Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(Cl)c1
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(Cl)c3)nnnc12

Procedure:
Compound 16 was prepared following general synthetic scheme 7 wherein (S)-2-(Azetidin-1-yl)-1-(3,4-dichlorophenyl)ethanamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [417 (M+1)].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[C:14](OCCC)(=O)[C:15]1C=CC(C([O-])=O)=CC=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:14][CH3:15]
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Reactant: CCCOC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the procedure described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monopropyl terephthalate (49.0g, 0.20 mole), thionyl chloride (29.8g, 0.25 mole) and 100 ml of toluene. The product was used without further purification.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C@@:17]1([C:25]#[CH:26])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([OH:8])[C:26]#[C:25][C@:17]2([O:16][CH3:15])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C#C[C@@]1(OC)CN2CCC1CC2
Reactant: O=C(c1ccccc1)C1CCCCC1
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCC2)CN2CCC1CC2

Procedure:
1-cyclohexyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 201 was prepared as described in 4.1 (method 1) using cyclohexyl(phenyl)methanone and (3R)-3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl methyl ether 53.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[CH3:10][C:9]1([CH3:11])[O:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)=[CH:3][C:4]1=2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)Nc2ccc(I)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 6-iodo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Yellowish solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ 10.38 (s, 1H, D2O exchangeable), 8.47 (s, 1H), 8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01 (d, 1H, J=8.1 Hz), 1.68 (s, 6H); MS (EI) m/z 297([M−H]−, 100%). Anal. Calc. For C16H14N2O4: C, 64.42; H, 4.73; N, 9.39. Found: C, 63.93; H, 4.91; N, 8.71.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].O[CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:15][C:14](=[CH2:16])[C:13]([O:18][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:17]
Reactant: O=Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Reactant: C=C(C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
Firstly 9.4 ml of triethylamine and then 2.63 ml of methanesulphonyl chloride were added dropwise at −25° C. to a solution of 2.9 ml of methacrylic acid in 30 ml of tetrahydrofuran. Thereafter, the mixture was stirred at −25° C. for 1 hour and then a solution of 9.9 g of trans-4′-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carboxaldehyde and 1.1 g of 4-dimethylamino-pyridine in 50 ml of tetrahydrofuran was added dropwise. Thereafter, the mixture was left to react at 0° C. for 2.5 hours and then at room temperature for 18 hours. Thereupon, the reaction mixture was filtered over Celite, the filtrate was partitioned between ether and water, the ether phase was dried over magnesium sulphate and evaporated. This gave 11.5 g of crude trans-4′-[4-[3-(2-methyl-acryloyloxy)-propyl]-cyclohexyl]-biphenyl-4-carboxaldehyde in solid form.
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15]>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]([CH2:15][CH:14]([CH3:16])[C:13]#[N:17])=[O:9]
Reactant: O=Cc1cccc(Cl)c1
Reactant: C=C(C)C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)CC(=O)c1cccc(Cl)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Sodium cyanide (1.47 g, 30 mmol) was combined with 100 ml N,N-dimethylformamide and then stirred at 35° C. for 1 hour under nitrogen to give a clear solution. To this solution was added dropwise over 1 hour 34.0 ml (0.3 mol) of 3-chlorobenzaldehyde dissolved in 50 ml N,N-dimethylformamide. After stirring an additional 1 hour at 35° C. a solution of 25.0 ml (0.3 mol) methacrylonitrile in 50 ml N,N-dimethylformamide was added dropwise over 2 hours and the reaction mixture was stirred at 25° C. for 16 hours. Methylene chloride (200 ml) and 4.0 g diatomaceous earth filter aid was added and the mixture was slurried and filtered. The filtrate was washed consecutively with 500 ml 0.22N hydrochloric acid, two 200 ml portions water, 200 ml 2.5% sodium bicarbonate aqueous solution, 200 ml 1N hydrochloric acid, 200 ml water and 200 ml brine. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 49.65 g of crude 3-(m-chlorobenzoyl)-2-methylpropionitrile as a yellow solid; mp: partial melt at 50° C., melt at 79°-81° C. 15.57 g (0.075 mol) of this product was combined with 25 ml concentrated hydrochloric acid and 25 ml formic acid and heated at reflux for 2.5 hours. After cooling, 150 ml water was added and the aqueous solution was extracted with two 150 ml portions ethyl acetate. The ethyl acetate extract in turn was extracted with two 150 ml portions 20% sodium hydroxide in water. The aqueous extract was acidified with concentrated hydrochloric acid to precipitate a solid which was collected by filtration, washed with water and dried to give 10.86 g 3-(m-chlorobenzoyl)-2-methylpropionic acid: mp 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([OH:16])=O>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(C(F)(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-amino-N-phenyl-6-trifluoromethyl-benzamide was prepared by addition of aniline (1.0 eq.) to a suspension of 2-amino-6-(trifluoromethyl)-benzoic acid trihydrate (1.0 g, 4.0 mmol, 1.3 eq.) and polystyrene-carbodiimide (3.6 g, 1.1-1.7 eq.) in THF (40 mL). The reaction was stirred at ambient temperature for 18 hours, then filtered. The filtrate was concentrated in vacuo and purified by flash chromatography to provide 2-amino-N-phenyl-6-trifluoromethyl-benzamide as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.CCOCC>[Br:7][C:8]1[CH:9]=[C:10]([C:16]2([C:17]#[N:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: BrCCOCCBr
Reactant: COc1ccc(CC#N)cc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C2(C#N)CCOCC2)cc1Br
Temperature: 0 °C
Yield: 62.5 %

