Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:26])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
19.5 g (73.13 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 860 ml of dichloromethane, and 0.5 ml of DMF was added. At −5° C. to −10° C. (ice/acetone cooling bath), 73 ml (146.26 mmol) of a 2 M solution of oxalyl chloride in dichloromethane were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was concentrated under reduced pressure and the residue obtained was taken up in 200 ml of dichloromethane and then once more evaporated to dryness. This gave 20.1 g (70.5 mmol, 96% of theory) of the title compound as a colourless oil. The product obtained in this manner was used without further purification and without further spectroscopic characterization in subsequent reactions.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.C(C1C=CC([Mg]Br)=CC=1)(C)(C)C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:4](=[O:5])[C:6]([C:15](=[O:16])[C:14]3[CH:9]=[CH:10][C:11]([C:6]([CH3:15])([CH3:7])[CH3:4])=[CH:12][CH:13]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.25 mL 2M 4-tert-butylphenylmagnesium bromide. Yield: 80 mg of a white solid. LC-MSD, m/z for C26H23BrN2O2 [M+H]+=475.0, 477.0; HPLC retention time: 2.9 min.
Reaction SMILES: CC1C(C(C2C=CC(C#N)=CC=2)C=C)=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH3:27][C:28]1([CH3:52])[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]2[CH:33]=[C:32]([CH:40]([C:43]3[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=3)[CH:41]=[CH2:42])[CH:31]=[CH:30][C:29]1=2.O.[NH2:54][C:55]1[NH:59][N:58]=[N:57][N:56]=1>C1COCC1>[CH3:27][C:28]1([CH3:52])[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]2[CH:33]=[C:32]([CH:40]([C:43]3[CH:51]=[CH:50][C:46]([C:47]([NH:54][C:55]4[NH:59][N:58]=[N:57][N:56]=4)=[O:48])=[CH:45][CH:44]=3)[CH:41]=[CH2:42])[CH:31]=[CH:30][C:29]1=2
Reactant: Nc1nnn[nH]1
Reactant: C=CC(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Solvent: O
Product: C=CC(c1ccc(C(=O)Nc2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
1 equivalent of N,N′-carbonyldi-imidazole (Aldrich, 0.46 g, 0.29 mmol) is added, at ambient temperature to a solution of acid (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzoic acid (0.10 g, 0.29 mmol) in 5 ml of anhydrous THF. Half an hour later, 1 equivalent of 5-aminotetrazole monohydrate (Aldrich, 0.30 g, 0.29 mmol) is added. The magnetic stirring is continued for 15 hours 30 minutes. A white precipitate forms in the reaction medium. The mixture is evaporated to dryness and 10 ml of HCl is added. The solution is filtered and the filtrate washed with water and with methanol. After drying one night in a desiccator (with P2O5), 15 mg of a white solid is obtained the compound (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]-N-(tetrazol-5-yl)-benzamide (compound CB73364) (yield=12%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:10][CH3:11].C(OCC)(OCC)(OCC)C.[ClH:29].[C:30](#[N:32])[CH3:31]>>[ClH:29].[CH3:31][C:30]1[N:10]([CH3:11])[N:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:32]=1
Reactant: CNN(Cc1ccccc1N)c1ccccc1
Reactant: CC#N
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Product: CC1=Nc2ccccc2CN(c2ccccc2)N1C
Yield: 60 %

