Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[S:8])[CH3:2].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C(O)C>[Cl:16][CH2:17][C:18]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[S:8][CH:20]=1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Temperature: 25 °C
Yield: 67.9 %

Procedure:
3,4-diethoxythiobenzamide (30.0 g, 133 mmol) was suspended in ethanol (300 ml), and 1,3-dichloroacetone (12.8 ml, 135 mmol) was added, followed by heating under reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 26.9 g (yield: 68%) of 4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole as yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:9]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[N:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:9]=1
Reactant: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of methyl 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylate (0.25 g, 0.66 mmol) in methanol (1.5 mL) and tetrahydrofuran (2.9 mL) was added sodium hydroxide (1.0 M, 3.98 mL, 3.98 mmol). The mixture was heated to 50° C. and stirred for 1.5 h. The mixture was cooled to ambient temperature and 1.0 M hydrochloric acid (ca 4.0 mL) was added until pH<3. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×7 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.24 g): LC-MS [M+1]=363.2.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11](=O)(OCC)[O:12]CC.C([O-])([O-])=O.[K+].[K+]>>[C:5]1([C@@H:2]2[CH2:3][O:4][C:11](=[O:12])[NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: N[C@@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N[C@H](c2ccccc2)CO1

Procedure:
7.54 g (55 mmol) of (2R)-(-)-2-amino-2-phenylethanol are dissolved in 8 ml (61 mmol) of diethyl carbonate, 770 mg (5.5 mmol) of K2CO3 are added, and ethanol is removed by distillation via a column. The crude product is recrystallized from ether/petroleum ether.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:23]=[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[CH2:21][C:22]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (1.0 g, 1.8 mmol) prepared in Example 116 and trifluoroacetic acid (1.4 mL, 18.0 mmol) were added at 0° C. to dichloromethane (9.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 1.1 g of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13]O)[N:8]=1)[CH3:6].S(Cl)([Cl:26])=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:26][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Yield: 87.9 %

Procedure:
To a solution of 2.62 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 60 ml of dry benzene was successively added 2.0 g of thionyl chloride and 0.67 g of pyridine with ice-cooling. After stirring and heating with reflux for 1 hour, the reaction mixture was washed with water. The organic phase was further washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to give 2.44 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, m.p. 72°-72.5° C.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=[C:5]1[C:14]1[N+:23]([O-])=[C:22]([CH3:25])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C>[C:16]([O:18][CH2:25][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:5]2[N:4]([C:1](=[O:3])[CH3:2])[C:8](=[O:9])[C:7]([CH:11]([CH3:13])[CH3:12])([CH3:10])[N:6]=2)[N:23]=1)(=[O:17])[CH3:15]
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1C1=NC(C)(C(C)C)C(=O)N1C(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(COC(C)=O)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O

Procedure:
A solution of 37.6 g of methyl 2-(1-acetyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methylnicotinate-1-oxide in 350 mL of acetic anhydride is stirred and heated at reflux for 31/2 hours. The reaction is concentrated in vacuo, and the residue is chromatographed on silica gel using hexane-ethyl acetate as eluant to give the desired product as a solid. Recrystallization of the solid from methylene chloride-hexanes affords analytically pure material, mp 111°-112° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>C(O)C>[CH2:25]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 70 %

Procedure:
4.17 g of sodium hydroxide was dissolved in 100 ml of ethyl alcohol. Then, 5.03 g of para-hydroxy benzoic acid and 12.2 ml of 1-bromododecane were added to the solution and refluxed for 15 hours. 50 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another 2 hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 7.66 g of pure product (yield 70%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Cl)[CH2:7]1)(=[O:3])[CH3:2].[Na+].[I-:27].FC(F)(F)C(O)=O>CC(=O)CC>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[I:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)=O
Product: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(I)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl acetate (185 mg, 0.45 mmol) in 2-butanone (8 mL) at 0° C. was added NaI (1.36 g, 9.08 mmol) followed by trifluoroacetic acid (174.8 μL, 2.27 mmol). The reaction was stirred for 3 hours at 0° C., quenched with saturated aq NaHCO3 and extracted with DCM. The organic phase was concentrated and the residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to obtain the title compound (140 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:6][C@H:5]2O.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O>[N:32]([C@@H:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:6]1)=[N+:33]=[N-:34]
Reactant: CC1(C(F)(F)F)C[C@@H](O)c2cc(Br)ccc2O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC1(C(F)(F)F)C[C@H](N=[N+]=[N-])c2cc(Br)ccc2O1
Reaction time: 0.33 h