Procedure:
A mixture of sodium tert-butoxide (6.7 g, 70 mmol) in 100 mL NMP stirred at 0° C. was treated dropwise with a mixture of 2-(3-bromo-4-methoxyphenyl)acetonitrile (6.3 g, 28 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.5 g, 28 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and was stirred for 3 hours, M+Na=318/320. The mixture was quenched with 100 mL H2O carefully and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.18 g of crude product as a yellow solid. MS m/e=318/320 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O>O1CCCC1.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of 4-hydroxy-3-nitrobenzotrifluoride (1.00 g) in tetrahydrofuran (20 ml), 10% palladium on activated carbon (100 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give 2-amino-4-(trifluoromethyl)phenol (780 mg) as a gray powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Clc1cc(Br)c2occc2c1
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(Cl)cc2ccoc12
Yield: 91 %

Procedure:
Beginning with 4.0 gm (17.3 mMol) 5-chloro-7-bromobenzofuran and 3.86 gm (19.0 mMol) 1-benzyl-3-methyl-4-oxo-piperidine, 5.6 gm (92%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:21][C:22]([C:24]2[N:25]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:27][C:28]=2/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:21][C:22]([C:24]2[N:25]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:27][C:28]=2[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2nc(-c3ccccc3)sc2/C=C/C(=O)O)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2nc(-c3ccccc3)sc2CCC(=O)O)CC1
Yield: 33.8 %

