Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([NH:13][CH2:14][C:15]#[N:16])[CH2:7]2.[CH:17](OCCCC)=[O:18]>>[C:15]([CH2:14][N:13]([C@H:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)[CH:17]=[O:18])#[N:16]
Reactant: CCCCOC=O
Reactant: N#CCN[C@H]1CCc2c(F)cc(F)cc2C1
Product: N#CCN(C=O)[C@H]1CCc2c(F)cc(F)cc2C1
Reaction time: 19 h

Procedure:
A solution of the (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino) acetonitrile in butyl formate (8.7 M, 240 mL, 2.10 mol) was heated to reflux and stirred under nitrogen for 19 hours. The solvents were removed under reduced pressure, toluene was added and then evaporated. Drying gave (S)-N-(cyanomethyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as an oily residue (53.2 g). A stirring mixture of the formamide (53.2 g) and ethyl formate (12.4M, 48.7 mL, 0.604 mol) in 0.925 L of anhydrous THF was cooled to -15° C. A solution of potassium tert-butoxide in THF (1.0 M, 302 mL, 0.302 mol) was added over 20 minutes and the mixture was stirred for 18 hours. Evaporation of the solvent gave potassium (S)-N-(1-cyano-2-oxyvinyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as a residue.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]1=[O:18].[CH3:19][C:20]1[C:28]([C@H:29]2[CH2:31][O:30]2)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:32]>C(O)C>[OH:30][C@@H:29]([C:28]1[CH:27]=[CH:26][C:25]2[C:24](=[O:32])[O:23][CH2:22][C:21]=2[C:20]=1[CH3:19])[CH2:31][N:15]1[CH2:16][CH2:17][C:10]2([C:9](=[O:18])[N:8]([C:3]3[CH2:4][O:5][C:6](=[O:7])[C:2]=3[CH3:1])[CH2:12][CH2:11]2)[CH2:13][CH2:14]1
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: CC1=C(N2CCC3(CCN(C[C@@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 140 °C

Procedure:
To a solution of 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17, 10 mg, 0.040 mmol) in ethanol (2 mL) in a microwave tube was added (S)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (I-4A, 9.9 mg, 0.052 mmol)) and the resulting solution was heated at 140° C. in microwave for 3 h. After concentration, the residue was purified by preparative TLC using 30% methanol/ethyl acetate to give the title compound. LC/MS, (M+1)+: 441.00, 1HNMR (500 MHz, CDCl3), δ7.840-7.804 (m, 2H), 5.304-5.240 (m, 4H), 5.134-5.107 (m, 1H), 4.066-4.038 (t, J=7.1 Hz, 2H), 3.185-3.161 (m, 1H), 2.8885-2.862 (m, 1H), 2.629-2.568 (m, 2H), 2.462-2.416 (m, 1H), 2.305 (s, 3H), 2.344-2.323 (m, 1H), 2.197-2.158 (t, J=7.1 Hz, 2H), 2.108-2.033 (m, 5H), 1.661-1.604 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][N:18](C=O)[CH3:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH2:17][NH:18][CH3:19])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1csc2ccc(F)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNCc1sc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 5-fluoro-3-methyl-benzo[b]thiophene (4.83 g, 29.1 mmol) in THF (50 mL) at −30° C. under N2 was added n-butyllithium (20.0 mL of a 1.6 M solution in hexanes, 32.0 mmol) dropwise. The resulting orange solution was stirred for 1 h and then DMF (3.4 mL, 43.7 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.55 g, 97%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.80 (dd, J=9.0, 4.8 Hz, 1H), 7.53 (d J=9.3, 2.6 Hz, 1H), 7.31-7.24 (m, 1H), 2.76 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:14][C:13]=2[CH:21]=1.C(=O)(O)[O-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:13]=2[CH:21]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 36 h
Yield: 38.1 %

Procedure:
To a solution of ethyl bromoacetate (1.2 ml, 11 mmol) and 6-hydroxy-2-sulfamoylbenzo[b]thiophene (2.29 g, 10 mmol) in DMSO (10 ml) was added dropwise a solution of potassium bicarbonate (1.0 g, 10 mmol) and potassium carbonate (0.13 g, 1 mmol) in water (7 ml). The mixture was stirred for 1-2 days, then diluted with water. The precipitated product was collected dissolved in ethyl acetate, dried (Na2SO4) and evaporated to dryness. The residue was recrystallized from hot ethyl acetate, boiling off solvent until crystallization began, to give 1.2 g of product, m.p. 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17](Cl)[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][NH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[N:14]=[C:15]([Cl:19])[N:16]=[C:17]([NH:22][CH3:21])[C:12]=3[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccc(Br)cc1)COC2
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Br)cc1
Yield: 42.6 %

