Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O.ClCCl>C(O)C>[N:11]1([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nccc2occc12
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: c1cc2occc2c(N2CCNCC2)n1

Procedure:
A solution of 0.065 mol of 4-chlorofuro[3,2-c]pyridine and 5 equivalents of piperazine in 25 ml of ethanol is heated for 17 hours at 120° C. under an inert atmosphere. After cooling and concentration under reduced pressure, the residue obtained is stirred in the presence of 150 ml of water and 150 ml of dichloromethane. After decanting and extraction with dichloromethane, the organic phases are dried and filtered and then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([O:19][C@H:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C@@H:23]([NH2:30])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:34][C:35](=[O:53])[NH:36][C:37]1[N:38]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[N:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1.CCN(C(C)C)C(C)C.C(O)=O>O1CCOCC1>[CH:35]([OH:53])=[O:34].[C:42]([C:40]1[CH:41]=[C:37]([NH:36][C:35]([NH:30][C@@H:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[N:11][N:12]=4)[CH:15]=3)[CH2:21][CH2:22]2)=[O:34])[N:38]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[N:39]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCN(CCc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O=CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CCN5CCN(C)CC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
Intermediate 2c (85.0 mg, 0.21 mmol) was dissolved in 1,4-dioxane (2 mL) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 96.0 mg, 0.24 mmol) and DIPEA (75.0 μL, 0.43 mmol) were added. The reaction was heated to 60° C. for 18 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 10-40% MeCN in H2O, 0.1% formic acid) to give the title compound mainly as formic acid salt (43.0 mg, 0.065 mmol, 31%). LCMS (Method 5) Rt 3.54 mins, m/z 662 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.90-2.05 (2H, m), 2.06-2.15 (1H, m), 2.20-2.30 (1H, m), 2.38 (3H, s), 2.40 (3H, s), 2.55-2.75 (8H, br s), 2.90-2.95 (2H, t, J 7.4), 3.29-3.32 (2H, t, J 7.4), 4.86-4.92 (1H, dd, J 8.8, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H, s), 7.21-7.35 (11H, m), 7.60-7.64 (1H, d, J 9.9), 8.07-8.09 (1H, d, J 1.9), 8.40-8.50 (0.4H, br s, formate).
Reaction SMILES: [Cl-].[Li+].[Cu](C#N)C#N.[CH:8]([Mg]Cl)([CH3:10])[CH3:9].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].[I:19]I>O1CCCC1>[CH3:18][O:17][C:13](=[O:16])/[C:14](/[I:19])=[CH:15]\[CH:8]([CH3:10])[CH3:9]
Reactant: C#CC(=O)OC
Reactant: CC(C)[Mg]Cl
Reactant: II
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)/C(I)=C\C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A mixture of lithium chloride (1.69 g, 40 mmol, predried at 130° C. under high vacuum for 2 h) and copper cyanide (1.79 g, 20 mmol) in dry tetrahydrofuran (20 mL) was stirred at 25° C. under argon for 10 min to obtain a clear solution. The reaction mixture was cooled to −70° C. and then slowly treated with a 2M solution of isopropylmagnesium chloride in tetrahydrofuran (10 mL, 20 mmol). After addition, the reaction mixture was allowed to warm to −30° C. where it was stirred for 5 min. The resulting reaction mixture was again cooled back to −70° C. and then slowly treated with methyl propiolate (1.52 g, 18 mmol). The reaction mixture was stirred for 4 h at −40° C. to −30° C. and then cooled to −70° C. to −60° C., at which time, the reaction mixture was treated slowly with a solution of iodine (6.86 g, 27 mmol) in dry tetrahydrofuran (20 mL). After addition of the iodine solution, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then poured into a solution consisting of a saturated aqueous ammonium chloride solution (90 mL) and ammonium hydroxide (10 mL), and the organic compound was extracted into diethyl ether (3×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium thiosulfate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 20/1 hexanes/diethyl ether) afforded (E)-2-iodo-4-methyl-pentenoic acid methyl ester (2.23 g, 49%) as a colorless oil: EI-HRMS m/e calcd for C7H11IO2 (M+) 253.9804, found 253.9805.
Reaction SMILES: FC(F)OC1C=C(C(O)=O)N(C)N=1.[CH:14]1([C:17]2[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]([O:28]CC)=[O:27])[N:19]([CH3:31])[N:18]=2)[CH2:16][CH2:15]1>>[CH:14]1([C:17]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:20]([C:26]([OH:28])=[O:27])[N:19]([CH3:31])[N:18]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C2CC2)nn1C
Agent: Cn1nc(OC(F)F)cc1C(=O)O
Product: Cn1nc(C2CC2)c(C(F)(F)F)c1C(=O)O

