Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][C:19]([O:21]CC)=[O:20])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A mixture of ethyl 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoate obtained in Example 8 (300 mg), lithium hydroxide monohydrate (840 mg), water (10 mL), and tetrahydrofuran (10 mL) was stirred at room temperature for 3 h. 6 M hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (199 mg, 73%) as a colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.[Br:13]CC(C1C=C(Cl)C=CC=1Cl)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH2:11][Br:13])[C:4]=2[O:3][CH2:2]1
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1cccc2c1OCO2
Product: O=C(CBr)c1cccc2c1OCO2
Yield: 48 %

Procedure:
This compound was prepared from 1-benzo[1,3]dioxol-4-yl-ethanone (2.15 g, 13.1 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.54 g (48%) of 1-benzo[1,3]dioxol-4-yl-2-bromo-ethanone as an off-white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:27]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18](C)[C:19](OC(C)(C)C)=O)[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].O1CCOCC1.[ClH:41]>CO>[ClH:41].[NH2:27][CH:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([NH:18][CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNc1ccc2onc(OCC(N)COC(N)=O)c2c1

Procedure:
To a solution of 0.10 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-(N-methyl-N-tert-butoxycarbonylamino)-1,2-benzoisoxazole in 5 ml of methanol is added 1.2 ml of a dioxane solution (2.2N) of hydrogen chloride at 5°-10° C., and they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from 2-propanol, after which the crystals are collected by filtration to obtain 0.03 g of colorless, crystalline 3-(2-amino-3-carbamoyloxypropoxy)-5-methylamino-1,2-benzoisoxazole hydrochloride having a melting point of 179°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:5][CH:4]=1.Cl.Br[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH3:17])[CH:9]2[CH2:14][CH2:13][N:12]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:11][C:10]2([CH3:16])[CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(C)C2CCNCC2(C)C)cc1
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)C2CCN(c3ccncc3)CC2(C)C)cc1
Yield: 40 %

Procedure:
N-(4-Methoxybenzyl)-N,3,3-trimethylpiperidin-4-amine (5.17 mmol, 1 eq) and 4-bromopyridine hydrochloride (1.509 g, 7.76 mmol, 1.5 eq) were dissolved in n-butanol (40 ml) and DIPEA (4.26 ml, 25.87 mmol, 5 eq) and refluxed for 16 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 40% (700 mg, 2.06 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:17]=[CH:18][C:13]([CH:19]([C:26]3[CH:27]=[CH:28][C:29]([C:8](=[O:9])[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)=[CH:30][CH:31]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(c1ccccc1)c1ccccc1
Agent: Cl[Fe]Cl
Solvent: ClCCCl
Product: CCCCCCC(c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.3 %

Procedure:
In a 200-milliliter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 17.4 g of iron chloride, 16.7 g of paranitrobenzoyl chloride and 40 milliliters of 1,2-dichloroethane were introduced. Then, a solution of 9.0 g of 1,1-diphenyl heptane in 10 milliliters of 1,2-dichloroethane was added dropwise for 15 minutes with an ice bath. Thereafter, the solution was stirred for 3 hours and 40 minutes with heating to a reflux temperature. After the end of the reaction was confirmed by a liquid chromatography, the solution was poured in ice water containing dilute hydrochloric acid, and then extracted with chloroform. The solution was washed with hydrochloric acid, an aqueous solution of sodium hydroxide and water, and then dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, the solution was dissolved in chloroform and subjected to a separating operation by a column chromatography with silica gel, to obtain 14.4 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)heptane as red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[N:21]([O-])=O.[Na+].[OH-].[Na+].C(O)(=O)C>O.Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:2]2[N:1]=[N:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[C:4](=[O:5])[C:3]=2[CH:16]=1
Reactant: CC(CNC(=O)c1cc(Cl)ccc1N)Cn1ccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(Cn1ccnc1)Cn1nnc2ccc(Cl)cc2c1=O

