Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CN(CCOc2ccc(F)cc2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(CCOc2ccc(F)cc2)CCN1
Yield: 100.4 %

Procedure:
Ethyl 1-benzyl-4-[2-(4-fluorophenoxy)ethyl)-2-piperazinecarboxylate (977 mg) synthesized in accordance with Example 241 described later was dissolved in ethanol (15 ml), and 210 mg of 10% Pd-C was added. After replacing the atmosphere with hydrogen, the mixture was stirred. After completion of the reaction, the solution was evaporated, to give 752 mg (100%) of the title compound as a crude product.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Agent: Cl
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. M+(LC/MS(ESI)): 552.7. HPLC (Condition A), Rt: 4.85 min (HPLC purity: 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13]O)[CH:7]=[CH:6]2.O=S(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(CO)ccc2c1
Solvent: ClCCl
Product: COc1ccc2cc(CCl)ccc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A cooled (0° C.) mixture of (6-methoxynaphthalen-2-yl)methanol (90 mg; 0.48 mmol) in anh. DCM (2 ml) was treated dropwise with SOCl2 (89 mg; 0.75 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. The volatiles were removed under reduced pressure, and the solid residue was triturated with Et2O. Filtration afforded 2-(chloromethyl)-6-methoxynaphthalene which was directly used for the next reaction. LC-MS (conditions E): tR=0.75 min.; no ionisation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Yield: 49.1 %

Procedure:
A solution of pyrimidin-4-amine (2.0 g, 21 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (6.2 g, 23.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.96 g, 1.1 mmol), Xantphos (1.03 g, 1.79 mmol), and cesium carbonate (7.5 g, 23 mmol) in dioxane (25 mL) was heated in a sealed tube at 130° C. for 18 hours. The mixture was diluted with CH2Cl2 (100 mL) and filtered through a plug of celite. The solution was concentrated in vacuo on the rotary evaporator. The material was then dissolved in minimal CH2Cl2 (5 mL) and was triturated with Et2O (80 mL). The product was then filtered and washed with Et2O (100 mL) to afford 2.9 g (49%) of 109b.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(OC(=O)C)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Yield: 75.1 %

Procedure:
After 20 g of 4-nitroimidazole was put in a flask, 144.5 mL of acetic anhydride was added thereto and while the temperature was kept at 25° C., 14.5 mL of 69 mass % nitric acid was added dropwise thereto. After the addition of nitric acid was completed, the resultant mixture was stirred at 25° C. for 3 hours. The reaction solution was added into 100 g of iced water and extracted with 300 mL of dichloromethane. The organic layer was washed with 300 mL of a saturated sodium hydrogen carbonate aqueous solution and dried over 30 g of magnesium sulfate. The organic layer was filtered and the solvent was evaporated under reduced pressure to obtain 21 g of 1,4-dinitroimidazole (yield 75.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>ClCCl.OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11]
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#CCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a solution of 2,6-dichloro-phenyl-acetonitrile (15.0 g, 80.62 mmol) in the dichloromethane (50 mL) and H2SO4 (40 mL) is added (slowly) a mixture of H2SO4 (14 mL) and HNO3 (5.5 mL) at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, warned to room temperature for half hour, and then concentrated to remove organic solvent. The solution is poured into a beaker containing ice-water (400 mL) to give a crystalline precipitate, which is collected by vacuum filtration and washed with water to afford the product (20.44 g, 82.4%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6]C[CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=[CH2:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1.BrC1C=C2C(=CC=1)NC=C2C1C(=O)N(C)C(=O)C1>>[CH3:1][N:2]([CH2:3][CH2:4][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=[CH2:17])[CH:14]=2)[NH:9][CH:8]=1)[CH3:6]
Reactant: C=Cc1ccc2[nH]cc(C3CCN(C)C3)c2c1
Agent: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Product: C=Cc1ccc2[nH]cc(CCN(C)C)c2c1

