanol and stirred overnight at RT after the addition of 1.6 ml (2 eq) of 1N NaOH solution. After evaporation of the solvent the residue is taken up in a mixture of 10 ml CH2Cl2 and 10 ml 0.1N HCl, the organic phase is separated, dried over Na2SO4 and the solvent removed in vacuo yielding 75 mg (31%) of 5-(2,2-Dimethyl-propionylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid. This material is used in the amide coupling steps.