Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])=[CH:14][CH:13]=1>>[CH2:1]([C:5]1[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[N:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1ncn[nH]1
Product: CCCCc1ncnn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 20.5 %

Procedure:
Following General Procedure A, 5.0 g (39.9 mmol) of 5-butyl-1H-1,2,4-triazole was coupled with 12.2 g (39.9 mmol) of the alkylating reagent prepared in step 1 of Example 1 to give 3.1 g (22%) of a faster moving isomer: NMR (CDCl3) δ 0.90 (t, J=8 Hz, 3H), 1.29–1.45 (m, 2H), 1.63–1.76 (m, 2H), 2.71 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.34 (s, 2H), 7.14–7.20 (m, 2H), 7.24–7.33 (m, 3H), 7.40 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.82 (dd, J=8 and 2 Hz, 1H), 7.85 (s, 1H) and 3.7 g (26%) of a slower moving isomer: NMR (CDCl3) δ 0.92 (t, J=8 Hz, 3H), 1.31–1.46 (m, 2H), 1.66–1.79 (m, 2H), 2.73 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.28 (s, 2H), 7.21–7.34 (m, 5H), 7.39 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.83 (dd, J=8 and 2 Hz, 1H), 7.94 (s, 1H). The faster moving isomer was hydrolyzed to give 2.75 g (92%) of 4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ 0.85 (t, J=8 Hz, 3H), 1.23–1.38 (m, 2H), 1.52–1.65 (m, 2H), 2.76 (t, J=7 Hz, 2H), 5.41 (s, 2H), 7.16–7.24 (m, 2H), 7.27–7.37 (m, 3H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H), 7.86 (s, 1H); MS (FAB) m/e (rel intensity) 336 (100), 307 (7), 289 (7), 224 (8), 211 (100), 193 (9).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.CNOC.[NH4+].[Cl-].[CH3:33][C:34]([CH3:38])=[CH:35][Mg]Br>C(Cl)Cl.CCOCC>[CH3:1][O:2][CH2:3][C:4](=[O:6])[CH:33]=[C:34]([CH3:38])[CH3:35]
Reactant: CC(C)=C[Mg]Br
Reactant: COCC(=O)O
Agent: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COCC(=O)C=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
According to a reported procedure41 with some modifications, a solution of α-methoxyacetic acid (6e, 1.17 g, 13.0 mmol) in anhydrous CH2Cl2 (20 mL) was treated portionwise with 1,1′-carbonyldiimidazole (2.54 g, 15.7 mmol) at 0° C. under argon. The ice bath was removed, and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was treated with triethylamine (2.18 mL, 15.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.53 g, 15.6 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature under argon. Saturated aqueous NH4Cl was added. The organic phase was washed with water, dried (Na2SO4) and concentrated to a transparent oil. A solution of the crude amide was treated dropwise with 2-methyl-1-propenylmagnesium bromide (28.7 mL, 14.4 mmol, 0.5 M in THF) at −20° C. under argon. The reaction mixture was stirred for 2 h under argon at 0° C. upon which a white precipitate was formed. The mixture was diluted with Et2O and treated with saturated aqueous NH4Cl. The aqueous phase was extracted with ether (3×50 mL). The combined organic extract was washed (water, brine), dried (Na2SO4), concentrated and chromatographed [silica, hexanes/EtOAc (3:1)] to afford an orange liquid (360 mg, 22%): 1H NMR δ 1.93 (s, 3H), 2.20 (s, 3H), 3.43 (s, 3H), 4.01 (s, 2H), 6.19-6.20 (m, 1H); 13C NMR δ 21.4, 28.2, 59.4, 78.5, 119.6, 158.3, 197.9; ESI-MS obsd 151.0731, calcd 151.073 [(M+Na)+, M=C7H12O2]; IR (neat) 3451, 2979, 2935, 2825, 1699, 1618, 1447, 1379, 1227, 1200, 1109, 1038, 986, 934, 815 cm−1.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].Cl.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[N:23]1([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:14]3[O:4][C:5](=[O:6])[C:7]4([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]4)[N:13]=3)=[CH:21][CH:20]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(c2ccc(CN3CCOCC3)cc2)=NC12CCCCC2
