Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([NH:50][CH2:51][CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([N:50]([CH2:51][CH3:52])[C:18](=[O:20])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:16][CH2:15]1)=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: CCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.100 g, 0.34 mmol) in methylene chloride (6.0 mL) was added EDCI (0.085 g, 0.44 mmol) and HOBt (0.060 g, 0.44 mmol) at room temperature. After 1 h N-benzyl-N-ethyl amine (0.050 g, 0.37 mmol) was added at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 0:100 heptane/ethyl acetate, gradient elution) to provide N-benzyl-2-(4-(2-tert-butylphenyl)piperazin-1-yl)-N-ethyl-2-oxoacetamide as a mixture of cis and trans isomers (0.026 g, 19%) as a white foam.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:49]=[CH:48][S:47][CH:46]=3)[C:19]2=[O:50])=[N:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:49]=[CH:48][S:47][CH:46]=3)[C:19]2=[O:50])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccsc3)c3ccccc32)C(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccsc3)c3ccccc32)C(C)C)cc1
Reaction time: 4 h
Yield: 14.9 %

Procedure:
To 590 mg (0.80 mmol) of crude 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-thiophen-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 59, is added 10 mL of 4N HCl in dioxane at RT. The resulting solution is stirred 4 h and 100 mL of Et2O is added. The precipitate is filtered and purified by RP-HPLC (30-60% acetonitrile/ H2O over 30 min) to afford 71 mg of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ7.78 (d, 1H, J=8.1), 7.59-7.24 (m, 9H), 7.06 (m, 9H), 4.75 (m, 1H), 4.47 (d, 1H, J=17.1), 4.15 (m, 3H), 3.82 (s, 3H), 3.44 (m, 2H), 0.98 (d, 3H, J=6.9), 0.94 (d, 3H, J=6.9); low resolution MS (FAB) m/e 594 (MH+); RP-HPLC Tr =16.2 min (30-60% acetonitrile/ H2O).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 86 %

Procedure:
A solution of 5 g (19 mmol) of (4-iodo-phenyl)-acetic acid in 50 mL of methanol (MeOH) was added dropwise 3.5 mL (48 mmol) of thionyl chloride (SOCl2), and the resulting mixture was stirred at rt for 36 h, after which time analysis by thin layer chromatography (TLC) indicated product formation. The mixture was concentrated to give 4.5 g (86% yield) of (4-iodo-phenyl)-acetic acid methyl ester as a pale beige oil as indicated by 1H NMR.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]>C1COCC1>[OH:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:15][CH2:16]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane 1-carboxylic acid (IX, Example 85a, 1 wt) and tetrahydrofuran-(1 l vol) are mixed under nitrogen. Borane tetrahydrofuran complex (1 M) in THF (5.1 vol) is added at such a rate as to maintain the internal temperature between 10 to 20°. The mixture is stirred at 10 to 20°for 17 to 20 hours until all of the acid (X) is consumed (TLC; dichloromethane/methanol, 9/1, visualization UV then potassium permanganate). Methanol (4.2 vol) is added to the reaction, prior to heating at reflux for 45 to 75 min. The reaction is cooled to between 15 and 40°and the solvent removed by reduced pressure at 40 to 45°. The residue is partitioned between ethyl acetate (16.6 vol) and hydrochloric acid (1 M, 2.5 vol) and the aqueous layer is removed with any undissolved solid material. This mixture is clarified and the residual organic phase from the filtration of the aqueous layer/solid mixture is combined with the bulk organic phase. Saturated sodium hydrogen carbonate (2.5 vol) is added and the layers separated, retaining any solids with the aqueous phase. This aqueous phase/solid mixture is filtered and the residual organic phase from these mother liquors is combined with the bulk organic phase. The combined organic phases are washed with saline (2.5 vol), the layers are separated and any residual solid is retained with the aqueous phase. The aqueous phase/solid mixture is filtered and any organic in the mother liquors from the filtration is combined with the bulk organic phase, dried with magnesium sulphate (0.5 wt) for 5 to 15 mins, filtered, washed with ethyl acetate (1 vol) and the solvent removed under reduced pressure at 40 to 45°to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:16][C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)=[O:4].[OH-].[K+].Cl>CO.O>[N+:13]([C:11]1[CH:12]=[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[NH:16][C:8]2=[N:9][CH:10]=1)([O-:15])=[O:14]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Yield: 98 %

Procedure:
5-Nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (6 g, 27.1 mmoles) was dissolved in methanol/water mixture (1/1). Potassium hydroxide (3 eq) was added and the mixture was heated at reflux overnight. After cooling down, the mixture was acidified until pH=3 by hydrochloric acid 3N. The precipitate was filtered off, washed with water, then diethyl ether, and dried under vacuum. A brownish solid, 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, is obtained (5.47 g). Yield=98%. ESI-MS: m/z 208 ([M+H]+). HPLC purity: 100%
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:11][CH2:12][CH:13]1[O:15][CH2:14]1)(=[O:10])[C:7]([CH3:9])=[CH2:8]>C(OCC1OCCC1)(=O)C(C)=C>[C:6]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: CNCCO
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C=C(C)C(=O)OCC1CCCO1
Product: C=C(C)C(=O)OCC(O)CN(C)CCO

