Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=[O:15])[C:8]([OH:19])=[N:7]2>CC(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([OH:16])=[O:15])[C:8]([OH:19])=[N:7]2
Reactant: CCOC(=O)c1nc2ccc(Cl)cc2nc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1nc2ccc(Cl)cc2nc1O

Procedure:
Potassium hydroxide (1.25 g, 22.2 mmol) was added to a suspension of 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline (0.56 g, 2.22 mmol) in 2-propanol (5 mL) and water (7.5 mL) and the resulting solution were heated at reflux for 12 h. The cooled mixture was acidified to pH 2 and the solvents were removed under reduced pressure, after which the residue was taken up in water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic extracts were combined and the solvents were removed under reduced pressure, producing a residue that was purified by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:9), to provide 6-chloro-3-hydroxyquinoxaline-2-carboxylic acid as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.91 (d, 1H), 7.45 (d, 1H), 7.37 (dd, 1H) ppm; ESI MS m/z 223 [M−H]−.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([OH:24])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([Cl:27])=[O:24])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Product: O=C(Cl)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Yield: 81 %

Procedure:
Intermediate k (3.0 g, 0.01 mol) was added to thionyl chloride (10 V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (2.8 g) in a yield of 81%.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.O>CS(C)=O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]1[O:4][CH3:3]
Reactant: CO[C@H]1CCCC[C@H]1O
Reactant: Fc1ccccc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H]1CCCC[C@H]1OCc1ccccc1F
Temperature: 45 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
772 g (19.3 mol) of sodium hydroxide powder were added in portions to 1,672 g (12.8 mol) of cis-2-methoxycyclohexanol and 1,853 g (12.8 mol) of 2-fluorobenzyl chloride in 10 l of dimethylsulphoxide, whilst cooling with water. The mixture was stirred at 35° C. for 2 hours and at 45° C. overnight. Thereafter, it was cooled to 18° C., 10 l of petroleum ether were added and the mixture was discharged onto 10 ml of ice-water. The organic phase was separated off, extracted by shaking with water, dried over sodium sulphate and filtered and the filtrate was concentrated. The oily residue was distilled. 2,685 g (87.5% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclohexane of boiling point 150° C./2 mm Hg were obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Yield: 112.3 %

Procedure:
(S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (330 mg, 1.3 mmol), was dissolved in dry THF with srirring and treated with ethyl chloroformate (136 uL, 1.4 mmol) and NaHCO3 (218 mg, 2.6 mmol) at room temperature (20° C.) overnight. The mixture was concentrated in vacuo and the residue purified by flash chromatography using a mixture of 0-100% petrol ether/ethyl acetate as eluent, yielding the title compound (475 mg, 1.46 mmol, 41%).
Reaction SMILES: [B:1]([O-:7])([O-:6])[O:2][CH:3]([CH3:5])[CH3:4].O[C:9]([C:12](O)([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[CH:3]([O:2][B:1]1[O:7][C:12]([CH3:14])([CH3:13])[C:9]([CH3:11])([CH3:10])[O:6]1)([CH3:5])[CH3:4]
Reactant: CC(C)OB([O-])[O-]
Reactant: CC(C)(O)C(C)(C)O
Product: CC(C)OB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A 5 L 4-neck flask equipped with a reflux condenser, mechanical stirrer, N2 inlet, and thermowell was flushed well with N2 and charged with isopropyl borate (2.673 L, 11.5 mol, 1.15 equiv) and pinacol (1.179 kg, 10 mol). The resulting mixture was heated at reflux) (80-85° for overnight. The mixture was then cooled to room temperature, transferred to a 5 L 4-neck flask equipped with a 24 inch Vigreux column, magnetic stirrer, and thermowell. The mixture was distilled at atmospheric pressure under nitrogen. After the low boiling fraction (bp 90-180°) which contained predominately 2-propanol and isopropyl borate (GC analysis) was removed, the completed distillation afforded 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (10, 1.628 kg, 1.86 Kg theoretical, 87.5%) as a colorless liquid (bp 180-185° C. with GC purity >97.5%). This material was stored in Sure/Seal bottles to minimize hydrolysis.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].[CH2:14]([NH:17][C:18]1[C:19]2[CH2:27][CH2:26][C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(C)[C:20]=2[N:21]=[C:22](Cl)[N:23]=1)[CH:15]=[CH2:16].OS(O)(=O)=O>CN1CCCC1=O>[CH2:14]([NH:17][C:18]1[C:19]2[CH2:27][CH2:26][CH:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:20]=2[N:21]=[C:22]([NH:13][C:11]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:12]=2)[N:23]=1)[CH:15]=[CH2:16]
Reactant: C=CCNc1nc(Cl)nc2c1CCC2(C)c1ccc(F)cc1
Reactant: C=CCOc1cc(N)ccc1C#N
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Product: C=CCNc1nc(Nc2ccc(C#N)c(OCC=C)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-(allyloxy)-4-aminobenzonitrile (Preparation D, 168 mg, 0.963 mmol), and N-allyl-2-chloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ua, 204 mg, 0.642 mmol) in N-Methyl-2-pyrrolidinone (5135 μL) was added H2SO4 (54.7 μL, 1.027 mmol). The mixture was stirred at 100° C. overnight. The crude reaction mixture was purified by PREP HPLC: (50×250 mm HPLC XTerra C18.15 to 100% A:B over 40 min, 3 min at 100% B (A is 90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). The appropriate fractions were concentrated in vacuo to afford 4-(4-(allylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2-(allyloxy)benzonitrile (74 mg, 25% yield). LC-MS (M+H)+=456.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH3:27].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH3:27])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCC(c2ccc(OC)c3c2CC(=O)N3)C1
Reaction time: 1.5 h

