Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][C:9]1=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:26])[CH2:10][CH2:11]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
8.9 g of (S)-5-biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1-a, R1=BOC) (25.3 mmol) is dissolved in 90 ml methylene chloride. Then 5 ml CF3COOH are added. This mixture is stirred at rt for 1.5 h. The reaction mixture is concentrated. Heptane fraction is then added to the residue. The product is crystallized. The obtained product is dissolved in toluene and then it is washed with NaHCO3 (aq) solution. The organic layer is evaporated to yield (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)]. Spectroscopic data as in Example 3.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCO1
Temperature: 0 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
Tetrahydrofurfuryl alcohol (2.01 g, 19.7 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL) under an argon atmosphere, cooled to 0° C. and treated sequentially with triethylamine (3.02 mL, 21.7 mmol, 1.1 eq) and methanesulfonyl chloride (1.60 mL, 20.7 mmol, 1.05 eq.). The ice bath was removed and stirring continued for 14 h before the mixture was poured into a separatory funnel containing water. The phases were separated and the organic layer was washed with water (4×), dried on MgSO4, filtered and concentrated in vacuo to yield 3.26 g [92%] of tetrahydrofurfuryl methanesulfonate as a crude pale yellow oil, used in the subsequent displacement step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.[NH:44]1[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH2:21][N:44]4[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]4)[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: OC[C@@H]1CCNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CC[C@@H](CO)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.310 g, 0.537 mmol) and (R)-pyrrolidin-3-yl-methanol (0.163 mL, 1.610 mmol) in dichloromethane (0.035 mL, 0.537 mmol) and methanol (0.022 mL, 0.537 mmol) was treated with sodium triacetoxyborohydride (0.341 g, 1.610 mmol). The solution was stirred at room temperature overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give (R)-(1-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)pyrrolidin-3-yl)methanol (0.188 g, 0.284 mmol, 52.9% yield). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reactant: CB1OB(C)OB(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: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H)
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1>C(O)(=O)C>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)ccc1-n1cccc1

Procedure:
100 g (0.75 mole) of 2,5-dimethoxytetrahydrofuran are added dropwise to a stirred solution of 86.3 g (0.5 mole) of 4-chloro-2-nitroaniline in 500 ml. of glacial acetic acid. The solution is refluxed under a nitrogen atmosphere for 30 minutes, filtered, and poured into 2500 ml. of water. The aqueous solution is extracted with chloroform. The chloroform solution is dried with anhydrous sodium sulfate and concentrated to a brown oil. The brown oil is dissolved in an ether-petroleum ether-mixture and placed in a refrigerator overnight. An orange solid precipitates and is recrystallized from an ether petroleum ether mixture to give 1-(4-chloro-2-nitrophenyl) pyrrole, m.p. 55°-56° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](OC(OCC)OCC)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:17]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: Brc1ccc(-c2nnco2)cc1
Temperature: 2.5 °C
Yield: 89.9 %

Procedure:
To a suspension of 4-bromobenzoic hydrazide (200 g) in industrial methylated spirit (700 ml) was added triethylorthoformate (309 ml), industrial methylated spirit (100 ml) and sulphuric acid (0.8 ml). The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to 0-5° C. and product crystallised. Product was isolated, washed and dried to yield 2-(4-bromophenyl)-1,3,4-oxadiazole (186.1 g, 89.9%). 400 MHz NMR Spectrum: (DMSOd6) 9.35 (s, 1H), 7.98 (d, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.81 (d, 1H); Mass Spectrum MH+ 224.9663 (calc. using 79-Br) Found 224.9701.
Reaction SMILES: [CH3:1][CH:2]([N:11]([C:13]([CH2:15][NH2:16])=[O:14])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:22]1([CH2:28][CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.CCOC(C)=O>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:13](=[O:14])[C@H:15]([NH2:16])[CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:1]
Reactant: BrCCCc1ccccc1
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol), prepared and used by the method of Myers et al. (J. Am. Chem. Soc. 1997, 119, 656), and LiCI (1.71 g, 40.5 mmol) in THF (30 mL) was cooled to −78° C. and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution). After stirring for 20 min at −78° C., the reaction was warmed to 0° C. and stirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL, 7.42 mmol) was added and the reaction was stirred for 2 h at 0° C. Aqueous 1 N HCl (50 mL) and EtOAc (50 mL) were added, the organic phase was separated and extracted with 1 N HCl (50 mL). The aqueous extracts were combined, cooled in an ice bath and slowly basified to pH 14 with 6 N NaOH. The product was extracted with CH2Cl2 (4×50 mL) and the combined extracts were dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography (SiO2 gel, 92:4:4, CH2Cl2:MeOH:triethylamine) delivered 400 mg (78%) of the Product of Example 199, Step A: +APcI MS (M+1)+ 341; 1H NMR=400 MHz (CDCl3) δ: 7.38 (m, 10H), 5.26 (m, 1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
First, 1.0 g (6.1 nmmol) of trans-4-ethylcyclohexane carboxylic acid was mixed with 1.1 g (9.2 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 60° C. for hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude trans-4-ethylcyclohexylcarbonylchloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (0.051 g, 0.484 mmol). After 10 minutes stirring at room temperature pentyl iodide (0.063 ml, 0.484 mmol) was added and stirring continued under nitrogen at room temperature for 18 hours. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated. Purification by SPE (Si, 5 g) eluting with 4:1 EtOAc/cyclohexane afforded the title compound as a white solid (96 mg, 74%); m/z 297.2[MH+].
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:17])=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[C:2]1([CH2:1][S:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:17])=[N:12][N:11]=2)=[O:46])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CSCc4ccccc4)s3)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Reaction time: 2 h

