Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[N:31][CH:30]=[CH:29][N:28]=2)[S:22][C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:24]([C:23]3[S:22][C:21]([C:27]4[CH:32]=[N:31][CH:30]=[CH:29][N:28]=4)=[N:20][C:19]=3[CH3:18])=[O:25])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Reactant: Cc1nc(-c2cnccn2)sc1C(=O)Cl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cnccn4)nc3C)CCC2)ccc1OC
Yield: 86.4 %

Procedure:
Analogously to Example 2, reaction of 300 mg of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 307 mg of 4-methyl-2-pyrazin-2-yl-thiazole-5-carbonyl chloride (“BC”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-yl-thiazol-5-yl)methanone (484 mg, HPLC-MS m/e 438).
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][CH:9]([O:12][C:13](=[O:16])[CH2:14][NH2:15])[C:10]#[CH:11].C(N(CC)CC)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[I:8][CH:9]([O:12][C:13](=[O:16])[CH2:14][NH:15][C:34](=[O:35])[C@H:32]([CH3:33])[NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[C:10]#[CH:11]
Reactant: C#CC(I)OC(=O)CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C#CC(I)OC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 90 %

Procedure:
To a magnetically stirred, anhydrous dichloromethane (20 ml.) solution of glycine iodopropargyl ester trifluoroacetate (Compound #7) (2.00 g., 5.66 mmole) held at 0° C. with an ice-bath was added triethylamine (0.79 ml., 5.67 mmole), followed by N-t-butoxycarbonyl-L-alanine (1.07 g., 5.66 mmole), 1-hydroxybenzotriazole hydrate (0.77 g., 5.70 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g., 6.78 mmole). The reaction mixture was held at 5° C. for 17 hours. The resultant solution was transferred to a separatory funnel and diluted to an approximate volume of 100 ml. with dichloromethane, then washed successively with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium bicarbonate, water and a final wash with saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo with a rotary evaporator to give 2.09 g. (90% yield) of the desired N-t-butoxycarbonyl-L-alanylglycine iodopropargyl ester as a dry white foam. 1H-NMR (200 MHz, CDCl3) δ=1.40, d, 3H; 1.47, 1.77, two s, 9H; 4.08, d, 2H; 4.24, m, 1H; 4.90, s, 2H; 5.06, d, 1H; 6.81, s, 1H. IR (CHCl3) 1160, 1375, 1495, 1690, 1755, 2200, 2985, 3440 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH3:22])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CN(C)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.283 g, 1.1 mmol) and dimethylamine (2.7 mL, 2M solution in THF, 5.4 mmol) gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:55][C@@H:56]([C:58]1[CH:59]=[C:60]([CH:65]=[CH:66][CH:67]=1)[C:61]([O:63][CH3:64])=[O:62])[CH3:57]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:55][C@@H:56]([C:58]3[CH:59]=[C:60]([CH:65]=[CH:66][CH:67]=3)[C:61]([O:63][CH3:64])=[O:62])[CH3:57])=[O:21])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cccc([C@@H](C)N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H](C)c3cccc(C(=O)OC)c3)cn2)C1
Temperature: 22.5 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a stirred solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (797 mg, 2.32 mmol) in dry DMF (2.5 mL) at 0° C. were added triethylamine (0.36 mL, 2.5 mmol), 1-hydroxybenzotriazole (470 mg, 3.48 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1666 mg, 3.48 mmol). The mixture was stirred for 5 min and methyl (R)-3-(1-aminoethyl)benzoate (500 mg, 2.32 mmol) was added. The reaction mixture was allowed to warm to 20-25° C. and was stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 times with 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified via column chromatography to afford methyl 3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoate (890 mg, 76%). MS (ES+) 505.2 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:32])([F:31])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1.Cl[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[Cl:40][C:39]1[C:34]([N:28]2[CH2:29][CH2:30][C:20]3[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:31])([F:10])[F:32])=[CH:13][CH:14]=4)=[N:24][C:23]([S:25][CH3:26])=[N:22][C:21]=3[CH2:27]2)=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1cccnc1Cl
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Agent: CCN(CC)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 180 °C
Yield: 17 %

