Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=[CH:23]1)=O.CNC.C(OC(C)C)(C)C>O1CCCC1.C(O)(C)C>[CH3:20][N:22]([CH3:23])[C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: CNC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(-c2nc3cccnc3n2CC(=O)N(C)C)s1
Temperature: 40 °C
Yield: 20.6 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 33/4 hours with a stream of nitrogen bubbling through it. A solution of dimethylamine (48 ml of a 2.29M solution in tetrahydrofuran, 0.1098 mole) was added and the mixture was heated at 40° C. overnight under nitrogen. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with a saturated sodium chloride solution, twice with a 5% potassium hydroxide solution and twice again with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered and evaporated under reduced pressure to give a residue which was dissolved in hot isopropyl alcohol and brought to the cloud point by addition of isopropyl ether. Upon cooling to room temperature, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature to give 1.13 g of title compound (20%), mp 193°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23]>ClCCl>[C:22]([O:10][C:9]([C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:13]([O:15][C:6]([CH3:13])([CH3:7])[CH3:5])=[O:14])[CH:7]=1)=[O:11])([CH3:23])([CH3:21])[CH3:24]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (4.22 g, 20 mmol) was suspended in dichloromethane (80 ml) and concentrated sulphuric acid (1 ml) was added. The solution was stirred and then saturated with isobutylene gas. The reaction vessel was stoppered and stirred at room temperature overnight. The solution was filtered and anhydrous potassium carbonate was added to the filtrate the solution was filtered and evsaporated and the residue recrystallised from ethanol to leave the title compound as a white solid (2.2 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chloro-2-nitrobenzonitrile (2.0 g, 11 mmol) in THF (40 mL) was added morpholine (1.0 g, 11 mmol). The reaction was heated at reflux overnight. After this time the reaction was cooled to rt and then it was partitioned between EtOAc (150 mL) and NaHCO3 (50 mL, satd aq. solution). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 1:1) gave 4-morpholino-2-nitrobenzonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:22][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 211.7 %

Procedure:
Compound 3-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (262 mg) and compound 3-7 (250 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (520 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:55][CH:53]([C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([Cl:49])[CH:51]=2)[CH3:54])=[CH:18][CH:17]=1
Reactant: CC(O)c1cccc(Cl)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 61.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 15 min. Subsequently, 3-chloro-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (71 mg, yield 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 60 mg (0.22 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride, 62 mg (0.26 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 29 mg of a white solid: LC-MSD, m/z for C24H18F3N3O2 [M+H]+=438.1; HPLC retention time: 1.4 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:14](I)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:11])=[N:8][N:9]([CH2:14][CH3:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCI
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)nc1N
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 32 mmol) in acetonitrile is added sodium hydride (1.28 g, 32 mmol) at RT. After 30 min of stirring, a solution of ethyl iodide (2.57 ml, 32 mmol) in acetonitriloe is added dropwise. The reaction mixture is stirred at RT for 16 h. Water is added followed by anhydrous sodium sulfate. The mixture is filtered and concentrated at reduced pressure. The crude product is chromatographed on silica gel using 30% ethyl acetate in hexanes to provide a regioisomeric mixture of N-ethylated 3-amino-1H-pyrazole-4-carboxylic acid ethyl esters. This mixture is used in the following reaction step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([CH:15]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13].[C:43]([O-])([O-])=O.[K+].[K+].IC.ClCl>CN(C)C=O.O>[CH3:43][N:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[S:12]([CH:15]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13]
Reactant: N#Cc1ccc(CC(NC(=O)C(Cc2ccccc2)S(=O)(=O)Nc2ccc3ccccc3c2)C(=O)N2CCCC2)cc1
Reactant: O=C([O-])[O-]
Agent: ClCl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc2ccccc2c1)S(=O)(=O)C(Cc1ccccc1)C(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCCC1
Reaction time: 24 h
Yield: 86.1 %

