Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1([CH3:17])[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C:14]3([CH3:17])[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Solvent: CC#N
Product: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)c(F)c32)CC1

Procedure:
To 1.24 g (4.27 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.77 (4.27 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 0.63 g (4.27 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether. The solids were dissolved in 10 ml of acetic acid at 100° C. and 2 ml of 3N hydrochloric acid was added. This mixture was heated at 100° for four hours, concentrated, triturated with 2-propanol, and the solid filtered, washed with ether, and dried (24 hours, 80° C., 125 mmHg) to give 0.90 g of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3quinolinecarboxylic acid as the hydrochloride salt, mp >300° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH:5]([OH:7])=[O:6].[CH:8](O)=[O:9]>C(OC(=O)C)(=O)C>[CH3:1][C:2]([CH:4]1[C:8](=[O:9])[O:7][C:5]1=[O:6])=[O:3]
Reactant: O=CO
Reactant: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C1C(=O)OC1=O
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To acetic anhydride (350 ml) at 0° acetone dicarboxylic acid (200 g, 1.37 mole) was added slowly over 1/2 hour with vigorous stirring. After stirring 3 hours, a white solid was filtered and washed with ether (100 ml). Drying the solid 3 hours at 50° C. (0.1 mm) gave acetone dicarboxylic acid anhydride (149 g), m.p. 134°-136° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:16])OCC)=[CH:7][CH:6]=1)([O-:4])=[O:3].CO[CH:19](OC)[CH2:20][NH2:21]>C(O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[NH:16][CH:19]=[CH:20][N:21]=2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: COC(CN)OC
Reactant: CCOC(=N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Temperature: 60 °C
Yield: 51.6 %

Procedure:
To a solution of ethyl 2-(4-nitrophenyl)-acetimidate hydrochloride (3.5 g, 14.3 mmol) in ethanol (15 mL) was added amino acetaldehyde dimethyl acetal (1.87 mL, 17.2 mmol) and the reaction heated at reflux for 18 h. The reaction mixture was concentrated which was mixed with 2N hydrochloric acid (30 mL) and heated to 60° C. for 18 h. The solvent was evaporated, diluted with water and extracted with ethyl acetate. The organic layer was separated, the aqueous layer basified with sodium carbonate and extracted with chloroform (×2). The combined chloroform extracts was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain 2-(4-nitro-benzyl)-1H-imidazole (1.5 g, 51%) as a brown solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2.[OH-].[Na+]>OS(O)(=O)=O>[Br:8][C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cccnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Br)c2cccnc12
Temperature: 5 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
NBS (13.7 g, 76.9 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) solution of 8-methyl-quinoline (10 g, 69.9 mmol) in concentrated H2SO4 (150 mL). The reaction mixture was stirred for 18 h at 5° C., diluted in ice (300 mL) and basified by addition of an aqueous solution of NaOH (10% wt). The resulting white solid was collected by vacuum filtration, rinsed with water, and dissolved in DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 15.2 g of the title compound as a beige solid: ESI-MS: 221.9/223.9 [M+H]+; tR=3.59 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:38])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfinyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (1.4 g), prepared as in Preparation II above, in dichloromethane (300 ml), cooled to 0° C., was added m-chloroperbenzoic acid (660 mg). After stirring for 24 hours, the reaction mixture was washed with aqueous NaHCO3, dried over MgSO4, and evaporated to dryness. The residue was chromatographed on silica gel (1:1 dichloromethane/ethyl acetate) and recrystallized from dichloromethane/hexane to give (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 200°-202° C., [α]D =-126° (C=0.031, methanol) [93% enantiomeric excess (ee)].
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].[CH:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[O:12][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=1)[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: C=CCc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1

Procedure:
The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12].N[C:14]1C(Cl)=NC(CC)=NC=1NC>>[Cl:1][C:2]1[N:10]=[C:9]([CH2:11][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:12]
Reactant: CCc1nc(Cl)c(N)c(NC)n1
Reactant: Cc1nc(Cl)c2ncn(C)c2n1
Product: CCc1nc(Cl)c2ncn(C)c2n1
Yield: 65 %

Procedure:
This was prepared in a manner similar to that described in Example 27 for 6-chloro-2,9-dimethylpurine, except that 5-amino-4-chloro-2-ethyl-6-methylaminopyrimidine was used as the starting material, and the final product was purified by chromatography. The title compound was obtained in 65% yield. NMR (CDCl3, δ from TMS): 1.4 (t, CH2CH3), 3.06 (q, CH2CH3), 3.88 (s, NCH3), 8.00 (s, H8).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][CH2:40][Cl:41].O>CN(C)C=O>[Cl:41][CH2:40][CH2:39][CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: ClCCCBr
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(O)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Propyl 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (240 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Potassium carbonate (822 mg) and 1-bromo-3-chloropropane (0.29 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (230 mg, yield 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:29]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>ClC(Cl)C.C(O)(=O)C>[CH:24]1([CH2:29][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCCC1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CCCC3)cn(C)c12
Yield: 30.6 %