Procedure:
A mixture of diisopropylethylamine (252 mg, 1.95 mmol), N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (443 mg, 1.3 mmol) and 2,3-dichloropyridine (386 mg, 2.6 mmol) in dioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was heated via microwave in a sealed tube at 180° C. for 10 h. Solvent was removed in vacuo and residue was purified by column chromatography. The product was obtained as a beige solid (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:17])=O>ClCCl>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: COc1cc(OC)c(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)Cl)cc1Cl

Procedure:
A solution of 5-chloro-2,4-dimethoxybenzoic acid (6.4 g) in dichloromethane (250 ml) was treated with thionyl chloride (30 ml) and the mixture heated at reflux for 18h. Removal of volatile material in vacuo afforded the title compound as a white solid (6.6 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:35]
Reactant: COc1ccccc1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-methoxyphenyl isocyanate (0.162 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 219 mg (68.2%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[NH3:30].[BH4-].[Na+].[OH-].[NH4+]>C(Cl)Cl.CCO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([NH2:30])[CH2:15][N:16]3[C:20]([CH3:21])=[C:19]([Cl:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: N
Reactant: COc1cc(N2CCC(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Product: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (825 mg, 1.832 mmol) in DCM (5 mL) was treated with ammonia (9.16 mL of a 2.0 M solution in EtOH, 18.32 mmol) and stirred at RT in a sealed flask for 20 min. The flask was then charged with titanium(IV) isopropoxide (2.163 mL, 7.33 mmol) and re-sealed. The reaction mixture was stirred at RT for 16 h before being treated with sodium borohydride (0.259 mL, 7.33 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, after which time the mixture had become thick and foamy. DCM (5 mL) was added to the reaction mixture in order to facilitate stirring and the reaction continued for an additional 1.5 h. After this time, the mixture was treated with concentrated ammonium hydroxide (10 mL) and DCM (15 mL), stirred vigorously at RT for 20 min and then filtered through Celite. The filtrate was placed in a separatory funnel and the phases were separated. The aqueous phase was extracted with DCM, and the combined DCM extracts were dried (Na2SO4) and concentrated on a rotary evaporator to give the crude product. The crude product was purified by flash chromatography (40 g silica gel cartridge; 40% EtOAc/Hex used to elute the less polar materials; 3% MeOH in EtOAc used to elute the amine) to afford 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (500 mg, 1.108 mmol, 60% yield) as a clear gum. LC-MS: 451.19, [M+H]+; tR=3.07 min (b).
Reaction SMILES: [CH2:1]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].[F:19][C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]I.O>CS(C)=O.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:8]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([F:29])([F:30])[C:20]([F:19])([F:31])[F:32])([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: FC(F)(F)C(F)(F)CCCCCCI
Reactant: C=CCCCCCC(C(=O)OC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Dimethyl 2-hept-6-enylpropan-1,3-dioate(5 g, 21.9 mmol) prepared in Step 3 was dissolved in anhydrous DMSO(50 ml), 60% sodium hydride(0.96 g, 24.09 mmol) was added at room temperature, and the resulting mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added 1,1,1,2,2-pentafluoro-8-iodooctane(8.7 g, 26.28 mmol) prepared in Step 2, which was then stirred overnight under heating at 70˜80° C. The temperature was lowered to 0° C. and water was added. The mixture thus obtained was extracted with ethyl acetate, washed with water and saturated saline solution in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography(eluent:n-hexane/ethyl acetate=30/1, v/v) to give 9.3 g(Yield 98.8%) of the pure title compound as a colorless oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CCN(C(C)C)C(C)C.Br[CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]>C1COCC1>[OH:4][CH2:3][CH2:2][S:1][CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]
Reactant: OCCS
Reactant: O=C1OCCC1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCCC1SCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-mercapto-ethanol (2560 μmol) in THF (4 ml) were added DIEA (1.1 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reaction mixture was stirred at RT for 4 hours. The precipitate was filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[CH:14]([P:19]([OH:23])([O:21]C)=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C[Si](C)(C)Cl.[I-].[Li+]>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[CH:14]([P:19]([OH:23])([OH:21])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COP(=O)(O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1P(=O)(O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-(2-phenylacetamido)-2,2-dimethyl-3-(O-methylphosphono)penam (384 mg., 1.0 millimole) is dissolved in 4 ml. of dry pyridine then trimethylchlorosilane (0.381 ml., 3.0 millimoles) and lithium iodide (536 mg., 4.0 millimoles) are added. The reaction mixture is stirred under nitrogen at 25° C. for 5 hours after which 2 ml. of water is added. The mixture is stirred for 10 minutes then the volatiles removed by evaporation in vacuo. The residue was taken up in water, adjusted to pH 8.0 and extracted with 3 × 10 ml. of chloroform. The aqueous phase was then acidified to pH 1.5 and extracted with 3 × 10 ml. of ethyl acetate. The ethyl acetate extracts were dried over sodium sulfate then evaporated to dryness to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
The titled compound was prepared following the procedure E using methyl 4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and hexanoyl chloride as a colorless oil (69%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, 1H), 7.97 (d, 1H), 7.54-7.40 (m, 4H). 7.27-7.09 (m, 6H), 4.62 (m, 2H), 4.46 (m, 2H), 3.92 (m, 3H), 2.62 (t, 2H), 2.40 (m, 2H), 1.77-1.54 (m, 4H), 1.43-1.23 (m, 6H), 0.96-0.83 (m, 6H). M+ (ESI): 510.4. HPLC, Rt: 6.25 min (Purity: 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:20]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=2[F:18])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C=O)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 2-(benzyloxy)-5-bromobenzaldehyde (5.00 g) in toluene (70 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (4.40 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (710 mg), tris(dibenzylideneacetone)dipalladium(0) (790 mg) and 2.0M aqueous sodium carbonate solution (25.8 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.00 g) as orange crystals.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[CH2:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:4]2[CH2:3][CH:2]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:8]3[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:15]=1
Reactant: CSc1ccc2c(c1)C(Cl)Cc1ccc(C)cc1S2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(C)cc1S2