Procedure:
10.0 g (133.1 mmol) of 2-(methylamino)ethanol and 85 g of tetrahydrofurfuryl methacrylate were weighed into a 250 ml three-neck flask with magnetic stirrer bar, thermometer and reflux condenser. At room temperature, 19.5 g (137.1 mmol) of glycidyl methacrylate were slowly added dropwise while stirring constantly. In the course of this, slight exothermicity was observed, but the temperature never exceeded 70° C. After stirring at 70° C. for 6 hours, it was possible to detect only small traces of 2-(methylamino)ethanol by means of a gas chromatograph. This approx. 25% product solution in tetrahydrofurfuryl methacrylate was transferred into a glass bottle and used in the model formulations without further workup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:56][C:53]1[CH:54]=[CH:55][C:50]([NH:49][C:22](=[O:23])[CH2:21][O:20][C:19]2[CH:25]=[CH:26][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:51][CH:52]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4ccc(C)cc4)cc3)c2cc1OC
Yield: 41 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. p-Toluidine (0.055 ml) was then added to the solution, and the mixture was heated under reflux for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (76 mg, yield 41%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[OH:17])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:24]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([OH:17])[CH:11]=1)(=[O:26])[CH3:25]
Reactant: OCc1ccc(Oc2cccc(F)n2)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Oc2cccc(F)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
To a solution of 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol (0.42 mmol; 104 mg) under argon, in anhydrous DMF (0.8 mL), were added K2CO3 (0.5 mmol; 68 mg), DMAP (0.08 mmol; 12 mg), and acetic anhydride (0.41 mmol; 0.04 mL). The reaction was stirred at room temperature overnight. After dilution with ethyl acetate (4 mL), the organic phase was washed with saturated NaHCO3 (3*3 mL), dried (MgSO4), concentrated in vacuo, purified by preparative TLC (dichlorométhane) to yield the title compound as a clear oil (3 mg; 0.01 mmol; 3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:33]=[N:34][CH:35]=2)[C:5]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.C(Cl)[Cl:37].O1CCOCC1>Cl>[ClH:1].[ClH:37].[Cl:1][C:2]1[C:3]2[N:4]([CH:33]=[N:34][CH:35]=2)[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCNCC1
Reaction time: 0.25 h
Yield: 199.1 %

Procedure:
To tert-butyl 4-{8-chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}piperazine-1-carboxylate (8.0 mg, 0.016 mmol) in methylene chloride (0.5 mL, 8 mmol), 4.0 M hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was stirred for 15 minutes. Evaporation gave the desired compound (7.5 mg, 99%). LCMS calculated for C18H21ClN9 (M+H)+: m/z=398.2. found: 397.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH2:11](I)[CH3:12].O1CCOCC1>C(OCC)C>[CH2:11]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:12]
Reactant: CCI
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCSc1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of 25 grams (0.193 mole; M.W. 125.19) of 3-aminothiophenol in 200 ml. of 5N sodium hydroxide was added, dropwise, over a period of 1 hour, a solution of 29.9 grams (0.193 mole) of ethyl iodide in 50 ml. of 1,4-dioxane. The resulting suspension was allowed to stir at room temperature for 1 hour, 200 ml. of ethyl ether were then added, and stirring was continued for an additional 30 minutes. The ether layer was separated, washed with a saturated aqueous solution of sodium bisulfite, dried over Na2SO4, and evaporated in vacuo to yield 28.10 grams of m-ethylthioaniline.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1>C1(C)C(C)=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])[CH:12]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)c1
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 16.0 g (0.1 mole) 3-toluoyl chloride in 250 ml xylene was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and the resulting precipitate removed by filtration. The crude product was washed with petroleum ether and then recrystallized twice from toluene to obtain 4.0 g (12% yield) of pure product; m.p. 142° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C:6]1[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.O.C(Cl)Cl>[CH3:21][O:22][C:23](=[O:32])[CH:24]([N:9]1[C:8](=[O:12])[CH:7]=[C:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[C:2]([F:1])([F:17])[F:18])[CH:11]=[N:10]1)[CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1cc(Cc2ccccc2C(F)(F)F)cn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
A solution of 5-(2-trifluoromethyl-benzyl)-2H-pyridazin-3-one (219.6 mg, 0.86 mmol) in tetrahydrofuran (4.32 mL, 0.2M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (41 mg, 1.03 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 223 mg, 0.95 mmol). The reaction was then warmed to 50° C., where it stirred overnight. After this time, the reaction was diluted with water (150 mL) and methylene chloride (30 mL) and the resulting bilayer was extracted with methylene chloride (3×75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 25-40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid methyl ester (155.9 mg, 44%) as a yellow oil; ES+-HRMS m/e calcd for C21H23N2O3F3 [M+H+] 409.1734, found 409.1733.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)\[C:13]#[N:14])=[CH:7][CH:6]=1)C.O.S(=O)(=O)(O)O>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15](/[C:12](=[CH:11]/[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)/[C:13]#[N:14])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(OCC)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1ccc(/C(C#N)=C/c2ccc(C=O)cc2)cc1OC
Yield: 81.7 %

