Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccccn3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCc3ccccn3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(2-picolylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (180 mg), 1 N aqueous sodium hydroxide solution (0.77 ml), ethanol (1 ml), and tetrahydrofuran (1 ml) was stirred at room temperature for one hour. 1 N hydrochloric acid (0.77 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(2-picolylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (120 mg, yield: 71%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 83–85° C. (decomposition).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][C:9]=2[O:8]1.[K].C(S([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][N:24]=1)(=O)=O)C>CS(C)=O.C1COCC1>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:23]([O:16][C:11]2[CH:12]=[CH:13][C:14]3[O:15][CH2:7][O:8][C:9]=3[CH:10]=2)=[N:24][CH:25]=1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc3c(c2)OCO3)nc1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
Into a reaction flask was weighed 5.6 g of t-BuOK and then 50 ml of THF was added. In 50 ml of DMSO was dissolved 6.2 g of 3,4-methylenedioxyphenol which was then slowly added to the t-BuOK solution with stirring. To the resulting potassium phenate solution was added 10.5 g of 2,5-bis(ethylsulfonyl)pyridine and this mixture heated at 50°-55° C. for 3 hrs. After cooling, the reaction mixture was poured into 400 g of ice, stirred and then filtered. The solid which was recovered was dissolved in CH2Cl2, treated with charcoal, dried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 50 ml, diluted with an equal volume of hexane and then chilled and a crystalline material recovered, which provided 9.9 g, (80% yield), of 5-(ethylsulfonyl)-2-(3,4-methylenedioxyphenoxy)pyridine, m.p. 97°-99° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:6].Cl>O1CCCC1.CO>[C:12]([N:10]1[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[N:8]=[CH:9]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
Add 1N sodium hydroxide (22.8 mL, 22.8 mmol) to 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.8 g, 7.60 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) at room temperature. Stir the reaction mixture at room temperature for 5 hrs. Acidify the reaction mixture with 5N aqueous hydrochloride to pH about 6. Filter and dry the solid to give the title compound as a white solid (2 g, 5.64 mmol).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:19].Cl>C1COCC1.O.CO>[CH2:1]([O:8][NH:9][CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]([OH:18])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CCCCCC1=CN(OCc2ccccc2)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 1-benzyloxy-3-pentylazetin-2-one (1.82 g, 7.37 mmol) in a mixture of THF—H2O-MeOH (100 mL, 3:1:1 v/v) was added LiOH monohydrate (3.60 g, 73.68 mmol). After stirring at room temperature overnight, water (50 mL) was added to the mixture. The solution was acidified to pH 6 with 3N HCl and extracted with EtOAc (100 mL×2). The combined organic layers were dried over MgSO4, and evaporated under vacuum to yield the title compound (1.60 g, 82%). 1H NMR (400 MHz, CHCl3) δ 9.80 (br s, 1H), 7.37 (m, 5H), 4.75 (m, 2H), 3.14 (m, 2H), 2.74 (m, 1H), 170 (m, 1H), 1.53 (m, 1H), 1.38–1.25 (m, 6H), 0.91 (t, J=6.8 Hz, 3H). MH+ 266.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.36 mmol 2-chloro-6-ethoxy-benzothiazole (CA=[79071-17-3]), 3.00 mmol of piperazine and 3.00 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:18])[N:6]([CH2:13][C:14]([O:16]C)=[O:15])[C:7]2=[O:12].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:18])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]2=[O:12]
Reactant: COC(=O)CN1C(=O)c2cccc(OC)c2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc2c1C(=O)N(CC(=O)O)C2=O
Yield: 47 %

Procedure:
To a solution of methyl 2-(4-methoxy-1,3-dioxoisoindolin-2-yl)acetate (130 mg, 0.522 mmol) in dioxane (15 ml) a 12 N aqueous solution of HCl (15 ml) was added and the mixture was reacted overnight at room temperature. The organic layer was evaporated and the desired compound was extracted with EtOAc (2×20 ml) obtaining the title compound that was used in the next step without further purification (57 mg, 0.242 mmol, 47% yield). MS/ESI+ 236.1 [MH]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([F:36])[CH:23]=1.CN([CH:40]=[O:41])C>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]([F:36])[C:25]([O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:26]([F:28])[C:27]=1[CH:40]=[O:41]