Procedure:
10.0 G. of 10-chloro-10,11-dihydro-3-methyl-8-methylthio-dibenzo[b,f]thiepin, 300 ml. of chloroform and 9.8 g. of N-methylpiperazine are heated at reflux for 30 hours. The mixture is evaporated under reduced pressure. The residue is worked up in an analogous manner to that described in Example 1, and there is obtained 1-(10,11-dihydro-3-methyl-8-methylthio-dibenzo[b,f]-thiepin-10-yl)-4-methylpiperazine whose dimethanesulfonate crystallizes from acetone and melts at 199°-200°C.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccccc2N2CCCCC2)cc1

Procedure:
The product (644 mg) is obtained according to the method of stage 1 of Example 3, by using 1 g of 2-piperidinoaniline, 982 μL of 4-methoxybenzyl bromide (1.2 equivalents) and 1.6 g of potassium carbonate (2 equivalents) in 10 mL of DMF.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([CH3:12])[CH2:7][CH:6]1[CH3:13])=[O:4].[S-:14][C:15]#[N:16].[K+].[I-].[Na+].C(O)C>C1C=CC=CC=1>[S:14]([CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([CH3:12])[CH2:7][CH:6]1[CH3:13])=[O:4])[C:15]#[N:16]
Reactant: CC1CC(C)N(C(=O)CCl)C(C)C1
Reactant: N#C[S-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CC1CC(C)N(C(=O)CSC#N)C(C)C1

