Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC)ncn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 73 mg of diethylamine, followed by stirring at a bath temperature of 50° C. for 4 hours. Then, 73 mg of diethylamine was further added, followed by stirring at a bath temperature of 50° C. for 5.5 hours. Then, 146 mg of diethylamine was further added, followed by stirring at a bath temperature of 40° C. for 6 hours. The reaction mixture was left for cooling to room temperature, diluted with ethyl acetate, and washed three times with an aqueous sodium chloride solution. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 136 mg of 4-(2-butynyloxy)-6-(N,N-diethylamino)pyrimidine (the present compound (144)).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:42]1[CH2:43][CH2:44][CH:39]([C:37]2[O:36][N:35]=[C:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[N:38]=2)[CH2:40][CH2:41]1)=[O:7]
Reactant: CC(C)CCC(=O)O
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
86 mg (2 eq.) of 4-methylvaleric acid, 141 mg (2 eq.) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) and 207 μl (4 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride were then added to the reaction medium, which was then stirred at room temperature for 24 hours. The reaction medium was evaporated under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3×30 ml), with aqueous 1N hydrochloric acid solution (3×30 ml) and with saturated aqueous NaCl solution (30 ml) and then dried over MgSO4 and concentrated under reduced pressure to give 102 mg (83%) of the expected compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].C[O:17][C:18](=O)[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]Br.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[C:18](=[O:17])[N:15]([C@H:9]1[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)[CH2:11][CH2:10]1)[CH2:26]2
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (1.757 mmol, 1 eq) was added to a solution of 2-bromomethyl-6-chlorobenzoic acid methyl ester (1 eq) in toluene (5.4 ml) and triethylamine (2.1 eq). The reaction mixture was refluxed for 16 h. Then sat. NaHCO3 solution (20 ml) and ethyl acetate (50 ml) were added to the mixture and the phases were separated. The organic phase was extracted with 0.05 N HCl solution and sat. NaCl solution and dried over MgSO4. Concentration of the organic phase yielded the crude product, which was purified by column chromatography (ethyl acetate:cyclohexane, 3:1). The desired product (R)-methyl 3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (D-01) was thus obtained. Yield: 72%
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]([NH2:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:27][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 68.7 h
Yield: 98.7 %

Procedure:
2-Nitrobenzenesulfonyl chloride (2.50 g) was added to a methylene chloride solution (30 ml) containing benzhydrylamine (1.87 g) and triethylamine (1.58 g) under ice cooling, followed by stirring for 3.3 hours under ice cooling and for 68.7 hours at room temperature. Water (40 ml), 6 N hydrochloric acid (2 ml) and methylene chloride (10 ml) were added to the reaction mixture, followed by extraction and solution separation, and the aqueous layer was extracted again with methylene chloride (10 ml). The resulting extract was dried over sodium sulfate, filtered, concentrated and further dissolved again in ethyl acetate (70 ml), followed by washing with water (20 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain N-(2-nitrobenzenesulfonyl)benzhydrylamine (3.71 g; yield: 98.7%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH:16]4[CH2:18][CH2:19][CH2:20][CH2:21][CH:15]4[CH2:14][CH2:13][C:12]=3[C:11]([CH3:22])=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:22][C:11]1[C:12]2[CH2:13][CH2:14][CH:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:16]3[C:17]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-n2nc(C)c3c2C2CCCCC2CC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nn(-c2ccc(O)cc2)c2c1CCC1CCCCC21
Temperature: -40 °C
Reaction time: 2 h

Procedure:
1-(4-Methoxyphenyl)-3-methyl-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[g]indazole (0.44 g, 1.49 mmol) was dissolved in dichloromethane (4 mL) and cooled to −40° C., and boron tribromide (0.5 mL) was added. The reaction was stirred for 2 hours, then carefully quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic extracts were washed with brine, dried over MgSO4, and concentrated. The reaction was assumed to be quantitative. LC-MS (C18H22N2O calculated 282) m/z 283 (M+H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([S:16]([NH:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
HCl (20 ml, 4M solution in dioxane) was added in one portion to a stirred solution of 4-(4-Nitro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.92 g, 4.9 mmol) in dioxane (5 ml) and the suspension was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum and the resulting solid was collected by filtration, washed with TBME (3×100 ml) and dried under vacuum to give the title compound (1.4 g, 100% yield) as a white solid. Tr=0.91 min m/z (ES+) (M+H+) 286.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O>[F:17][C:4]1[CH:3]=[C:2]([CH3:18])[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(F)cc(Br)c3n21
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3=O
Temperature: 110 °C

