Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:7][N:6]([CH2:8][C@@H:9]([C:11]2[C:12]([CH3:21])=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[O:15][CH2:14]3)[OH:10])[CH2:5]1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31](Cl)(=[O:33])=[O:32])=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][S:31]([NH:2][CH2:3][CH:4]2[CH2:7][N:6]([CH2:8][C@H:9]([OH:10])[C:11]3[C:12]([CH3:21])=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[O:15][CH2:14]4)[CH2:5]2)(=[O:32])=[O:33])=[CH:28][CH:29]=1)#[N:23]
Reactant: Cc1c([C@@H](O)CN2CC(CN)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(CS(=O)(=O)Cl)cc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CC(CNS(=O)(=O)Cc3ccc(C#N)cc3)C2)ccc2c1COC2=O

Procedure:
(R)-1-(4-Cyanophenyl)-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)methanesulfonamide was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from (R)-5-(2-(3-(aminomethyl)azetidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride [INTERMEDIATE 12] and (4-cyanophenyl)methanesulfonyl chloride.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].C(Cl)Cl.[CH2:14]([NH:16][S:17]([Cl:20])(=[O:19])=[O:18])[CH3:15]>O>[C:7]([N:16]([CH2:14][CH3:15])[S:17]([Cl:20])(=[O:19])=[O:18])(=[O:9])[CH3:8]
Reactant: CCNS(=O)(=O)Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCN(C(C)=O)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
197.8 parts of pyridine are introduced in the course of 20 minutes at -10° C., whilst stirring, into a solution of 196.3 parts of acetyl chloride in 1,350 parts of methylene chloride. 359 parts of ethylsulfamic acid chloride are then added at the same temperature. The reaction mixture is stirred for half an hour at 0° C. and one hour at 22° C. Thereafter, the mixture is stirred for 5 minutes with 800 parts of water at 9° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 367 parts (79% of theory) of N-acetyl-N-ethylsulfamic acid chloride, of boiling point 34°-40° C./0.11 mbar and nD25 =1.4595, are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([NH2:11])=[C:2]([NH2:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)c(N)c1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
76 g of 3,4-diaminobenzoic acid (0.5 mol) and 300 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 6 mL concentrated sulphuric acid was added slowly under stirring at room temperature. After refluxing for 3 h, the reaction was completed. After concentration under reduced pressure, the residual solution was poured into ice water. The resulting mixture was adjusted to pH 7 with saturated sodium carbonate aqueous solution. After sucking filtration and drying, 81.5 g solid was obtained. Yield: 90.4%. MS: 181(M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([OH:16])[CH2:15][CH2:14]C[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrC1C=C2C(=CC=1)[NH:23][CH:22]=C2.[Li]C(C)(C)C.CCCCC.C1(=O)CCCCC1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([OH:16])[CH2:15][CH2:14][N:23]([CH3:22])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OC1(c2ccc3[nH]ccc3c2)CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O=C1CCCCC1
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3[nH]ccc3c2)CC1

Procedure:
1-(1H-Indol-5-yl)cyclohexanol (1.95g 35%): from 5-bromo-1H-indole (5 g, 25.5 mmol) with KH (1.127 g, 28.1 mmol) in THF at −10° C., then treated with 1.7 M t-BuLi in pentane (37.5 mL, 63.8 mmol) and cyclohexanone (5.68 mL, 54.8 mmol) at −78° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([NH:1][C:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)=[O:22])[CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Reactant: Cc1ccc(C(N)CCN2CCCCC2)cc1
Product: Cc1ccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)cc1
Yield: 90.5 %