Procedure:
A suspension of Example 19 (53 mg) and Pd/C (10%, 62 mg) in MeOH (2 mL) was stirred at RT under H2 atmosphere until reaction completion. The reaction mixture was filtrated over celite and the filtrate evaporated to dryness. Preparative HPLC (I) gave 18 mg of the desired product as yellow foam.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CN(C)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 11, piretanide can be reacted with 2-chloro-N,N dimethylacetamide, triethylamine and sodium iodide in DMF to yield N,N-dimethylaminocarbonylmethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[CH:10][CH:11]=[CH2:12].OP(O)(O)=O>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[CH2:9][CH2:10][CH:11]([CH3:12])[O:5][C:4]=2[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: C=CC=C
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC1CCc2ccc(O)cc2O1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A 100 ml autoclave was charged wtih 20 g of resorcinol, 12 g of butadiene, 4 ml of H3PO4 and 60 ml of toluene, and purged with nitrogen. The mixture was then heated at 100° C. for 3.5 hours. The crude product was purified by column chromatography to give 24.1 g (yield 82%) of the desired product as a brown liquid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:23][C:24]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1)=[CH2:24]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Yield: 85 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-one (802 mg, 2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (462 mg, 3 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (8 mL/4 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol) and Ph(PPh3)4 (46 mg, 0.04 mmol, 2 mol %) was added and the resulting mixture was purged with argon, then microwaved 3 h at 120° C. After aqueous workup, the solution was extracted with EtOAc and was purified by flash chromatography (Hex/EtOAc 1:1) to give the crude title compound as a light yellow foam (512 mg) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.10-6.88 (m, 5H), 6.54 (t, J=7.4 Hz, 1H), 6.06 (d, J=18.0 Hz, 1H), 5.92 (d, J=7.6 Hz, 1H), 5.49 (d, J=7.6 Hz, 1H), 3.46 (d, J=8.2 Hz, 1H), 2.30-2.18 (m, 2H); MS ESI 302.0 [M+H]+, calcd for [C19H15N3O+H]+ 302.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:15]=1.C(O)C.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a mixture of 5-chloro-1H-indole-7-carboxylic acid (500 mg), triphenylphosphine (1.01 g), ethanol (235 mg) and toluene (20 mL) was added dropwise diethyl azodicarboxylate (2.2 M toluene solution, 1.74 mL) at room temperature. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-chloro-1H-indole-7-carboxylate (550 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]([N:23]([CH3:32])[C:24](N1C=C[N+](C)=C1)=[O:25])([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:24](=[O:25])[N:23]([CH:20]([CH3:22])[CH3:21])[CH3:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)N(C)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane 1:5) (77%, white crystals). HPLC-MS m/z=355.1 (M+1), Rt: 4.80 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][O:16][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added isobutyryl chloride (0.15 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (380 mg, 66% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.86-0.89 (m, 4H, 2CH2), 1.10 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 1.73-1.81 (m, 1H, CH), 2.62-2.73 (m, 1H, CH), 3.02-3.05 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 11.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.76, 14.69, 15.46, 18.65, 31.27, 34.64, 46.59, 51.07, 55.47, 63.80, 111.93, 112.09, 116.82, 117.32, 117.50, 119.27, 131.23, 132.77, 136.98, 142.25, 147.95, 148.58, 166.61, 168.04, 171.72, 174.29; Anal Calcd for C28H33N3O7+0.11H2O: C, 63.99; H, 6.37; N, 8.00; H2O, 0.38. Found: C, 63.64; H, 6.37; N, 7.70; H2O, 0.39.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][C:14]=1[CH3:28].[C:29]([C:31]1[CH:41]=[CH:40][C:34]([C:35]([N:37]=[C:38]=[O:39])=[O:36])=[CH:33][CH:32]=1)#[N:30].C(N(C(C)C)CC)(C)C>C(#N)C>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:37][C:38](=[O:39])[NH:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:15][C:14]=2[CH3:28])=[O:36])=[CH:40][CH:41]=1)#[N:30]
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
In a similar manner to Example 1, starting material step (a), the product of step (b) (2.9 g), 4-cyanobenzoyl isocyanate (1.23 g), diisopropylethylamine (1.23 ml) and acetonitrile (125 ml total) were reacted to give, after stirring at ambient temperature overnight, a solid, which was crystallised from acetonitrile/ether to give t-butyl 4-[3-(4-cyanobenzoyl)ureido]-3-methylphenoxyacetate (611 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.73 (1H, dd), 6.81 (1H, d), 7.72 (1H, d), 8.00 (2H, d), 8.13 (2H, d), 10.41 (1H, s), 11.23 (1H, s); Mass Spectrum m/Z 432 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16]1([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11](=[O:13])[NH:33][CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:8])=[CH:14][CH:15]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)NCC(=O)O)cc1
Reactant: NC(c1ccccc1)c1cccc(C(F)(F)F)c1
Product: N#Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from (4-cyano-benzoylamino)-acetic acid (CA [90290-83-8]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 436.1 (MH−, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](c5ccccc5)CO4)c3)cc12
Yield: 13.2 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-2-phenylethanol (148 mg, 1.080 mmol) in PhCl (3 mL) at rt. It was subjected to two interations of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 13%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1 H, s), 7.94-8.00 (4 H, m), 7.91 (1 H, d, J=7.94 Hz), 7.64-7.73 (2 H, m), 7.61 (1 H, t, J=7.78 Hz), 7.32-7.42 (6 H, m), 7.26 (2 H, t, J=8.55 Hz), 5.45 (1 H, t, J=9.16 Hz), 4.94 (1H, t, J=9.31 Hz), 4.36 (1 H, t, J=8.24 Hz), 2.97 (3 H, s). LC-MS retention time 1.75 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=18.11 min, purity=97%.