Procedure:
A solution of 5.86 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide in 30 ml of water and 8.3 ml of concentrated hydrochloric acid was cooled in an ice bath and a solution of 1.42 g of sodium nitrite in 10 ml of water was added dropwise. The mixture was stirred, treated for 50 minutes with 10 ml of 10N sodium hydroxide, stirred for 50 minutes and acetic acid was added until a pH of 6-7 was reached. The product was extracted into methylene chloride and the organic layer was washed with water, dried over magnesium sulfate and concentrated. Treatment with ethyl ether resulted in crystals of the desired product, mp 100°-102° C. A sample was converted to the hydrochloride salt, mp 185°-188° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH:17]3[CH:22]=[CH:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]3)=[C:12]([F:25])[CH:11]=2)[CH2:5]1.[F:26][CH:27]([F:33])[C:28](OCC)=[O:29].C(N(CC)CC)C>CO>[O:24]=[S:20]1(=[O:23])[CH:19]=[CH:18][CH:17]([C:13]2[C:14]([F:16])=[CH:15][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:28](=[O:29])[CH:27]([F:33])[F:26])[O:8][C:7]3=[O:9])=[CH:11][C:12]=2[F:25])[CH2:22][CH2:21]1
Reactant: CCOC(=O)C(F)F
Reactant: NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Yield: 80.9 %

Procedure:
(5S)-5-(aminomethyl)-3-[4-(1,1-dioxido-3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one monohydrochloride from Step 1 (0.400 g, 1.02 mmol), ethyl difluoroacetate (0.633 g, 5.1 mmol), and triethylamine (0.284 ml, 2.04 mmol) in methanol (8 ml) were stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give white solid (0.36 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromopyridine (156 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (80 mg, 17%). MS (ISP) 448.2[(M+H)+]; mp 227-229° C.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]([O-])(=O)(=O)=O.[Na+].II.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[I:15])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCC2)c(I)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (168.1, 2.00 g, 10.5 mmol, 1.00 equiv) in acetic acid (30 mL) were carefully added sodium periodate (1.00 g, 4.68 mmol, 0.50 equiv), iodine (3.00 g, 11.8 mmol, 1.10 equiv) and sulfuric acid (0.15 g, 0.15 equiv). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction was then quenched by carefully adding 30 mL of Na2S2O3 (aq., sat.) and the resulting mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1.50 g (45%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Solvent: O
Solvent: CCO
Product: O=C(CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1 h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1 h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:18]([NH:17][CH2:16][C:15]1[CH:29]=[CH:30][C:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)=[CH:13][CH:14]=1)=[O:28]
Reactant: CC(C)(C)Oc1cc(-c2ccc(CNC(=O)c3c(F)ccc(F)c3Cl)cc2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(-c2cc[nH]c(=O)c2)cc1)c1c(F)ccc(F)c1Cl

Procedure:
The compound N-(4-(2-tert-butoxypyridin-4-yl)benzyl)-2-chloro-3,6-difluorobenzamide was re-dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuum and then purified by reverse phase chromatography to afford 2-chloro-3,6-difluoro-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[C:68]([CH3:69])=[CH:67][CH:66]=[C:65]([F:70])[C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[C:68]([CH3:69])=[CH:67][CH:66]=[C:65]([F:70])[C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: Cc1ccc(F)c(C(=O)Cl)c1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)ccc(C)c4F)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 165 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,6-difluoro-3-methyl benzoyl chloride.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:3]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:12]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.9 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (462 mg, 3 mmol, Aldrich) in DMF (6 mL) at rt was added 3-aminopyridine (282 mg, 3 mmol). The reaction mixture was stirred overnight at rt, treated with EDCI.HCl (650 mg, 3.4 mmol) and DMAP (200 mg), stirred for an additional 24 h, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product (980 mg, 95%) as a beige solid. 1 H NMR (CDCl3) δ 13.00 (br s, 1H), 8.83 (br s, 1H), 8.74 (br s, 1H), 8.29 (dd, 1H, J=7.2, 1.7 Hz), 8.18 (d, 1H, J=8.3 Hz), 7.73 (dd, 1H, J=7.7, 5.0 Hz ), 7.66 (dd, 1H, J=6.6, 1.6 Hz), 6.42 (t, 1H, J=7.1 Hz), 3.87 (s, 3H).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([C:29]([NH2:31])=[O:30])[CH:22]=1>[OH-].[K+].CCO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:26]2[CH:25]=[CH:24][C:23]([C:29]([NH2:31])=[O:30])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: NC(=O)c1ccc(C=O)cc1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)cc1