Reactant: CC(C)(C)C(=O)Oc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C(=O)Oc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Add n-butyl lithium 1.6N (23 ml, 36.8 mmol) to diisopropylamine (5.0 ml, 35.6 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 2,2-Dimethyl-propionic acid 4-bromo-2,6-difluoro-phenyl ester (8.01 g, 27.33 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 1 h at −78° C. Add anhydrous DMF (2.8 ml, 35.0 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 8.35 g of the title compound (95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])O1>C(#N)C.CCO.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>[C:11]([O:10][C:9]([NH:8][C:6]1[CH:7]=[C:2](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:3]=[CH:4][C:5]=1[Cl:16])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K2CO3 (2.0 equiv.). The reaction was degassed and flushed with N2, then added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100° C. overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1:1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]P(=O)(OCC)OCC)[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH:23]([C:25]1[N:26]=[C:27]2[C:32]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:30]=[C:29]([C:39]3[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][CH:40]=3)[N:28]2[CH:52]=1)=O>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:23]/[C:25]2[N:26]=[C:27]3[C:32]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:31][CH:30]=[C:29]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[CH:41][CH:40]=4)[N:28]3[CH:52]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Reactant: CCOP(=O)(Cc1cccc(OC)n1)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2cn3c(-c4ccc(C(=O)OC(C)(C)C)cc4)cnc(N4CCOCC4)c3n2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl ((6-methoxypyridin-2-yl)methyl)phosphonate (76.2 mg, 0.29 mmol, prepared according to literature procedure: J. Med. Chem. 2005, 48, 5884-5887), n-BuLi (0.184 mL, 0.29 mmol, 1.6 M in hexanes) was added dropwise. After stirring the resulting mixture for 15 min at rt, it was slowly added to a suspension of compound 67a (100 mg, 0.25 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 30 min and quenched with saturated NH4Cl (2 mL). The reaction mixture was treated with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-100% EtOAc/heptanes) to give (E)-tert-butyl 4-(2-(2-(6-methoxypyridin-2-yl)vinyl)-8-morpholinoimidazo[1,2-a]pyrazin-5-yl)benzoate, which was subjected to TFA deprotection using the methods described in Example 57, Step A to yield the title compound 7 containing 0.1 eq. of TFA. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 8.11 (m, J=7.8 Hz, 2H), 7.83 (m, J=7.8 Hz, 2H), 7.63-7.69 (m, 1H), 7.69-7.75 (m, 1H), 7.49 (s, 1H), 7.40 (d, J=15.7 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 4.29 (br. s., 4H), 3.92 (s, 3H), 3.80 (br. s., 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H23N5O4: 458.2 [M+H]. found 458.4.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.C([O:42][C@@H:43]([CH3:47])[C:44](Cl)=[O:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:44](=[O:45])[C@@H:43]([OH:42])[CH3:47])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@H](C)O)c1
Reaction time: 4 h

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (100 mg, 0.2 mmol) in DCM (5 mL) and triethylamine (0.28 mL, 2 mmol) was treated with the (S)-2-acetoxypropionyl chloride (0.065 mL). After 4 h, the solvent was removed by evaporation and the residue was dissolved in methanol (10 mL) and then treated with solid potassium carbonate (277 mg, 2 mmol) and the mixture was stood at RT for 3 days. The mixture was concentrated under reduced pressure, and the residue was partitioned between 2M HCl and ethyl acetate. The organic solution was washed with more HCl, brine and dried (MgSO4). The filtrate was evaporated under reduced pressure to give a white solid (113 mg). The sample was dissolved in 1:1 MeOH-DMSO 2 mL and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (86 mg, 80%): LCMS (System A) RT=0.97 min, 100%, ES+ve m/z 535/537 (M+H)+; NMR δ (CD3OD) 7.27-7.15 (5H, m), 7.05 (1H, br d, J 7 Hz), 6.97 (1H, d, J 8 Hz), 6.89 (1H, d, J 4 Hz), 6.42 (1H, d, J 8 Hz), 5.47 (2H, s), 4.33 (2H, s), 4.12 (1H, q, J 7 Hz), 3.76 (3H, s), 1.30 (3H, d, J 7 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:13]([O:12][C:10]([N:5]1[C:6]([B:17]([OH:22])[OH:18])=[CH:7][C:8]2[S:9][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2sc(Cl)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2sc(Cl)cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of tert-butyl 2-chloro-4H-thieno[3,2-b]pyrrole-4-carboxylate (0.52 g, 2 mmol) and B(OiPr)3 (0.7 mL, 3 mmol) in 10 mL of THF cooled at 0° C. was added a LDA solution (4 mmol, prepared from 0.56 mL of iPr2NH, 5.84 mL of THF and 1.6 mL of 2.5 M n-BuLi solution in hexane) by a syringe pump over a period of 2 h. The reaction mixture was stirred for additional 6 h at 0° C. before being quenched by addition of 20 mL of saturated NH4Cl solution. The product was extracted with 2×20 mL of EtOAc, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient of up to 60% EtOAc/hexanes to give 0.3 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]([CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]([CH2:18][CH:19]3[CH2:23][CH2:22][O:21][CH2:20]3)=[N:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2nnc(CC3CCOC3)[nH]2)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)O
