Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 83.8 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.25 g, 4.13 mmol) obtained in Example 5 and t-butyl 4-hydroxy-1-piperidinecarboxylate (1.70 g, 8.44 mmol) were dissolved in toluene (50 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (2.00 g, 8.29 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title compound (1.68 g, 3.46 mmol, 84%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)=[O:21])([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-nitro-1,2,3,4-tetrahydro-isoquinoline (CA [42923-79-5]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]O)=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[CH2:26][CH2:27][CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:30]>ClCCCl.ClCCl>[Br:30][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:9]3[C:8]([CH2:26][CH2:27][CH3:28])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: BrP(Br)Br
Reactant: CCCc1c(-c2nc(-c3ccc(CCO)cc3)no2)noc1-c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(CCBr)cc3)no2)noc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (400 mg, 1.065 mmol) in DCE (20 mL) was added phosphorus tribromide in DCM (1.065 mL, 1.065 mmol). The reaction mixture was heated at 70° C. overnight. The reaction mixture was diluted with dichloromethane and washed with 1N NaOH. The organic layer was dried MgSO4, filtered, and concentrated. The crude material was purified on a 40 gram silica column and eluting with EtOAc/Hex (0-50% gradient over 20 minutes) to afford 77 mg of 3-(4-(2-bromoethyl)phenyl)-5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazole. MS (m+1)=440. HPLC Peak RT=2.40 minutes. (Analytical Method B).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO.O>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2c(C#N)cc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN1CCOc2c(C#N)cc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a stirred solution of Methyl 4-butyl-8-cyano-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (184 mg) in methanol (3 mL) was added potassium hydroxide (7 mL of a 1.0 M solution in water). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 154 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.62, 7.46, 4.44, 3.41, 3.33, 1.60, 1.41, 0.98.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl.C(=O)(O)[O-]>[F:28][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][O:25][S:37]([CH3:36])(=[O:39])=[O:38])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-5-[4-(6-hydroxymethyl-pyridin-3-yl)-phenyl]-2,2-dimethyl-oxazolidin-3-yl}-ethanone (1.1 g, 2.792 mmol) in CH2Cl2 (50 mL) is added triethyl amine (0.564 g, 5.584 mmol) followed by methanesulphonyl chloride (0.365 g, 3.071 mmol) at 0° C. then stirred for 30 minutes at 0° C. Reaction mixture is diluted with saturated aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 30% ethyl acetate in hexane as an eluent to afford the title compound (0.875 g). 1H-NMR (400 MHz, DMSO) δ: 1.53 (s, 3H), 1.60 (S, 3H), 3.30 (s, 3H), 4.54-4.58 (m, 0.5H), 4.60-4.70 (m, 1H), 4.82-4.83 (m, 0.5H), 4.90-4.94 (m, 1H), 5.28 (d, J=3.68 Hz, 1H), 5.36 (s, 2H), 6.64 (t, J=52.4 Hz, 1H), 7.61-7.64 (m, 3H), 7.82 (d, J=8.08 Hz, 2H), 8.19-8.21 (dd, J1=2.4 Hz, J2=8.16 Hz, 1H), 8.94 (d, 2.2 Hz, 1H). LC-MS (m/z): [M+H]=473.2.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.C([Li])(C)(C)C.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:2]1[O:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1coc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Product: C[Si](C)(C)c1cc(C=O)co1

Procedure:
According to the above procedure, 3-furaldehyde is brominated to give 5-bromo-3-furaldehyde which is then reacted with a Grignard reagent (R3MgX) and the resulting mixture treated with t-butyl lithium and trimethylsilyl chloride to give 4-[R3 --CH(OH)]-2-trimethylsilylfuran. Alternatively, 5-bromo-3-furaldehyde is converted to the dimethylacetal, then treated with t-butyl lithium and trimethylsilyl chloride to give 5-trimethylsilyl-3-furaldehyde which is reacted with R3MgX or R3Li to give 4-[R3 --CH(OH)]-2-trimethylsilylfuran. Treating this intermediate with oxygen and irradiation using an initiator such as Rose Bengal gives 4-[R3 --CH(OH]-5-hydroxy-2(5H)-furanone.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=[O:5].[CH2:27]([Li])[CH3:28]>C1COCC1>[CH2:19]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:6]([C:4](=[O:5])[CH2:27][CH3:28])[CH2:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [Li]CC
