Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(N(CC)CC)C.Cl[C:12]1[CH:13]=[CH:14][C:15]([O:39][CH3:40])=[C:16]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[O:26])(=[O:20])=[O:19])[CH:17]=1>CS(C)=O.O>[Cl:1][C:12]1[CH:13]=[CH:14][C:15]([O:39][CH3:40])=[C:16]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[NH:35])[NH:2][OH:3])=[CH:30][CH:29]=2)=[O:26])(=[O:19])=[O:20])[CH:17]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C#N)cc2)c1
Reactant: NO
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (0.24 mg, 3 mmol) was suspended in dimethyl sulfoxide under an argon atmosphere. Triethylamine (0.34 g, 3 mmol) was added dropwise. The mixture was stirred at room temperature for 15 min then filtered, washing with dry tetrahydrofuran. The filtrate was concentrated under vacuum. The resulting solution in dimethyl sulfoxide was treated with 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-(4-cyano-phenyl)-benzamide (0.30 g, 0.68 mmol) and the mixture was warmed to 75° C. and stirred for 2 hours. The mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The organic phase was extracted with HCl 0.5 N. The heterogeneous aqueous solution was adjusted to pH 9-10 with NaOH 0.5N, then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to yield 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide as a light green solid, MS (ISP): m/e=473.2 (M−H), which was used as such in the following reaction (0.23 g, 73%)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>O1CCCC1.O>[C:17]1(=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCCCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (969 mg) in tetrahydrofuran (50 mL) was added ethyl diethylphosphonoacetate (5.48 mL) dropwise under ice cooling. After stirring the solution under ice cooling for 30 minutes, a solution of cyclooctanone (2.52 g) in tetrahydrofuran (70 mL) was added dropwise to the solution under ice cooling. The resulting solution was stirred under ice cooling for 2 hours and at room temperature for 40 hours. Water and 3N hydrochloric acid were then added to the solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=9:1) to give the title compound (1.96 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C@:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:10][CH2:9]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH3:45][S:46]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:12][CH2:13]1)(=[O:48])=[O:47]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCNCC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), methanesulfonyl chloride (14 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the mixture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 53 mg.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:20]O.Cl>[OH-].[Na+].O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]2[O:20][CH:9]2[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: OO
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 18.9 g of 4-carboxybenzalacetophenone in 7.5 ml of 1N sodium hydroxide solution and 225 ml of water was added 15 ml of 30% hydrogen peroxide. After cooling in an ice-water bath, 50 ml of 0.5N sodium hydroxide was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 31/4 hrs. and acidified to pH of 6.5 with 1N hydrochloric acid. After stirring at room temperature for 1 hr., the solid was collected on a filter, washed with water and air-dried. Recrystallization from ethanol gave 11 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone as colorless crystals, m.p. 170°-172° C after drying at 80° C under vacuum for 3 hrs.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Cl)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:13]=[CH2:12]
Reactant: C=CCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Yield: 100.3 %

Procedure:
A solution of methyl 4-hydroxybenzoate (15.21 g, 0.10 mol), allyl chloride (11.48 g, 0.15 mol) and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (40 mL) was stirred at 50° C. overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 19.27 g of the title compound (yield: 100%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:24]([O:26]CC)C>>[S:4]1[CH:5]=[CH:6][C:2]([CH:24]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[OH:26])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCCC1
Reactant: CCOCC
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Product: OC(c1ccsc1-c1cccs1)C1CCCCC1
Reaction time: 0.25 h
Yield: 49 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (0.50 g, 2.04 mmol) in dry diethylether (20 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 1.25 mL, 2.04 mmol) in dry diethylether (20 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled cyclohexanone (0.21 mL, 2.04 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 10 mL) and water (10 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIk) as a yellow oil (0.264 g, 49.0%). 1H-NMR (CDCl3): δ=7.27 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 7.14 (d, J=5.4 Hz, 1H), 7.14 (dd, J=3.8 Hz, J=1.2 Hz, 1H), 7.07 (d, J=5.4, 1H), 6.95 (dd, J=5.2 Hz, J=3.8 Hz 1H), 2.32 (br s, 1H), 1.84-1.72 (m, 4H), 1.69-1.51 (m, 4H), 1.50-1.39 (m, 2H).
Reaction SMILES: C([O:9][C@H:10]1[CH2:33][C@H:32]([O:34]C(=O)NC)[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=O)C1C=CC=CC=1.COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:25][O:24][CH:21]([O:22][CH3:23])[CH:20]([CH3:26])[C@@H:19]1[C@:27]2([CH3:40])[C@H:16]([C:15]3[C@H:30]([CH2:29][CH2:28]2)[C@:31]2([CH3:39])[C:12]([CH2:11][C@@H:10]([OH:9])[CH2:33][C@@H:32]2[OH:34])=[CH:13][CH:14]=3)[CH2:17][CH2:18]1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 91.8 %

Procedure:
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-5,7-diene was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 65 mg of 21,21-dimethoxy-20-methylpregna-5,7-diene-1α,3βdiol showing the following physical properties.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][CH:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:23]([OH:31])([CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)[CH:22]([CH3:21])[CH3:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)C(=O)CCc1ccsc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)(CCc1ccsc1)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in General Method 9 using t-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi (42.6 mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3 mmol), and THF (100 mL). The title compound was purified by flash chromatography over silica gel eluting with hexane:EtOAc 97:3. 1NMR (CDCl3): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.0 (m, 3H), 2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:16][NH2:17].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(O)C>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:11]3[CH:14]=[N:17][NH:16][C:12]=3[N:13]=[C:23]([C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc(C(C#N)C=O)cc1OC
Reactant: O=Cc1ccc(O)cc1
Reactant: NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2c(-c3ccc(O)cc3)nc3[nH]ncc3c2cc1OC
Temperature: 70 °C
Yield: 31 %