Procedure:
3-(N-Methylpyrrolidin-3-yl)-5-vinyl-1H-indole: from 3-(5-bromo-1H-indol-3-yl)-N-methylsuccinimide (Example 4) (27% over 2 steps, HRMS-FAB+ for C15H18N2 : calculated MH+ : 227.15483; found MH+ : 227.15356).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(S)cc1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.637 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert -butoxide (11.029 g), 4-methoxybenzenethiol (4.9 ml) and tetrakis(triphenylphosphine)palladium(0) (0.454 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using 1:1, hexane:dichloromethane as the eluent to yield 6-(4-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.823 g) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:25][CH3:26])=[C:19]([N+:22]([O-])=O)[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:3].O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:25][CH3:26])=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN1CCN(C(C)C)CC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN1CCN(C(C)C)CC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 1-{[4-(1-methylethyl)-1-piperazinyl]acetyl}-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.60 g, 1.66 mmol) in absolute ethanol (100 mL) and DMA (20 mL) was added tin(II)chloride dihydrate (2.24 g, 9.93 mmols) and 1M HCl(1.0 mL). After overnight stirring, reaction was quenched with excess saturated NaHCO3 solution, stirred for one hr, and filtered through celite which was rinsed with methanol. After organic solvent removal, the aqueous layer was extracted with dichloromethane (2×200 mL), organic layers combined, adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 1-{[4-(1-methylethyl)-1-piperazinyl]acetyl}-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=333.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>ClCCl>[C:36]1([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][Br:20])=[CH:31][CH:32]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
Triphenylphosphine (1.58 g) and N-bromosuccinimide (1.07 g) were added to a stirred solution of 4-hydroxymethylbiphenyl (1.01 g) in dichloromethane (10 mL) under nitrogen. The mixture was stirred at room temperature for 15 hr and evaporated in vacuo. The residue was diluted with chloroform, and washed with saturated sodium hydrogencarobonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:100 to 1:50, v/v) to give the titled compound (1.26 g) as colorless crystals: 1H-NMR (400 MHz, CDCl3) δ 4.55 (s, 2H), 7.33-7.38 (m, 1H), 7.41-7.49 (m, 4H), and 7.54-7.60 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2O)c1
Solvent: CO
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2O)c1
Yield: 33.1 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 1.4 g of methyl (2RS,5SR)-3-{3-{2-[2-(2-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate in 30 cm3 of solution in methanol and 0.49 g of potassium hydroxide in solution in 6 cm3 of water, and after treatment and recrystallization in diisopropyl ether, 0.45 g of (2RS,5SR)-3-{3-{2-[2-(2-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at about 165° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1COCC1.[Pd].O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a degassed sample of 4-methylenepiperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.67 mmol) was added 9-borabicyclic[3,3,1]nonane (5.6 mL of a 0.5 M solution in THF, 2.8 mmol). The resulting solution was refluxed for 1 hour. After cooling to ambient temperature, the solution was added to a mixture of 1-iodo-2-trifluoromethylbenzene (0.707 mg, 2.600 mmol), Pd-catalyst (3 mol %), DMF (25 mL), water (1 mL), and K2CO3 (0.6 g). The resulting mixture was heated at 60° C. for 3 hours. The mixture was cooled to ambient temperature and then poured into water. The pH of the solution was adjusted to 11 with 10% NaOH solution and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and evaporated to give a crude oil, which was further purified by column chromatography to afford 4-(2-trifluoromethylbenzyl)piperidine-1-carboxylic acid tert-butyl ester as a waxy solid (0.638 g) in 70% yield.
Reaction SMILES: N[C@@H](C(O)=O)C(C)C.COC1C=CC(C=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]O)=[O:27])[CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([OH:28])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(C)[C@@H](N)C(=O)O
Agent: COc1ccc(C=O)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 5 °C

Procedure:
23.4 g (0.1 mol) of the Schiff base of D-valine and anisaldehyde prepared according to Ia) was dissolved, with stirring, in 130 ml of dry dichloromethane. The solution was cooled to 5° C. or lower in an ice bath. Then 20.6 g (0.12 mol) of meta-chloroperbenzoic acid was added, with stirring, to the solution cooled to 5° C. or lower. The stirring was continued and the temperature was allowed to rise to room temperature, after which the stirring was continued for 4 more hours. After about 0.5 hour's stirring at room temperature the mixture became turbid as a result of the crystallization of meta-chlorobenzoic acid. After the reaction, in which all the meta-chlorobenzoic acid formed crystallized, the reaction mixture was filtered and the filtered solution was evaporated until dry.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:23][CH:22]=2)=[O:20])[C@@H:11]([CH3:37])[CH2:10]1)=[O:7])(=O)C.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:44][C:41]1[CH:40]=[CH:39][C:38]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:43][CH:42]=1
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(CCCC(C)(C)C(=O)O)cc1
Temperature: 45 °C
Yield: 69.9 %