Procedure:
The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-[3-amino-3-(4-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.09 g (yield: 94%) of the subject compound as a pale yellow oily product.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)O)=[O:4].[OH-].[Na+].Cl[C:16]([O:18]CC)=[O:17]>>[C:7]1([N:5]2[C:3](=[O:4])[N:2]([CH3:1])[C:16](=[O:17])[O:18]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=O)N(O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)on(-c2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
1-Methyl-3-phenyl-3-hydroxyurea (10 g; 0.06 mole) was dissolved in a cooled (10° C.) 2 N aqueous sodium hydroxide (0.068 mole) solution (34 ml.). Ethyl chloroformate (6.3 ml; 0.066 mole) was added dropwise at 10°-15° C. with stirring. The stirring was continued for about 1/2 hour after the addition was completed. The desired compound, which precipitated as formed, was removed by filtration, washed with water and dried. The compound was recrystallized from methanol and dried under vacuum to yield solid 2-phenyl-4-methyl-1,2,4-oxadiazolidine-3,5-dione having a melting point of 98°-99° C. and the following elemental analysis as calculated for C9H8N2O3 :
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:61][C@H:58]4[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)[CH2:60][CH2:59]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CCC3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (200 mg) and 1-hydroxybenzotriazole (146 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (207 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (323 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (326 mg) and triethylamine (0.2 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 10 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent and the residue was then subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-2-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 64) (253 mg) as colorless crystals.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:13][N:14]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:15].[CH3:23][OH:24].S(=O)(=O)(O)O>O>[CH3:13][N:14]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][OH:24])[CH:18]=1)[CH3:15]
Reactant: CN(C)Cc1ccncc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CN(C)Cc1ccnc(CO)c1

Procedure:
Ammonium persulphate (102.7 g) in water (200 ml) was added over 40 minutes to a refluxing solution of 4-dimethylaminomethylpyridine (40.86 g), methanol (450 ml), water (210 ml) and concentrated sulphuric acid (30 ml). The resulting solution was refluxed for 2 hours, water (300 ml) was added and the methanol was distilled off. The cooled solution was basified and extracted with chloroform to give 4-dimethylaminomethyl-2-hydroxymethylpyridine (19.65 g) b.p. 92°-120°/0.06 mm Hg.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:21])=[C:9]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH:1]1([N:6]([CH3:22])[C:7]2[C:8]([CH3:21])=[C:9]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 3-(cyclopentylamino)-2-methyl-5-(trifluoromethyl)benzoate (1.6 g, 5.38 mmol) in acetonitrile (25 mL) was added cesium carbonate (3.5 g, 10.7 mmol) and methyl iodide (3.8 g, 26.8 mmol). The mixture was heated at 80° C. for 8 h. On completion, the reaction was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give methyl 3-(cyclopentyl(methyl)amino)-2-methyl-5-(trifluoromethyl)benzoate.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:44]1([N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([N:35]4[C:39]5=[N:40][CH:41]=[CH:42][CH:43]=[C:38]5[CH:37]=[CH:36]4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:46][CH2:45]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (417) (96 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was added tetrabutylammoniumfluoride 1M in tetrahydrofuran (0.7 mL, 0.75 mmol) at room temperature and stirring was continued for 1 h. The tetrahydrofuran was removed from the reaction mixture, diluted with ethyl acetate (50 mL) and washed with water (2×30 mL) and brine (30 mL). The organic phase was thereafter dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (418) (60 mg, crude) as an off-white sticky solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH2:15])[CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16].[CH2:17]1[CH:21]2[CH2:22][C:23](=O)[CH:19]([CH2:20]2)[CH2:18]1.[Na].C([BH3-])#N.[OH-].[Na+]>C(O)(=O)C.CCOCC.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][CH:18]3[CH2:17][CH:21]4[CH2:20][CH:19]3[CH2:23][CH2:22]4)[CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16]
Reactant: O=C1CC2CCC1C2
Reactant: COc1ccc(C2CNC(=O)N2C)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2CNC(=O)N2C)cc1NC1CC2CCC1C2
Temperature: 5 °C