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a round-bottom flask was added a solution of methyl 2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate (compound 130.5, 600 mg, 1.90 mmol, 1.00 equiv) in methanol (10 mL). A solution of sodium hydroxide (381 mg, 9.53 mmol, 5.00 equiv) in water (5 mL) was added and the resulting mixture was stirred for 3 h at 70° C. in an oil bath. After cooling to room temperature, the organic solvent was then removed under reduced pressure and the pH of the remaining aqueous phase was adjusted to 3-4 with hydrogen chloride (aq., 1 M). The resulting solids were collected via filtration and dried in an oven under reduced pressure to yield 0.500 g (87%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[OH:27].O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
A reaction vessel was charged with 22.67 g of 1,4-dibromobutane, 11.06 g of potassium carbonate and 200 ml of N,N-dimethylformamide, to which a solution of 20.16 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 80 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 300 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 21.77 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (yield, 74%), nD25.0 1.5666.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][OH:33]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=2)[CH:7]=1
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(C(F)(F)F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 3-(trifluoromethyl)benzyl alcohol (132 mg; 0.736 mmol), example 69 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:5]=2[CH2:4][O:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1.CCOC(C)=O>[CH3:16][S:17]([O:14][CH2:13][CH2:12][C:11]1[C:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2c(CCO)cccc2O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OCc2c(CCOS(C)(=O)=O)cccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethanol (400 mg, 1.92 mmol, 1 eq.) in THF (20 mL) were added MsCl (438 mg, 3.84 mmol, 2.0 eq.) and TEA (0.8 mL, 5.76 mmol, 3.0 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (400 mg, crude) as a pale brown oil, which was used for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH2:9][CH3:10])[CH3:8])[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>C(Cl)Cl>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH2:9][CH3:10])[CH3:8])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCC(C)c1cc(N)on1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.2 %

Procedure:
To a solution of 5-amino-3-sec-butylisoxazole (500 mg; 3.57 mmol; 1 equiv.) and pyridine (0.58 mL; 7.13 mmol; 2 equiv.) in DCM (30 mL) was added 0.74 mL (5.35 mmol; 1.5 equiv.) of 2,2,2-trichloroethyl chloroformate dropwise. The reaction mixture was stirred overnight at room temperature, then diluted with DCM, and washed sequentially with water, 1N HCL aqueous solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue, 1.58 g of (3-sec-Butyl-isoxazol-5-yl)-carbamic acid 2,2,2-trichloro-ethyl ester was isolated as a pale yellow oil, and used as is in the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>C1COCC1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccn1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.7 g (241.7 mmol) of NaH (60%) in 400 mL of anhydrous THF at 0° C. there are added 20 g (161.13 mmol) of methyl 1H-pyrrole-2-carboxylate (see Tetrahedron 2008, 64, 7745). The whole is subsequently stirred at ambient temperature for one hour. Then, there are added 95 mL of 1,4-dibromobutane. After the addition, the reaction mixture is heated at reflux for 12 hours. The precipitate obtained is filtered off and then washed with THF. The filtrate is subsequently concentrated to dryness. The compound is then isolated by chromatography over silica gel (cyclohexane/ethyl acetate gradient: 0 to 20%) in the form of an oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH2:4].Br[CH2:6]/[CH:7]=[CH:8]/[CH:9]=[CH2:10]>>[CH:9]12[CH2:10][NH:1][CH2:2][CH:3]1[CH2:4][CH2:6][CH:7]=[CH:8]2
Reactant: C=CCN
Reactant: C=C/C=C/CBr
Product: C1=CC2CNCC2CC1

Procedure:
Introduce 228 g (4.0 mol) of 1-amino-2-propene. Add dropwise with stirring 58.8 g (0.4 mol) of (E)-1-bromo-2,4-pentadiene (title compound of Example A.1.). Keep the internal temperature in a range of 20°-30° C. by means of cooling. Stir for 5 h at room temperature. Concentrate batch at 150 mbar. Add 20 g (0.5 mol) of sodium hydroxide, dissolved in 200 ml of water, extract the mixture twice using in each case 100 ml of methylene chloride, dry using sodium sulphate, add 0.1 g of 4-hydroxyanisole, concentrate and distil at 40 mbar. 10-20 ppm of 4-hydroxyanisole are added to stabilize the distillate.