Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([O:50][CH3:51])[C:44]=1[O:45]S(C)(=O)=O)[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl.O1CCOCC1>ClCCl.ClCCl.CO.CO>[CH3:51][O:50][C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:44]=1[OH:45])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OS(C)(=O)=O)c(OC)c4)C3)CC2)nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(O)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium carbonate (0.5 g). After 18 hours, add a 1 M aqueous sodium hydroxide solution (1 mL) and extract with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 6/1/0.1 to give a residue. Combine the residue and dichloromethane (4 mL). Add a solution of hydrochloric acid in dioxane (0.12 mL, 4 M, 0.48 mmol). Warm to ambient temperature. After 1 hour, evaporate in vacuo to give a residue. Triturate with diethyl ether to give a solid. After 1 hour, collect the solid by filtration and dry to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:19]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (1000 mg, 4.37 mmol), phenol (493 mg, 5.24 mmol), potassium carbonate (1200 mg, 8.73 mmol) and acetone (20 mL) was stirred at 60° C. under nitrogen atmosphere for 4 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1) to give methyl 4-(phenoxymethyl)benzoate as a white solid (1100 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.35-7.30 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 6.98 (t, J=7.2 Hz, 1H), 5.23 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [ClH:1].[CH:2](=[C:9]1[C:14](=O)[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][NH:26][NH2:27]>CO>[ClH:1].[C:3]1([CH:2]2[CH:9]3[CH2:10][NH:11][CH2:12][C:13](=[CH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[N:27][N:26]2[CH2:25][C:24]([F:29])([F:28])[F:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNCC(F)(F)F
Reactant: O=C1C(=Cc2ccccc2)CNCC1=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: FC(F)(F)CN1N=C2C(=Cc3ccccc3)CNCC2C1c1ccccc1
Yield: 107 %

Procedure:
3,5-Dibenzylidene-4-piperidone, hydrochloride (10.0g) is reacted with 5.8 g of 70% aqueous 2,2,2-trifluoroethylhydrazine in 220 ml of methanol at reflux for 4 hours. Evaporation of the methanol on a rotary evaporator leaves 14 g of a foamy residue which crystallizes when triturated with 50 ml of boiling acetonitrile to yield (after cooling for about 16 hours) 10.3 g of material, melting point 206°-209° C (sintering at 195° C). Crystallization from 80 ml of ethanol yields 6.7 g of product, melting point 207°-209° C, sintering at 196° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]CC2C=CC=CC=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:28]([F:30])[F:29])[N:6]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:28]([F:30])[F:29])[N:6]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(c1ccccc1)n1c(C(F)F)cc2c(Cl)c(OCc3ccccc3)ccc21
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1c(C(F)F)cc2c(Cl)c(O)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (2.6 g, 5.82 mmol) in anhydrous CH2Cl2 (80 mL), under N2, at −78° C., was slowly added a solution of BBr3 in CH2Cl2 (1M, 6.1 mL). After stirring at −78° C. for 30 min, additional BBr3 solution (1M, 0.3 mL) was added and stirring was continued at −78° C. for 30 min. While at −78° C., sat'd aqueous NaHCO3 solution (˜10 mL) was added slowly, the cold bath was then removed and the reaction mixture brought to rt. The mixture was partitioned between CH2Cl2 and sat'd NaHCO3 solution. The aqueous phase was washed with CH2Cl2. The combined organic phases were washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc-hexanes gradient) to afford the title compound (1.87 g, 89% yield): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.32 (t, J=54.2 Hz, 1H), 7.12-7.08 (m, 2H), 5.42 (bs, 1H); MS (ES) m/z 356 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[CH2:29]([CH2:31][NH2:32])[OH:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[OH:30][CH2:29][CH2:31][NH:32][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with ethanolamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=419.3 [M+H]+.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1Br
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmol) and bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol), capped with a rubber septum, evacuated, and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol), 2-bromochlorobenzene (191 mg, 1.0 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 5 minutes, then heated at 80° C. for 2 hours and 5 minutes. The reaction mixture was cooled to room temperature and washed with saturated aqueous sodium chloride (2 mL). The organic layer was filtered through celite and concentrated in vacuo. The product was isolated as a yellow solid (208 mg, 71%) by flash chromatography on silica gel using 5% ethyl acetate in hexanes as eluent.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][O:16][CH2:17][CH2:18][C:19](OCC)=[O:20])=[CH:13][CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][CH2:17][CH2:18][C:19](=[O:20])[CH2:1][C:2]#[N:3])=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCOCc1ccc(OC)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COCCC(=O)CC#N)cc1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of MeCN (31.8 mL, 611.0 mmol) in anhydrous THF (500 mL) at −78° C. was slowly added n-BuLi (2.5 M, 244.4 mL, 611.0 mmol) The mixture was stirred at the same temperature for 1 h and to it was added a solution of at −78° C. was slowly. The mixture was stirred added n-BuLi (2.5 M, 244.4 mL, 611.0 mmol). The mixture was stirred ethyl 3-((4-methoxybenzyl)oxy)propanoate (112 g, 470.0 mmol) in THF (200 mL). The resulting mixture was stirred at −40° C. for 2 h and then quenched with 1 N aqueous HCl (300 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and then concentrated in vacuo to give 5-((4-methoxybenzyl)oxy)-3-oxo-pentanenitrile (78 g, 79%) as yellow oil.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-cyclopentene-1-ol (9.00 g, 107 mmol) in dry methylene chloride (150 mL) was added TEA (23.0 mL, 160 mmol) followed by DMAP (100 mg). To this solution was added methanesulfonyl chloride (14.72 g, 128 mmol) at 10-20° C. slowly over 15 minutes and stirred overnight at room temperature. To the reaction mixture was added aqueous saturated NaHCO3 (50 mL) and stirred for 15 minutes at room temperature. The organic layer was separated, washed with water, followed by brine and dried over NaSO4. It was filtered and concentrated to give the title compound as an oil that was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3): δ=5.72 (s, 2H), 5.38 (mc, 1H), 3.00 (s, 3H), 2.81-2.61 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C=C>>[CH2:22]([N:7]1[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[C:6]1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=1)[CH:21]=[CH2:20]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Product: C=CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.3 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1M solution, 1.08 mmol) and allyl bromide (0.041 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.3%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]([CH3:12])[N:5]=2)[CH2:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([CH3:12])[C:7]=1[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: Cn1nc(C2CC2)cc1C(=O)O
Solvent: CC(=O)O
Product: Cn1nc(C2CC2)c(Br)c1C(=O)O