Procedure:
A mixture of 2 g of the product of Example 1 in 40 ml of dimethylformamide, 3.39 g of potassium carbonate and 1.6 ml of propyl iodide was stirred under inert atmosphere for 90 minutes. After adding water, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure and purifying the residue by chromatography over silica (eluent: methylene chloride - methanol 9-1), 1.6 g of 1,3-dihydro-7-methoxy-4-(1-propyl-3-piperidinyl)-2H-indol-2-one melting at ≃120° C. were obtained.
Reaction SMILES: Br[CH2:2][Cl:3].C[O:5][C:6]([C@@H:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=O.[Li]CCCC.CCCCCC>C1COCC1.O.C(O)(=O)C>[Cl:3][CH2:2][C:6]([C@@H:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=[O:5]
Reactant: ClCBr
Reactant: COC(=O)[C@@H]1C=Cc2cc(F)ccc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)[C@@H]1C=Cc2cc(F)ccc2O1
Yield: 116.7 %

Procedure:
2.5 g of bromochloromethane (18.8 mmol) were added at room temperature to a solution of 2.0 g of crude (S)-6-Fluoro-1-benzopyran-2-carboxylic acid methyl ester, obtained after separation of the corresponding racemic mixture on a chiral chromatography column (9.4 mmol, 87.9% A, ee>99%), in 40 ml THF. The solution was then cooled to −80/−85° C. and 7.7 ml of 2.5 M n-BuLi in hexane (19 mmol) were slowly added to maintain the internal temperature between −75° C. and −80° C. The reaction progress was monitored by TLC. The solution was then acidified by the addition of 2 ml glacial acetic acid in 2 ml THF between −70° C. and −80° C. 10 ml of water were then added at −20/0° C. and the aqueous layer was then removed after decantation. The organic layer was concentrated under reduced pressure to give the title compound (2.54 g) as a yellow oil (ee: 99%, 94.8% A).
Reaction SMILES: [Cl:1][C:2]([S:7][CH:8]([CH3:10])[CH3:9])=[C:3]([Cl:6])[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[Cl:1][C:2]([S:7]([CH:8]([CH3:10])[CH3:9])=[O:19])=[C:3]([Cl:6])[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)SC(Cl)=C(Cl)C#N
Solvent: ClCCl
Product: CC(C)S(=O)C(Cl)=C(Cl)C#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Four grams of isopropyl 1,2-dichloro-2-cyanovinyl sulfide, prepared in Example 1, was dissolved in 50 milliliters methylene dichloride and the solution was cooled to 0° C. Four grams of solid 85% m-chloroperbenzoic acid was added in portions over one half hour. The reaction mixture was stirred for two hours while the temperature was maintained at 0° C. The reaction mixture was then filtered and washed with 5% potassium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and stripped of volatiles. A yield of 3 grams of isopropyl 1,2-dichloro-2-cyanovinyl sulfoxide having a refractive index--nD30 =1.5112 was obtained. The structure of the product was confirmed by IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20]
Reactant: Nc1cccc(Cl)c1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)CC(=O)Nc1cccc(Cl)c1