Procedure:
2-[3,4-bis(methyloxy)phenyl]-3-oxopropanenitrile (100 mg, 0.49 mmol) was dissolved in ethanol (1 mL), and anhydrous hydrazine (98%, 19 μL, 0.52 mmol) was added. The resulting mixture was heated at reflux for 1 hour. It was cooled, concentrated, and the residue was dried in vacuum for one hour. To this residue was added of 4-hydroxybenzaldehyde (89 mg, 0.61 mmol) and trifluoroacetic acid (1 mL), and the mixture was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration and lyophillization of the pure fractions 4-[7,8-bis(methyloxy)-3H-pyrazolo[3,4-c]isoquinolin-5-yl]phenol trifluoroacetic acid salt (60 mg, 0.15 mmol, 31% yield) was obtained. 1H NMR (400 MHz, d6-DMSO): 8.62 (s, 1H), 7.90 (s, 1H), 7.62-7.60 (d, 2H), 7.48 (s, 1H), 6.98-6.96 (d, 2H), 4.06 (s, 3H), 3.78 (s, 3H); MS (EI) for C18H15N3O3: 322 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[CH3:8][O:9][CH2:10][C:11](=O)[CH3:12].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:8][O:9][CH2:10][CH:11]([NH:7][C:4]1[NH:3][C:2]([CH3:1])=[N:6][N:5]=1)[CH3:12]
Reactant: COCC(C)=O
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCC(C)Nc1nnc(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and 1-methoxypropan-2-one (2.7 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (1.4 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and 4-amino-1-N-Boc-piperidine (Astatech, >96%) using the procedure described in Step B, Example 6. HRMS, observed: 415.2143, Calcd for (M+H)+: 415.2140.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1.Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCC2)cc1
Yield: 11 %

Procedure:
1-Fluoro-4-nitrobenzene (5.0 g, 35.5 mmol) was added to a suspension of azetidine.HCl (3.98 g, 42.55 mmol) and K2CO3 (7.34 g, 53.19 mmol) in EtOH (100 mL) at r.t., and the reaction was stirred at 40° C. overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give compound 700 mg (11%) of the title compound as a yellow solid. [M+H] Calc'd for C9H10N2O2, 180. Found, 180.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[C:24]([CH2:30][OH:31])[C:23]=1[OH:32].Cl.C(N([CH2:39][CH3:40])CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][C:22]1[C:23]([OH:32])=[C:24]([CH2:30][O:31][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25]([CH2:28][O:29][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:39][CH3:40])=[CH:26][N:27]=1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ncc(CO)c(CO)c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCc1cnc(C)c(O)c1COC(=O)CCCC/C=C\C/C=C\C/C=C\CCCCC

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoyl chloride (650 mg, 2.2 mmol) in methylene chloride (10 ml) was added slowly dropwise to a mixture of pyridoxine hydrochloride (206 mg, 1 mmol), triethylamine (0.7 ml, 5 mmol) and 4-(N,N-dimethylamino)pyridine (few mg, catalytic amount) in methylene chloride (20 ml) at 0° C.l under nitrogen. On completion, as indicated by tic, (4 h) the mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane), yielding 2-methyl-3-hydroxy-4,5-di(z,z,z-octadeca-6,9,12-trienoyloxy)methyl pyridine as a colourless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.COB(OC)OC>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COB(OC)OC
Solvent: CC#N
Product: COc1c(N2CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 2.95 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.42 g of pyrrolidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 20 ml of acetonitrile was refluxed with heating for 3.5 hours. The reaction solution was cooled to room temperature, acetonitrile was distilled under vacuum and 15 ml of ethanol was added into the resultant product. Separated crystals were filtered and dried to obtain 3.05 g of the objective compound (88.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7]2.Cl.Cl.Cl.[N:18]1([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:18]1([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=4)=[O:14])[CH2:31][CH2:32]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
A solution of 4-Methoxy-1H-indole-2-carboxylic acid (930 mg, 4.86 mmol), amine 5 (1.63 g, 4.86 mmol) and DIEA (2.5 ml, 14.58 mmol) in 20 ml of DMF is treated with solid TBTU (1.56 g, 4.86 mmol). The mixture is stirred over night and then evaporated. The crude residue is dissolved in EtOAc and washed twice with sodium bicarbonate (10%). The aqueous layers are re-extracted with DCM, the combined organic layers are washed with brine and dried over sodium sulfate. The crude product is then purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 0% to 2%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[C:29]4[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[C:29]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Reaction time: 1 h
Yield: 63.4 %

Procedure:
Trifluoroacetic acid (0.62 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D8) (80 mg) in dichloromethane (1 mL) at RT. The resulting solution was stirred for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from ether/hexane to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E2) (45 mg) as a pale yellow solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.65 (2H, q), 2.96 (2H, t), 3.63 (3H, s), 4.89 (1H, m), 7.18 (1H, t), 7.20 (1H, s), 7.45 (2H, m), 7.81 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.14 (1H, br s). MS (ES): C23H22ClN3O4 requires 439; found 440.0 (M+H+).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)[C@@H:16]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][CH:37]=2)[C@H:15]([CH2:50][OH:51])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25]=3[CH:35]=2)[C@@H:16]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][CH:37]=2)[C@H:15]([CH2:50][O:51][CH3:1])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COC)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.568 mmol of methyl iodide are added to a suspension of 0.642 mmol of (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 1a) and 0.963 mmol of sodium hydride (60% dispersion in oil) under argon at 0° C. After stirring for 1 hour at 0° C. and 1 hour at room temperature, the reaction mixture is partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.41 (EtOAc-heptane 1:1); Rt=5.87 (gradient I).