Procedure:
To a cooled (ice bath) solution of (4R)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-ol (277 mg, 890 μmol) was added drop wise diphenylphosphoryl azide (249 μl, 1158 μmol). After stirring 20 min, 1,8-diazabicyclo(5.4.0)undec-7-ene (173 μl, 1158 μmol) was added drop wise. The reaction was stirred at the same temperature for 2 h, then stirred 15h at ambient temperature. Water was added to quench the reaction. The resulted mixture was extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column (5-20% EtOAc/hexane) to afford the title compound. MS m/z: 308(M−N2).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:18][CH:19]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH3:20])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:18][CH:19]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH3:20])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl pentanoate (800 mg, 2.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 12 (150 mg, 16% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 5H), 1.22-1.38 (br. m, 5H), 1.42 (d, J=5.2 Hz, 3H), 1.44-1.56 (m, 2H), 1.72-1.74 (m, 2H), 1.90-1.93 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.30 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 6.68 (q, J=5.6 Hz, 1H), 7.47 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: C(=O)(O)[O-].[Na+].[N:6]#[C:7]Br.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:13]([NH:15][NH2:16])=[O:14].CCOC(C)=O>C(O)C>[NH2:9][C:10]1[CH:11]=[C:12]([C:13]2[O:14][C:7]([NH2:6])=[N:16][N:15]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: NNC(=O)c1cc(N)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(-c2nnc(N)o2)cc(C(F)(F)F)c1
Yield: 71.7 %

Procedure:
Add sodium bicarbonate (270 mg, 3.21 mmol) and cyanogen bromide (187 mg, 1.76 mmol) to the solution of 3-amino-5-(trifluoromethyl)benzohydrazide (400 mg, 1.6 mmol) in ethanol (5 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate the mixture, partition the residue between EtOAc and water, collect the organic layer, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to afford the crude product. Recrystallization in ethyl acetate yields the pure product (280 mg, 63%).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[N:6](C(=O)C(F)(F)F)[CH2:5]1.C([O-])([O-])=O.[Cs+].[Cs+].CO>C1COCC1.[Cl-].[Na+].O>[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17]([NH2:1])(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[NH:6][CH2:5]1
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reaction time: 0.12 h
Yield: 96.3 %

Procedure:
Conc. aqueous NH3 (0.5 mL, 7.3 mmol) was added to a solution of 116 (299 mg, 0.65 mmol) in THF (10 mL) at 0° C., and the ice bath was removed. The mixture was stirred for 7 min and then Cs2CO3 (0.55 g, 1.7 mmol) and MeOH (4 mL) were added. After stirring for a further 15 min the mixture was diluted with brine and extracted with CH2Cl2 (×3). The combined extracts were dried and evaporated to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-7-sulfonamide (117) (214 mg, 96%) as an orange solid. A sample was triturated with EtOAc: mp 183-187° C. (dec.); 1H NMR [(CD3)2SO] δ 8.59 (d, J=1.7 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.85 (dd, J=8.9, 1.7 Hz, 1H), 7.75 (s, 1H), 7.42 (s, 2H), 6.68 (s, 1H), 4.28-4.21 (m, 1H), 3.95-3.85 (m; 2H), 3.81 (dd, J=11.2, 8.3 Hz, 1H), 3.73 (dd, J=10.4, 3.0 Hz, 1H). Anal. (C13H12ClN3O4S) C, H, N.
Reaction SMILES: [N:1]([CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[N+]=[N-]>[Pd].CCO>[NH2:1][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)CC1(C(N=[N+]=[N-])C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC1(C(N)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of tert-butyl α-azido-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (159 mg, 0.397 mmol), palladium on carbon (10%, 40 mg) and EtOH (2.0 mL) is hydrogenated overnight at 30 psi. The mixture is filtered and concentrated to give 145 mg (97%) of the title compound as an oil:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].ClC1C=C(NC2C=CC(F)=CC=2F)C=C[C:39]=1[C:40](C1C=C(C2N=NN(CC(O)=O)C=2)C=CC=1C)=[O:41].Cl.N1CCOCC1>>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([N:21]3[CH2:39][CH2:40][O:41][CH2:23][CH2:22]3)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Solvent: C1COCCN1
Product: Cc1ccc(-c2cn(CC(=O)N3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.12 mmol) and morpholine hydrochloride (0.12 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 5:95 as the eluent to afford the title compound as almost yellow syrup. 13C NMR (CDCl3) δ 196.0, 163.5, 147.9, 147.3, 139.8, 138.0, 135.3, 133.7, 131.9, 129.2, 128.0, 127.7, 126.5, 124.4 (dd), 124.2 (dd), 121.4, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 66.6, 66.4, 50.9, 45.9, 42.6, 20.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(O)C>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:29][CH:28]=1)[CH3:43]
Reactant: CCOC(=O)CCCBr
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reaction time: 0.5 h