Procedure:
This compound is prepared analogously to the preparation of 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid from ethyl 3-cyclopropyl-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate:
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([NH2:14])[CH3:13])=[C:10]([F:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:23][C:21]1[N:22]=[C:17]([NH:14][CH:12]([C:11]2[C:2]([F:1])=[C:3]3[C:8](=[CH:9][C:10]=2[F:15])[N:7]=[CH:6][CH:5]=[CH:4]3)[CH3:13])[C:18]([NH2:24])=[N:19][CH:20]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(N)c1c(F)cc2ncccc2c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Temperature: 180 °C
Yield: 35.2 %

Procedure:
A mixture of 1-(5,7-difluoroquinolin-6-yl)ethanamine (800 mg, 3.8 mmol), 3,5-dibromopyrazin-2-amine (972.0 mg, 3.8 mmol) and DIPEA (2.0 g, 15.4 mmol) in acetonitrile (50 mL) was heated with microwave irradiation at 180° C. for 45 min. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with DCM three times. The combined organic layers were separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM/MeOH) to give the title compound as a yellow solid (508 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.46 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.11 (s, 1H), 7.08 (dd, 1H), 6.36 (bs, 2H), 5.45 (m, 1H), 1.70 (d, 3H). LCMS (method A): [MH]+=380/382, tR=5.03 min.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:47][CH3:48])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:36]1[O:37][C:38]([CH3:39])=[C:34]([CH2:33][O:32][C:31]2[CH:45]=[CH:46][C:28]([CH2:27][O:1][C:2]3[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[N:3]=3)=[CH:29][C:30]=2[O:47][CH3:48])[N:35]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (3.00 g), potassium carbonate (2.52 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.30 g, yield: 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[ClH:30].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(OC2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(OC3CCN(c4ccncc4)CC3)cc2)cc1
Product: Cl
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-[1-(4-pyridyl)piperidin-4-yloxy]aniline was reacted with 4-toluenesulphonyl chloride to give N-{4-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}-4-toluenesulphonamide, hydrochloride salt, in 54% yield, m.p. 270-272° C.;
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([Cl:25])[CH:5]=1.[OH-].[K+]>CO.O.C(O)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:26])=[O:2]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 90.5 %

Procedure:
The title compound is prepared by the procedure of Example 32 using 125.0 g of product from Example 36 in 1 L of methyl alcohol, 60 ml of water, 400 ml of ethyl alcohol and 54.94 g of potassium hydroxide. The residue is recrystallized from chloroform/hexane to give 109 g of the desired product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.C(O)C>[OH-].[Na+].O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 0.01 mole of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 12 ml. (0.012 mole) of IN sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water and the ethanol evaporated in vacuo. The remaining solution is filtered and the filtrate acidified with dilute HCl. The precipitated solid is collected by filtration and recrystallized from methanol-water to yield the product, 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>C1COCC1.CCOC(C)=O>[OH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NCCOCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCOCCO)c3)n2)n1
Yield: 61.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.300 g, 0.613 mmol) by treatment with commercially available 2-(2-aminoethoxy)ethanol (0.194 mg, 1.84 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.210 g, 61%) as a white solid. MS (ISP) 558.2 [(M+H)+]; mp 123° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([C:6]2[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:24]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccnc2C=O)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
A stirred solution of 3-Tributylstannanyl-pyridine-2-carbaldehyde (256 mg, 0.65 mmol) and methyl 3-bromobenzoate (128 mg, 0.59 mmol) in DMF (2.1 mL) was degassed with Ar for 5 minutes, after which PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuO (34 mg, 0.43 mmol) was added and the mixture heated to 110° C. overnight. The reaction was cooled to room temperature, and diluted with saturated aqueous NaHCO3 (15 mL) and EtOAc (40 mL). The organic phase was separated, washed with brine (3×15 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 60:40) gave 3-(2-Formyl-pyridin-3-yl)-benzoic acid methyl ester (25 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.47-7.56 (m, 2H), 7.58 (d, 1H, J=4.9 Hz), 8.03 (s, 1H), 8.07-8.20 (m, 1H), 8.86 (dd, 1H, J=4.9, 1.8 Hz), 10.08 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(F)(F)F)c(C=O)cn1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cnc(OC)cc1C(F)(F)F
Temperature: 110 °C
Yield: 73.4 %