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CCC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (described herein above) 377 mg (0.959 mmol) dissolved in THF (4 mL) was added 0.676 mL (1.15 mmol) of ethyllithium (1.7M in dibutylether) dropwise at −78° C. and stirred for one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (10:1) yielding 212 mg (61%) of the title compound as a light yellow oil. ES-MS m/e: 362.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:49][CH2:48][C:47]2[N:46]3[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:40][C:39]=2[C:38]1=[O:50])(=O)C>>[OH:20][CH2:21][C:22]1[C:27]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:49][CH2:48][C:47]2[N:46]3[C:41]([CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:40][C:39]=2[C:38]1=[O:50]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Product: Cc1cc(Nc2cc(-c3cccc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Yield: 17 %

Procedure:
Using the same general procedure as described for 118, reaction of 112a (200 mg, 0.706 mmol) and 118f (330 mg, 0.710 mmol) afforded a 17% yield (60 mg) of 225 as a green-yellow solid: mp 199-200° C.; 1H NMR (500 MHz, DMSO-d6) d 11.69 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.41 (t, 1H, J=8.0 Hz), 7.25 (d, 3H, J=8.5 Hz), 6.00 (s, 1H), 5.86 (s, 1H), 4.69 (br s, 1H), 4.31 (m, 2H), 3.97 (m, 1H), 3.91 (m, 1H), 3.79 (m, 2H), 3.56 (s, 3H), 3.01 (m, 1H), 2.90 (m, 1H), 2.70 (m, 2H), 2.15 (s, 3H), 1.90 (m, 2H), 1.74 (m, 2H); MS (ESI+) m/z 499.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Cl>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH2:33][O:32][CH3:31])=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: COCOc1ccccc1CCl
Product: COCOc1ccccc1COc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1OC)C(C)(C)CCC2(C)C
Yield: 98.5 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 2-methoxymethoxybenzyl chloride obtained above, 3.2 g (94%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1cc(Cl)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CCC(=O)O)CC1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
4-[4-Chloro-2-(2-ethoxycarbonyl-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (5.7 g, 13.9 mmol) was set stirring in MeOH (40 mL). A solution of NaOH (1.4 g, 34.7 mmol) in water (10 mL) was added and the mixture stirred at room temperature. After 3 h the mixture was acidified to pH 7 and MeOH was evaporated. The aqueous layer was extracted with CH2Cl2 (3×100 mL). The organics were combined, dried over Na2SO4 and concentrated to afford 3.9 g (73%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.4. MS (electrospray): exact mass calculated for C19H27ClN2O4, 382.17; m/z found, 381.1 [M31 −H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[C:17]4[C:22](=[N:23][CH:24]=3)[NH:21][CH2:20][CH2:19][CH2:18]4)[CH:12]=[N:13][CH:14]=2)[CH2:3][CH2:2]1.FC(F)(F)[C:27]([OH:29])=[O:28]>C(Cl)Cl>[C:9]([O:29][C:27]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([CH2:8][O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:10]=3)=[CH:24][N:23]=2)[CH2:18][CH2:19][CH2:20]1)=[O:28])([CH3:10])([CH3:14])[CH3:8]
Reactant: c1ncc(-c2cnc3c(c2)CCCN3)cc1COC1CCOCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(COC4CCOCC4)c3)cnc21

Procedure:
6-[5-(Tetrahydro-pyran-4-yloxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method IV, as illustrated above. It is then used to prepare 6-[5-(tetrahydro-pyran-4-yloxymethyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6](C(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[H-].[Na+].[F:24][C:25]1[C:30]([CH:31]=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(OCC)C>C1COCC1>[F:24][C:25]1[C:30](/[CH:31]=[C:3](/[C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)\[C:1]#[N:2])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc2c(c1)c(CC#N)cn2C(=O)OC(C)(C)C
