Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11](I)[C:10]=2[CH:9]=1)#[N:2].[CH3:36][S:37]([O-:39])=[O:38].[Na+]>CN1C(=O)CCC1.[Cu]I>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11]([S:37]([CH3:36])(=[O:39])=[O:38])[C:10]=2[CH:9]=1)#[N:2]
Reactant: CS(=O)[O-]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(S(C)(=O)=O)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 125 °C
Yield: 39.1 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.171 mmol) in NMP (2 mL) was added copper(I) iodide (162 mg, 0.853 mmol) and sodium methanesulfinate (102 mg, 0.853 mmol). The reaction mixture was heated at 125° C. under nitrogen protection for 8 h. The solid was filtered and washed with ethyl acetate. The filtrate was washed with water and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was purified by column chromatography to give the title compound (36 mg). LCMS m/z=539.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 9H), 1.40 (d, J=6.0 Hz, 6H), 2.46-2.55 (m, 1H), 2.74 (dd, J=16.0, 9.0 Hz, 1H), 2.88-2.98 (m, 1H), 3.12 (s, 3H), 3.08-3.14 (dd, J=16.0, 3.6 Hz, 1H), 3.95-4.02 (m, 1H), 4.05-4.20 (m, 2H), 4.62-4.69 (m, 1H), 5.03 (s, 2H), 6.95 (dd, J=8.8, 2.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H),
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=O)=[CH:3][CH:2]=1.[NH2:33][OH:34]>C(O)C>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[N:33][OH:34])=[CH:3][CH:2]=1
Reactant: CO[C@@H](Cc1ccc(C(=O)CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C(CCCCOc2ccc(-c3ccccc3)cc2)=NO)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionic acid from Example 52, (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C27H29NO5 [M+H]+: 448.2.2, [M−H]−: 446.2.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C@@:29]12([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:36]([CH3:38])([CH3:37])[CH:33]([CH2:34][CH2:35]1)[CH2:32][C:30]2=[O:31]>CO>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH3:37][C:36]1([CH3:38])[C@:29]2([CH2:39][S:40]([OH:43])(=[O:42])=[O:41])[C:30]([CH2:32][C@H:33]1[CH2:34][CH2:35]2)=[O:31]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Temperature: 10 °C

Procedure:
12.25 g (0.03 mol) of amlodipine was dissolved in 50 ml of methanol, cooled to 10° C., and a solution of 7.8 g (0.336 mol) of (1R)-(−)-10-camphor sulfonic acid (Aldrich) in 19.5 mg of methanol was gradually added thereto. 15.4 g (yield: 80.0%) of the title compound in the form of a white crystal was obtained by using the same method described in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1N1CC2CC1CN2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CC2CC1CN2Cc1ccccc1