Reaction time: 1 h
Yield: 67.8 %

Procedure:
18 ml of 2N aqueous sodium hydroxide solution was added to a solution of 2.07 g (5.7 mmol) of 1-[[[4-(4-morpholinylmethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester in 18 ml of tetrahydrofuran, and the mixture was heated under reflux overnight. After the reaction solution was neutralized by concentrated hydrochloric acid, the reaction solution was distilled off under reduced pressure. 30 ml of methylene chloride, 1.74 g (17 mmol) of triethylamine and 1.65 g (8.6 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.27 g (60%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:19][C:20]1([F:30])[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]1([F:30])[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:28])[CH2:22][CH2:21]1
Reactant: O=C(O)CC1CCC(F)(F)CC1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)CC1CCC(F)(F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt (EXAMPLE 34 Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12]([NH:17][NH2:18])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Solvent: O
Solvent: CO
Product: CC(C(=O)NN)c1ccc2ncccc2c1
Yield: 82 %

Procedure:
2-Quinolin-6-yl-propionic acid (5.6 g, 26.1 mmol), hydrazine hydrate (1.6 mL) and methanol (150 mL) were combined and heated to reflux for 72 hours. After such time the mixture was concentrated in vacuo and portioned between NaHCO3 (200 mL) and dichloromethane (150 mL). The aqueous phase was extracted with dichloromethane (2×150 mL) and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to return the title compound as a white solid (4.6 g, 21.4 mmol, 82%). 1H-NMR (DMSO-d6, 500 MHz): 9.30 (1H, bs), 8.85 (1H, dd), 8.33 (1H, dd), 7.95 (1H, d), 7.86 (1H, d), 7.74 (1H, dd), 7.51 (1H, dd), 4.22 (3H, s), 3.74 (1H, q), 1.44 (3H; MS: m/z 216 [M+H+]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[CH:36]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)(Cl)Cl.[F-].[Cs+]>CN1CCCC1=O.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].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH2:27][C@H:26]1[CH2:29][O:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]([CH2:8][C@@H:9]([OH:17])[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Reactant: O[C@@H](Cc1ccccc1)Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@@H](O)Cc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
To a solution/suspension of 1-(3-bromophenyl)-3-phenyl-2(S)-propanol (260 mg, 0.89 mmol), 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5(trimethylstannyl)pyridine (417 mg, 0.98 mmol, 1.1 equiv.), Pd2dba3.CHCl3 (13.8 mg, 13.5 μmol, 15 mequiv.) and CsF (270 mg, 1.78 mmol, 2.0 equiv.) in N-methylpyrrolidone (1.0 mL) contained in a dried 100 mL round-bottom flask was added P(t-Bu)3 (10 wt % in hexane, 106 μL, 33 μmol) by syringe at room temperature under N2. The mixture was stirred for 3 h at 80° C., after which time TLC analysis indicated that the starting material had disappeared. After cooling, the reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied onto a silica gel column, which was eluted with CH2Cl2/MeOH 70:1 to give the product (280 mg, 66%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.48 (br s, 1H), 8.35 (br s, 1H), 7.52-7.41 (m, 3H), 7.39-7.25 (m, 7H), 4.58 (m, 1H), 4.43 (m, 1H), 4.23 (dd, 1H, J=9.9, 3.0 Hz), 4.15 (m, 1H), 3.94 (t, 2H, J=7.2 Hz), 3.12-2.78 (m, 4H), 2.43-2.27 (m, 2H), 1.58 (OH and water), 1.43 (s, 9H). LC-MS (ESI) m/z 475 (M+H+).
