Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.BrC1C=C(C(N[C@H:38]([C:43]([NH:45][CH2:46][C:47]#N)=O)[CH2:39]C(C)C)C(F)(F)F)C=CC=1>>[C:23]([CH2:22][NH:21][C:19](=[O:20])[C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:13][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([C:39]2[CH:38]=[CH:43][N:45]=[CH:46][CH:47]=2)[CH:4]=1)[C:9]([F:12])([F:11])[F:10])#[N:24]
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Reactant: CC(C)C[C@H](NC(c1cccc(Br)c1)C(F)(F)F)C(=O)NCC#N
Product: CC(C)C[C@H](NC(c1cccc(-c2ccncc2)c1)C(F)(F)F)C(=O)NCC#N

Procedure:
Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide, the title compound was obtained as a colorless gum.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.[OH-].[Na+].Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)=[N:20][CH:21]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)OCO4)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
9.8 g of 5H-1,3-dioxolo(4,5-f)-benzimidazole-6-thiol were suspended in 200 ml of alcohol in a 500 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and reflux condenser and treated dropwise while stirring well with a solution of 4.47 g of sodium hydroxide in 100 ml of water. The mixture was stirred at room temperature for an additional 30 minutes. Then 9.15 g of 2-chloromethyl-5-methylpyridine hydrochloride were added thereto. The mixture was left to boil at reflux overnight and subsequently evaporated. The residue was taken up in 500 ml of ethyl acetate, extracted with 100 ml of 3N sodium hydroxide and washed neutral with water. The aqueous extracts were extracted once more with 500 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. After recrystallization from acetonitrile, the residue gave 13.3 g (87.6% of theory) of 6-[[(5-methyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 187°-188° C. When the residue was dissolved with heating in 50 ml of methanol and treated with 100 ml of 5N hydrochloric acid in ethyl acetate, there were obtained, with the same yield, 16.5 g of dihydrochloride of melting point 232°-234° C.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:13]=[C:12]([CH:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[F:3][C:4]1[CH:13]=[C:12]([CH:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1F
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of Lithium hydroxide (420 mg, 10.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 2-fluoro-4-(1-phenoxyethyl)benzoate (600 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was quench with 10% hydrochloric acid (aqueous), extracted with dichloromethane and menthol (30 mL, 10:1), the combine organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to give product 2-fluoro-4-(1-phenoxyethyl)benzoic acid (450 mg, 82%). LCMS (M+H+) m/z: calcd 260.08. found 260.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: OC1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1N1CCC(O)CC1
Yield: 58.4 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (36 g) and 4-hydroxypiperidine (50 g), the title compound (25 g) was obtained. melting point: 144-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH:11]=[CH:15][CH:14]=[CH:13]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Product: Oc1ccccc1-n1cccc1

Procedure:
109 g of o-aminophenol and 132 g of 2,5-dimethoxy-tetrahydrofurane in 700 ml of glacial acetic acid are heated to the boil for 30 minutes. After cooling, the reaction mixture is filtered and the polymeric material is thus removed. The filtrate is evaporated in vacuo, the residue is dissolved in approx. 1 liter of ethyl acetate and the solution is washed with 200 ml of water. The dark oil which remains after drying and evaporating the organic phase is distilled in a bulb tube under a high vacuum. This gives o-(pyrrol-1-yl)-phenol of boiling point 115°-125° C/0.05 mm Hg gives an oil which gradually crystallises and melts at 46°-49° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[CH:14]=[CH:13][NH:12][C:7]=2[N:8]=[C:9](Cl)[N:10]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[CH:14]=[CH:13][NH:12][C:7]=2[N:8]=[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=2)[N:10]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: NCCNc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NCCN)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-(2-aminoethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (71 mg, 0.34 mmol), N-(4-aminophenyl)-N-methylacetamide (110 mg, 0.67 mmol) and trimethylsilyl chloride (0.085 mL, 0.67 mmol) in nBuOH (2 mL) was heated at 116° C. for 3 h. More trimethylsilyl chloride (0.100 mL, 0.79 mmol) was added. After being stirred at 116° C. for another 2 h, the mixture was purified by HPLC to give the titled compound (28 mg). MS 340.2 (M+H); UV 201.4, 262.7, 303.1 nm.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:34](O)=[O:35].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][N:9]1[C:34](=[O:35])[C:33]1[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=[C:31]([C:30]([F:29])([F:44])[F:45])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(CCc1ccccc1)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 78.9 %