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with benzamide-4-carboxaldehyde (0.178 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.197 (42%) of the title compound as an off-white powder, mp dec. >230° C.: CI-MS m/e 388 (M+ +1).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:24])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27]>>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:6](=[O:24])[O:7]2)=[CH:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2oc1=O
Product: C[C@H](NC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2oc1=O)C(=O)O

Procedure:
2-(S)-[(7-Benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-propionic acid was prepared from 7-benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester and L-alanine under conditions analogous to example 49-a. MS ESI(−) m/e: 382.03 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (171 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12]OC(C)(C)C>C(Cl)Cl.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([NH2:11])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OCl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(F)c(Cl)cc1C(=O)O
Reaction time: 1.5 h
Yield: 111.2 %

Procedure:
To a solution of 4-fluoroanthranilic acid (0.882 g, 5.69 mmol) in methylene chloride (50 mL) and acetic acid (10 mL) is added tert-butyl hypochlorite (0.71 mL, 6.25 mmol) solution in dichloromethane (1 mL) dropwise over 1 minute. After 90 minutes, the reaction mixture is washed with water and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford 5-chloro-4-fluoroanthranilic acid (1.20 g). MS CI: m/e 188 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].O>CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)c(I)c1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 37.5 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
A 3-neck, 3 L, round-bottom flask was equipped with an over-head stirrer, thermometer, and a pressure-equalizing dropping-funnel was charged with the solution of 4-benzyloxy-3-iodo-benzenesulfonyl chloride. The flask immersed in a cold water bath (Tint=22° C.) and tert-butylamine (90.1 g, 0.710 mol, 2.1 eq) was added drop-wise (Tint no change). The resulting reaction mixture was stirred overnight at the ambient water-bath temperature. After 17 h, the reaction mixture was worked-up and the organic layer was separated and concentrated to approx. ⅓ (˜500 mL) of its original volume at which point the product started to precipitate. The reaction mixture was warmed to 35-40° C. at atmospheric pressure till the solids had re-dissolved. The solution was then allowed to cool, with gentle stirring, to room temperature. Within 2 days a white precipitate had formed. The suspension was stirred vigorously while hexane (1.5 L) was slowly added, then stirred overnight, and then cooled in an ice-bath for 1-2 h The precipitate was collected by filtration and washed with hexane, dried, first under suction to give 4-benzyloxy-N-tert-butyl-3-iodo-benzenesulfonamide (238, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:22](OCC)(=[O:24])[CH3:23]>>[C:22]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methoxypyridine-2-carbonyl)indole (Example 72). m.p.: 207-208° C. (ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])=[O:28])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)cc(S(=O)c2c(C(C)C)nc(C)n2C)c1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
In methylene chloride (10 ml)was dissolved 150 mg (0.55 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1,2-dimethyl-1H-imidazole, followed by addition of 177 mg (0.82 mmol)of 80% metachloroperbenzoic acid under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture, an aqueous solution of sodium thiosulfate and then, an aqueous sodium hydrogen carbonate solution was added, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by silica gel chromatography (ethyl acetate), and recrystallized from n-hexane to give 100 mg of Compound I-104 (yield 63%). mp 100-101° C.