Procedure:
0.1 g of tert-butyl trans-{4-[4-(5-benzylsulfanylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acetate (0.11 mmol, 1 eq.) is placed in 10 mL of dichloromethane with stirring. 0.027 g of 70% meta-chloroperbenzoic acid (0.11 mmol, 1 eq.) is added. After 2 hours, 0.01 g of 70% meta-chloroperbenzoic acid (0.41 mmol, 0.37 eq.) is added. After 16 hours, the reaction medium is diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried and evaporated. The residue is triturated in ethyl acetate to give 0.072 g of tert-butyl trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:18][CH2:17][C:10]3([NH:14]C(=O)N[C:11]3=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>O1CCOCC1>[NH2:14][C:10]1([C:11]([OH:19])=[O:16])[CH2:17][CH2:18][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C1NC(=O)C2(CC[C@H](c3ccc(Br)cc3)C2)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 95 °C
Reaction time: 24 h
Yield: 109.5 %

Procedure:
To (7S)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (I-1B, 13.9 g, 45.0 mmol) in 1,4-dioxane (40 mL) in a round bottom flask was added aqueous NaOH (2N, 100 mL, 200 mmol). The mixture was heated to 95° C. and stirred for 24 hours. Additional NaOH (25 mL, 50 mmol) was added and heating continued for another two days. The solution was cooled with an ice-bath, neutralized with 5N HCl to approximately pH 7 resulting in the formation of a white precipitate. The solids were collected by filtration and dried under high vacuum for 2 days to provide 14 g of (3S)-1-amino-3-(4-bromophenyl)cyclopentanecarboxylic acid as a white solid which was used as such for the subsequent step without further purification. HPLC retention time=0.64 min (Condition G) LC/MS M+1=284/286.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH3:29]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:29])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)Cl)cc1-c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(N)(=O)=O)cc1-c1ccccc1