Procedure:
150 mg (0.384 mmol) of (2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 93 mg (0.461 mmol) of 3,5-bis(trifluoromethyl)benzoic acid, 117 mg (0.461 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 118 μl (0.845 mmol) of triethylamine. The title compound (191 mg, 79%) is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.79, FD-MS: M+ =630.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+]>O.C1COCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:17](=[O:16])[NH:18][C:4]2=[O:5]
Reactant: N#C[O-]
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a mixture of 25.36 g of 2-amino-5-iodobenzoic acid in 250 ml of water and 90 mL of THF was added 7.40 g of glacial acetic acid and stirred at room temperature. Then was added 7.82 g of potassium cyanate in water dropwise. Left to overnight. Added another 5.47 g of potassium cyanate. Stirred overnight. A total of 160 g of NaOH pellets were added portionwise, keeping the mixture cool in ice-water bath. The mixture was stirred at room temperature overnight. The mixture was cooled in a refrigerator and the precipitate filtered through a sintered glass funnel. The precipitate was then dissolved in water and acidified with 4N HCl. The precipitate was collected by filtration. The solid was dried in a vacuum oven to yield 25.44 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+].Cl>CO>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([NH2:16])[CH3:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)c1cccnc1
Reaction time: 0.33 h

Procedure:
To a solution of 3-acetylpridine (82.6 mmol) in methanol (200 mL) was added ammonium acetate (1.03 mol) in one portion at room temperature. After the mixture has been stirred for 20 min, sodium cyanoborohydride (57.8 mmol) was added to this mixture. After being stirring for one day, 6 M hydrochloric acid was added to the reaction mixture. The resulting solution was washed with diethyl ether, and then the aqueous phase was basified to PH=10 with potassium hydroxide. The liberated amine was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude amine was obtained as a colorless oil, which was further purified by distillation under reduced pressure. 1H NMR (300 MHz, CDCl3), δ: 8.552 (d, 1H), 8.453 (dd, 1H), 7.678 (m, 1H), 7.206-7.261 (m, 1H), 4.148 (q, 1H), 1.378 (d, 3H).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:11]C)[CH2:9][CH3:10])C.[N+:13]([C:16]1[CH:25]=C2[C:19]([CH2:20][CH2:21][CH2:22]C2O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O1CCCC1>[CH3:11][N:8]([CH3:6])[CH:9]1[C:10]2[C:19](=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:25]=2)[CH2:20][CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
With cooling with ice, 0.16 mL of methanesulfonyl chloride and 0.29 mL of triethylamine were added to a tetrahydrofuran (5 mL) solution of 200 mg of 7-nitro-1,2,3,4-tetrahydronaphthalen-1-ol obtained according to the method described in WO2004/087124, and stirred for 1 hour. The insoluble matter was removed through filtration through Celite, the solvent was evaporated away from the filtrate, the residue was dissolved in 3 mL of N,N-dimethylformamide, then 1.55 mL of 2 M dimethylamine/tetrahydrofuran solution was added to it, and stirred overnight at 60° C. After left cooled, water was added to the reaction solution, and then diluted with ethyl acetate. The organic layer was washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 100 mg of the entitled compound as a yellow oil.
Reaction SMILES: [CH2:1]([S:16][CH:17]([CH2:23][CH3:24])[C:18]([O:20]CC)=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:16][CH:17]([CH2:23][CH3:24])[C:18]([OH:20])=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Ethyl 2-((3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenylthio)butanoate (14.1 g, 40.2 mmol) was dissolved in ethanol (200 mL) and added a solution of LiOH×H2O (13.5 g, 322 mmol) in water (50 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 90 minutes, cooled, added water (100 mL) and 3M HCl until pH=2. The mixture was extracted three times with heptane (100 mL each). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 11.8 g (91% yield) of the title compound as oil.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH2:4][CH2:3]1>O1CCCC1>[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([SiH:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:10][CH2:9]1)[CH2:4][CH3:3]
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([SiH]2CCC(c3ccc(F)c(F)c3)CC2)CC1

Procedure:
4.1 g (20 mmol) of 4-n-propylcyclohexyl bromide was dropped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of tetrahydrofuran (THF) to obtain Grignard reagent. This solution was then dropped into a 50 ml THF solution of 4.9 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl)-1,2-difluorobenzene to obtain 4-(4-(trans-4-n-propylcyclohexyl)-4-silacyclohexyl)-1, 2-difluorobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[C:13]([O:16][C:17](=O)C)(=O)[CH3:14].C(OCC)(OCC)OCC>>[CH2:1]([O:3][C:4](=[O:12])/[C:5](=[CH:17]/[O:16][CH2:13][CH3:14])/[C:6](=[O:11])[C:7]([F:10])([F:8])[F:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Yield: 96.4 %