Procedure:
5.0 g (124) in 360 mL ethanol and 20 mL water with 4 g NH4Cl and 6.7 iron powder were heated to reflux temperature under 4 hours of mechanical agitation. The reaction solution is filtered over Celite and active carbon, evaporated, absorbed in 100 mL water, brought to pH 10 by means of K2CO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 5 mbar; 160–170° C.): 2.20 g (48.8% of the theoretical yield.) (125) as colorless oil. DC: CHCl3/methanol (9:1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].CO[C:15]1[CH:20]=[C:19](OC)[CH:18]=[CH:17][C:16]=1[C:23]1[CH:28]=[CH:27][C:26](C(O)=O)=[CH:25][C:24]=1C.C1(C2C=CC=CC=2)C(B(O)O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.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.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:28]1[C:23]([C:16]2[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2-c2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (3 g; 13.10 mmol; 1 eq.), 2-biphenylboronic acid (2 852.77 mg; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) were taken in Toluene (15 mL) and water (15 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and then refluxed for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford brown oil, which was taken in EtOAc (200 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (70 mL), water (70 mL) and brine (70 mL), dried over MgSO4 and concentrated affording methyl 2-methyl-1,1′:2′,1″-terphenyl-4-carboxylate as a brown oil (3.9 g, 98%, HPLC (Method A) Rt 5.51 min), which was used further without purification. A solution of methyl 2-methyl-1,1′:2′,1″-terphenyl-4-carboxylate (3.50 g; 11.58 mmol; 1 eq.) in EtOH (105 mL) at rt was treated with sodium hydroxide (6.95 mL; 5 M; 34.73 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated giving a brown solid. It was taken up in water (400 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc (2 mL) to pH 2, then it was concentrated until precipitation (volume divided /5). The suspension was filtered affording the title compound as an orange solid (2.41 g, 72%). 1H NMR (DMSO-d6, 300 MHz) δ 12.71 (br s, 1H), 7.54-6.91 (m, 12H), 1.76 (s, 3H). LC/MS (Method A): 286.9 (M−H)−. HPLC (Method A) Rt 4.85 min (Purity: 97.1%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[N:10][CH:11]=1.CC(C[AlH]CC(C)C)C.Cl.C(=O)(O)[O-].[Na+].[CH3:33][C:34]([S@:37](N)=[O:38])([CH3:36])[CH3:35]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2].CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[CH:12]=[N:13]/[S@@:37]([C:34]([CH3:36])([CH3:35])[CH3:33])=[O:38])=[N:10][CH:11]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: N#Cc1ccc(OCc2ccccc2F)cn1
Agent: [Cu+2]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OCc2ccccc2F)cn1
Temperature: -78 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
To a solution of Reactant 5-(2-fluorobenzyloxy)picolinonitrile (690 mg, 3.0 mmol) in dichloromethane (20 mL) was added DIBAL-H (3.7 mL, 3.6 mmol, 0.99 M) at −78° C. After being stirred at −78° C. for 4 hours, methanol (2 mL) was added to the mixture. 1N hydrochloric acid (0.5 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. Sat. sodium bicarbonate aqueous solution was added to the mixture until the pH was neutrized. The organic layer was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL). Copper(II) sulfate (1.2 g, 7.6 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (370 mg, 3.0 mmol) were added to the mixture respectively and the mixture was stirred for overnight at room temperature. The reaction mixture was filtrated off through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 360 mg (36% yield) of the title compound as a colorless oil:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:14](OCC)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30](OCC)(=O)C.C(O)C>C1C=CC=CC=1.C(O)(=O)C>[CH3:30][C:14]([C:13]1[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=1)=[O:15]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCO
Product: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
5.0 g of 50% sodium hydride suspension and a few ml of benzene were introduced in a 500 ml three-necked flask, supplied with a stirrer, reflux condenser and dropping funnel. 18.1 g of ethyl 3,5-dibenzyloxybenzoate in 150 ml of dry benzene were added. The reaction mixture was stirred and heated on an oil bath (90°-100°C.), and 4.5 g of ethyl acetate in 25 ml of dry benzene were slowly added and then heated and stirred for 7 hours. The reaction mixture was cooled. A few ml of ethanol were added and the whole was then poured into 150 ml of 50% acetic acid solution. The acidic water phase was extracted with ether. The ether phase was washed with water, sodium bicarbonate solution and water, and then dried with magnesium sulphate. After evaporation an oil was recovered. This oil was treated with 80 ml of dioxane, 16 ml of water and 8 ml of concentrated hydrochloric acid and the mixture was heated on an oil bath at 130°-140°C. for 15 hours. After evaporation, ether was added and the ether phase washed with water, 2-N sodium hydroxide solution and water. The ether phase was then evaporated and the residue was dissolved in hot ethanol and 200 ml of 1-N sodium hydroxide solution was added. The mixture was refluxed for 5 hours in order to hydrolyze remaining ethyl 3,5-dibenzyloxybenzoate. The ethanol was evaporated and the water phase extracted with ether. The ether phase was washed with water, dried with magnesium sulphate and evaporated. The remaining oil crystallized from petroleum ether (B.p. 80°-110°C.). M.p. 61.5°-62.0°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH2:10][CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)=[CH:4][C:3]=1[CH:18]=[C:19]([Cl:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:17])[CH2:10][CH:11]([CH3:16])[CH2:12][C:13]2=[O:15])=[CH:4][C:3]=1[CH:18]=[C:19]([Cl:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(Cl)=Cc1cc(NC(=O)CC(C)CC(=O)O)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)CC(C)CC2=O)ccc1Cl