Procedure:
The product from Example 44A (55 mg, 0.166 mmol) and cyclopentanecarbaldehyde (58.64 mg, 0.597 mmol) in dichloroethane/acetic acid (1:1, 1 mL) was heated in a sealed tube at 60° C. for 24 hours, cooled, and concentrated. Purification by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.021 g, 31%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(OC)nc2)cc1
Yield: 61.4 %

Procedure:
According to Scheme 4 Method B: The title compound was prepared according to Example 1 Step 3 from 5-bromo-2-methoxypyridine (12.1 mmol, 2.30 g) and 4-methoxyphenylboronic acid (18.2 mmol, 2.76 g), then purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/MeOH 100/0 to 95/5), yielding the title compound (1.60 g, 61%).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:36])[CH2:21][CH2:22][CH2:23][C:24]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:46]N1C(=O)C(C)(C)N(Br)C1=O>CCCCCC>[Br:46][CH:14]1[CH:13]=[C:12]2[C@:41]([CH3:44])([CH2:42][CH2:43][C@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11]2)[C@@H:40]2[C@@H:15]1[C@H:16]1[C@:37]([CH3:45])([CH2:38][CH2:39]2)[C@@H:19]([C@H:20]([CH3:36])[CH2:21][CH2:22][CH2:23][C:24]([O:27][C:28](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:26])[CH3:25])[CH2:18][CH2:17]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCCCCC
Product: C[C@H](CCCC(C)(C)OC(=O)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3C(Br)C=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
To a boiling solution of 2.02 gm. of 3β,25-dibenzoyloxycholest- 5-ene (3.3 mmole) in 90 ml. of hexane, and 720 mg. (2.52 mmole) of dibromo-dimethylhydantoin. Reflux for 30 minutes, cool to room temperature, filter and wash with 2 ml. of carbontetrachloride. Concentrate the combined filtrate to dryness to obtain the title product. (2.3 gm.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.Cl.[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)(Cl)Cl>[Br:17][C:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:19]1[CH2:20][CH2:21][N:22]([C:12](=[O:14])[C:11]([C:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[NH:10][CH:9]=2)=[O:15])[CH2:23][CH2:24]1
Reactant: BrC(=C1CCNCC1)c1ccccc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(C(=O)N1CCC(=C(Br)c2ccccc2)CC1)c1c[nH]c2c(Cl)ccnc12
Reaction time: 48 h

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (191 mg, 0.87 mmol), 4-(bromophenylmethylene)-piperidine hydrochloride salt (245 mg, 0.85 mmol) and diisopropylethylamine (440 mg, 3.4 mmol) in chloroform (10 mL) was added BOPCl (261 mg, 1.02 mmol). The reaction solution was stirred two days, treated with additional diisopropylethylamine (440 mg, 3.4 mmol) and BOPCl (130 mg, 0.50 mmol) and stirred three days. The reaction mixture was concentrated, dissolved into MeOH and purified by preparative HPLC to yield title compound shown (293 mg, 0.64 mmol, 75%) as a white solid.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2-(N-benzylmethylamino)methyl-6-methoxy-1-phenyl-3,4-dihydronaphthalene (0.375 g; prepared according to Process 1) in dichloromethane (15 cm3) being stirred at 0° C. under nitrogen was added a solution of boron tribromide in dichloromethane (1 M, 2.2 cm3). The resulting solution was stirred at 0° C. for 30 min and then at room temperature for 1.5 h. Methyl alcohol (5 cm3) was added and the solvents were removed under reduced pressure. The residue was treated with hydrochloric acid (6 M, 2 cm3) and dichloromethane (4 cm3) and stirred at room temperature for 30 min. The mixture was basified with potassium carbonate, diluted with water (50 cm3), and extracted with dichloromethane (3×25 cm3). The combined organic extracts were washed with brine (25 cm3), dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by column chromatography [silica, eluting with ethyl acetate-heptane (1:1)] to yield the title compound (0.202 g) as a brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][C@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47]>C(Cl)Cl>[ClH:47].[ClH:47].[ClH:47].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]([CH2:30][C@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH:16]=2)=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2C[C@H]2CCCCN2C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC[C@@H]1Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
Dissolve (R)-benzyl 2-((2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate (2.6 g, 0.004 mol, 1.0 eq) in DCM (15 mL). Cool the reaction mass to 0° C. and add HCl (4.0 M in dioxane, 5 mL, 0.020 mol) drop-wise. Allow the reaction to warm up to RT and stir for 16 h. After completion, concentrate the reaction and co-evaporate with methanol (5×20 mL) under high vacuum to get 2.2 g (83.6%) of the title compound. (ES+): m/z=545 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Clc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(-c2nccc3ccccc23)c(F)c1
Temperature: 25 °C