Reaction SMILES: [N:1]1([C:6]2([CH2:16][CH:17]=O)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][NH2:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>>[N:1]1([C:6]2([CH2:16][CH2:17][NH:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reactant: NCc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1csc(CNCCC2(n3cccn3)CCOC3(CCCC3)C2)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg, 0.06 mmol) and thiophen-2-ylmethanamine (19 uL, 0.18 mmol) was stirred at rt for 1 h before NaBH(OAc)3 (25.4 mg, 0.12 mmol) was added. The solution stirred overnight. After removal of solvent, the residue was purified by HPLC to provide {2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine (17 mg, 61% yield) as a TFA salt. LCMS m/z 346 (M+1) observed.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)[CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:12][CH:10]1[CH2:11][N:8]([C:6]2[CH:5]=[C:4]([C:13]([F:14])([F:16])[F:15])[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:9]1)=[O:26]
Reactant: O=C=Nc1ccccc1Br
Reactant: Cc1cc(C(F)(F)F)cc(N2CC(N)C2)n1
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CC(NC(=O)Nc3ccccc3Br)C2)n1
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 1-(6-methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine, D12 (100 mg, 0.432 mM) and 2-bromophenyl isocyanate (86 mg, 0.432 mM) in dichloromethane (5 ml) was kept at room temperature overnight. The resultant solid was removed by centrifugation, washed with diethyl ether and dried in vacuo, to give the title compound as a colourless solid, (119 mg, 64%). MH+ 429 and 431; 1H NMR (250 MHz, d6DMSO) δ: 2.39 (3H, s), 3.75-3.88 (2H, dd), 4.30 (2H, t), 4.50-4.66 (1H, m), 6.48 (1H, s), 6.78 (1H,s), 6.92 (1H, m), 7.28 (1H, m), 7.57 (1H, dd), 7.76 (1H, d), 7.86 (1H, s), and 8.04 (1H, dd).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH2:5]2.C([Li])CCC.B(OC(C)C)(OC(C)C)[O:25]C(C)C.[OH-].[Na+].OO.Cl.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O.C(O)C>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:25])[CH:3]=2)[O:8]1
Reactant: Cc1ccccc1C1CCc2cc(Br)ccc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1C1CCc2cc(O)ccc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-2-o-tolyl-chroman (1 g, 3.3 mmol) in tetrahydrofuran (3 ml) at −78° C. n-butyllithium (2.2 M in cyclohexan, 1.8 ml, 1.2 eq) was slowly added and the mixture kept at −78° C. for 30 min. Triisopropyl borate (1.9 g, 2.3 ml, 9.9 mmol, 3 eq) was added and stirring was continued at the same temperature for 1 h. The cold solution was poured in a solution of ethanol (1.1 ml), water (3.0 ml) and aqueous sodium hydroxide (8 M, 1.6 ml). To this solution hydrogen peroxide (aqueous 35%, 0.9 ml, 3.1 eq) was slowly added while the temperature was kept <30° C. Stirring at room temperature was continued for 15 min, the suspension was cooled to 0° C. and adjusted to pH<7 using aqueous hydrochloric acid. To the resulting solution a saturated aqueous solution of sodium sulfite (4 ml) was added and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). 2-o-Tolyl-chroman-6-ol was obtained as a pale yellow solid (480 mg, 60%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][OH:7])([CH3:3])[CH3:2].[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][O:7][CH2:11][O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)CO
Reactant: COCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOCC(C)NC(C)C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
A THF solution (15 mL) of 2-isopropylamino-1-propanol (1.23 g, 10.5 mmol) was added dropwise to a suspension of sodium hydride (504 mg, 0.29 mmol, 60% oil) in THF (9 mL), and the mixture was stirred at the same temperature for 15 minutes. Next, chloromethyl methyl ether (1.20 mL, 15.8 mmol) was added thereto, and the mixture stirred at room temperature for 45 minutes. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and isopropyl-(2-methoxymethoxy-1-methylethyl)amine (0.91 g; yield 54%) was thus obtained. 1H-NMR (CDCl3) δ(ppm): 1.05 (d, J=6.1 Hz, 3H), 1.06 (d, J=5.3 Hz, 3H), 1.08 (d, J=5.3 Hz, 3H), 2.94 (m, 2H), 3.36 (s, 3H), 3.38 (m, 1H), 3.47 (m, 1H), 4.63 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([O:10]CC)=O)[C:4](=[O:13])[CH2:3]1.[NH2:14][CH2:15][C:16]([NH2:18])=[O:17]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:10])[C:4](=[O:13])[CH2:3]1
Reactant: CCOC(=O)CN1CC(O)CC1=O
Reactant: NCC(N)=O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
