Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:10][C:5]2([CH2:11][OH:12])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1.[C:13](OC)(=[O:17])[C:14]([CH3:16])=[CH2:15]>>[CH3:1][CH:2]1[O:10][C:5]2([CH2:11][O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[O:6][CH:7]([CH3:9])[CH2:8][N:4]2[CH2:3]1
Reactant: CC1CN2CC(C)OC2(CO)O1
Reactant: C=C(C)C(=O)OC
Product: C=C(C)C(=O)OCC12OC(C)CN1CC(C)O2
Temperature: 110 °C

Procedure:
In an oven dried 300 mL round-bottom flask equipped with a reflux condenser were added 2,6-Dimethyl-tetrahydro-oxazolo[2,3-b]oxazol-7a-yl-methanol (789 g, 0.45 mol), methyl methacrylate (180.0 g, 1.80 mol), Prostab® 5415 (3.00 g, Ciba Specialty Chemicals, Basel, Switzerland) and titanium (iv) n-butoxide (6.00 g, 0.024 mol). The reaction content was heated to 110° C. for ˜8 hours GC analyses indicated ˜44% conversion. The reflux condenser was replaced with an oven dried distillation head and the distillate boiling between 60-70° C. collected. The distillation head was replaced with a reflux condenser and the reaction content heated to 120° C. for ˜4 hours, at the end of which GC analyses indicated the conversion to be ˜75%. Again the reflux condenser was replaced with a distillation head and the distillated boiling between 60-70° C. collected for ˜8 hours, at the end of which GC analyses indicated the conversion to be ˜90%. The reaction content was cooled to room temperature and the unreacted methyl methacrylate removed under vacuum and then the remaining reaction content vaccuum fractionally distilled affording four fractions:
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH:3]1[CH2:8][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:11]>CC(C)=O>[OH:11][CH:2]1[CH:7]([OH:1])[CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2
Reactant: C1CC2CC1C1OC21
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: OC1C2CCC(C2)C1O

Procedure:
Into a four-neck flask (200 ml) were fed 20.3 g (185 mmol) of 2,3-epoxynorbornane, 50 ml of water, 25 ml of acetone, and 50 μl of sulfuric acid, and the reaction mixture was refluxed at 40° C. for 6 hours. After complete reaction, an object compound was extracted with each 40 ml of diethylether five times, and the resultant extract was washed with saturated salt solution (braine), and was dried with sodium sulfate to obtain 2,3-dihydroxynorbornane.
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([NH:7][C:8]([C:10]1[S:35][C:13]2[N:14]=[C:15]([NH2:34])[N:16]=[C:17]([C:18]3[CH:23]=[C:22]([O:24]CC4C=CC=CC=4)[C:21]([Cl:32])=[CH:20][C:19]=3[Cl:33])[C:12]=2[CH:11]=1)=[O:9])[CH3:6].CO>ClCCl>[CH2:5]([NH:7][C:8]([C:10]1[S:35][C:13]2[N:14]=[C:15]([NH2:34])[N:16]=[C:17]([C:18]3[CH:23]=[C:22]([OH:24])[C:21]([Cl:32])=[CH:20][C:19]=3[Cl:33])[C:12]=2[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron trichloride solution (1M in dichloromethane) was added to a suspension of 2-Amino-4-(5-benzyloxy-2,4-dichlorophenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in dichloromethane, at −78° C. under a nitrogen atmosphere. The suspension was stirred for ˜3 hrs at room temperature. The suspension was cooled in ice and methanol added, the resulting mixture was stirred for ˜1 hr. and concentrated to a yellow green solid. The solids were suspended in aqueous sodium acetate (10%) and extracted with ethyl acetate. The extracts were washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale brown solid, washed with hexane dried in vacuo.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c1

Procedure:
The title compound was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-methoxyphenylboronic acid (9 mg, 0.06 mmol). MS (ESI+) calcd mass for C18H15N5O3S2 413.061631, found 413.062021.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) and mixing the mixture under ice cooling was added dropwise with a solution of 3-(4-hydroxyphenyl)propionic acid (16.6 g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, warmed to room temperature, and further stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with diethyl ether (200 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1, 17.95 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:29][NH:30][CH3:31]>CN(C)C=O>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][N:30]([CH3:31])[CH3:29])[CH:8]=[CH:7][CH:6]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CCl)c4)sc23)c(F)c1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 60 °C
Yield: 48 %