Procedure:
4-Diethoxymethyl-benzaldehyde (4.16 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (6.54 g, yield: 89%). The thus-produced (Z)-3-(4-diethoxymethyl-phenyl)-2-(3,4-dimethoxy-phenyl)-acrylonitrile (1.84 g) was dissolved in methanol, and water and 2N sulfuric acid were added to the resultant solution, followed by stirring, to thereby produce the target product (1.20 g, yield: 82%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([S:7][C:8]([F:11])([F:10])[F:9])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([S:7]([C:8]([F:11])([F:10])[F:9])=[O:24])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1cc(Br)c(-c2ccc(Cl)cc2)[nH]1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(c1cc(Br)c(-c2ccc(Cl)cc2)[nH]1)C(F)(F)F
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 3-bromo-2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (0.65 g, 0.00182 mol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.52 g, 60% pure, 0.00182 mol) in chloroform, stirred for two hours, treated with saturated sodium metabisulfite solution, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a white solid. Flash chromatography of the solid using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (0.34 g, mp 177°-179° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25](F)=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH2:32]([SH:34])[CH3:33].[H-].[Na+]>C1COCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25]([S:34][CH2:32][CH3:33])=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCSc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 90.4 %

Procedure:
To a solution of the 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)piperidin-4-ol (described in e. above) (2.00 g, 5.00 mmol, 1 eq) in THF (50 mL) under nitrogen was added the sodium salt of ethanethiol (0.90 g, 10.7 mmol, 2.2 eq). The thiolate salt was prepared from ethanethiol and sodium hydride under standard conditions. The reaction was heated to reflux for 18 h and quenched by pouring into water (100 mL). The aqueous phase was extracted with diethyl ether (2×100 mL), dried over anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (200 mL, eluent: 50% ether in hexane) to yield 2.00 g (90%) of the title compound. TLC analysis (Rf 0.29, 50% ether in hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23]#[N:24].[I-].[K+]>CC(C)=O>[C:23]([CH2:22][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)#[N:24]
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: N#CCOC(=O)CCc1c[nH]c2ccccc12

Procedure:
3-(1H-Indol-3-yl)propanoic acid (5 g, 26 mmol) was dissolved in acetone (50 ml), and caesium carbonate (4.2 g, 13.0 mmol), chloroacetonitrile (1.8 ml, 28.6 mmol) and potassium iodide (20 mg) were added in succession. After a reaction time of 3 d at room temperature with exclusion of moisture, the solid residues were separated off by filtration and the filtrate was concentrated. The crude product of the ester was obtained only in a yield of 3.6 g by this procedure. The filtrate was taken up again in acetone (25 ml) and, for better solubility of the caesium salt formed as an intermediate product, DMF (25 ml) was added. The residue separated off previously, chloroacetonitrile (1.8 ml, 18.6 mmol) and potassium iodide (20 mg) was added to this solution. The reaction mixture was stirred at 60° C. for 3 h and at room temperature for 16H, with exclusion of water. The solid residues was separated off by filtration and the filtrate was concentrated. It was possible to obtain further crude product of the ester, which still contained DMF. The two crude products were combined and purified by chromatography on silica gel with ethyl acetate/cyclohexane (1:3). The desired cyanomethyl ester was obtained as a beige-coloured compound with a melting point of 72° C. in a yield of 91% (5.36 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:15]=1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([N:16]2[CH2:17][CH2:18][N:19]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:21]2)[N:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
3-(1H-benzo[d]imidazol-2-yl)-5-(piperazin-1-yl)pyrazin-2-amine (50 mg, 0.169 mmol) was dissolved in DCM (3 mL) and Et3N (70.0 μL, 0.507 mmol) followed by ethanesulfonyl chloride (17.6 μL, 0.186 mmol) were added. The reaction was allowed to stir for 30 mins and then diluted with dichloromethane and washed with water. The aqueous layer was extracted further with dichloromethane and the organics washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (42.6 mg, 65% Yield). MS (ES+) 388.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: BrBr
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CBr)cc1F
Reaction time: 0.17 h
Yield: 6.2 %

Procedure:
To a solution of 3′-fluoro-4′-methoxyacetophenone (1 g, 5.9 mmmol) (Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine (1.13 g, 7.1 mmol) in dioxane (30 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:4 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone as a white powder (91,0 mg, 63% yield).