Procedure:
4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (16 g, 86.4 mmol) was dissolved in acetic anhydride (33.6 g, 329.6 mmol) and triethyl orthoformate (38.4 g, 260 mmol) was added to the mixture. The resultant mixture was refluxed for 18 hours. The mixture was concentrated under reduced pressure to obtain 20 g of 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester as crude. This was taken in EtOH (50 mL) and added to a suspension of cyclopropyl hydrazine hydrochloride (9.95 g, 91.7 mmol) and DIPEA (28.3 ml, 166.7 mmol) in EtOH (150 mL) at −20° C. The resultant mixture was slowly warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure and residue formed was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with 2N HCl (25 mL), water (25 mL), brine (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:Hexane 5:95) to afford the title compound as off white sticky solid in 7% yield, 1.4 g.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][CH3:14].[C-:16]#[N:17].[Na+].C(OCC)(=O)C.O>C(#N)CC.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:16]#[N:17])[C:7]([CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][CH3:14]
Reactant: [C-]#N
Reactant: CCOc1cc(C)c(Br)cc1C(=O)NC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC#N
Solvent: O
Product: CCOc1cc(C)c(C#N)cc1C(=O)NC
Yield: 58 %

Procedure:
After dissolving N1,4-dimethyl-5-bromo-2-ethoxybenzamide (200 g) in propionitrile (1.51), sodium cyanide (72 g), copper iodide (14 g) and tetrakis(triphenylphosphine)palladium (42 g) were added under a nitrogen atmosphere and the mixture was heated to reflux for 5 hours. Ethyl acetate and water were added and the reaction mixture was filtered through celite. The precipitated crystals in the filtrate were filtered off (15.4 g). This filtrate was then separated and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and was concentrated after filtering off the insoluble portion. The obtained crystals were filtered off and washed with ethyl acetate (77.64 g). The crystals were combined to yield the title compound (93.04 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cnc(Cl)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cnc(Cl)nc1
Yield: 39.7 %

Procedure:
2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30% ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7% yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14.
Reaction SMILES: [OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15]1([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:1][C@H:2]1[CH2:14][N:5]2[C:6]3[C:11]([N:12]([C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]5[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=5[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:34][CH:33]=4)[CH2:13][C@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: O[C@@H]1C[C@@H]2CNc3ccccc3N2C1
Product: O=C(Nc1ccc(C(=O)N2C[C@H]3C[C@@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 53.1 %

Procedure:
The same procedures used in Example 1 were repeated using (2R, 3aR)-2-hydroxy-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 17 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound after recrystallization from ethyl acetate-hexane. Yield 53.1%.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:14]([OH:16])=[O:15].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 250 ml of tetrahydrofuran were added at 10° C. to a mixture of 2.6 g of sodium hydride in 100 ml of tetrahydrofuran and the mixture was stirred at 15° C. for 30 minutes. A solution of 35 ml of benzyl bromide in 100 ml of tetrahydrofuran was added to the mixture which was heated at 50° C. for 48 hours and then was cooled and poured into aqueous monosodium phosphate solution. The mixture was extracted with isopropyl ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-isopropyl ether mixture to obtain 30 g of benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: NCCO
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 76 mg (68%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1cnc(-c2c(F)cccc2F)nn1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccc(F)c1-c1ncc(C=Cc2ccc(Cl)cc2)nn1
Reaction time: 2 h

Procedure:
140 mg of 1-(4-chlorophenyl)-2-[3-(2,6-difluorophenyl)-[1,2,4]triazin-6-yl]-ethanol and 10 mg of p-toluenesulfonic acid in 10 ml of toluene are boiled under reflux using a water separator for 2 h; the reaction mixture is then poured into water, and the toluene phase is separated off, dried with sodium sulfate and concentrated by evaporation. After recrystallisation of the residue from cyclohexane, the title compound having a melting point of 135-140° C. is obtained.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([CH3:41])[N:35]=2)=[CH:30][CH:29]=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:40][C:39]1[C:34]([C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=2)=[N:35][C:36]([CH3:41])=[N:37][CH:38]=1
Reactant: Cc1ncc(C)c(-c2ccc(Cl)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ncc(CBr)c(-c2ccc(Cl)cc2)n1
Yield: 63.5 %

Procedure:
2.26 g (12.7 mmol) of NBS and 3 mg of dibenzoyl peroxide were added to a solution of 2.73 g (12.5 mmol) of 4-(4-chlorophenyl)-2,5-dimethylpyrimidine in 48 ml of CCl4, and the mixture was refluxed for 5 minutes with stirring and irradiation (cf. Example 25). The NBS had then been converted into succinimide. This was filtered off at room temperature through a filtration aid and washed with CCl4, and the filtrate was evaporated in vacuo. The residue was dissolved in about 60 ml of diisopropyl ether/n-pentane 1:1, the slightly turbid solution was clarified using kieselguhr and again filtered under suction, and the clear filtrate was evaporated in an oil-pump vacuum to constant weight. According to the 1H NMR spectrum, the residue (3.4 g) comprised 69.5% purity 5-bromomethyl-4-(4-chlorophenyl)-2-methylpyrimidine (=63.5% yield). This bromomethyl compound was used in this form for the reaction with 1-(4-hydroxyphenyl)piperazine (cf. Example 23, No. 5.19).