Procedure:
To a suspension of the chloride 148 (3.8 g, 8.42 mmol) in dimethylformamide (42 mL) was added dimethylamine (8.4 mL, 16.84 mmol) and the reaction mixture was heated to 60° C. After few hours the reaction was complete and the dimethylformamide was evaporated. The residue was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to afford title compound 149 as a yellow solid (1.71 g, 48% yield). MS (m/z): 424.0 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:35]([O:37][CH3:38])=[O:36])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9].[CH3:39]I>C(#N)C.C(OCC)(=O)C>[CH3:38][O:37][C:35]([C@@H:2]([NH:1][CH3:39])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:9])=[O:36]
Reactant: CI
Reactant: COC(=O)[C@@H](N)CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN[C@@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Yield: 26.7 %

Procedure:
A solution of 1.90 g of p-nitrobenzyl (R)-2-[[[2-amino-2-methoxycarbonyl-ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate and 0.91 g of methyl iodide in 5 ml of acetonitrile was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 0.52 g of p-nitrobenzyl (R)-2-[[[2-methoxycarbonyl-2-(methylamino)ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]2[O:31][CH2:30][CH2:29][O:28]2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:29][O:28][CH:27]([O:31][CH3:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:7])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCCCCCC2OCCO2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(CCCCCOc1cccc(C(N)c2ccccc2)c1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl((3-((5-(1,3-dioxolan-2-yl)pentyl)oxy)phenyl)(phenyl)-methyl)carbamate (0.483 g, 1.10 mmol) in methanol (4 mL), was added hydrogen chloride in dioxan (4 M, 4 mL, 16 mmol). The reaction was stirred at ambient temperature for 7 hours. The solvent was evaporated at reduced pressure, and the residue loaded onto an SCX-2 cartridge. The cartridge was eluted with methanol (eight column volumes) followed by ammonia/methanol. Fractions containing the product were combined and evaporated at reduced pressure to afford the title compound as a colourless oil (0.322 g, 85%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[Br:12]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:12][C:8]1[C:7]([O:10][CH3:11])=[CH:6][C:4]([NH2:5])=[C:3]([Cl:2])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.5 %

Procedure:
A stirred solution of 9.7 g (0.050 mole) of 2-chloro-5-methoxyaniline hydrochloride in 120 mL of acetic acid was cooled to 15° C. To this cold mixture was added 4.0 g (0.025 mole) of bromine. After complete addition, the mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was poured into ice water. To the resultant mixture was added a solution of 2.0 g (0.05 mole) of sodium hydroxide in 10 mL of water. This mixture was extracted with 200 mL of diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 7.3 g of 4-bromo-2-chloro-5-methoxyaniline as a solid, mp 40°-41° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:25])[CH:7]=[C:8]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[CH3:26][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:11]=[C:10]2[C:5]=1[C:6](=[O:25])[CH:7]=[C:8]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:9]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Cc1cc(N2CCOCC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (68.3 mg, 0.189 mmol) and morpholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80° C. for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 5-methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH+: 413.4, Rf=0.49 (EtOAc).
Reaction SMILES: [CH3:1]O[Na].[NH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:1][NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: CO[Na]
Reactant: N#Cc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 220.8 %

Procedure:
To methanol (45 ml) is added CH3ONa (4.05 g, 75 mmol, 0.5 eq), and to this solution is dropwise added a solution of 3-aminobenzonitrile (17.70 g, 150 mmol, 1.0 eq) in methanol (60 ml). The mixture is stirred for 0.5 h. Then the reaction mixture is poured into a solution of polyformaldehyde (6.30 g, 210 mmol, 1.4 eq) in methanol (90 ml). After stirring at room temperature for 5.0 h, NaBH4 (content 96%) (6.00 g, 150 mmol, 1.0 eq) is added in portions. The mixture is stirred at room temperature for 10 min, and then is refluxed at elevated temperature for 10 min. The reaction mixture is cooled under ice-water bath, and added with 10% NaOH (aq) (90 ml) and stirred for 5 min. Methanol is removed under reduced pressure, and the left aqueous solution is extracted with ethyl acetate (150 ml*2). The organic phases are combined, washed with saturated brine twice, dried over anhydrous sodium sulfate, and concentrated to yield 21.89 g of brown oily crude product. The crude product is purified by neutral alumina column chromatography (eluent: petroleum ether/CH2Cl2=2/1) to give a light yellow oily pure product (17.34 g, yield: 87.6%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]2[CH2:7][CH2:8][NH:9][CH:21]([CH2:20][CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:14][CH:15]=3)[C:6]=12
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(I)cn1CCN
Product: Cc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 110° C.; 8 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (373.8 mg; 1.489 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (301 mg; 1.489 mmol) afforded 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=25/1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1C(F)(F)F