Procedure:
1.2 g (R)-6-bromo-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one was dissolved in 12 ml N,N-dimethylformamide under argon. 0.45 gTetrakis-(triphenylphosphine)palladium, 1.56 g potassium carbonate and 0.55 ml trimethylboroxine were added. The mixture was heated overnight at 110° C., allowed to cool to room temperature, filtered over dicalite and washed through with tetrahydrofuran. The solvents were evaporated under reduced pressure and the residue purified by column chromatography on silica gel (1:1 to 1:3 toluene/ethyl acetate) to afford the title product as an off-white solid. Yield: 300 mg ISP-MS: m/e 233.1 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1
Reactant: COC(=O)CBr
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.70 g, 1.80 mmol) in dimethylformamide (14 ml) was added cesium carbonate (2 g) followed by methyl bromoacetate (2551 μl, 2.70 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and water. The aqueous phase was extracted with three portions of ethyl acetate, and the combined organic phases dried over magnesium sulfate and concentrated in vacuo to provide a yellow solid. No further purification was required. Yield: 0.51 g, 61%; LCMS method: basic, RT: 3.77 min, MI: 462 [M+1].
Reaction SMILES: [CH3:1][C:2]1[N:7]2N=N[N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:27][O:28][N:29]=[C:30]([CH3:32])[CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:3]=1[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[NH2:10][C:6]1[C:5]2[N:11]=[C:12]([CH2:27][O:28][N:29]=[C:30]([CH3:31])[CH3:32])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:3]([CH3:33])=[C:2]([CH3:1])[N:7]=1
Reactant: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A mixture of N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide (1.9 g, 4.2 mmol), triphenylphosphine (2.2 g, 8.4 mmol), and 1,2-dichlorobenzene (40 mL) was heated at 125° C. for 2 days. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and 1 M aqueous hydrochloric acid (20 mL) and heated at 40° C. for 6 hours. The reaction was allowed to stand at room temperature overnight and a white precipitate formed that was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (10 mL). The aqueous layer was extracted with chloroform (3×10 mL). The organic layers were combined, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 10-35% CMA in chloroform, where CMA is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide). The appropriate fractions were combined and concentrated under reduced pressure. The solid was triturated with ethyl acetate and was isolated by filtration, washed with ethyl acetate, and dried under vacuum at 50° C. overnight to provide 0.85 g of N-{4-[4-amino-6,7-dimethyl-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]butyl}benzamide as a white powder, mp 206.0-208.0° C. Anal. Calcd for C23H30N6O2.0.06 CHCl3: C, 64.46; H, 7.05; N, 19.56. Found: C, 64.31; H, 7.06; N, 19.55.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][OH:12].[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:16][C:14]1([C:13]([OH:18])=[O:17])[C:1]2=[C:9]3[C:4]([CH:3]=[C:2]2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH2:8]3
Reactant: CCOC(=O)C(C)=O
Reactant: OCCC1=Cc2ccccc2C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(C(=O)O)OCCC2=CC3=CC=CCC3=C21

Procedure:
Indene-2-ethanol (3.5 g) described in Examples 474 and 476, is treated with ethyl pyruvate (4 g) and boron trifluoride-etherate (2 ml) in benzene (50 ml) according to the procedure of Example 2 to yield the title compound, m.p. 171°-173° C., νmaxnujol 1720 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Brc1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccncc2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), 4-bromopyridine (0.316 g, 2 mmol), K3PO4 (0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-pyridin-4-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (30 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 8.95 (d, 2H), 8.21 (d, 2H), 7.65 (d, 1H), 7.21 (s, 1H), 7.21 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.95-3.9 (m, 1H), 3.6-3.50 (m, 2H), 3.25 (m, 1H), 3.2 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=[O:5])C.[O-]CC.[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.[OH-].[Na+]>[O:16]1[CH2:15][CH2:14][CH:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)[C@H]1CC[C@H](OC2CCOCC2)CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](OC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of cis/trans-4-(tetrahydro-pyran-4-yloxy)-cyclohexanecarboxylic acid ethyl ester (7:1) (0.385 g, 1.50 mmol) and sodium ethoxide (0.204 g, 3.00 mmol) in dry toluene (1.5 ml) was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with 1,4-dioxane (7.5 ml) and 2 M aqueous sodium hydroxide solution (7.5 ml). Stirring for 16 h was followed by partitioning between 2 M aqueous sodium hydroxide solution (50 ml) and dichloromethane. The layers were separated. The aqueous layer was extracted with one portion of dichloromethane. The combined organic layers were washed with two 50 ml portions of 2 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 1 by addition of concentrated hydrochloric acid solution (100 ml). The aqueous layer was extracted with two 150-ml portions of dichloromethane. The combined organic layers from the acidic extraction were dried over anhydrous sodium sulfate and dried in vacuo to give the title compound (0.358 g, 93%) as yellow solid. MS m/e: 229 (M+H+)
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]([C:16]([O:18]C)=[O:17])=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O>[CH:1]1([CH:7]([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C1CCCCC1)n1cncc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C1CCCCC1)n1cncc1C(=O)O
Yield: 64.7 %