Procedure:
2 g of compound 4 are dissolved in 20 ml of dimethylformamide at 0° C. and 0.475 g of K2CO3 and 0.214 ml of ICH3 are added. After 24 hours at 5° C., 20 ml of H2O and 40 ml of CH2 Cl2 are added. The organic phase decanted is washed, dried and concentrated to dryness. The residue is recrystallized from (CH3)2CHOH to give 1.76 g of final product which melts at 186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH2:17][O:18][C:19](=[O:33])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+]([O-])=O)=[CH:22]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C.O.[Cl-].[NH4+:40]>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:33])[CH2:20][N:21]1[C:29]2[C:24](=[C:25]([NH2:40])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH3:10]
Reactant: [NH4+]
Reactant: CCOC(=O)C(COC(=O)Cn1cc([N+](=O)[O-])c2ccccc21)(C(=O)OCC)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(COC(=O)Cn1ccc2c(N)cccc21)(C(=O)OCC)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
The 2-[2-(3-Nitroindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethyl ester (100 mg) obtained in Example 9c) was dissolved in tetrahydrofuran (2 mL), ethanol (4 mL) and water (1 mL), and to the solution were added ammonium chloride (57 mg) and reduced iron (60 mg). The mixture was stirred at 100° C. for 2 hours, cooled, and filtered through a Celite pad. The filtrate was concentrated and diluted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, and concentrated to give the title compound (93 mg).
Reaction SMILES: C([O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].[C].CO.O1CCCC1>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:23]1[C:9]([OH:8])=[CH:10][C:11]2[NH:15][C:14]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[N:13][C:12]=2[CH:22]=1
Reactant: Fc1ccccc1Oc1cc2[nH]c(-c3cnccn3)nc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F

Procedure:
500 mg of 20% palladium hydroxide-carbon catalyst was added to a suspension of 697 mg of 5-benzyloxy-6-(2-fluorophenoxy)-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 250, in 10 ml of methanol and 10 ml of tetrahydrofuran, and the reaction liquid was stirred in a hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: ethyl acetate) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][CH:41]=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[CH2:22]([C:21]1[N:39]2[N:40]=[CH:41][N:42]=[C:38]2[N:37]([CH:34]2[CH2:33][CH2:32][C:31]3([O:27][CH2:28][CH2:29][O:30]3)[CH2:36][CH2:35]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.9 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.6 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.75 g, 53%).
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:14](=[O:15])[CH:13]([CH2:16][CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[OH:19])[CH:12]2C2C=CC=CC=2C#N)=[CH:7][CH:6]=1.C([N:37]([CH2:40][CH3:41])CC)C>C(O)(C)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:14](=[O:15])[CH:13]([CH2:16][CH2:17][CH:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[OH:19])[CH:12]2[C:5]2[CH:10]=[CH:9][C:41]([C:40]([NH:3][OH:2])=[NH:37])=[CH:7][CH:6]=2)=[CH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccccc1C1C(CCC(O)c2ccc(F)cc2)C(=O)N1c1ccc(F)cc1
Reactant: [NH3+]O
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
199 mg of hydroxylammonium hydrochloride were added to a solution of 200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzonitrile and 0.45 ml of triethylamine in 15 ml of isopropanol, and the mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 451.48 (C25H23F2N3O3); MS (ESI): 452.10 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1cc(-c2ccco2)nc(Cl)n1
Temperature: 130 °C
Yield: 116.9 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (0.5 g, 2.73 mmol), 2-furanboronic acid (0.152 g, 1.36 mmol), potassium carbonate (0.377 g, 1.36 mmol)) in toluene (2.5 ml) was added tetrakis(triphenylphosphine)palladium (0.08 g, 0.068 mmol). The reaction vessel was sealed and heated under the influence of microwave radiation (130° C., 600 seconds, low absorption setting). The crude reaction was concentrated in vauo to give an orange oil which was purified by flash chromatography (SiO2) (19:1—Hexanes:EtOAc) to give the title compound (342 mg, 58%) in suitably clean form to be used without further purification. m/z (LC-MSW, ESP):215.1 [M+H]+, R/T=4.68 mins
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[CH3:11][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (5.0 mmol, 721 mg), K2CO3 (15.0 mmol, 2.07 g) in DMF (17 mL) is added iodomethane (6.0 mmol, 0.374 mL). After stirring for 2 h, the mixture is diluted with EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4 and concentrated. The residue is used to next reaction without further purification (643 mg, 81%); ESI-MS m/z: 159 [M+1]+, Retention time 1.34 min. (condition A).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](C(O)=O)[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: O=S(=O)(O)O
Product: Cc1cccc2c1CCCC2=O
Temperature: 60 °C
Yield: 87 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (22.0 g, 116 mmol) in methanol (132 mL) was added sulfuric acid (22.7 g, 231 mmol) and the solution was heated to 60° C. for 4 h. Crystallization started when the solution was cooled, and then water (130 mL) was added. The slurry was filtered and the solid dried under vacuum to afford methyl 5-oxo-5,6,7,8-tetrahydronapthalene (20.6 g, 101 mmol, 87%) as an off-white solid. MS ESI calcd for C12H12O3 [M+H]+ 205, found 205.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].O>C(Cl)(Cl)Cl>[CH2:19]([NH:23][C:24]([NH:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([CH3:17])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:7]2)=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN1CCc2c(C)cc(C)c(N)c21
Reactant: CCCCN=C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCN1CCc2c(C)cc(C)c(NC(=O)NCCCC)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.1 %