Procedure:
8-(4-bromophenyl)-2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation L) (500 mg, 1.389 mmol) and methanamine hydrochloride (141 mg, 2.083 mmol) were combined and purified as per Preparation Ha to give 8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (210 mg, 0.592 mmol, 42.6% yield). LC-MS (M+H)+=356.0. 1H NMR (500 MHz, MeOD) δ ppm 7.46 (2 H, d, J=8.24 Hz), 7.13 (2 H, d, J=8.55 Hz), 4.43-4.71 (2 H, m), 4.09 (1 H, dd, J=11.44, 4.12 Hz), 3.92-4.03 (1 H, m), 3.86 (1 H, d, J=3.05 Hz), 3.00 (3 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[N:19][CH:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[N:19][CH:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(=O)N2CCOc3cnccc32)cc1Br
Agent: BrB(Br)Br
Product: O=C(c1ccc(O)c(Br)c1)N1CCOc2cnccc21

Procedure:
By the same method as in Example 3, (3-bromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone (200 mg, 0.58 mmol) and 1M solution of boron tribromide (2.9 ml, 2.9 mmol)) were reacted to obtain the target compound 40, i.e., (3-bromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone, as beige solid (95 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:43][CH3:44])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32]>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>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:43][CH3:44])[CH2:31][CH3:32])=[CH:35][CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCN(CC)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)cc3)c2)cc1
Yield: 102.3 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1 g of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (2 mmol) with 580 mg of 4-diethylaminophenylboronic acid (3 mmol) in the presence of tetrakis(triphenylphosphine)palladium. 1.15 g of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate (yield=100%) are obtained in the form of a colorless oil.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([CH3:26])[C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]([CH3:26])[C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](CCSC)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Condensation of BocLeuOH (5.00 g.) and HMeMetNH2 (4.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocLeu-MeMetNH2 in 81% yield. De-t-butoxycarbonylation of BocLeu-MeMetNH2 (5.96 g.) using hydrogen chloride in ethyl acetate gave HLeu-MeMetNH2 hydrochloride salt in 98% yield. Condensation of BocDTrpOPFP (7.56 g.) and HLeu-MeMetNH2 hydrochloride salt (5.00 g.) by the activated ester method gave BocDTrp-Leu-MeMetNH2 in 56% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeMetNH2 (2.0 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeMetNH2 trifluoroacetate salt in 79% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8](O)[CH3:9].[Cl:28]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[CH3:9]
Reactant: ClCCl
Reactant: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a solution of 0.96 g of 3-[3-chloro-4-(1-hydroxyethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of dichloromethane, 0.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into 20 mL of ice water, and the organic phase was collected, washed with water (20 mL×1) and then saturated sodium hydrogen carbonate aqueous solution (20 mL×3), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 0.88 g of the aimed product as yellow oily substance.
Reaction SMILES: [OH:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH:9](O)[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[CH2:5][CH2:4]1.[OH-:40].[Na+]>C(O)C>[OH:1][C:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[OH:40])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)(C)c1ccc(CCCC(O)N2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
According to the described procedure of Carr et al., U.S. Pat. No. 4,254,129, to a solution of 0.6 g of ethyl 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3½ hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCl is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting precipitate is recrystallized from methanolbutanone to give 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid, M.P. 195°-197° C.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][N:8]=1.[CH3:15][C:16](N(C)C)=[O:17]>C1COCC1>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:16](=[O:17])[CH3:15])[N:12]=1
Reactant: CC(=O)N(C)C
Reactant: COc1ccnc(I)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccnc(C(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A solution of isopropylmagnesium chloride (4.2 mmol) in THF (2.0M, 2.1 ml) was added dropwise to a stirred solution of 2-iodo-4-methoxypyrimidine (prepared according to Leprete et al. in Tetrahedron, 2000, 56, 265-273) (1.0 g, 4.2 mmol) in THF (12 ml) at 0° C. under N2. The reaction was stirred for 30 min at 0° C. and then DMA (409 μl, 4.4 mmol) was added. The reaction was stirred for 1 h and then quenched by addition of NH4Cl solution (15 ml) and extracted with EtOAc (50 ml and 20 ml). The combined organics were concentrated under reduced pressure and purified by column chromatography on silica, using 75% Et2O/iso-hexanes as eluent, to yield 1-(4-methoxypyrimidin-2-yl)ethanone (206 mg, 32%): 1H NMR (360 MHz, CDCl3) δ 8.59 (1H, d, J 5.7), 6.83 (1H, d, J 5.7), 4.08 (3H, s), 2.74 (3H, s); m/z (ES+) 153 (M+).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:20][CH2:21][C:22]([CH2:24]Cl)=O>C(O)C>[Cl:20][CH2:21][C:22]1[N:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:12][CH:13]=2)[S:19][CH:24]=1
Reactant: NC(=S)c1ccc(Cn2cnc3ccccc32)cc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: ClCc1csc(-c2ccc(Cn3cnc4ccccc43)cc2)n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A stirred solution of 4-(1H-benzimidazol-1-ylmethyl)benzenecarbo-thioamide (0.50 g, 1.87 mmol) in ethanol was treated with 1,3-dichloroacetone (0.235 g, 1.85 mmol), heated at reflux temperature for 3 h, allowed to cool to room temperature and filtered. The filtercake was washed with cold ethanol and dried under vacuum to afford the title compound in 60% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 4.85 (s, 2H), 5.67 (s, 2H), 7.34-7.35 (m, 2H), 7.48 (d, J=7.6 Hz, 2H), 7.64-7.65 (m, 1H), 7.74-7.76 (m, 1H), 7.80 (s, 1H), 7.92 (d, J=7.6 Hz, 2H), 8.94 (s, 1H). LCMS (ESI+) 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH3:31]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]([CH2:29][CH2:28][OH:27])[CH3:31])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CNCCO
Solvent: CC(=O)N(C)C
Product: CN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 441 (MH+, 1Cl).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH2:12])=[NH:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[N:12][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N=C(N)c1ccc2c(c1)OCO2
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc3c(c2)OCO3)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=388.2 (M+), was prepared from benzo[1,3]dioxole-5-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N.[Cl-].[Na+].O>[F:30][C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[N:13]=1
Reactant: F[B-](F)(F)F
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c(F)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 22.8 %

