Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:15])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:15])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 217.6 %

Procedure:
To a stirred mixture of 4-isopropoxy benzoyl chloride (15 mmol, 2.97 g) and hydroquinone (7.5 mmol, 0,825 g) in CH2Cl2 (50 ml), pyridine (2 ml) was added in 15 minutes. After stirring for 1 hour, the mixture was extracted with water, 10% HCl and water (100 ml each). Then the solvent was evaporated and the remaining solid recrystallized from ethanol/CH2Cl2 (70/30), giving 2.56 g of the product (yield 79%, melting point (mp) 195° C.).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[C:35]([S:42](Cl)(=[O:44])=[O:43])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[F:32][C:33]1[CH:34]=[C:35]([S:42]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:44])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 0 °C
Yield: 52.7 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydro chloride (500 mg, 1.25 mmol, Example 91, Step 1), CH2Cl2 (10 mL) and triethylamine (0.52 mL, 3.74 mmol). 3-Fluoro-4-nitrobenzenesulfonyl chloride (328 mg, 1.371 mmol, Matrix Scientific, Columbia, S.C.) was added and after 10 min the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si]([C:17]#[CH:18])(C)C>C(NCC)C.[Cu]I>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:17]#[CH:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCNCC
Product: C#Cc1ccc(CCCCC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.1 mol of 4-pentyliodobenzene, 0.12 mol of trimetylsilylacetylene, 0.0014 mol of bis(triphenylphosphine)-palladium(II) Chloride Pd(PPh3)2Cl2 and 0.7 mmol of copper (I) iodide in 250 ml diethylamine is stirred at room temperature for 20 hours. After evaporation of the solvent the crude product is purified by chromatography on alumina (4:1 petrol/dichloromethane) to give 2-(4-pentylphenyl)-1-trimethylsilyacetylene. Removal of the trimethylsilylgroup is accomplished by treatment this acetylene is methanol with 1 M KOH for 1 hour at room temperature. Evaporation of the methanol and either extraction yields 4-pentylphenylacetylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[NH3:11].[OH-].[Na+]>C(#N)C>[NH2:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: N
Reactant: ClCc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 14.99g of 2-chloro-5-(chloromethyl) pyridine, 63.01g of 25% ammonia water and 60ml of acetonitrile in a stainless steel autoclave was stirred for 2 hours in an oil bath of 80° C. After adding 12.3g of 30% sodium hydroxide aqueous solution, the reaction mixture was concentrated. The residue to which 200ml of ethanol were added was dried over anhydrous magnesium sulfate and, filtered to remove insoluble materials. The filtrate was concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 7.66g of 5-(aminomethyl)-2- chloropyridine as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(CN)O.OCCN1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:27]>>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:14](=[O:27])[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20]=2[C:21](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:23]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCO
Reactant: NCCCO
Solvent: NCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCO

Procedure:
Following the procedure of example 1(a) and (b) but substituting 3-aminopropanol for the ethanolamine in part (a) one obtains 2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1([O:15][CH2:16][CH3:17])[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH2:9]1.Cl[CH2:22][C:23]([NH2:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][C:8]1([O:15][CH2:16][CH3:17])[CH:9]=[CH:10][C:11]([NH:14][CH2:22][C:23]([NH2:25])=[O:24])=[CH:12][CH2:13]1
Reactant: CCOC1(OCc2cccc(Cl)c2)C=CC(N)=CC1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC1(OCc2cccc(Cl)c2)C=CC(NCC(N)=O)=CC1
Reaction time: 40 h

Procedure:
31 g (0.104 mol) of 4-(3-chlorobenzyloxy)phenetylamine hydrochloride are suspended in 450 ml of anhydrous ethanol. To this mixture, 9.7 g (0.104 mol) of chloroacetamide and 28.8 g (0.208 mol) of anhydrous potassium carbonate are added. After heating to reflux, stirring is continued for 40 hours. The hot mixture is filtered, then evaporated to dryness and the crude residue chromatographed on silica gel (eluant CHCl3/MeOH/conc. NH4OH; 97/3/0.3). The free compound obtained (20.2 g; 60.7%) is treated with gaseous HCl in ethanol to give a quantitative yield of the corresponding [4-(3-chlorobenzyloxy)phenetyl]aminoacetamide, hydrochloride, m.p. 248°-251° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 2.24 g (10.7 mmol) 2,4-Dichlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 0.75 g (22%) of the title compound. MS (m/e): 481.1 (MH+, 100%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (23.4 g, 110 mmol) described in Manufacturing Example 2-1-2, nitromethane (33.6 g, 550 mmol), ammonium acetate (17.0 g, 220 mmol) and acetic acid (200 mL) was stirred for 1 hour and 45 minutes at 100° C. The reaction solution was stirred on an ice bath while adding a small amount of water, and the precipitated solids were filtered to obtain the title compound (21.0 g, 74.5%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)C.[NH3:21]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:21])=[O:3])=[C:8]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[CH:9]=1
Reactant: N
Reactant: CCOC(=O)COc1ccc(Cl)cc1Cc1ncc[nH]1
Product: NC(=O)COc1ccc(Cl)cc1Cc1ncc[nH]1