Procedure:
7-Amino-4,6-dimethyl-1-hexylindoline (800 mg) was dissolved in chloroform (20 ml) and butyl isocyanate (400 mg) was added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent : chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 450 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:14][NH2:15])[CH2:9]1)=O)(C)(C)C.[O:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1.[C:42](=[O:45])(O)[O-:43].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[O:27]1[C:31]([C:32]2[CH:33]=[CH:34][C:35]([S:38]([NH:15][CH2:14][C@H:13]([C@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)(=[O:40])=[O:39])=[CH:36][CH:37]=2)=[CH:30][N:29]=[CH:28]1.[C:42]([OH:43])([C:23]([F:26])([F:25])[F:24])=[O:45]
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CN)Oc2ccc(C(F)(F)F)cc2)C1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(F)(F)F
Product: O=S(=O)(NC[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1)c1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-[(S)-2-Amino-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (35.0 mg, 0.093.5 mol, 1.0 eq.) was dissolved in DCM (1.2 mL) and triethylamine (39.1 μL). A solution of 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (56.9 mg, 234 μmol, 2.5 eq.) in DCM (0.4 mL,) was then added. The resulting mixture was stirred for 1 hour at room temperature. Saturated sodium bicarbonate was then added (1 mL) and the mixture was diluted with DCM (2 mL). The organic layer was collected and concentrated under reduced pressure. The crude material was redissolved in 1.2 M of HCl in EtOH (1.9 mL) and stirred at room temperature overnight. The mixture was then concentrated under reduced pressure then redissolved in 1:1 AcOH/H2O (1.5 mL) and purified by preparative HPLC to yield the title compound as a TFA salt (20.1 mg). MS m/z: [M+H]+ calcd for C22H22F3N3O4S, 482.13. found 482.4.
Reaction SMILES: [Na].[CH2:2]([C:4]1[NH:5][C:6](=[O:23])[NH:7][C:8]=1[C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[CH:12][CH:11]=1)[CH3:3].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:2]([C:4]1[N:5]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:6](=[O:23])[N:7]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]=1[C:9](=[O:22])[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[CH:14][CH:15]=1)[CH3:3].[CH2:2]([C:4]1[NH:5][C:6](=[O:23])[N:7]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]=1[C:9](=[O:22])[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[CH:14][CH:15]=1)[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2C)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCc1[nH]c(=O)n(C(=O)Cc2ccccc2)c1C(=O)c1ccc(-n2ccnc2C)cc1
Product: CCc1c(C(=O)c2ccc(-n3ccnc3C)cc2)n(C(=O)Cc2ccccc2)c(=O)n1C(=O)Cc1ccccc1
Temperature: 65 °C
Reaction time: 40 h

Procedure:
To a suspension of 4.2 g (13.2 mmol) of the product of Example I in 35 mL of dimethylformamide is added 3.1 g (19.3 mmol) of phenylacetylchloride in a dropwise fashion. The resulting mixture is stirred at 65° C. under nitrogen for 40 hours. The reaction mixture is cooled and filtered. The filtrate is diluted with 200 ml of ethyl ether and the resulting precipitate is subjected to flash chromatography on silica gel utilizing 5% methanol in methylene chloride as the eluent. The eluates are analyzed utilizing thin layer chromatography and appropriate fractions are combined and evaporated to produce the above referenced products (1) and (2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(N)c(CO)c1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-piperidine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and piperidine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylene-chloride): 3260 cm-1NH2 ; 3410 cm-1NH2 ; 2830 cm-1OCH3 ; 2800 cm-1N-alkyl; 1510 cm-1C=C; 1600 cm-1C=C.