Procedure:
2,4-difluorophenylboronic acid (Aldrich Chemical Co., 13.8 g, 87.4 mmol), 1-chloroisoquinoline (Adrich Chemical Co., 13 g, 79.4 mmol), tetrakistriphenylphosphine palladium(0) (Aldrich, 3.00 g, 2.59 mmol), potassium carbonate (EM Science, 24.2 g, 175 mmol), water (300 mL), and dimethoxyethane (Aldrich, 300 mL) were allowed to stir at reflux for 20 h under N2, after which time the mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted with 3×150 mL of diethyl ether, and the combined organic fractions were dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude material was chromatographed on a silica gel column, first by eluting the catalyst byproduct with 4:1 hexanes/CH2Cl2, and finally the product was eluted with CH2Cl2/MeOH (9.5:0.5, product Rf=0.7). The pure product fractions were collected and dried in vacuo, to afford 17.7 g (92% isolated yield) of a light yellow solid, >95% pure NMR spectroscopy. 1H NMR (CDCl3, 296 K, 300 MHz): δ 8.61 (1H, d, J=5.7 Hz), 7.89 (1H, d, J=8.2 Hz), 7.67–7.85 (3H, m), 7.52–7.63 (2H, m), 6.95–7.12 (2H, m) ppm. 19F NMR (CDCl3, 296K, 282 MHz) δ −109.01 (1F, brs), −109.87 (1F, d, JF-F=8.5 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:17]#[N:18])=[C:8]([CH3:19])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:21]>CCOCC>[CH2:1]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:17]#[N:18])=[C:8]([CH:19]=[O:21])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)c(C#N)cc1C(=O)OCC
Reactant: O=[Se]=O
Solvent: CCOCC
Product: CCCCNc1nc(C=O)c(C#N)cc1C(=O)OCC

Procedure:
130.5 g of 2-butylamino-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (0.5 mol) are dissolved in 400 ml of diethyleneglycoldimethyl ether. 61.1 g of selenium dioxide are added and the mistrue is heated at reflux temperature for 1 hour. The mixture is filtered hot and evaporated to dryness. The resulting yellow oil of 2-butylamino-5-cyano-6-formyl-3-pyridine-carboxylic acid, ethyl ester is crystallized with diethyl ether. Yield 95 g (69%); m.p. 81°-83° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>ClCCl>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:30][C:31]4[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCc4ccc(C(F)(F)F)o4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 2-(Bromomethyl)-5-(trifluoromethyl)furan (252 mg, 1.1 mmol) was added in portions over a period of 30 minutes. The reaction mixture was stirred for 1 hour and then the heat source was removed. The reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-15 CMA in chloroform 700 mL and then with 15% CMA in chloroform over 200 mL. The resulting solid was recrystallized from acetonitrile to provide 125 mg of 2-ethyl-7-{[5-(trifluoromethyl)furan-2-yl]methoxy}thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 152-154° C. MS (ESI) m/z 394 (M+H)+; Anal. calcd for C18H14F3N3O2S: C, 54.96; H, 3.59; N, 10.68. Found: C, 54.90; H, 3.46; N, 10.52.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:6]([C:14]([O:16][CH3:17])=[O:15])=[N:7][C:8]([N+:11]([O-])=O)=[CH:9][N:10]=1>C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-].C(O)(=O)C>[NH2:11][C:8]1[N:7]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:5]([O:4][CH3:3])=[N:10][CH:9]=1
Reactant: COC(=O)c1nc([N+](=O)[O-])cnc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)cnc1OC
Yield: 71.8 %

Procedure:
At room temperature and under a pressure of 1 atmosphere, hydrogen gas was introduced into a mixture of 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate, 480 mL of acetic acid and 1.2 g of lead-poisoned palladium-calcium carbonate until the mixture became showing no further absorption of hydrogen. After filtering off insoluble matter from the reaction mixture, the solvent was removed under reduced pressure, and the solid product thus obtained was washed with ethyl acetate and diethyl ether. Thus, 15.0 g of methyl 6-amino-3-metoxy-2-pyrazinecarboxylate was obtained as a solid product. Furthermore, the solvent was removed from the filtrate under reduced pressure to obtain a solid product, and the solid product was washed with ethyl acetate to obtain 2.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1.Cl>ClCCl>[CH:12]1([C:16]([C:8]2[CH:9]=[CH:10][C:5]([OH:11])=[CH:6][CH:7]=2)=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCC1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCC1
Reaction time: 0.75 h
Yield: 51.7 %

Procedure:
Aluminum chloride (1.59 g, 11.9 mmol) was added to a dichloromethane (10 mL) solution of phenol (1.03 g, 10.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 45 minutes. Cyclobutanecarboxylic acid chloride (1.33 mL, 11.7 mmol) was added dropwise to the obtained reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4 hours. Further, aluminum chloride (1.58 g, 11.8 mmol) was added at room temperature, and the mixture was stirred. The aluminum chloride was confirmed to be dissolved thoroughly, and then the mixture was stood still overnight. The reaction mixture was added to hydrochloric acid under ice cooling, and the mixture was subjected to extraction once with ethyl acetate. The organic layer thus obtained was washed with brine twice, and then was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10->80:20, v/v) to give the title compound (993 mg, yield: 51%).