Procedure:
Treatment of 4-chloro-2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester with ammonia as described in Example 8 gave 4-chloro-2-(1-imidazolylmethyl)phenoxyacetamide, m.p. 162°-164° C. (from isopropanol/petrol). Found: C, 53.91, H, 4.51, N, 15.79. C12H12ClN3O2 requires: C, 54.23, H, 4.57, N, 15.81%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]([CH3:16])([CH3:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([CH:17]([CH3:19])[CH3:18])[C:3]=1[C:20](=O)[CH3:21].Cl.[CH3:24][O:25][NH2:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:24][O:25][N:26]=[C:20]([C:3]1[C:4]([CH:17]([CH3:19])[CH3:18])=[N:5][N:6]([C:7]([CH3:16])([CH3:15])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2]=1[OH:1])[CH3:21]
Reactant: CC(=O)c1c(C(C)C)nn(C(C)(C)Cc2ccccc2)c1O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1c(C(C)C)nn(C(C)(C)Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
150 mg (0.50 mmol) of 1-(5-hydroxy-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)ethanone, 209 mg (2.50 mmol) of methoxyamine hydrochloride and 286 mg (3.49 mmol) of sodium acetate were mixed with 1.3 ml of distilled water and 1.3 ml of ethanol and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 4 g, ethyl acetate:hexane=1:99) to give 70 mg of the desired product as an orange oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][C:14]=2[F:23])[N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[NH:5][CH:4]=[C:3]([C:1]#[N:2])[C:11]=23)=[C:14]([F:23])[CH:15]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(C#N)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
30 mg (0.065 mmol) of N-[4-({3-cyano-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide are dissolved in a mixture of 3 ml of ethanol and 3 ml of THF. 1.5 ml of 20% strength aqueous sodium hydroxide solution are added, and the mixture is heated at 90° C. overnight. Another 1 ml of 20% strength-aqueous sodium hydroxide solution is then added, and a further ml after 6 hours. The mixture is again stirred overnight. The reaction mixture is then partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is reacted without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(N(CC)CC)C.Cl[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([F:45])([F:44])[F:43])[CH:40]=2)[N:35]=[CH:34][N:33]=1>CCO>[OH:23][C@@H:19]([C:20]#[C:21][CH3:22])[C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([F:44])([F:45])[F:43])[CH:40]=2)[N:35]=[CH:34][N:33]=1)[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CN
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
Benzyl (2S,3S)-2-(2-aminoacetamido)-3-hydroxyhex-4-ynylcarbamate (194 mg, see procedure 15a) was dissolved in EtOH (3 mL) and the resultant solution was charged with triethylamine (0.42 mL) and 4-chloro-6-(trifluoromethyl)quinazoline (141 mg). The mixture was heated at 80 C for 14 h, cooled to RT, and concentrated in vacuo to afford benzyl (2S,3S)-3-hydroxy-2-(2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamido)hex-4-ynylcarbamate (186 mg). MS found: (M+H)+=516.3.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1.O>CN(C=O)C>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=1)[CH2:27][N:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[N:12]=[C:11]2[NH:16][CH2:17][C:18]#[CH:19])[CH2:5][CH2:4]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)SC1=CC1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (198 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (164 mg).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CN1CCOCC1.[CH3:15][O:16][C:17](Cl)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])=[O:18]
Reactant: O=C1CCC(=O)N1
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)N1C(=O)CCC1=O
Reaction time: 2 h