A mixture of ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (0.5 g) and glycinamide (0.6 g) was stirred under nitrogen at 80° C. for 4 hours. After cooling, the mixture was chromatographed on a silica gel column, by eluting with dichloromethane/methanol 7:3, affording the title compound (250 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1)[CH2:20][CH3:21].ClCCl>C(N(CC)CC)C>[CH2:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1)[CH2:20][CH3:21]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1ccc(OB(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-propoxyphenylboric acid (536 mg), cupric acetate (271 mg), MS (molecular sieves) 4A (1.0 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 20 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2) to obtain methyl 7-(4-propoxyphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.31 g) as a light yellow, oily substance.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].Cl>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCC(F)(F)CC1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4,4-Difluorocyclohexyl)methanol (0.7 g, 4.11 mmole) was stirred in CH2Cl2 (5 ml) and cooled in an ice bath. TEA (0.499 g, 4.93 mmoles) was added followed by methanesulfonyl chloride (0.518 g, 4.52 mmoles). Stirring was continued overnight while allowing to warm to room temp. 1.0 N HCl (30 ml) and CH2Cl2 (30 ml) was added and stirred for 5 min. The organic layer was dried over Na2SO4 and evaporated giving (4,4-difluorocyclohexyl)methyl methanesulfonate (142) as an oil. Yield (0.92 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 4.06 (d, J=6.4 Hz, 2H), 3.14 (s, 3H), 2.04-1.95 (m, 2H), 1.88-1.70 (m, 5H), 1.29-1.19 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28](O)=[O:29])=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([NH:15][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[CH3:14])=[O:29])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Product: Cc1ccc(-c2ccc(F)cc2)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 4′-fluoro-4-methylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluoro-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>CO.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of 1-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol (245.0 g, 0.667 mol) in methanol (3 L) was added to a pressure vessel containing 5% platinum on carbon (7.35 g). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) at 55° C. for five hours. The reaction was allowed to cool to 40° C., and dichloromethane (2.5 L) was added. The reaction mixture was then filtered through CLARCEL filter aid at 30-40° C., and the filter cake was washed with methanol. The filtrate was concentrated to a volume of 1.5 L, cooled to 5-10° C., and stirred for two hours. A solid formed and was isolated by filtration, washed with a small amount of methanol, and dried under vacuum at 50° C. to provide 199.4 g of 1-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:4]1>O1CCOCC1>[ClH:1].[O:29]=[C:24]1[CH2:25][O:26][CH2:27][CH2:28][N:23]1[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]([C@H:5]2[CH2:4][C@@H:3]([OH:2])[CH2:7][NH:6]2)=[O:30])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
7.1 16 g (12.86 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 15 g (64.86 mmol) of cis-N′-BOC-4-hydroxy-D-proline and 12.47 g (64.86 mmol of 1-(4-amino-phenyl)-1H-pyridin-2-one in 250 ml of toluene, and the mixture is stirred at room temperature for 18 hours. The precipitated product is subsequently filtered off, washed successively with 50 ml of toluene and 50 ml of diethyl ether and dried in a desiccator, giving 24.5 g (93.2%) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a grey-white powder. ESI 406. 7.2 300 ml of 4N hydrochloric acid in dioxane are added to a solution of 15 g (37 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 200 ml of dioxane, and the mixture is stirred at room temperature for 12 hours. The precipitate is subsequently filtered off, washed with 50 ml of dioxane and 50 ml of diethyl ether and dried in a desiccator, giving 12.64 g (100%) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride as a white powder. ESI 306. 7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chloro-phenyl isocyanate in 100 ml of dichloroethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution, is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.