Procedure:
To a solution of 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (150 mg, 0.73 mmol) in toluene (8 mL) was added methyl(triphenylphosphoranylidene)acetate (270 mg, 0.81 mmol). The mixture was heated at 110° C. for overnight, cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/hexanes=1/4) to give 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)-acrylic acid methyl ester (140 mg, 73.3%) as a mixture of cis- and trans-isomers (cis-/trans-=1/10). The trans-isomer was then isolated by recrystallization from hexanes to give 60 mg as a solid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][I:20]>CCO>[IH:20].[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]([S:18][CH3:19])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Product: I
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of cis-4,5-diphenylimidazolidine-2-thione (25) (58.16 g, 0.229 mol) and methyl iodide (35.6 mL, 0.87 mol) in abs. EtOH (500 mL) is heated at 95° C. overnight. The reaction mixture is cooled to RT, concentrated in vacuo, and the residue suspended in Et2O. The insoluble material is filtered, washed with Et2O to give 88.9 g of the product 42. 1H NMR (DMSO-d6) δ 10.75 (s, 2H), 7.25-6.95 (m, 10H), 5.85 (s, 2H), 2.82 (s, 3H); MS: m/z 269 (M++1).
Reaction SMILES: C1(P([C:14]2[CH:19]=[CH:18]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(C)C.[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[NH:39][N:38]=1>C1COCC1>[Cl:36][C:37]1[C:45]2[C:40](=[N:41][C:42]([S:46][CH3:47])=[N:43][CH:44]=2)[N:39]([CH:19]([CH3:18])[CH3:14])[N:38]=1
Reactant: CSc1ncc2c(Cl)n[nH]c2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CSc1ncc2c(Cl)nn(C(C)C)c2n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (387 mg, 1.5 mmol) was dissolved in THF (15 mL) and the solution was cooled to −78° C. Diethyl azodicarboxylate (225 uL, 1.5 mmol) was added slowly to the reaction mixture. The reaction was stirred for 5 min and then isopropanol was added (115 uL, 1.5 mmol) dropwise. After stirring an additional 5 min. the 3-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (305 mg, 1.6 mmol) was added as a solid. The resulting suspension was kept at −78° C. for 5 min then the cooling bath was removed. The reaction was stirred for 3 hours at room temperature. After concentration the desired 3-Chloro-1-isopropyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine was obtained by column chromotography (0–5% MeOH/methylene chloride); 1H-NMR (CDCl3): • 1.46 (d, 1H), 2.66 (s, 3H), 4.53 (q, 6H), 8.87 (s, 1H); LC/MS (m/e)=243.0 (MH+), Rt=2.25 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.CCN(C(C)C)C(C)C.I[CH:41]1[CH2:44][N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:42]1.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[C:48]([O:47][C:45]([N:43]1[CH2:44][CH:41]([S:26][C:18]2[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]([C:15](=[O:27])[N:14]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:29][CH3:30])[CH3:28])[CH:17]=2)[CH2:42]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2CN(C(=O)OC(C)(C)C)C2)cc(C(F)(F)F)c1

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.35 g, 802 μmol, example 216, intermediate a) in acetonitrile (4 mL) was added DIPEA (259 mg, 350 μL, 2.00 mmol). The instantly formed yellow solution was treated with tert-butyl 3-iodoazetidine-1-carboxylate (284 mg, 1.0 mmol) and heated to reflux for 75 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.405 g; 85%). MS (ESI): m/z=592.19 [M+H]+.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[CH2:27][CH2:28]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Product: O=C(c1ccc2ccccc2n1)N1CCN(CCc2ccc(F)cc2)CC1

Procedure:
Analogously to Example 1, quinaldic acid is reacted with 1-[2-(4-fluoro-phenyl)ethyl]piperazine, giving {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-quinolin-2-ylmethanone.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:57][CH2:58][N:59]([C:17](=[O:19])[CH2:16][NH:15][C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)=[O:14])[CH2:60][CH2:61]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (0.07 g, 0.00027 mol) in DMF (1.5 mL) was added DIPEA (0.105 g, 0.000819 mol), HOBt (0.044 g, 0.00033 mol) and EDCI.HCl (0.062 g, 0.00033 mol) at ambient temperature. After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.087 g, 0.00033 mol) was and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure afford 0.069 g (54%) of 5-phenyl-pyridine-2-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 468.14 (M+1)+, 82.99%, 1H NMR (DMSO-d6): δ 9.0 (d, 1H), 8.8 (t, 1H), 8.3 (dd, 1H), 8.1 (d, 1H), 7.8 (d, 2H), 7.6-7.4 (m, 4H), 7.2 (dd, 1H), 6.9-6.8 (m, 1H), 4.9-4.8 (m, 1H), 4.3 (d, 2H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.1-1.9 (m, 2H), 1.8-1.5 (m, 2H).