Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][N:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CO>CN(C=O)C.C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[C:10](=[N:9][N:8]=3)[CH:11]=[C:12]3[O:13][CH2:1][O:2][C:3]3=[CH:4]4)[N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: CCCCN(C(=O)c1cc(OC)c(OC)cc1I)c1cnnc2cc3c(cc12)OCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2cc(OC)c(OC)cc2c2nnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of N-(6,7-Methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide (1.0 mmol equiv.), Pd(OAc)2 (0.2 mmol equiv.), P(o-tolyl)3 (0.4 mmol equiv.), and Ag2CO3 (2.0 mmol equiv) was heated to reflux in DMF (30 mL per mmol equiv.) with stirring. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3, and filtered through Celite. The sicciate was extensively washed with 10% CH3OH in CHCl3. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel using chloroform:methanol to provide the title compound (123 mg, 0.2 mmol) in 27% yield with a reaction time 90 min; mp 299° C.; IR (KBr) 1654; 1H NMR (CDCl3) δ 1.06 (t, 3H, J=7.4), 1.56 (m, 2H), 2.13 (m, 2H), 4.09 (s, 3H), 4.17 (s, 3H), 4.49 (m, 2H), 6.26 (s, 2H), 7.62 (s, 1H), 7.85 (s, 1H), 7.87 (s, 1H), 8.65 (s, 1H); 13C NMR (CDCl3) δ 13.8, 20.2, 31.1, 48.6, 56.3, 56.6, 98.8, 102.7, 104.2, 106.5, 107.9, 119.7, 149.1, 150.1, 150.9, 151.4, 153.6, 154.2, 162.9; HRMS calcd for C22H21N3O5H: 408.1559. Found 408.1543.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Yield: 101.4 %

Procedure:
Prepared from (2′,3′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B19) (3.14 g, 8.96 mmol) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a green solid (2.91 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:38]=[CH:37][C:23]([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.Br[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>>[C:25]1([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][C:20]([C:3]3[N:2]([CH3:1])[C:6]([C:40]4[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=4)=[CH:5][CH:4]=3)=[CH:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)n1C
Product: Cn1c(-c2ccc(C=O)cc2)ccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1([C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7].C1COCC1.O>CO>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([NH:12][C:11]([C:8]2([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]2)=[O:25])=[CH:14][CH:15]=1
Reactant: COC(=O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
KOH (420 mg, 7.5 mmol) was added to a solution cyclopropane-1,1-dicarboxylic acid diethyl ester (1 g, 6.3 mmol) in methanol (7 mL). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to afford 680 mg (75%) of cyclopropane-1,1-dicarboxylic acid methyl ester. HOBt (764 mg, 5.6 mmol), DMAP (1.72 g, 14.15 mmol) and EDCI.HCl (1.08 g, 5.6 mmol) followed by biphenyl-4-ylamine (957 mg, 5.6 mmol) were added to a stirred solution of cyclopropane-1,1-dicarboxylic acid methyl ester (680 mg, 4.7 mmol) in DMF (7 mL) and the resulting mixture was stirred at ambient temperature overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethylacetate layer was washed with brine solution and concentrated to afford 1.1 g (79%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester. LiOH.H2O (234 mg, 5.5 mmol) was added to a solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester (1.1 g, 3.7 mmol) in a mixture of methanol (5 mL), THF (11 mL) and H2O (3 mL) and the resulting mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 340 mg (33%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropane carboxylic acid.