Procedure:
The aniline of Example 51 (3.07 g, 17.95 mmol) is dissolved in 60 ml of glacial acetic acid and to this is added norcamphor 2.37 g, 21.54 mmol). The reaction is cooled to 5° C. and to it is added sodium, cyanoborohydride (1.36 g, 21.54 mmol). The reaction is poured onto ice and is pH adjusted to 7 with 1 normal NaOH solution. The aqueous is extracted with methylene chloride dried over MgSO4, filtered and concentrated vacuo to afford a brown oil which is flashed on SiO2 with ethyl acetate as the eluent. The appropriate fractions are combined and concentrated in vacuo to yield a white paste which is tritarted with ether to yield (0.57 g 10%) of the product as a white crystalline solid. MP=171°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6].[O:14]=[O+][O-].O=O>[Cl-].[Na+].O>[CH3:1][O:2][C:3]1([F:13])[O:14][C:4]1([C:5]([F:7])([F:6])[F:8])[C:9]([F:12])([F:10])[F:11]
Reactant: COC(F)=C(C(F)(F)F)C(F)(F)F
Reactant: O=[O+][O-]
Agent: O=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC1(F)OC1(C(F)(F)F)C(F)(F)F
Reaction time: 0.3 h
Yield: 36.5 %

Procedure:
200 g (0.88 moles) of heptafluoroisobutenyl methyl ether (purity: 93%) was charged into a three-necked flask having a capacity of 300 ml, provided with a Dimroth condenser, a stirrer and a gas feed tube, and a brine at -20° C. was passed through the Dimroth condenser. About 340 liters of ozone-containing oxygen gas (ozone concentration: 125 mg/liter) was bubbled through the ether compound at 0° C. with stirring over 11 hours 18 minutes (total ozone amount: about 0.88 moles). After the reaction, 134.8 g of the reaction product was recovered therefrom and distilled, whereby 73.0 g of perfluoro(2-methyl-1,2-epoxypropyl) methyl ether was obtained as a fraction having a boiling point of 82° to 85° C. (yield: 36.5%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(#N)C>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[O:17])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: O=Cc1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of (3-(piperidin-1-ylsulfonyl)phenyl)methanol (160 mg, 0.627 mmol) in acetonitrile (5 mL) was added dropwise over 3 minutes to a stirred, ice-cold solution of pyridinium chlorochromate (203 mg, 0.944 mmol) in acetonitrile (5 mL). On completion of the addition the mixture was allowed to attain room temperature, and then heated to reflux for 1 hour. After cooling to ambient temperature and concentrating in vacuo, the residue was then taken up with a mixture of ethyl acetate and saturated sodium bicarbonate solution. The biphasic mixture was transferred to a separating funnel and further partitioned using brine solution. The separated organic phase was passed through a short pad of silica gel, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-1-ylsulfonyl)benzaldehyde (130 mg, 0.51 mmol, 81%) which was used directly without further purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[N:17]=[C:16]([C:22]([OH:24])=O)[C:15]([OH:25])=[N:14]2.[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:22]([C:16]1[C:15]([OH:25])=[N:14][C:13]2[C:18](=[CH:19][C:20]([F:21])=[C:11]([F:10])[CH:12]=2)[N:17]=1)=[O:24]
Reactant: Clc1cccc(CC2CCCN2)c1
Reactant: O=C(O)c1nc2cc(F)c(F)cc2nc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nc2cc(F)c(F)cc2nc1O)N1CCCC1Cc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Diisopropylethylamine (0.32 mL, 1.8 mmol) was added dropwise to a mixture of 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylic acid (100 mg, 0.44 mmol), racemic 2-(3-chlorobenzyl)pyrrolidine (72 mg, 0.37 mmol) and O-HATU (210 mg, 0.55 mmol) in anhydrous DMF (2.0 mL) at room temperature under nitrogen, after which the mixture was heated to 85° C. and stirred for 4 h. The cooled mixture was directly purified by flash column chromatography on silica gel, eluting with 10% concentrated ammonium hydroxide in methanol/methylene chloride (gradient from 2:98 to 10:90), to provide a yellow solid. The residue was further purified by preparative reverse phase HPLC to provide (+/−)-[2-(3-chlorobenzyl)pyrrolidin-1-yl](6,7-difluoro-3-hydroxyquinoxalin-2-yl)methanone as a light yellow solid: 1H NMR (400 MHz, CDCl3, ˜2:1 mixture of rotamers) δ 7.72-7.63 (m, 2H, rotamers A and B), 7.38-7.21 (m, 2H, rotamers A and B), 7.10-7.03 (m, 1H, rotamers A and B), 6.90-6.79 (m, 1H, rotamers A and B), 4.63-4.56 (m, 1H, rotamers A and B), 3.89-3.82 (m, 1H, rotamer B), 3.76-3.69 (m, 1H, rotamer A), 3.56-3.47 (m, 1H, rotamers A and B), 3.33 (dd, 1H, rotamer A), 3.17 (q, 1H, rotamer B), 2.94-2.89 (m, 1H, rotamer A), 2.86-2.63 (m, 1H, rotamer B), 2.12-1.92 (m, 2H, rotamers A and B), 1.91-1.73 (m, 2H, rotamers A and B) ppm; ESI MS m/z 404 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][CH:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][N:24]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Nc1ccncn1
Product: O=C(Nc1ccncn1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-pyrimidinamine (CAN 591-54-8, 31.4 mg, 0.33 mmol) as starting materials; off white solid (50 mg, 39.8%). MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [Na][Na].[OH:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1C(=O)O
Agent: [Na][Na]
Product: CC(=O)Oc1cccc(C(=O)O)c1C

