Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18].CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 21 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 55) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in EtOAc. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH. The residue was diluted with DCM (30 mL) and washed with 0.1M HCl (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was further purified by SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH followed by silica gel column chromatography eluting with 0-7% MeOH in EtOAc to give the title compound (5.5 mg, 21%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:19]=2[C:31]([F:34])([F:33])[F:32])=[O:17])=[CH:11][C:10]=1[CH2:35][NH3+:36].N1C=CC=CC=1>C1COCC1>[C:1]([NH:36][CH2:35][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:29])([F:30])[C:25]([F:28])([F:26])[F:27])[C:19]=2[C:31]([F:32])([F:33])[F:34])=[O:17])[CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C[NH3+])c1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC(=O)NCc1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 20 h
Yield: 73.1 %

Procedure:
Butanoyl chloride (24 mg, 0.23 mmol, 1.1 eq.) in THF (1.5 ml) was added to a solution of [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (100 mg, 0.21 mmol) and pyridine (34 mg, 0.43 mmol, 2.1 eq.) in THF (3 ml). After 20 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate) to give N-{3-[(butyrylamino)methyl]-4-chlorophenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].[CH3:18][Si](C)(C)N[Si](C)(C)C.[Na].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a −78 ° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0→15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3H), 1.3 (s, 9H), 1.4 (m, 2H), 1.9 (m, 2H), 3.0 (d, J=13.2 Hz, 1H), 3.1 (m, 1H), 3.3 (m, 1H), 3.5 (s, 3H), 3.7 (d, J=13.4 Hz, 1H).
Reaction SMILES: B(Cl)(Cl)Cl.[C:5](Cl)(=[O:12])C1C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[OH-].[Na+]>ClCCl.C1C=CC=CC=1>[OH:24][C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:21]([O:22][CH3:23])=[CH:20][C:19]=1[CH:5]=[O:12]
Reactant: COc1ccc(O)cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1cc(O)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A 1.0M solution of boron trichloride (210 ml, Aldrich) in dichloromethane was added to benzoyl chloride (130 g. Aldrich) in benzene (350 ml). Next, 3,4-dimethoxyphenol (30.0 g, Aldrich) in benzene (130 ml) was added and the reaction mixture was stirred at room temperature for 21/2 hours. 50% NaOH (55 ml) was then added and the mixture was stirred for 15 minutes. The organic layers were separated, dried and concentrated in vacuo. The resulting residue was triturated with 1N NaOH for 40 minutes then filtered. The aqueous basic filtrate was acidified with conc. HCl to give the title product as a yellow solid (25.9 g), mp 104-105° C. 1H NMR was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][S:6][CH2:7][CH:8]([OH:12])[CH:9]([OH:11])[CH3:10].C[O-].[Na+].Cl>CO.O>[OH:12][CH:8]([CH:9]([OH:11])[CH3:10])[CH2:7][S:6][CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CCSCC(O)C(C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(O)CSCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
6,7-dihydroxy-4-thiaoctanoic acid methyl ester as obtained in Reference Example 44 (1.47 g) was dissolved in a mixture of methanol (20 ml) and water (1 ml). To this solution, sodium methylate (1.5 ml) was added under ice cooling conditions, followed by stirring at room temperature for 1 day. To the reaction mixture, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate; the solvent was distilled off under reduced pressure to yield the title compound (1.00 g, yield 73%) as a colorless oily substance.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)(=O)C.O>[CH2:3]1[C:2]2[NH:17][C:11]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[C:8]([OH:10])=[O:9]
Reactant: NNc1ccccc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCc2c([nH]c3ccccc23)C1
Yield: 75.4 %

Procedure:
A mixture of 3-ketocyclohexanecarboxlic acid (4.78 g, 33.9 mmol) and phenyihydrazine (3.66 g, 40 mmol) in 35 mL of acetic acid was heated under reflux for one hour, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 5.5 g of the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:24])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:15]=2)[O:8]1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([B:9]2[O:8][C:7]([CH3:24])([CH3:6])[C:11]([CH3:12])([CH3:13])[O:10]2)=[CH:15][CH:16]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.33 mL) was added to a mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanol (0.92 g) and triethylamine (0.73 mL) in methylene chloride (18 mL), and the mixture was stirred at room temperature for 1 hr. 1 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.28 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[CH:28]=[CH:27][C:26]2[C@@H:25]3[C@H:16]([C@H:17]4[C@@:21]([CH2:23][CH2:24]3)([CH3:22])[CH:20]=[CH:19][CH2:18]4)[CH2:15][C:14](=[O:29])[C:13]=2[CH:12]=1)(=O)C>C1COCC1>[CH3:22][C@:21]12[CH2:23][CH2:24][C@H:25]3[C@@H:16]([CH2:15][CH:14]([OH:29])[C:13]4[CH:12]=[C:11]([OH:10])[CH:28]=[CH:27][C:26]=43)[C@@H:17]1[CH2:18][CH:19]=[CH:20]2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2