Procedure:
1-(α-Chloroacetyl)-2,4,6-trimethylpiperidine (18 grams; 0.9 mol), potassium thiocyanate (18 grams; 0.2 mol), sodium iodide (a few crystals) and ethanol (100 ml) were charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux for a period of about 3 hours. After this time the mixture was cooled and filtered. The filtrate was evaporated leaving a solid product. The solid was then extracted with two 150 ml portions of hot benzene. The extracts were combined and evaporated under reduced pressure to yield an oil. This oil was refined by chromatography using Fuller's earth as an adsorbent and benzene as the elluent. The first 1000 ml of eluent were collected from the column and were stripped of benzene to yield 1-(α-thiocyanoacetyl)-2,4,6-trimethylpiperidine as a yellow oil having a refractive index of 1.5183 at 25° C. and having the following elemental analysis as calculated for C11H18N2OS.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]4[C:12]=3[CH2:13][N:14]([CH3:24])[C:15]4=[O:23])=[CH:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.CCOC(C)=O>[CH3:24][N:14]1[CH2:13][C:12]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=2[C:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=2)[C:15]1=[O:23]
Reactant: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc([N+](=O)[O-])c2C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1Cc2c(C3=CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 193E, 515 mg, 1.56 mmol) was dissolved in THF (10 mL) and aq. 3N HCl (3 mL). The resulting mixture was stirred at rt for 4 h. The mixture was diluted with EtOAc (40 mL), washed with brine (2×10 mL), and dried over anhydrous sodium sulfate. Evaporation afforded a yellow oil, which was used to next step without further purification. MS (ES+): m/z=287.10 [MH+]. HPLC: tR=3.13 min (ZQ3, polar—5 min).
Reaction SMILES: ClN1C(=O)CCC1=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:22][S:23][CH3:24].C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[C:11]([CH2:22][S:23][CH3:24])=[C:12]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(N)c1CSC

Procedure:
N-chlorosuccinimide (215 g) was added during 10 minutes to a solution containing ethyl 3-amino-4-chlorobenzoate (108 g) and dimethyl sulphide (117 ml) in dichloromethane maintaining below 0° C. Triethylamine (80 ml) was added and after 20 minutes further additions of dimethyl sulphide (117 ml), N-chlorosuccinimide (215 g) and triethylamine (80 ml) were made. After 0.5 hours additional triethylamine (280 ml) was introduced, the mixture heated under reflux conditions overnight and evaporated. Ether was added and this was washed with water, dilute sodium bicarbonate, dried (magnesium sulphate) and evaporated. Purification by chromatography, eluting with ethyl acetate/petroleum ether gave ethyl 3-amino-4-chloro-2-methylsulphenylmethylbenzoate (47.6 g), NMR (CDCl3) 1.45 (t,3H), 2.1 (s,3H), 4.1 (s,2H), 4.3 (q,2H), 4.7 (s,2H), 7.2 (m,2H).
Reaction SMILES: S(=O)(=O)(O)O.C[O:7][CH:8](OC)[C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[C:25]([F:28])([F:27])[F:26])[N:10]=1>ClCCl>[CH:8]([C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=2[C:25]([F:28])([F:26])[F:27])[N:10]=1)=[O:7]
Reactant: COC(OC)c1nn(-c2ccc(C#N)cc2C(F)(F)F)c2c1CCC2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#Cc1ccc(-n2nc(C=O)c3c2CCC3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4.7 mL (12.2 mmol) of sulfuric acid is added dropwise with stirring to a suspension of 32 g of silica gel in 175 mL of dichloromethane. Then 4.3 g (12.2 mmol) of 4-(3-dimethoxymethyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl)-3-trifluoromethylbenzonitrile in 75 mL of dichloromethane is added and the mixture is stirred for 20 hours at ambient temperature. The silica gel is filtered off and the solution is concentrated. Yield: 3.7 g (99%).