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-propionamide (140 mg, 0.31 mmol) was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture allowed to stir 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (80/20 hexanes/ethyl acetate—50/50 hexanes ethyl acetate gradient) to afford the product (171 mg, 0.304 mmol, 98%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19](=[O:28])[N:18]([CH3:29])[C:17]2=[O:30])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=[O:35].NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19](=[O:28])[N:18]([CH3:29])[C:17]2=[O:30])[C:10](=[O:35])[CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Product: COc1ccc2c(=O)n(C)c(=O)n(CCN3CCC(N)CC3=O)c2c1

Procedure:
tert-Butyl{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 111, 350 mg, 0.83 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as a black oil, 395 mg (quantitative), and used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N:12]1[NH:13][N:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>O.[Cu]I.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)ccc1-n1nccn1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 5-fluoro-2-iodo-benzoic acid (3.86 g, 14.65 mmol), 2H-[1,2,3]triazole (2.5 g, 36.2 mmol), Cs2CO3 (8.62 g, 24.5 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.4 mL), CuI (244 mg) and DMF (13 mL) were added to a microwave ready vessel and heated to 100° C. for 10 min. The mixture was cooled, diluted with water, and extracted with EtOAc. The aqueous layer was acidified and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by FCC (SiO2, gradient DCM to 10% MeOH/1% HOAc/DCM) gave the product as a white powder, (2.14 g, 71%). 1H NMR (400 MHz, CD3OD): 7.91 (s, 2H), 7.76 (dd, J=8.9, 4.8 Hz, 1H), 7.59 (dd, J=8.5, 2.9 Hz, 1H), 7.49-7.42 (m, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[Si:23]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34][C:33](=O)[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1>[Si:23]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:34]/[C:33](=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\C(=O)OCC)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 1.6 mL, 4 mmol) was added to a solution of diisopropylamine (0.56 mL, 4 mmol) in 5 mL of tetrahydrofuran at −78° C. After 30 minutes, ethyl trimethylsilylacetate (0.73 mL, 4 mmol) was added. After stirring 30 minutes, a solution of the compound of Example 16J (787 mg, 2 mmol) in 8 mL of tetrahydrofuran was added, followed by a rinse of 2 mL of tetrahydrofuran. After 2 hours, the reaction was quenched by the addition of 10 mL of saturated aqueous NH4Cl. After warming to ambient temperature, the mixture was poured into 100 mL of 20% NaCl, then extracted twice with 100 mL of tert-butyl methyl ether. The combined tert-butyl methyl ether extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (300 mL of SiO2, elution with a gradient of 1:1 dichloromethane:hexanes to dichloromethane) to afford 538 mg (58% yield) of a ˜4:1 mixture of isomers favoring the title compound (538 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (200 mg, 0.77 mmol), phenyl boronic acid (114 mg, 0.93 mmol), 2N aqueous potassium carbonate (1.15 mL, 3.10 mmol) in toluene (3.3 mL) and EtOH (1.1 mL) was degassed with N2, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56.6 mg, 0.077 mmol), and degassed again with N2. The mixture was subjected to microwave irradiation conditions at 120° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (0-46% EtOAc/petroleum ether) to afford the title compound (190 mg, 98% yield) as a yellow solid.