Yield: 10 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 95%, 46.9 mg, 1.17 mmol) in 5 mL of anhydrous THF was added estra-1,3,5(10),16-tetraen-6-one-3-yl acetate, 6 (422.9 mg, 1.360 mmol) in 5 mL of anhydrous THF dropwise, with stirring. See FIG. 13. The reaction was stirred 50 min., after which further LAH (46.5 mg, 1.16 mmol) was added and the reaction stirred 22 h. After refluxing 4 h TLC still showed starting material. The reaction was quenched with 0.5 mL of water+0.5 mL of 20% (w/w) sulfuric acid and concentrated under reduced pressure. The residue was extracted four times with 10 mL portions of hot ethyl acetate and filtered through Celite. The combined filtrates were concentrated and purified twice by flash chromatography to give solid product (0.05 g, 0.2 mmol, 10%), m.p. 150-157° C. (NA-1993B-29, 32B)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc2C1=O
Temperature: 0 °C
Yield: 83.8 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-morpholino-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (451 mg, 1.29 mmol) in THF (7.0 mL) in an ice bath was added 1.00 M potassium t-butoxide in THF (1.42 mL, 1.42 mmol) and the resulting solution was stirred in the ice bath for 30 minutes. Methyl bromoacetate (184 uL, 1.94 mmol) was added and the solution was stirred for 1 hour in the ice bath. The reaction was quenched with saturated NH4Cl (10 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→40/60) to give 455 mg (84% yield) of the title compound as a light yellow oil. LC/MS (FA) ES+ 421. 1H NMR (400 MHz, CDCl3) δ: 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 5.38 (s, 1H), 4.09 (d, 1H, J=17.2 Hz), 4.06-4.01 (m, 1H), 3.99 (d, 1H, J=17.2 Hz), 3.63-3.61 (m, 4H), 3.57-3.53 (m, 2H), 3.52 (s, 3H), 2.99-2.97 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CC[O:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:14]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of nitrile 1 (900 mg, 5.02 mmol) in ether (45 mL) at 0° C. was added via syringe p-fluorophenylmagnesium bromide (5.0 mL, 2.0 M solution in ether 10 mmol). The resulting turbid mixture was stirred at 0° C. for 5 min then warmed to r.t. and stirred for 6 h. At that time, the reaction was quenched with H2O (3 mL) and then diluted with ether (25 mL) and H2O (25 mL). The organic phase was separated, and the aqueous phase was extracted with ether (80 mL×2). The organic portions were combined, washed with saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (30 g short path, 1%→10% EtOAc/hexane) to give the desired product (700 mg, 2.53 mmol, 50%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2H), 7.11 (m, 2H), 5.79 (d, J=2.0 Hz, 1H), 3.41 (s, 3H), 2.97-2.81 (m, 3H), 2.00 (m, 2H), 1.82 (m, 1H), 1.74 (m, 2H), 1.65 (m, 1H), 1.53 (m, 3H), 1.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 199.0, 165.3 (d, J=253 Hz), 140.4, 133.7 (d, J=3.0 Hz), 130.4 (d, J=9.1 Hz), 118.8, 115.3 (d, J=22.0 Hz), 59.0, 36.6, 32.5, 31.6, 28.2, 26.4, 25.7, 21.6.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[NH:8][C:7](=[O:19])[CH2:6][CH2:5]2.[OH-].[Na+].Cl.O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[NH:8][C:7](=[O:19])[CH2:6][CH2:5]2
Reactant: CCOC(=O)CCc1cc2c(cc1I)CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1cc2c(cc1I)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 16.23 g of ethyl 3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoate in 200 ml of ethanol was added 150 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 hours. The reaction mixture was made weakly acidic by the addition dropwise of concentrated hydrochloric acid and diluted by the addition of water. The precipitated solid was collected by filtration and dried to obtain 8.88 g of 3-(6-iodo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)propanoic acid as a pale brown solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([C:34]2([C:49]([F:52])([F:51])[F:50])[O:38][N:37]=[C:36]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=O)=[C:41]([CH3:48])[CH:40]=3)[CH2:35]2)[CH:29]=[C:30]([Cl:33])[C:31]=1[F:32].Cl.[NH2:54][CH2:55][C:56]1[CH:67]=[CH:66][C:59]2[B:60]([OH:65])[O:61][C:62]([CH3:64])([CH3:63])[C:58]=2[CH:57]=1.Cl>CC#N>[Cl:25][C:26]1[CH:27]=[C:28]([C:34]2([C:49]([F:51])([F:52])[F:50])[O:38][N:37]=[C:36]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([NH:54][CH2:55][C:56]4[CH:67]=[CH:66][C:59]5[B:60]([OH:65])[O:61][C:62]([CH3:64])([CH3:63])[C:58]=5[CH:57]=4)=[O:45])=[C:41]([CH3:48])[CH:40]=3)[CH2:35]2)[CH:29]=[C:30]([Cl:33])[C:31]=1[F:32]