Procedure:
Dissolved in toluene were 2.5 g (0.02 mole) of m-chloroaniline and a catalytic amount of pyridine, followed by dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the dropwise addition, the resultant mixture was heated under reflux for 3 hours. Under ice-cooling, ligroin was added, and precipitated crystals were collected by filtration and were then washed first with ligroin and then with hexane. The crystals were then dried under reduced pressure to obtain 3'-chloroacetoacetanilide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]#[N:31])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][N:10]1[C:29]([C:30]#[N:31])=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[CH:15]=2)[C:11]1=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)N(CC#N)CCNC(=O)OC(C)(C)C)c(C(=O)c2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Yield: 100 %

Procedure:
A solution of 112 (3.16 g, 7.23 mmol), sodium methoxide (0.5M, 31.8 mL, 15.9 mmol) and methanol (100 mL) was heated at reflux for 1 h. The solvent was removed in vacuo and sat. sodium bicarbonate was added. Extracted with methylene chloride (3×). The combined organic extracts were dried with magnesium sulfate (anh.) and filtered. The filtrate was removed in vacuo to give 113 as a white solid (3.04 g, 7.23 mmol, 100%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH2:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:46]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:45]=[N:44][N:43]=2)=[CH:32][CH:31]=1>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]=[N:44][N:43]=3)=[CH:34][CH:35]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH2:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a suspension of 4.49 g of 2-Butyl-6-ethenyl-4(1H)-quinazolinone in 70 ml of dry tetrabydrofuran at room temperature is rapidly added 23.63 9 of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 21.94 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is concentrated in vacuo to a residue which is purified by chromatography on silica gel by eluting with 1:3 ethyl acetate-hexanes to give 9.58 g of the desired product as a yellow solid. FAB MASS SPEC 705 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:24]=[C:25]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([NH:31][C:32](=[O:34])[CH3:33])=[CH:24][C:23]=1[NH:11][C:7]1[N:8]=[CH:9][C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:5]2[N:6]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: COc1ccc(NC(C)=O)cc1Br
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(NC(C)=O)cc1Nc1ncc2c(C)nc(-c3cccc(C(F)(F)F)c3)n2n1
Yield: 17 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (intermediate 45) (0.025 g, 0.09 mmol), N-(3-bromo-4-methoxyphenyl)acetamide (0.044 g, 0.18 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-[4-methoxy-3-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]acetamide (0.007 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.15 (s, 1H), 9.06 (bs, 1H), 8.98 (d, J=7.6 Hz, 1H), 8.73 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 7.83-7.70 (m, 3H), 7.30 (dd, J=8.7, 2.3 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 2.59 (s, 3H), 2.09 (s, 3H). MS m/z 457 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=2)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47](O)=[O:48]>C(Cl)Cl>[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([N:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=2)[CH2:3]1)=[O:48]
Reactant: Clc1ncc(Br)c(C2CNC2)n1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.5 %

Procedure:
To a solution of 4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine hydrochloride (0.57 mg, 2.0 mmol) in DCM (20 mL) were added HATU (1.5 g, 4.0 mmol), TEA (404 mg, 4 mmol) and 1H-benzoimidazole-2-carboxylic acid (398 mg, 2.4 mmol). The reaction mixture was stirred at RT for 12 h. TLC showed that most of starting materials were consumed completely. Then the solution was washed with aqueous HCl (1 mol/L) (50 mL×3), saturated aqueous NaHCO3 (50 mL×3) and brine, dried over MgSO4. The solution was evaporated, the residue was purified by column chromatography to give the product (206 mg, 0.53 mmol, yield: 27%). ESI-MS (M+1): 392 calc. for C15H11BrClN5O 391
Reaction SMILES: [Na].[CH2:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:16]([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCCCCCCCCCCCO
Reactant: CCCCCBr
Agent: [Na]
Product: CCCCCOCCCCCCCCCCCCO
Yield: 52 %