Procedure:
A solution, cooled to 0° C., of 100 mg (0.60 mmol) of 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid in 5 ml of acetic acid is admixed with 173 mg (1.08 mmol) of bromine and afterstirred overnight at room temperature. Acetic acid and bromine are drawn off on a rotary evaporator and the solid residue is washed with cyclohexane and a small amount of diethyl ether. This gives 69.0 mg of 4-bromo-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (47%) as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([I:18])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][N:6]([OH:9])[CH:7]=[O:8].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:14]([O:13][C:12]1[C:2]([NH:1][CH3:19])=[CH:3][C:4]([CH2:5][N:6]([OH:9])[CH:7]=[O:8])=[CH:10][C:11]=1[I:18])[CH2:15][CH2:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCCCOc1c(N)cc(CN(O)C=O)cc1I
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCOc1c(I)cc(CN(O)C=O)cc1NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A mixture of N-(3-amino-4-butoxy-5-iodo-benzyl)-N-hydroxy-formamide (36 mg, 0.1 mmol), potassium carbonate (11 mg, 0.11 mmol) and iodomethane (9.2 ul, 0.15 mmol) in DMF (1 ml) was stirred 18 h at room temperature. The mixture was partitioned between ethyl acetate and water, the organic extract was washed with brine then dried with sodium sulfate and all voltiles removed. Purification by preparative HPLC afforded the title compound (8 mg, 22%) 1H NMR (400 MHz, CD3OD) δ 8.36* 7.16 (s, 1H), 7.00 (s, 1H), 6.59 (s, 1H), 4.58* 4.54 (s, 2H) 3.84 (t, j=6.2 Hz, 2H), 2.83* 2.81 (s, 3H) 1.83-1.87 (m, 2H), 1.54-1.59 (m, 2H), 1.03 (t, j=7.1 Hz, 3H). M+1=379.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccccn1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
2-Ethylpyridine (20.0 g, 186.65 mmol) was placed in carbon tetrachloride (830 mL) and benzoyl peroxide (4.5211 g, 18.665 mmol) and 1-bromopyrrolidine-2,5-dione (33.221 g, 186.65 mmol) were added. The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified over a plug of silica to give 2-(1-bromoethyl)pyridine (17.312 g, 49.9%). 1H NMR (CDCl3) δ 8.58 (d, 1H), 7.69 (td, 1H), 7.76 (d, 1H), 7.20 (dd, 1H), 5.24 (q, 1H), 2.08 (d, 3H)
Reaction SMILES: [CH3:1][N:2](C)[CH2:3]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][CH2:43][C:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48](O)=[O:49])=[O:45])[N:41]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([C:37]2[S:38][CH:39]=[C:40]([CH2:42][CH2:43][C:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48]([N:2]([CH3:3])[CH3:1])=[O:49])=[O:45])[N:41]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)O)cs2)cc1OCC
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3C(=O)N(C)C)cs2)cc1OCC
Reaction time: 2 h
Yield: 59.8 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) (54 mg, 0.29 mmol), 1-hydroxybenzotriazol (HOBT) (43 mg, 0.29 mmol), and a 50% aqueous dimethylamine solution (0.025 ml, 0.29 mmol) were added at room temperature to a solution (2 ml) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoic acid (100 mg, 0.24 mmol) in DMF, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated salt solution in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, to thereby obtain 65 mg (yield: 61%) of 2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}-N,N-dimethylbenzamide as a colorless oil.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][C:17]=1[O:23][CH2:24][CH3:25])#[N:20]
Reactant: CCOc1cc(N)ccc1C#N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: CCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-ethoxy-benzonitrile.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:26])[CH:9]=1)[CH2:6][CH3:7])[CH3:4].[CH3:35][O:36][CH2:37]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([C:5]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH3:34])[CH:28]=1)([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:25][CH2:35][O:36][CH3:37])([C:21]([F:22])([F:23])[F:24])[C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:26])[CH:9]=1)[CH2:6][CH3:7])[CH3:4]
Reactant: COCCl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 33 %