Procedure:
4-hydroxy-2-trifluoromethyl-benzoic acid (5.0 g, 24.0 mmol) was dissolved in MeOH (50 mL) and a catalytic quantity of sulfuric acid was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[O:16][C:15]([CH3:23])([CH3:22])[C:14]3=[O:24])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]3[C:14](=[O:24])[C:15]([CH3:23])([CH3:22])[O:16][C:17]([CH3:20])([CH3:21])[C:18]=3[O:19][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-2,2,6,6-tetramethylpyran-3,5-dione (49 mg, 0.125 mmol) in dichloromethane (2 ml) is added triethylamine (87 μl, 0.625 mmol), followed by pivaloyl chloride (78 μl, 0.625 mmol), and the reaction mixture is stirred at room temperature for 17 hours. The reaction mixture is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 4-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:36])#[N:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:42][O:41][C:37](=[O:40])[CH2:38][N:13]1[C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:36])[CH:5]=2)([OH:11])[CH3:10])=[CH:16][N:15]=[CH:14]1
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorophenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol from Step F (200 mg, 0.42 mmol), methyl glycolate (35 mg, 0.39 mmol), and N,N-diisopropylethylamine (65 mg, 0.51 mmol) in dry CH2Cl2 (10 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (110 mg, 0.39 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL) and the solution was heated to reflux for 1 hr, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with 4% MeOH—0.4% NH4OH in CHCl3, to yield the titled product as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([NH:13][C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10]1)(=[O:8])C1C=CC=CC=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=C=O>>[O:24]=[C:18]1[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[C:15]2[C:20](=[N:21][CH:22]=[CH:23][C:14]=2[NH:13][CH:11]2[CH2:10][N:9]([C:1]([NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:8])[CH2:12]2)[NH:19]1
Reactant: O=C(c1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 359 using the amine intermediate from example 366 and isocyanato benzene to provide 367. LC-MS (M+H=386, obsd.=386).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(Cl)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-chlorophenyl isothiocyanate (11 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 14 in Table 1, below (8.2 mg, 21%). 1H NMR (300 MHz, CDCl3) δ 9.03 (s, 1H), 8.51 (s, 1H), 7.10 (s, 1H), 7.04-6.93 (m, 2H), 6.90-6.84 (m, 1H), 4.14 (q, J=6.90 Hz, 2H), 4.00-3.74 (m, 8H), 1.23 (t, J=7.01 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([N:17](CC)[CH2:18]C)C.Cl.CNC>C(Cl)(Cl)Cl>[CH3:15][N:17]([CH3:18])[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)=[O:13]
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of the resultant 2-chloroquinoline-4-carbonyl chloride in chloroform (50 ml) was treated with triethylamine (4.4 ml, 31.5 mmol), followed by solid dimethylamine hydrochloride (1.28 g, 15.7 mmol). The reaction stirred for one hour at ambient temperature at which time it was washed with 10% aqueous sodium hydroxide and 15% aqueous citric acid. Drying over anhydrous sodium sulfate, followed by evaporation under reduced pressure gave 2-chloroquinoline-4-carboxylic acid dimethylamide (1.5 g, 40%) as a tan solid. [M+H]+ 235.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=[CH2:19]>CC(C)=O>[C:17]([O:22][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: C=C(C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCc1ccc(O)c(C=O)c1

Procedure:
5-Chloromethylsalicylaldehyde (34 g) (prepared by the method of Angyal et al., J. Chem. Soc. 2141, (1950)) was added to a stirred mixture of acetone (250 ml), sodium hydrogen carbonate (33.6 g), and methacrylic acid (34.4 g)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1ccc(OC(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(OC(F)(F)F)cc1Cl

Procedure:
The preparation takes place in analogy to Example 6A from the compound from Example 3A with subsequent treatment with 4N hydrochloric acid in dioxane.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopentanol (2.28 mL, 25.1 mmol) in THF (10 mL) was added dropwise with ice cooling to a suspension of sodium hydride (60% dispersion in oil, 1.054 g, 26.3 mmol) in THF (20 mL). The mixture was stirred with ice cooling under nitrogen for 30 minutes, and then a solution of ethyl bromoacetate (2.66 mL, 23.95 mmol) in THF (10 mL) was added dropwise, followed by a THF (10 mL) rinse. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. Water (60 mL) was added cautiously, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined extract was washed with saturated brine (40 mL), dried (MgSO4), filtered, and concentrated to provide the title compound, used directly in the next step.