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[CH:18][N:17]=1
Reactant: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO3. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (382 mg, 1.68 mmol, 95% yield). LCMS m/z 228.1 (M+H)+, Rt 0.44 min.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4].O>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C#N)c1
Solvent: CCOCC
Solvent: O
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Br2 (1 mmol) was dropwise added to a solution of 3-acetylbenzonitrile (1 mmol) in Et2O (15 ml) at 0° C., and then the mixture was stirred at r.t. for 4 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and was concentrated to give an oil, i.e., 3-(2-bromoacetyl)benzonitrile, which was directly used for the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C@@H:54]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[S:69](=[O:71])(=[O:70])[NH:68][C:67](=[O:72])[CH:66]=2)=[CH:61][CH:60]=1)[C:55]([OH:57])=[O:56]>CN1CCCC1=O.CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:53][C@@H:54]([CH2:58][C:59]1[CH:60]=[CH:61][C:62]([C:65]2[S:69](=[O:71])(=[O:70])[NH:68][C:67](=[O:72])[CH:66]=2)=[CH:63][CH:64]=1)[C:55]([OH:57])=[O:56])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (98.5 mg, 0.371 mmol) in N-methylpyrrolidinone (2.2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (128 mg, 0.337 mmol) and N,N-diisopropylethylamine (180 μL, 0.001 mol) and premixed for 5 minutes. To the solution was added (2S)-2-amino-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]propanoic acid (100 mg, 0.338 mmol) with several drops of DMSO to dissolve and the mixture was stirred overnight. The product was purified by preparative LCMS to afford the desired product (96 mg, 52%). 1H NMR (400 MHz, CD3OD): δ 7.81 (d, J=8.2, 2H), 7.42 (d, J=8.2, 2H), 7.18–7.36 (m, 5H), 6.98 (s, 1H), 4.70–4.73 (m, 1H), 4.26–4.30 (m, 1H), 3.02–3.13 (m, 3H), 2.71–2.76 (m, 1H), 1.33 (s, 9H); LCMS found for C26H9N3O8SNa (M+Na)+: m/z=566.0.
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Cl:29][C:14]1[C:15]2[C@:20]([CH3:21])([C@H:19]3[CH2:27][C@H:18]3[C:17](=[O:28])[CH:16]=2)[C@@H:22]2[C@H:12]([C@H:11]3[C@:25]([CH3:26])([CH2:24][CH2:23]2)[C:5]([C:6](=[O:8])[CH3:7])=[CH:9][CH2:10]3)[CH:13]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 44.4 %

Procedure:
One gram of 17α-acetoxy-6-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione is heated analogously to Example 1 in "Dowtherm" for 90 minutes to 285° C., worked up, separated, and combined. Recrystallization from ethanol yields 380 mg of 6-chloro-1α,2α-methylene-4,6,16-pregnatriene-3,20-dione (89% of theory), m.p. 243°-246° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])=[CH:26][CH:27]=2)[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc2ccccc2c1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1sc2ccccc2c1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 85 %

Procedure:
Using 4-{[cyclohexyl(2-methyl-1-benzothiophen-3-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example A8(4) and ethyl 3-(methylamino)propanoate (124 mg) and in the same manner as in Example A1(4), the title object compound (312 mg, 85%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6]3=[C:7]([CH2:13][CH2:14][O:15][C:5]3=[CH:4][CH:3]=1)[CH:8]=[C:9](Cl)[N:10]=2>FC(F)(F)C(O)=O.[Zn]>[Br:1][C:2]1[C:11]2[C:6]3=[C:7]([CH2:13][CH2:14][O:15][C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][N:10]=2
Reactant: Clc1cc2c3c(ccc(Br)c3n1)OCC2
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c3c(ccnc13)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
To a solution of 7-bromo-5-chloro-2,3-dihydropyrano[4,3,2-de]quinoline (0.220 g; 0.773 mmol) in trifluoroacetic acid (7.5 ml) was added zinc dust (0.253 g; 3.87 mmol) and the reaction was stirred at room temperature for 16 h. The suspension was filtered, concentrated under reduced pressure, diluted with a solution of sodium hydroxide 1N and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-80%) in heptane furnished 0.047 g (24%) of 7-bromo-2,3-dihydropyrano[4,3,2-de]quinoline as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-:29].[Na+]>>[OH:1][C:2]1[C:7]([N:27]=[N+:28]=[N-:29])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19])=[O:11]