Procedure:
Sodium hydride (60%, 513 mg, 12.84 mmol) was added to a solution of 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenol (Example 26-(1); 5.91 g, 12.84 mmol) in N,N-dimethylformamide (60 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred for 30 minutes. Then, methoxymethyl chloride (1.45 mL, 19.26 mmol) was added, and the mixture was stirred at room temperature for 30 minutes and at 60° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1, 10:1 and 4:1) to give the target product as a colorless oil (2.14 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:29]3[CH2:30][C@@H:25]4[CH2:31][C@H:28]3[CH2:27][O:26]4)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: C1O[C@@H]2CN[C@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3C[C@@H]4C[C@H]3CO4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate. Orange oil. MS (m/e): 317.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[CH:2].[CH2:18]([N:25]=[N+:26]=[N-:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(C)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:18]([N:25]1[CH:2]=[C:1]([C:3]2[N:4]=[C:5]3[C:11]([C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:10][NH:9][C:6]3=[N:7][CH:8]=2)[N:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cn(Cc4ccccc4)nn3)nc12
Yield: 22.7 %

Procedure:
A solution of 1-(2-ethynyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.100 g, 0.44 mmol), benzyl azide (0.055 mL, 0.44 mmol), CuSO4 (0.007 g, 0.04 mmol), and L-ascorbic acid (0.078 g, 0.44 mmol) in 3 mL of tert-butanol and 3 mL of water was stirred for 1.5 h, then diluted with 30 mL of water and extracted with 100 mL of ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->50% EtOAc/hexanes) afforded 0.036 g (23%) of 1-[2-(1-benzyl-1H-[1,2,3]triazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as an off-white solid. MS: 361 M+1, M.P. 235.0-237.0° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)C(C)C)(C)C.[F:16][C:17]([F:38])([F:37])[C:18]([N:20]([CH:28]1[CH2:30][CH:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:19]>C(#N)C>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:20]([CH:28]2[CH2:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18](=[O:19])[C:17]([F:16])([F:37])[F:38])[CH2:27][CH2:26]1)#[N:6]
Reactant: O=C(N(CC1CCNCC1)C1CC1c1ccccc1)C(F)(F)F
Reactant: N#CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CCCCN1CCC(CN(C(=O)C(F)(F)F)C2CC2c2ccccc2)CC1

Procedure:
Added 4-bromobutanenitrile (100 mg, 0.674 mmol) to a solution of N,N-diisopropylethylamine (0.353 mL, 2.022 mmol), 2,2,2-trifluoro-N-(2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (220 mg, 0.674 mmol) in acetonitrile (25 mL) and heated to reflux for 16 hours. Concentrated on rotovap and the residue was purified via Biotage (0% to 100% EtOAc:Hex; then 0% to 20% MeOH:DCM to get off more product: 10 g-HP—silica gel column).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12](C(OC)=O)[CH2:11][CH2:10]1.O.NN.[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)N1CCN(c2ccncc2OC)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnccc1N1CCNCC1
Yield: 46.2 %

Procedure:
A solution of methyl 4-(3-methoxy-4-pyridinyl)-1-piperazinecarboxylate (1.2 g, 4.7 mmol) in 50 mL of EtOH containing 1 mL of 85% hydrazine hydrate and potassium hydroxide (12 g, 210 mol) was heated to reflux for 12 h. The reaction mixture was cooled, concentrated in vacuo and the residue dissolved in EtOAc. The organic extracts were dried (brine, MgSO4), filtered and concentrated in vacuo. Silica gel chromatography (3:1:0.01 CH2Cl2 -MeOH-Et3N) of the residue gave the desired compound (0.42 g, 46%).