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)C(C)(C)OB2O
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
HATU (350 mg, 0.92 mmol) was added to CH3CN (5 mL) at 0° C. After stirring for 5 min, the mixture was added to a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (200 mg, 0.46 mmol), 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (157 mg, 0.69 mmol), and TEA (186 mg, 1.83 mmol) in CH3CN (8 mL). Then the solution was stirred at rt for 2 h. The solution was acidified with HCl (1 N) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, yield 54%). 1H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.92 (t, J=6.0 Hz, 1H), 7.78 (d, 2H), 7.62-7.58 (m, 3H), 7.48-7.45 (m, 1H), 7.33-7.27 (m, 2H), 4.49 (d, 2H), 4.39-4.25 (m, 2H), 2.36 (s, 3H), 1.42 (s, 6H); HPLC purity: 97.6% at 254 nm; MS: m/z=609 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])[NH2:22]
Reactant: NC(=O)[C@@H](N)c1ccc(F)cc1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and (S)-2-amino-2-(4-fluoro-phenyl)-acetamide (119.2 mg, 0.64 mmol) as starting materials, and isolated (10 mg, 6.3%) as white solid; LC-MS (UV peak area, ESI) 95.12%, 384.8 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13](=NN)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[I:24]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]([I:24])=[CH2:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(=NN)C1(C)CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(I)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1-hydrazono-ethyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.076 g, 0.33 mmol) and triethylamine (0.169 g, 1.67 mmol) in THF (3 mL) was added dropwise a solution of iodine (0.127 g, 0.50 mmol) in THF (1 mL). The reaction mixture was stirred for 1 h at ambient temperature then concentrated in vacuo. The residue was dissolved in DCM (10 mL) and washed with aqueous Na2S2O3 (5%, 2 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give 3-(1-iodo-vinyl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.060 g, 55%), which was unstable and used without further purification. TLC: Rf=0.30 (eluting with 10% EtOAc in petroleum ether).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([OH:29])[CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:3]1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.Cl>N1C=CC=CC=1>[S:36]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([C@@H:5]([O:29][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:3]1)([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](OS(=O)(=O)c4ccc(C)cc4)[C@@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.5 g of 3α,6α-dihydroxy-5β-cholest-24-ene and 10.2 g of ρ-toluenesulfonyl chloride were dissolved in 90 ml of dry pyridine and then kept in a refrigerator for 48 hours. The mixture was poured into 300 ml of ice-water and the pH adjusted to 3 by adding concentrated HCl. After stirring for 30 minutes, the precipitate was removed by filtration, washed 4 times with 100 ml portions of water and dissolved in 300 ml of chloroform. The chloroform solution was washed with 30 ml of 5% sodium bicarbonate solution, four times with 50 ml of water solution, and dried. The solvent was evaporated and the residue dried. The yield was 5.1 g of a white solid (83%) identified from ir and nmr data as 3α,6α-ditosyloxy-5β-cholest-24-ene.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[S:32][CH:33]=[CH:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:32]1[C:31]2[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[CH2:26][C:27]3[N:28]([CH:35]=[CH:36][CH:37]=3)[CH2:29][C:30]=2[CH:34]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:80][CH2:81][N:82]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:83][CH2:84]1)([CH3:73])([CH3:71])[CH3:72]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-Bis-(4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred suspension of 0.489 g (0.94 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml of DMF and followed by N,N-diisopropylethylamine 0.242 g (1.88 mmol) while the temperature was maintained below 5° C. during the addition. The mixture was stirred for 10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 6 N HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with 10% solution of potassium hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated brine solution, and dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. Percentage purity: 36.3%, (M+1)=567.2. 1H NMR (DMSO-d6): δ 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (1H, t), 6.95 (1H, d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).