Reactant: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(NC(=O)Nc2ccccc2I)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N′-(2-iodophenyl)urea(77 mg, 0.21 mmol) was added to HCl/H2O (0.21 mL/0.42 mL), and cooled to 0° C. Sodium nitrate (14.5 mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5:1) gave product (20 mg, 24%). EI-MS m/z 396 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[B:16]1[O:24][C:21]([CH3:23])([CH3:22])[C:18]([CH3:20])([CH3:19])[O:17]1.C1C(=O)N([Br:32])C(=O)C1.C1(=O)NC(=O)CC1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([C:12]([F:14])([F:15])[F:13])=[CH:4][C:3]=1[B:16]1[O:17][C:18]([CH3:20])([CH3:19])[C:21]([CH3:23])([CH3:22])[O:24]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2cc(C(F)(F)F)cc(C(F)(F)F)c2CBr)OC1(C)C
Temperature: 25 °C
Yield: 90.7 %

Procedure:
2-Methyl-3,5-bis(trifluoromethyl)phenylboronic acid pinacol ester (24a, 2.0 g, 5.6 mmol) and 50 ml CCl4 were placed in a 250 ml round-bottom flask. NBS (1.05, 5.88 mmol, 1.05 eq) and AIBN (0.013 g, 0.078 mmol, 0.014 eq) were added and the reaction mixture was refluxed for 3 h in the presence of 75 W incandescent bulb. After 3 h the solution was cooled down to room temperature allowing the succinimide to precipitate out. The solid was filtered off. The solvent was removed and oily product was collected. The crude product was purified by triturating with hexane which resulted in 90% pure product (25a, 2.2 g, 90% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>ClCCl>[C:24]([O:23][C:21]([N:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:17][CH2:16]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
5-Chlorosulfonyl-2-fluorobenzoic acid (2 g) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere and cooled to 0° C. tert-Butyl 1-piperazinecarboxylate (3.12 g) was added portionwise to the solution at 0° C. and stirred for 3 hours at ambient temperature. The organic solvent was evaporated in vacuo, and the residue was dissolved in 1N-sodium hydroxide solution. The aqueous solution was washed with diethyl ether and acidified with 1N-hydrochloric acid. The precipitates were collected by filtration and washed with water to give 5-[4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl]-2-fluorobenzoic acid (2.26 g) as a colorless solid substance.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:30][O:29][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (242 mg) and morpholine (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. Water was added to the reaction solution and was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 27%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]([N:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:19][C:18]=3[CH2:17]2)=[O:15])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[F:33].C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]([N:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:19][C:18]=3[CH2:17]2)=[O:15])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:33]
Reactant: COC(=O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of 44 (610 mg, 1.28 mmol) and THF (5 mL) was added MeOH (1 mL) followed by the dropwise addition of 1M NaOH (5105 μL, 5.11 mmol). The reaction was stirred for 1 h, cooled to 0° C. and acidified to pH 3 with 1N HCl. The mixture was extracted twice with 10% MeOH in DCM (25 mL). The organic layers were combined and concentrated to afford 270 mg (45.6%) of 2-(4-chloro-3-fluorophenyl)-2-(2-(tetrahydro-2H-pyran-4-ylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)acetic acid (46) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([OH:24])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[NH3:33].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([NH2:33])=[O:24])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: N
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](CC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (82 mg) was dissolved in 1.5 ml of dry tetrahydrofuran, and 33 mg of triethylamine was added thereto. Ethyl chloroformate (35 mg) was added to the mixture under nitrogen stream at -10° to -15° C., followed by stirring at the same temperature for 30 minutes. 29% (w/w) Aqueous ammonia (13 mg) was added at -40° C. to the resulting mixture, followed by stirring at -30° to -40° C. for 30 minutes. The reaction mixture was acidified with dilute hydrochloric acid, diluted with ethyl acetate, washed successively with water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-aminocarbonylmethyl-4-acetylthiopyrrolidine.