Procedure:
The monosodium salt of 1,12-dodecanediol is reacted with pentyl bromide to give 12-pentoxydodecanol which, after elution on a silica gel column with ligroin-methyl ethyl ketone (4:1 v/v), gives a thin layer chromatographically uniform oil. The yield is 52% of theory. This is then brominated with phosphorus tribromide in the presence of pyridine and, after fractionation on a silica gel column (diethyl ether-ligroin 1:99 v/v as elution agent) gives 47% of theory of thin layer chromatographically uniform oily 12-pentoxydodecyl bromide. This bromide is reacted with the monosodium salt of 1,3-propanediol and then gives, in a yield of 56% of theory, after column purification (elution agent diethyl ether-ligroin 1:1 v/v), 3-(12-pentoxydodecyloxy)propanol; m.p. 25° C. Phosphorylation, hydrolysis and reaction with trimethylamine take place in the manner described in Example 1 to give a yield of 41% of theory of the desired product; m.p. 63° C. (sinters), 240°-243° C. (decomp.). It crystallizes with 1 mole of water of crystallization.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O-])([O-:13])([O:10]CC)C>>[OH:7][C@H:1]1[CH2:6][CH:5]=[CH:4][C@H:3]1[CH2:2][C:8]([OH:13])=[O:10]
Reactant: CCOC(C)([O-])[O-]
Reactant: Oc1ccccc1
Product: O=C(O)C[C@@H]1C=CC[C@@H]1O

Procedure:
In the same manner as described in Example 1 but using 0.5 part of phenol in place of the hydroquinone, 7 parts of unreacted ethyl orthoacetate was recovered and then 4.2 parts of the desired product, a lactone of cis-2-hydroxy-cyclopent-4-ene-1-acetic acid was obtained.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].Br[C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][N:11]=1>C1COCC1>[Br:16][C:15]1[C:10]([CH2:7][C:6]#[N:8])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccnc1Br
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCc1ncccc1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Dry THF (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes; 23 mL, 58 mmol) was added. Acetonitrile (3.3 mL, 64 mmol) was added dropwise maintaining the temperature below −60° C. A white precipitate formed and the reaction mixture was stirred at −78° C. for 45 min. A solution of 2,3-dibromopyridine (2.0 g, 8.4 mmol) in dry THF (10 mL) was added dropwise and the reaction mixture stirred at −78° C. for 1.5 h then allowed to warm to room temperature. The reaction was quenched by the dropwise addition of water. The aqueous was extracted with DCM (×3) and the combined organics washed with brine, dried (MgSO4) and concentrated in vacuo. (3-Bromo-pyridin-2-yl)-acetonitrile (Intermediate 1) was purified by flash column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:22])[CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]#[N:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH:19]([CH3:21])[CH3:20])[CH3:22])=[N:16][C:15]3[C:10]([N:9]=2)=[CH:11][CH:12]=[C:13]([C:23]2[N:25]=[N:26][NH:27][N:24]=2)[CH:14]=3)=[CH:6][CH:7]=1
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(C)c1nc2cc(-c3nn[nH]n3)ccc2nc1-c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 35.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.47 mmol) in DMSO (10.0 mL) and water (10.0 mL) was added NaN3 (90 mg, 1.38 mmol) and ZnBr2 (51.9 mg, 0.23 mmol), and the resulting mixture was stirred for 48 h at 130° C. in an oil bath. The reaction mixture was cooled down to room temperature, diluted with water (150 mL), extracted with dichloromethane (4×40 mL), and the organic layers combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% dichloromethane in methanol) to afford 3-(4-fluorophenyl)-N-isopropyl-N-methyl-7-(2H-tetrazol-5-yl)quinoxalin-2-amine as a light yellow solid (60 mg, 35.0%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:13][C:14]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]3[C:15]=2[CH2:16][CH2:17][C@H:18]([CH3:26])[NH:19]3)[CH2:12][CH2:11][CH2:10]1>C(#N)C.ClCCl>[Br:1][C:23]1[C:14]([O:13][CH:9]2[CH2:10][CH2:11][CH2:12]2)=[C:15]2[C:20](=[C:21]([F:25])[C:22]=1[F:24])[NH:19][C@@H:18]([CH3:26])[CH2:17][CH2:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1CCc2c(OC3CCC3)cc(F)c(F)c2N1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@H]1CCc2c(c(F)c(F)c(Br)c2OC2CCC2)N1
Temperature: -5 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of N-bromosuccinimide (0.703 g, 3.95 mmol) in acetonitrile (10 mL) was added dropwise to a −5° C. solution of (S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 3.95 mmol) in acetonitrile (80 mL) and dichloromethane (15 mL), and the resulting solution stirred for 4 h at −5° C. The reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 50% ethyl acetate/petroleum ether) to afford (S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.05 g, 81%) as a yellow solid. MS (ESI, pos. ion) m/z 332, 334 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:5]1[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1cn[nH]c1
Product: CC(C)(C)OC(=O)Cn1cc(C(F)(F)F)cn1
Yield: 24 %

Procedure:
The title compound was prepared according to the method described for Preparation 75 using 4-(trifluoromethyl)-1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid (24%, 1.32 g).