Procedure:
To a solution of 3.5 g (0.0154 m) of 1-[(2-aminophenyl)methyl]-2-methyl-1-phenylhydrazine of Example 9c in 40 ml of acetonitrile and 4.87 g (0.03 m) of triethyl orthoacetate was added sufficient ethereal HCl to make the solution acidic. The mixture was refluxed 5.5 hours. The solvents were evaporated and the residue was partitioned between 10% NaOH and ether. The ether extract was washed with water, dried (Na2SO4) and filtered. The product was precipitated with ethereal HCl to afford 2.63 g (60%) of 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3,4-benzotriazepine hydrochloride, m.p. 274°-277° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 65%), MS (ISP) m/z=415.5 [(M+H)+], mp 180.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and pentanoic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cc(-c2ccccc2)c(Br)s1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2ccccc2)c(C(O)c2ccccc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A solution of tert-butyl [(5-bromo-4-phenyl-2-thienyl)methyl]methylcarbamate (1.0 g) in tetrahydrofuran was cooled to −78° C., and 1.6 mol/L n-butyllithium-hexane solution (1.96 mL) was added dropwise. After stirring at the same temperature for 1 hr, benzaldehyde (334 mg) in tetrahydrofuran (3 mL) was added dropwise. The mixture was gradually warmed to room temperature, and stirred for 2 hr. The reaction mixture was treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the title compound as a pale-yellow oil (yield 607 mg, yield 57%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[N:2]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CC(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: OCc1ccc2[nH]nnc2c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: O=Cc1ccc2[nH]nnc2c1
Reaction time: 18 h
Yield: 52.3 %

Procedure:
A suspension of (1H-benzo[d][1,2,3]triazol-5-yl)methanol (0.860 g, 5.77 mmol) in acetone (25 mL) was purged with Ar, by bubbling through solution, then PDC (2.60 g, 6.92 mmol) was added portion-wise over 20 min. The reaction was stirred overnight (18 hrs). The acetone was removed in vacuo, the solids dissolved in MeOH and silica gel was added. The MeOH was then removed and the silica dry-loaded onto a silica gel column, and the product eluted with 1:1 Hexanes/EtOAc to give 444 mg, 52% of a white solid. 1H NMR (400 MHz, CD3OD) δ 10.14 (s, 1H), 8.55 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H); MS ESI 148.0 [M+H]+, calcd for [C7H5N3O+H]+ 148.14.
Reaction SMILES: [OH-].[Na+].C([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([O-:8])=[O:7])C.O.Cl>CO>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:5]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]([OH:8])=[O:7])=[CH:19][CH:18]=1
Reactant: CCC(C(=O)[O-])(c1ccc(Br)cc1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(c1ccc(Br)cc1)C1CCCC1

Procedure:
386 ml (96.4 mmol) of 10% strength aqueous sodium hydroxide solution were added to a solution of 30 g (96.4 mmol) of (+/−)-ethyl(4-bromophenyl)(cyclopentyl)acetate in 655 ml of methanol, and the mixture was heated under reflux for 3 h. After cooling, the solution was stirred into 2 liters of water, adjusted to pH 1-2 by addition of dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated. This gave 27.2 g (92% of theory) of the title compound.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17]#[N:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12.C(O)(=O)C.[Cl-].[NH4+:28]>CO>[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17](=[NH:28])[NH2:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: N#Cc1nc(Cc2ccccc2F)c2ncccn12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, 6.98 g (32.30 mmol) of sodium methylate (25% solution in methanol) was put in 50 ml methanol and 8.000 g (30.76 mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile dissolved in 40 ml of absolute methanol was added. The reaction mixture was stirred for 1 h at RT. 7.205 g (119.98 mmol) of acetic acid and 1.975 g (36.92 mmol) of ammonium chloride were added and the mixture was stirred for 2 h at 50° C. The reaction mixture was concentrated by evaporation and the residue was distributed between 150 ml water and 100 ml ethyl acetate. The aqueous phase was made basic (pH=10) with 2N sodium hydroxide solution and the phases were stirred for 1 h at RT. Water was added and it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, concentrated by evaporation and the residue was dried under high vacuum. 7.53 g (purity 73%, 66% of theor.) of the target compound was obtained.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[Cl:29][CH2:2][CH2:3][N:4]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C)CC3)ncc2c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 2 h