Procedure:
A mixture of 3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (49.0 mg, 0.128 mmol) and selectfluor (45.4 mg, 0.128 mmol) in MeCN (1 mL) was stirred at room temperature for 6 days. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (45.4 mg, 0.128 mmol) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added selectfluor (272 mg, 0.768 mmol) at room temperature. The mixture was stirred at room temperature for 3 days. The mixture was diluted with brine, extracted with AcOEt, dried over MgSO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and crystallized with AcOEt/hexane to yield the title compound (11.7 mg, 23% yield) as a pale yellow solid: mp 156-158° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.67 (1H, d, J=8.2 Hz), 7.33-7.50 (5H, m), 7.63-7.83 (4H, m), 7.97 (1H, d, J=4.1 Hz), 8.96 (1H, d, J=8.0 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[O:10][N:9]=[CH:8][CH:7]=1)[OH:5].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14](O)[CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:5][CH:4]([C:6]2[O:10][N:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: OC(CCCl)c1ccno1
Product: N#Cc1ccc(Cl)cc1OC(CCCl)c1ccno1

Procedure:
Prepared by the method of Example 8(a) using α-(2-chloroethyl)-5-isoxazolemethanol and 4-chloro-2-hydroxybenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]([OH:29])[CH2:26][CH:27]=[CH2:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CN(C=O)C>[C:36]([Si:39]([O:29][CH:25]([CH2:24][CH2:23][CH:12]1[CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:20]2[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=2[F:21])[O:14][CH2:13]1)[CH2:26][CH:27]=[CH2:28])([CH3:41])[CH3:40])([CH3:38])([CH3:37])[CH3:35]
Reactant: C=CCC(O)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 88.8 %

Procedure:
A solution of 1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-hex-5-en-3-ol (1.30 g, 2.93 mmol) in DMF (29 mL) 0° C. was treated with imidazole (0.41 g, 6.0 mmol), TBSCl (0.66 g, 4.4 mmol) and warmed to ambient temperature. After 36 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed H2O (3×), saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (1→10% EtOAc/Hex) afforded the title compound (1.45 g, 89%): 1H NMR (CDCl3 400 MHz) δ 7.71 (dd, J=8.1, 1.5 Hz, 2H), 7.52 (dd, J=8.1, 1.5 Hz, 2H), 7.03 (m, 1H), 6.42 (m, 1H), 5.72 (m, 1H), 5.01-4.89 (m, 3H), 4.33 (dd, J=11.0, 2.2 Hz, 1H), 4.27 (s, 1H), 3.62 (m, 1H), 2.74 (m, 1H), 2.12-2.10 (m, 2H), 1.55-1.24 (m, 4H), 0.78 (s, 4.5H), 0.76 (s, 4.5H), −0.01 (s, 3H), −0.08 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)CCC>[N:27]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: ClCCCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: c1ccc(NCC2(c3ccc(OCCCCN4CCCC4)cc3)CCOCC2)nc1
Yield: 28.7 %

Procedure:
A mixture of N-({4-[4-(4-chlorobutoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine (180 mg, 0.481 mmol), pyrrolidine (80 μl, 0.963 mmol), sodium carbonate (102 mg, 0.963 mmol) and sodium iodide (4 mg, 0.024 mmol) were stirred in butanol (5 ml) at 100° C. for 24 hours until complete. Butanol was removed in vacuo and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). Organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to give a brown solid. Solid was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:02 to 96:4:0.4 by volume), followed by recrystallisation from ether (1.5 ml) to give the title compound (56.6 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 1.78-2.00 (m, 12H), 2.08-2.20 (m, 2H), 2.54-2.90 (m, 4H), 3.50 (d, 2H), 2.54-2.63 (m, 2H), 3.79-3.88 (m, 2H), 3.96-4.08 (m, 2H), 6.23 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1
Product: COC(=O)c1nc(C)sc1-c1ccc(F)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3,4-difluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=270.3.