Procedure:
Methyl 5-(4-{[(2S,4R)-4-[[(acetyloxy)acetyl](4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoate (100 mg, 0.16 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (2 ml). A solution of sodium hydroxide (32 mg, 0.81 mmol, 5 eq.) in water (1 ml) was added and reaction mixture heated to 45° C. for 8 h and at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography gave pure 5-(4-{[(2S,4R)-4-[(4-chlorophenyl)(glycoloyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)-2,2-dimethylpentanoic acid (63 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10](O)=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:7][CH:6]=1)[CH3:2].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10]([Cl:25])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccccc2C(F)(F)F)cc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(-c2ccccc2C(F)(F)F)cc1Cl

Procedure:
Heat a mixture of 4-Hydroxy-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester (9.0 g, 0.029 mol) in POCl3 (22 g) at 110° C. for 2 hours. Evaporate the POCl3, and add ice (100 g) followed by careful addition of saturated NaHCO3. Extract with EtOAc, dry (MgSO4), and evaporate to provide 4-chloro-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH3:22])=[C:15]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:23]([C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:11][CH:10]=3)[CH:13]=2)[N:17]([CH3:21])[C:16]=1[CH3:22])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC(=O)O)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.151 g, 0.378 mmol) was reacted with 1N KOH (0.8 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.068 g, 0.176 mmol, 47%) as a yellow solid, mp 204-207° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.67 (s, 3H), 4.06 (s, 2H), 4.67 (s, 2H), 6.94 (d, J=8.9 Hz, 2H), 7.08-7.12 (m, 1H), 7.19-7.24 (m, 4H), 7.28 (dd, J=1.7, 8.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 2H), 7.56 (d, J=1.4 Hz, 1H); IR (solid) 3020, 2880, 1740, 1710, 1510, 1480, and 1230 cm−1; [ESI(+)], m/z 386 (M+H)+; Anal. Calcd. for C25H23NO3.0.3H2O: C, 76.82; H, 6.17; N, 3.58; Found: C, 76.66; H, 6.00; N, 3.46.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[CH:27]=[CH:26][N:25]=1)#[N:29]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: N#Cc1cc(N)ccn1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ccnc(C#N)c2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Amino-pyridine-2-carbonitrile instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=351.2 (M+H)+.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][CH:4]([C:7](OC)=[O:8])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:2][CH2:3]1)=[O:8]
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to −78° C. DIBAL-H (60.9 ml) was then added dropwise at −78° C. and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at −78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3×75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]3[N:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13](C(O)=O)[N:7]3[C:6]=2[CH:21]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:7]3[C:6]=2[CH:21]=1
Reactant: COC(=O)C1=NC2=COc3ccc(Cl)cc3N2C1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Yield: 95 %

Procedure:
5.4 g (17.5 mmol) of the 4H-8-chloro-2-methoxycarbonyl-imidazo-[2,1-c][1,4]-benzoxazine-1-carboxylic acid prepared in Step E were stirred in 50 ml of Dowtherm A on an oil bath. The solution obtained bubbled vigorously when the oil bath reached 185°-195° C. When the effervescence had ceased, the solution was cooled and diluted with ether. The product crystallized out and was filtered off, washed well with ether and dried under vacuum over P2O5 to obtain 4.4 g (95% yield) of methyl 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 239°-40° C. in the form of off-white needles.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
9.96 g (0.082 mole) of (R)-(+)-1-phenylethylamine and 10.54 g (0.086 mole) of p-hydroxybenzaldehyde were dissolved in 140 ml of ethyl alcohol, and the resulting solution was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, and the crystalline material thus formed was separated by filtration to give 13.0 g of (-)-N-(p-hydroxybenzylidene)-1-phenylethylamine. Yield: 70.4%.