Procedure:
To a solution of 8.0 g of ethyl 5,8-dihydro-8-(2-hydroxyethyl)-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate in 80 ml of chloroform was added with stirring 6 ml of thionyl chloride, the resulting mixture was allowed to react at room temperature for 30 minutes and then heated to refux for 2 hours. After removal of the solvent and an excess of the reagent, the residue was taken up in chloroform. The chloroform solution was washed with water, dried and the solvent distilled off. The solid obtained was recrystallized from ethyl acetate to give 6.9 g of the product, m.p. 154° - 155°C.
Reaction SMILES: [ClH:1].N[N:3]1[CH2:7][C:6](=[O:8])[N:5](CCCCN2CCN(C)CC2)[C:4]1=[O:20].[Cl:21]C1C=CC(C2OC(C=O)=CC=2)=CC=1>CN(C)C=O>[ClH:21].[ClH:1].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:20]
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: CN1CCN(CCCCN2C(=O)CN(N)C2=O)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-amino-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione, hydrochloride (0.0094 mole), dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarbox aldehyde [prepared as described in U.S. Pat. No. 4,882,354, to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued Nov. 21, 1984; see Cols. 7 and 8 hereby incorporated by reference herein] (1.94 g, 0.0094 mole) is stirred at ambient temperature for 72 hours. The mixture is filtered, collecting the solid. Recrystallization from absolute ethanol/H2O and air-drying gives 2.63 g (0.0050 mole) of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]3-[4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].[CH2:20](O)[CH3:21]>O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reactant: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To 70 mg of (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetic acid was added 3 ml of ethanol containing 7% hydrogen chloride, and the mixture was stirred under a dry atmosphere at room temperature for 2 hours. To this was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a residue, which was chromatographed over 7 g of silica gel and eluted with n-hexane/acetone (10/1), thereby yielding 70 mg (yield: 91%) of ethyl (10,11-dihydro dibenzo[b,f]thiepin-2-yl)-acetate as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][CH3:6])=[O:4].CO[C:18](OC)([CH3:20])[CH3:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:15][C:18]([CH3:20])([CH3:19])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)CC(O)CC(O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC1CC(C(=O)OC)OC(C)(C)O1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 1-methyl 6-ethyl 2,4-dihydroxyadipate (1.5 g, 6.81 mmol) in methylene chloride (60 ml), dimethoxypropane (1.672 ml, 78 mmol) and pyridinium p-toluenesulfonate (251 mg, 1 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 50° C. for one hour while azeotropically removing methanol with methylene chloride. Then, after adding methylene chloride (60 ml), the mixture was again stirred at 50° C. for one hour to remove methylene chloride (50 ml). To the residue, water was added, and the mixture was extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=5:1) to give pure 2-methoxycarbonyl-4-ethoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (1.29 g, 4.99 mmol). Yield, 73 %.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])\[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])\[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:10][C@H:9]3[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CO/N=C(\COc1ccc(C=O)cc1)c1ccccc1C
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Product: CO/N=C(\COc1ccc(CNc2ccc([C@@H]3C[C@H]3C(=O)O)cc2)cc1)c1ccccc1C
Yield: 28 %

Procedure:
Compound 15 was synthesized from methyl (1R,2R)-2-(4-aminophenyl)cyclopropane carboxylate (0.18 g, 0.9 mmol) and 4-{[(2Z)-2-(methoxyimino)-2-(2-methylphenyl)ethyl]oxy}benzaldehyde (0.31 g, 1.1 mmol) by following the procedure described in Scheme 3 (0.12 g, yield: 28%); Purity: 91.26%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C@H:10]([C:12]([CH:14]([SH:27])[C@@H:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])=[O:13])[CH3:11])=[O:8].[Na+].[I-:29]>CC#N>[I:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C@H:10]([C:12]([CH:14]([SH:27])[C@@H:15]([CH3:26])[C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)OCCCCCl)C(=O)C(S)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](NC(=O)OCCCCI)C(=O)C(S)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 100.4 %