Procedure:
A solution of 24 parts of methyl 1-(1-cyclohexylbutyl)-1H-imidazole-5-carboxylate in 50 parts of a sodium hydroxide solution 50% and 50 parts of water was stirred for 1.5 hours at reflux temperature. After cooling, the mixture was poured into 500 parts of water and the whole was neutralized with concentrated hydrochloric acid. The precipitated product was filtered off and dried, yielding 12.8 parts (64.7%) of 1-(1-cyclohexylbutyl)-1H-imidazole-5-carboxylic acid; mp. 201.7° C. (compound 27).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[NH:5][C:4]=2[N:3]=1.[CH:22]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23]1.[H-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[N:5]([CH2:26][CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:3]=1
Reactant: BrCC1CCC1
Reactant: C[C@H]1Nc2nc(Cl)ncc2N(c2cccc(C#N)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1CC1CCC1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirred solution of 3-[(7R)-2-chloro-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile (120 mg, 0.4 mmol) in anhydrous DMF (3 ml) was added cyclobutyl methyl bromide (119 mg, 0.8 mmol) at 0° C. under nitrogen. To the resulting solution was added sodium hydride (32 mg of 60% dispersion in oil, 0.8 mmol) at 0° C. The reaction was then allowed to warm up to rt in 20 min and then heated at 50° C. for 3 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried (Na2SO4) and evaporated to give a crude residue, which was then purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to give desired product (Yield: 41%). 1HNMR (300 MHz, CDCl3) δ 1.50 (d, J=6.9 Hz, 3H), 1.78-1.94 (m, 4H), 1.96-2.21 (m, 2H), 2.68-2.87 (m, 1H), 3.17 (q, J=6.9 Hz, 1H), 4.22-4.36 (m, 2H), 7.10 (s, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.66-7.78 (m, 1H) and 7.79-7.81 (m, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]3[CH2:19][CH2:20][CH2:21][C:14]=3[C:13]=2[CH:22]=1)(=O)=O.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:24][O:23][C:10]1[C:9]([O:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:22][C:13]2[C:14]3[CH2:21][CH2:20][CH2:19][C:15]=3[C:16](=[O:18])[O:17][C:12]=2[CH:11]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCOS(C)(=O)=O)CCC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 90 %

Procedure:
Method B (24 h at 80° C.); starting materials: 2,3-dihydro-8-[2-(methanesulfonyloxy)ethoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 81) and 1-phenylpiperazine; yield 90%; fusion point 155°-156° C. (from isopropanol). Fumarate: method E; yield 94%; fusion point 182°-185° C. (from acetone).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]2[CH2:24][N:23]([CH3:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20]2)[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].OC1C=CC(C(OC)=O)=C(Cl)C=1>CN(C)C=O.COCCOC>[Cl:7][C:8]1[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]2[CH2:24][N:23]([CH3:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20]2)[CH:14]=[CH:13][C:9]=1[C:10]([Cl:4])=[O:11]
Reactant: CN1C[C@@H](COc2ccc(C(=O)O)c(Cl)c2)Oc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Agent: COC(=O)c1ccc(O)cc1Cl
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CN1C[C@@H](COc2ccc(C(=O)Cl)c(Cl)c2)Oc2ccccc21

Procedure:
Under argon atmosphere, oxalylchloride (0.3 mL) and N,N-dimethylformamide (1 drop) were added to a solution (4.5 mL) of 2-chloro-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoic acid (488 mg: the compound produced by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2-chlorobenzoate instead of the compound produced in Example 3.) in 1,2-dimethoxyethane, which was stirred for 1 hour at 40° C. The title compound was obtained by concentrating the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:6]([F:9])([F:8])[F:7])[CH2:5][O:4]1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16]>O>[F:1][C:2]([F:11])([F:10])[C:3]([OH:4])([C:6]([F:9])([F:8])[F:7])[CH2:5][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 40 °C
Reaction time: 10 h

Procedure:
Using the 2,2-bis(trifluoromethyl)oxirane prepared in Synthesis Example 1-2, synthesis was carried out in accordance with the procedure described in US 20100209827. A mixture of 30 g of 2,2-bis(trifluoromethyl)oxirane, 26 g of sodium hydrogensulfite, and 120 g of water was stirred at 40° C. for 10 hours, obtaining an aqueous solution of sodium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate. Subsequently, 34 g of an aqueous solution of 2,000 g/mol of triphenylsulfonium chloride and 400 g of methylene chloride were added to the aqueous solution, which was stirred for 4 hours at room temperature. At the end of stirring, the organic layer was taken out, washed with water, and concentrated under reduced pressure. The concentrate was combined with methyl isobutyl ketone and concentrated again under reduced pressure to distill off the residual water. To the residue, diisopropyl ether was added for recrystallization, obtaining 74 g of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate (yield 85%).