Procedure:
To a solution of 4-chlorosulfonyl-2-phenylbenzoyl methionine methyl ester from Example 5E in dichloromethane is added aqueous ammonia and the mixture is stirred until the reaction is judged complete by TLC analysis. The organic phase is separated, dried and evaporated and the product is purified by chromatography on silica gel.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1)(C(C)(C)C)(C)C>CO>[OH:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Solvent: CO
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (1.8 g, 4.04 mmol) in MeOH (60 mL) was added MeOH pre-washed DOWEX-50W-X4 100-200 (3.60 g, 4.04 mmol) resin. After stirring at rt for 2 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (assume quantitative). LCMS: Rt=0.52 min, m/z=332.1 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C@@:2]12[C:8](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[C-:17]#[N:18].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C@:8]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@H:6]2[C@:2]1([CH3:1])[CH:3]=[CH:4][CH2:5]2)#[N:18]
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@]12C
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@@]1(C#N)C[C@@H]2CC=C[C@@]21C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Tert-butyl(±)-[(1S,5R)-5-methyl-bicyclo[3.2.0]hept-3-en-6-ylidene]acetate (300 mg, 1.36 mmol) and potassium cyanide (89 mg, 1.36 mmol) were mixed at room temperature in anhydrous dimethyl sulfoxide (2 mL), and the mixture was stirred for 2 hours and then left overnight. The mixture was further stirred for 10 hours in an oil bath at 100° C. and then left overnight. The reaction solution was diluted with ethyl acetate, then washed with water and saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil (128 mg). In this procedure, a by-product tert-butyl(±)-[(1S,5R,6R)-6-cyano-5-methyl-bicyclo[3.2.0]hept-3-en-6-yl]acetate was obtained as a colorless oil (45 mg).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:27]=[CH:26]C(C#N)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:28].[C:29]([OH:32])(=[O:31])[CH3:30]>O>[ClH:28].[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:27]=[CH:26][C:30]([C:29]([OH:32])=[O:31])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C#N)cc3)CC2)cc1
Agent: Cl
Solvent: O
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A solution of 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]-benzonitrile (0.582 g) in the mixture of conc. HCl (5.8 ml) and acetic acid (2.9 ml) was refluxed for 3 hours. The reaction mixture was pulverized with water (25 ml). The precipitate was collected by filtration to give 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (0.51 g).
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[C:3]([F:13])([F:12])[C:4]([F:11])([F:10])[CH2:5][CH2:6][CH2:7][CH2:8]O.[BrH:19].S(=O)(=O)(O)O>O>[Br:19][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:11])([F:10])[C:3]([F:13])([F:12])[C:2]([F:18])([F:1])[C:14]([F:17])([F:16])[F:15]
Reactant: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 12.50 g of 4-(nonafluorobutyl)-1-butanol and 150 mL of 48 weight percent hydrobromic acid was slowly added 15 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 18 hr, and then poured into 500 mL of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. Filtration and concentration afforded 12.50 g of crude 1-bromo-4-(nonafluorobutyl)butane as a light amber liquid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[NH:10])=[CH:4][CH:3]=1.Cl[C:20](=[CH2:23])[C:21]#[N:22].C(N(CC)C(C)C)(C)C.N#N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:23][CH:20]([C:21]#[N:22])[N:10]=[C:9]2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: C=C(Cl)C#N
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Part A: A magnetically stirred mixture of N-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (10.0 gram, 0.033 mol), 2-chloroacrylonitrile (5.7 gram, 0.065 mol) and N,N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) is heated at reflux temperature for 40 hours (N2 atmosphere). After cooling to room temperature the mixture is concentrated in vacuo. The residue is dissolved in a mixture of dichloromethane and water (200 ml/200 ml). The dichloromethane layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from ethanol/water to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carbonitrile (11.23 gram, 97% yield). 1H-NMR (400 MHz, CDCl3): δ 4.28 (dd, J=10 and 8 Hz, 1H), 4.36 (t, J=10 Hz, 1H), 5.07 (dd, J=10 and 8 Hz, 1 H), 6.68 (br d, J=8 Hz, 2H), 7.16 (br d, J=8 Hz, 2H), 7.32-7.36 (m, 2H), 7.45 (d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]2[CH:35]=1.C(OCC)(=O)C>C1COCC1>[N:28]1[C:27]([CH2:26][N:15]2[C:14](=[O:19])[C:13]3[CH:20]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=4)[CH:10]=[CH:11][C:12]=3[O:18][CH2:17][CH2:16]2)=[CH:35][N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: O=C1NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCCN1Cc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% in oil) was added, followed shortly by 2-(chloromethyl)imidazo[1,2-a]pyridine (29 mg) and stirred overnight at room temperature. Worked up with ethyl acetate and pH 7 buffer organic layer dried over MgS(O)4 and concentrated. Purification was conducted on normal phase (CH2Cl2/10% EtOH in ethyl acetate gradient) followed by reverse-phase (ACN/H2O, 0.1% TFA). Resulting glassy solid was dissolved in dioxane, diluted 10-fold with 0.1N HCl and lyophilized resulting in 4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one hydrochloride salt as a white solid (42.2 mg).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1.CC(C)=O>CC(=O)CC>[CH2:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CC(C)CCNCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Isoamylamine (4 mL, 34.5 mmol) was added to a solution of 1,3-propane sultone (4.7 g, 38 mmol) in 2-butanone (70 mL). The mixture was warmed to reflux. After 30 minutes, the mixture was too thick to stir. Acetone (15 mL) was added. The reflux was maintained for a total of 4 hours. The suspension was cooled at room temperature. The white solid was collected by filtration, rinsed with acetone (10 mL), then with ether (10 mL). Compound CH was obtained as a very light, fluffy white solid (4.48 g, 62% yield). m.p. 220° C.: decomposed. 1H NMR (500 MHz, D2O) δ 0.65 (d, J=6.3 Hz, 6H), 1.29 (q, J=7.7 Hz, 2H), 1.35-1.42 (m, J=6.6 Hz, 1H), 1.86 (qt, J=7.6 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.81 (t, J=8.1 Hz, 2H), 2.93 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.3, 21.4, 25.2, 34.2, 46.1, 46.2, 47.9