Procedure:
1-[(4-chlorobutoxycarbonyl)-L-alanyl-(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (3.15 g, 0.0078 Mol) was dissolved in CH3CN (100 ml) and NaI (11.7 g, 0.078 Mol) was added to the solution. The mixture was refluxed for 7 h, then concentrated and diluted with CH2Cl2. The solid formed was filtered off and the organic phase was washed with H2O (3×50 ml), dried over sodium sulphate and evaporated under reduced pressure affording 1-[(4-iodobutoxycarbonyl)-L-alanyl-(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (4.03 g) as a foam that was used without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@@H:27]2[C@:44]3([CH3:45])[C@H:30]([C@H:31]4[C@H:41]([CH2:42][CH2:43]3)[C@:39]3([CH3:40])[C:34]([CH2:35][C@@H:36]([O:53][CH:54]5[CH2:59][CH2:58][CH2:57][CH2:56][O:55]5)[CH2:37][C@@H:38]3[O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:33][CH2:32]4)[CH2:29][CH2:28]2)[CH2:14][CH2:15][C@@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])(=O)=O)=CC=1.[I-:60].[Na+].CC(C)=O.O>C(Cl)Cl>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][C@@H:38]1[C@@:39]2([CH3:40])[C:34](=[CH:33][CH2:32][C@@H:31]3[C@@H:41]2[CH2:42][CH2:43][C@@:44]2([CH3:45])[C@H:30]3[CH2:29][CH2:28][C@@H:27]2[C@H:13]([CH2:12][I:60])[CH2:14][CH2:15][C@@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])[CH2:35][C@@H:36]([O:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[CH2:37]1
Reactant: [I-]
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.223 g. (0.00026 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), and 0.150 g. (0.0010 mole) of sodium iodide in 2 ml. of acetone was heated at 50° for 18 hr and cooled. The mixture was poured into water and the product was isolated with methylene chloride. The organic layers were washed with aqueous sodium sulfite solution, and saturated aqueous sodium bicarbonate solution. The organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].N1CCCCC1.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14]
Reactant: CC(=O)c1ccc[nH]1
Reactant: COc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Temperature: 130 °C

Procedure:
Alternatively, a mixture of 5-methoxyindolin-2-one (0.50 g, 3.1 mmol), 2-acetylpyrrole (0.28 g, 2.4 mmol) and piperidine (0.60 g, 0.6 mmol) was placed in a sealed tube and melted. The reaction vessel was sealed and the mixture was heated to 130° C. overnight. The reaction was then cooled to ambient temperature and dissolved in ethyl acetate (2 mL). Chromatography (SiO2, 15 g) using 2:1 hexane/ethyl acetate afforded 5-methoxy-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (0.24 g); 1H NMR (400 MHz, DMSO-d6) δ 2.78 (s, 3H), 3.82 (s, 3H), 6.38 (m, 1H), 6.70–6.80 (m, 2H), 6.98 (m, 1H), 7.16 (m, 1H), 7.30 (m, 1H), 7.68 (m, 1H) ppm.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:28]=2)[N:23]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:22]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH2:10][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH:39]([CH3:40])[CH3:41])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:28]=2)[N:23]([C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:22]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2C(=O)c4ccccc4C2CCO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2C(=O)c4ccccc4C2CCO)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (123 mg, 0.1476 mmol) dissolved in THF (2 mL) under N2. TBAF in THF (442.8 μL of 1.0 M, 0.4428 mmol) in THF added and the mixture stirred for 90 mins. Reaction mixture partitioned between DCM and brine. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue purified by chromatography (silica, 0-100% EtOAc-petrol gradient). Title compound obtained as a yellow film, (87 mg, 82%), taken on directly to deprotection reaction; MS (ES+) 719.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]2[C:22]([CH:25]=O)=[CH:23][S:24][C:20]=2[CH:19]=1>>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]2[C:22]([CH2:25][N:15]3[CH2:16][CH:13]([CH2:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:14]3)=[CH:23][S:24][C:20]=2[CH:19]=1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: O=Cc1csc2cc(Cl)ccc12
Agent: Cl
Product: O=S(=O)(CC1CN(Cc2csc3cc(Cl)ccc23)C1)c1ccc(F)cc1

Procedure:
Prepared according to the method of Example 23 using 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 6-chloro-1-benzothiophene-3-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 7.92–7.88 (2H, m), 7.81 (1H, d, J=1.8 Hz), 7.72 (1H, d, J=8.5 Hz), 7.32 (1H, dd, J=1.9, 8.6 Hz), 7.26–7.22 (2H, m), 7.19 (1H, s), 3.73 (2H, s), 3.44 (2H, t, J=7.5 Hz), 3.37 (2H, d, J=7.3 Hz), 2.92 (2H, t, J=7.1 Hz), 2.87–2.80 (1H, m). m/z (ES+) 394 (M+H)+.