Procedure:
To a solution of 19.8 g (200 mmole) of succinimide and 22 ml (200 mmole) of N-methylmorpholine in 350 ml THF at -5° was added 15.5 ml (200 mmole) methylchloroformate over 20 minutes. After stirring for two hours at 25°, the solvent was removed under reduced pressure and the residue was taken up in EtOAc. The suspension was filtered, and washed with saturated NaCl, saturated NaHCO3, and saturated NaCl. After drying, the solution was concentrated under reduced pressure and Et2O was added, giving the product as a crystalline solid, 10.0 g. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1]([Mg]I)[CH3:2].[Mg].C(I)C.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([F:18])[CH:11]=1>C(OCC)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH3:2])=[C:12]([F:18])[CH:11]=1
Reactant: CC[Mg]I
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: CCI
Product: CCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a ice-cold solution of ethyl magnesium iodide prepared from magnesium (2.39 g, 98.51 mmoles) and ethyl iodide (7.88 ml, 98.51 mmoles) in diethyl ether (50 ml), 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmoles) in diethyl ether (10 ml) was added and warmed to room temperature. After 12 h, the reaction mixture was cooled to 0° C., quenched with dilute HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5.8 g, 99% yield) which is used as such for step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([O:24]CC)=O)[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:22]([NH2:27])=[O:24])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Solvent: CO
Product: Cn1c(C(N)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate and 2 M NH3 in MeOH following the method of example 36, step B (method B). LC-MS: Rt=3.6 min. m/e=379.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([N+:17]([O-])=O)=[CH:10][C:11]=1[CH2:12]2.O.O.Cl[Sn]Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[S:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:17])=[CH:10][C:11]=1[CH2:12]2
Reactant: COc1cccc2c1Sc1ccc([N+](=O)[O-])cc1C2
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2c1Sc1ccc(N)cc1C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-Methoxy-2-nitro 9H-thioxanthene (11.59 g, 42.40 mmol) was suspended in ethyl acetate (250 ml). SnCl2.2H2O (47.84 g, 212 mmol) was added and the clear yellow solution was stirred at 50° C. overnight. The reaction was the quenched with NaOH (2M) and then extracted with ethyl acetate (3×300 ml). The organics were washed with saturated brine (100 ml), dried over magnesium sulphate and the solvents were removed in vacuo to give the title compound (10.32 g, 100%) as viscous yellow oil. The oil was used without further purification. 1HNMR (300 MHz, DMSO-d6): δH=3.83 (3H, s), 3.67 (2H, s), 5.14 (2H, bs), 6.43 (1H, dd), 6.61 (1H, d), 6.89 (1H, d), 6.99 (1H, d), 7.06 (1H, d), 7.18 (1H, t). m/z (LC-MS, ESP), RT=3.88 min, (M++1)=244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(S(F)(F)[F:47])CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:38])([F:39])[F:40])[CH2:35][CH2:36]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([F:47])[CH2:18][CH2:19]2)[C:10]1=[O:21]
Reactant: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
Treat a 0° C. solution of 1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-3-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.090 g, 0.15 mmol) in CH2Cl2 (5 mL) with (diethylamino)sulfur trifluoride (0.049 g, 0.305 mmol) and stir for 1 hour at 0° C. under N2. Quench the reaction with saturated NaHCO3, dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.019 g (85%) of the titled product. Rf=0.56 (9/1 CH2Cl2/methanol). ES MS (m/z): 600 (M+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH:26]([OH:27])[C:34]([F:37])([F:36])[F:35])[CH2:28][CH3:29])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C(F)(F)F)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (100 mg, 0.218 mmol; Example 130, Step A) in THF (2.2 mL) was added trimethyl(trifluoromethyl)silane (97 μL, 0.66 mmol) at 0° C. and the reaction was stirred for 5 min. Then 1 M TBAF in THF (327 μL, 0.327 mmol) was added slowly at 0° C. After being stirred at 0° C. for 40 min, the reaction was quenched (sat. aq. NaCl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 13% and 23% EtOAc/Hex) provided the title compound as a mixture of two diastereomers.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C:6](=O)[CH3:7].[CH2:10]([C:17]#[N:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].CO>>[CH3:7][C:6]([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]#[N:18]
Reactant: CC(=O)CCC=C(C)C
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCCC(C)=C(C#N)c1ccccc1
Yield: 23.9 %

Procedure:
To the mixture of 6-methyl-hept-5-en-2-one (90.86 g, 0.72 mol) and benzyl cyanide (46.8 g, 0.40 mol) is added dropwise a 4 N solution of KOH in MeOH (25.0 ml, 0.10 mol). The resulting suspension is heated to reflux during 4.5 h. Then methanol is removed by distillation and the residue is washed with 6 N aq. HCl-solution, then water, sat. aq. NaHCO3-solution and brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled twice over a Widmer column to yield 3,7-Dimethyl-2-phenyl-octa-2,6-diene nitrile (21.5 g, 24%, (E/Z) mixture) as a colourless oil (b.p. 122DC/0.1 mbar).
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:15]([CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[OH:20])([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:20][CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)C(O)C(C)(C)C
Reactant: CC1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-2-amino 1-[di-(t-butyl)methoxy]propane.