Procedure:
A solution of 2.8 g of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)phenyl]-3-methylglutaric acid monoamide and 0.1 g of sodium acetate in 50 ml of acetic anhydride was stirred at 95° C. for 2 h. The solvent was then removed. After dissolving the residue in 150 ml of dichloromethane, it was washed with sodium hydrogen-carbonate solution, water and sodium chloride solution, dried and concentrated in vacuo. The residue which remained was crystallized using petroleum ether, and the crystals were removed and dried. Yield: 2.1 g; m.p.: 82°-84° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH:22]=1)(=O)C.C[O-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a suspension of compound 138 (50 mg, 0.09 mmol) in CH3OH (5.0 mL) was added NaOMe (100 μL, 25% solution in CH3OH) at room temperature. After 1 h, the resulting mixture was concentrated in vacuo. The crude was purified by preparative HPLC (reverse phase) to provide the title compound (29 mg, 74%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(F)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:21][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCCCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 155.9 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 26.0 g (0.2 mol, 2.0 eq.) of 1-octanol were added to 64 mL of toluene, and the mixture was heated to reflux for 3 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8 mL). Subsequently, the resultant was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 39.2 g of 4-octyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:24][CH3:25])=[CH:9][C:10]2[NH:16][C:15]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:14]=3[C:13](=[O:22])[NH:12][C:11]=2[CH:23]=1)(=O)=O.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.[Li+].[Cl-].CN(C=O)C>[F-].[K+].C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[C:13](=[O:22])[NH:12][C:11]3[CH:23]=[C:7]([CH:28]=[CH2:29])[C:8]([O:24][CH3:25])=[CH:9][C:10]=3[NH:16][C:15]=2[CH:17]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)NC(=O)c1ccc(Cl)cc1N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc2c(cc1OC)Nc1cc(Cl)ccc1C(=O)N2
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
A mixture of Example 515B (210 mg, 0.5 mmol), tributyl(vinyl)tin (175 μL, 0.6 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol), LiCl (169 mg, 4.0 mmol) and DMF was flushed with nitrogen, heated at 50° C. overnight, cooled to room temperature, diluted with a saturated potassium fluoride solution, stirred 15 minutes, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with a solvent gradient of 4:1 to 1:1 hexane/ethyl acetate to give 77 mg (52%) of the desired product. MS (ESI) m/e 301 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.72 (s, 1H), 8.14 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.94 (dd, J=2.0, 8.5 Hz, 1H), 6.80 (dd, J=11.2, 18.0 Hz, 1H), 6.63 (s, 1H), 5.56 (dd, J=1.5, 17.8 Hz, 1H), 5.14 (dd, J=1.7, 11.2 Hz, 1H), 3.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF, 4.0 g of 2-[4-(t-butyl)phenyl]ethanol was added, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature overnight. The mixture was then poured into a mixture of ice in water. The product was extracted into CH2Cl2, and the resulting solution was concentrated to dryness. TLC showed one major spot and five minor spots. The product was purified by HPLC (silica gel, CH2Cl2). The fractions containing the major product were collected and concentrated, giving 1.9 g of the title product. Yield: 28.4%. M.P. 70°-71° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH2:16])[CH:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.I[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=2)[N:34]=[CH:33][C:32]=1[F:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2].[Cl-]>[F:43][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:31]=1[CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH3:16])=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2
Reactant: COc1ccc2ncc(F)c(I)c2c1
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CCC(c1c(F)cnc2ccc(OC)cc12)C1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A solution of 1.45 g of methyl (3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate in 20-cm3 of tetrahydrofuran was slowly added, at a temperature in the region of 0° C. with stirring and under an inert atmosphere, to 16-cm3 of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran. The mixture was then brought to a temperature in the region of 20° C. while the stirring was continued for a further 4 hours. 1.52 g of 4-iodo-3-fluoro-6-methoxyquinoline in solution in 40-cm3 of tetrahydrofuran were added, followed by 100 mg of palladiumdiphenylphosphinoferrocene chloride and finally 3.18 g of tribasic potassium phosphate. The reaction mixture was heated for 15 hours under reflux and then filtered in the hot state on sintered glass. The filtrate was taken up in 50-cm3 of ethyl acetate and concentrated to dryness under reduced pressure (5 kPa). The residue was taken up in 75-cm3 of ethyl acetate and 40-cm3 of water. The organic phase was separated after settling out, washed twice with 40-cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 μ; diameter 2.5 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (75/25 by volume) and collecting 50-cm3 fractions. Fractions 16 to 22 were combined and then concentrated. 1,77 g of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate were obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[N:25]=[CH:24][N:23]=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH:9]2[CH2:8][CH2:7][N:6]([C@H:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:28]([C:27]3[C:22]([CH3:21])=[N:23][CH:24]=[N:25][C:26]=3[CH3:31])=[O:29])[CH2:11][CH2:10]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: COc1ccc(NC2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Yield: 91.8 %

Procedure:
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine (see EXAMPLE 230) (1.59 g, 5.48 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (834 mg, 5.48 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (2.07 g, 83%).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[F:29])[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:26]=[CH:27][C:28]=2[F:29])[CH2:19][CH2:18]1)=[O:5]
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(F)(F)c3ccccc3)CC2)c1

Procedure:
Example 136 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.61–7.56 (m, 2H), 7.41–7.34 (m, 4H), 7.21–7.17 (m, 1H), 7.14 (s, 1H), 6.88 (t, 1H, J=9.5 Hz), 3.39 (q, 2H, J=5.7 Hz), 3.08–3.01 (m, 2H), 2.84–2.74 (m, 1H), 2.50 (t, 2H, J=5.1 Hz), 2.38 (septet, 1H, J=7.2 Hz), 2.08–1.99 (m, 2H), 1.81–1.73 (m, 4H), 1.72–1.64 (m, 2H), 1.17 (d, 6H, J=7.2 Hz); ESMS m/e: 476.2 (M+H)+.