Procedure:
The disodium salt of 3-hydroxy-2-methylbenzoic acid (2) is reacted with acetic anhydride without intermediate isolation to give 3-acetoxy-2-methylbenzoic acid (3) ##STR3##
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:31]([Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:22])[C:9]=3[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: O=C1c2c(c(O)c3ncccc3c2O)C(=O)N1Cc1ccc(F)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O)(C(C)C)C(C)C

Procedure:
A solution of 7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 2 (1.039 g, 3.07 mmol) in 31 mL of DMF was stirred with imidazole (314 mg, 4.62 mmol) and triisopropylsilylchloride (TIPSCl, 0.723 mL, 3.38 mmol) under a N2 atmosphere for 1.5 days when most of the starting materials was converted to the regiospecific mono TIPS (triisopropylsilyl) protected compound. The solid bisphenol left in the reaction was filtered and recycled. The mother liquor was dried and the residue was suspended in EtOAc. The organic layer was washed with water and dried. The resulted solid 12 was carried to the next step. EI MS (m/z) 495.6 [MH+], 517.4 [M+Na].
Reaction SMILES: [H][H].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[N:25]O)[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1>C(O)C.O1CCCC1.[Ni]>[F:30][C:4]([F:3])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]([NH2:25])[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(C(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cccc21
Yield: 81.6 %

Procedure:
The procedure used in Example 6 is followed. In a 528 ml autoclave, dissolve 2.2 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 80 ml of ethanol and 80 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 412 ml. After filtration of the catalyst over Celite, concentrate under reduced pressure. In this way, we obtain 1.73 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a grey foam with the following characteristics:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:13]=2)[NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:1]1([C:7]2[CH:8]=[C:9]([NH:10][C:21]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[CH:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:13]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1cc(N2CCOCC2)cc(N2CCOCC2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ccc2c(Nc3cc(N4CCOCC4)cc(N4CCOCC4)c3)ccnc2c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
In a oven-dried flask and under a nitrogen atmosphere, were placed 3,5-bis(morpholin-4-yl)aniline (63 mg, 0.22 mmol), 4,7-dichloroquinoline (43 mg, 1 eq), (+/−) BINAP (7 mg, 0.1 eq), Cs2CO3 (99 mg, 1.4 eq), Pd2dba3 (5 mg, 0.02 eq) and 2 mL of dry 1,4-dioxane. The mixture was stirred at 90° C. for 24 h. The solution was filtered through a celite pad and evaporated. The residue was purified by preparative thin-layer chromatography (DCM/MeOH//95/5) to yield expected compound as a yellow solid (27 mg, 29% yield). m/z (ESI) 425.3 [M+H]+;