Reactant: O=Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3F)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-5-methoxy-1H-indol-1-carboxylate (719 mg, 2.51 mmol, 1.0 eq.) in anhydrous THF (30 mL) was added, under an argon atmosphere, NaH (106 mg, 80%, 3.52 mmol, 1.4 eq.). The mixture was stirred at room temperature for 2 hours, and then cooled to 0° C. before the addition of 2-fluoro-pyridine-3-carbaldehyde (440 mg, 3.52 mmol, 1.4 eq.) in anhydrous THF (6 mL). The reaction apparatus was protected from light and the mixture was stirred at 0° C. for 24 hours, at room temperature for 24 hours too and then, quenched with a saturated aqueous ammonium chloride solution. The mixture was stirred again at room temperature for 24 hours and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98/2) to afford, after trituration with diethyl ether, the compound (48) as a yellow powder (220 mg, 30%). IR νmax (cm−1): 2219 (νCN), 3228 (νN—H); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.81 (3H, s, 5′-methoxy), 6.91 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.42 (1H, d, J7′-6′=8.9 Hz, H7′), 7.43 (1H, d, J4′-6′=2.4 Hz, H4′), 7.53 (1H, m, H5″), 7.64 (1H, s, H3), 7.84 (1H, s, H2′), 8.29 (1H, d, J6″-5″=4.5 Hz, H6″), 8.49 (1H, m, H4″), 11.73 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.5 (5′-methoxy), 101.5 (C4′), 109.8 (C2), 110.0 (C3′), 112.5 (C6′), 113.3 (C7′), 117.3 (C1), 118.0 (1C, d, 2JC—F=28 Hz, C3″), 122.3 (1C, d, 4JC—F=4 Hz, C5″), 123.9 (C3a′), 125.8 (C3), 128.1 (C2′), 132.2 (C7a′), 139.4 (1C, d, 3JC—F=3 Hz, C4″), 147.5 (1C, d, 3JC—F=15 Hz, C6″), 154.7 (C5′), 159.7 (1C, d, 1JC—F=270 Hz, C2″); ESI: 294.1 ([M+H]+), 316.1 ([M+Na]+), 348.1 ([M+Na+MeOH]+); HRESI-MS: m/z 316.0861 (calcd for C17H12N3OFNa+, 316.0862).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:10]([CH:23]=[O:24])=[CH:9]3)[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:10]([CH2:23][OH:24])=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2-(6-(cyclopropylmethoxy)-3-formylquinolin-2-ylamino)ethyl)acetamide SLA 47092 (0.35 g, 1.1 mmol) in THF (10 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.04 g, 1.1 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution. After stirring for 15 min at RT, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was removed at 40° C. under vacuum and the residue was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum, to give N-(2-(6-(cyclopropylmethoxy)-3-(hydroxymethyl)quinolin-2-ylamino)ethyl)acetamide SLA 47096A as a yellow oil (0.39 g, quant. yield).
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COc1cccc(CO)c1I
Reactant: c1c[nH]cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(Cn2ccnc2)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of (2-iodo-3-methoxyphenyl)methanol (0.350 g, 1.33 mmol), (Organic Letters, 2001, vol. 3, #21 p. 3245-3248) imidazole (0.181 g, 2.65 mmol) and triphenyl phosphine (0.382 g, 1.46 mmol) in tetrahydrofuran (5 mL) at 0° C. was added Diethyl azodicarboxylate (40% solution in toluene; 0.664 mL). The yellow solution was allowed to warm to room temperature and stirred at 60° C. overnight. After evaporating the solvent under reduced pressure, the crude was purified by column chromatography (5% EtOAc:hexanes, 20% EtOAc; Hexanes). Yield=43%. 1H NMR: 3.90 (s, 3H), 5.19 (s, 2H), 6.43 (d, 1H, J=5.70 Hz), 6.77 (d, 1H, J=6.09 Hz), 6.93 (s, 1H), 7.10 (s, 1H), 7.24 (t, 1H, J=6.03 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1OC)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2-methoxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid methyl ester as light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH3:31])=[CH:23][CH:24]=1)=[O:30]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([NH2:26])=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Reactant: N
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(N)=O)ccc2n1C

Procedure:
The above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methylpropanoic acid and a saturated solution of ammonia in absolute tetrahydrofurane using a procedure analogous to that of Example 130.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (5.46 g) in THF (100 mL) was added CDT (6.14 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50° C. After stirring at 50° C. for 1 h, the mixture was cooled to room temperature. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (5.04 g) and DIPEA (9.02 mL) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.05 g).