Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](NCCCl)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][CH2:13][N:14](CC)CC.C(Cl)Cl>CN(C=O)C>[C:1]([CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCl
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN

Procedure:
Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][N:11]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30]Cl)[CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)=[CH:10][N:11]=3)=[N:5]2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazole (260 mg, 0.83 mmol), 2-chloro-4-(chloromethyl)pyridine (270 mg, 1.66 mmol) and Cs2CO3 (820 mg, 2.5 mmol) in dry DMF (5 mL) was stirred at RT for 72 h. The mixture was then diluted with H2O (50 mL) and extracted with DCM/MeOH (20/1 v/v, 4×50 mL). The combined organic layers were washed with H2O (3×40 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM:MeOH=20:1 to 15:1) to afford the title compound as a white solid (100 mg, 27%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH2:11]([NH:14][C:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: Oc1ccc(N=C=S)cc1
Reactant: C=CCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)Oc1ccc(N=C=S)cc1

Procedure:
By a procedure similar to that of Example I, the above compound (11.1 g.) in the form of a waxy solid, was prepared from 9.1 g. (0.06 m.) of p-hydroxyphenylisothiocyanate and 5.0 g. (0.06 m.) of allylisocyanate, using 35 mls. of chloroform as a solvent and 3 drops each of triethylamine and dibutyltin dilaurate as catalysts.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:15]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of allylamine (5 g, 88 mmol) and triethylamine (9.6 g, 95 mmol) in CH2Cl2 (200 mL) at -10° C. was added trichloroacetyl chloride (16.7 g, 92 mmol). The resulting solution was allowed to gradually warm to RT and stir for 24 h. The reaction solution was extracted with brine (satd., 100 mL) and dried (Na2SO4) to yield 17 g (96%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li+].[OH-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:5]2[C:9]3[C:8](=[CH:4][CH:3]=[C:2](/[CH:38]=[CH:37]/[CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:10]=3)[NH:7][C:6]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)/C=C/Cc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCOc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccc(/C=C/Cc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 11C (45.2 mg), (E)-3-phenylprop-1-enylboronic acid (21.1 mg), bis(triphenylphosphine)palladium(II) dichloride (catalytic), and 2M LiOH (0.3 mL) in 7/2/3 dimethoxyethane/ethanol/H2O (2 mL) was heated under microwave (CEM Discover) conditions at 150° C. for 30 minutes. The mixture was quenched with 1 MHCl (0.4 mL) and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The cruconcentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, DMSO-d6) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d, 1H), 7.88 (d, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m, 3H), 6.83 (d, 1H), 6.00 (m, 2H), 4.08 (t, 2H), 2.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(NC(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NC(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-acetamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound:Rf=0.18 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: O=Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cccc(CNc2cncc(Cl)n2)c1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
To a solution of 2-amino-6-chloropyrazine (100 mg, 0.77 mmol) in 7.7 mL of anhydrous toluene was added 3-chlorobenzaldehyde (87.4 μL, 0.77 mmol) followed by 50 mg of activated, powdered 4 Å molecular sieves. The reaction was refluxed under nitrogen for 3 h, then cooled to ambient temperature and treated with sodium borohydride (43.0 mg, 1.16 mmol). The resultant slurry was heated to reflux under nitrogen overnight. After cooling to ambient temperature the reaction was filtered through a pad of Celite®, and the flitrate was concentrated in vacuo to a brown residue. Chromatography on a silica gel preparatory TLC plate (1:1 hexane:ethyl acetate) provided 71.0 mg of the title compound I-2a.
Reaction SMILES: C(OC([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=3)[C:33]([OH:35])=[O:34])[CH:25]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(Sc3cccc(C(=O)O)c3)ccc2O1)C[C@H](O)c1cccnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Sc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To 670 mg (1.25 mmol) of crude 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid (Example 173) diluted in 5 mL 1,4-dioxane, was added 0.5 mL of 6N hydrochloric acid slowly. The resulting mixture was stirred at 45° C. for 2 hours. After this time the mixture was concentrated in vacuo, dissolved in 2 mL of 1:1 methanol to water, and purified by HPLC (0-70% acetonitrile/0.1% TFA) to afford 28.5 mg (5% yield) of the desired product as the bis TFA salt. MH+ 437.3. 1H NMR (CDCl3, δ): 8.91 (br. S, 1H), 8.63 (d, 1H), 8.56 (dd, 1H), 7.89 (m, 1H), 7.72 (dt, 1H), 7.62 (m, 1H), 7.49 (m, 1H), 7.39 (m, 1H), 7.31 (m, 1H), 7.27 (m, 1H), 7.24 (dd, 1H), 6.90 (d, 1H), 6.35 (br. S, 1H), 5.07 (m, 1H), 4.48 (m, 1H), 3.32 (m, 4H), 3.16 (m, 1H), 2.78 (m, 2H), 2.04 (m, 1H), 1.71 (m, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[CH3:46][N:47]([CH3:64])[CH2:48][CH2:49][CH2:50][NH:51]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.CC(NS(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:64])[CH3:46])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CN(C)CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(N)=O
Product: Cc1cc(OCCCNCCCN(C)C)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 51 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and N,N-dimethyl-N′-(2-nitrobenzenesulfonyl)-1,3-diaminopropane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide, respectively.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>C(O)C.O>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:12]([O-:15])(=[O:14])=[O:13])[CH3:11].[Na+:16]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCS(=O)(=O)[O-]
Yield: 100 %

Procedure:
To a solution of ethyl 6-bromohexanoate (61b) (2.48 g, 11.0 mmol) in ethanol (6 ml) a solution of sodium sulfite (2.16 g, 20.6 mmol) in water (9 ml) was added and the resulting mixture was refluxed for 1 hour. The reaction mixture was evaporated under reduced pressure and the obtained solid was extracted with boiling ethanol in Soxhlet extraction apparatus for 15-20 hours. The extract was evaporated and the residue was crystallised from ethanol-diethyl ether (1:10) giving the title compound (2.71 g, 99%) in a form of a white solid material. 1H NMR (DMSO-d6, HMDSO),δ:1.05-1.78 (6H, m); 1.17 (3H, t, J=7.2 Hz); 2.26 (4H, t J=7.5 Hz); 4.05 (2H, q, J=7.2 Hz).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg]Br>C(OCC)C>[CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
1-Benzhydryl-azetidin-3-one (335 mg) in diethyl ether (6.0 mL) was treated with 3.0 M methylmagnesium bromide in diethyl ether (0.52 mL) at 0° C., stirred for 10 minutes and quenched with saturated aqueous sodium bicarbonate. The solution was then extracted with methylene chloride (×3), and the combined organics were dried over magnesium sulfate, and concentrated to provide 363 mg of the title compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 1.53 (s, 3H), 1.96 (s, 1H), 1.96 (d, 2H, J=8.42 Hz), 3.19 (d, 2H, J=8.42 Hz), 4.34 (s, 1H), 7.17 (m, 2H), 7.26 (m, 2H), 7.31 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([F:18])=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[F:18][C:12]1[C:13]([NH2:15])=[CH:14][C:4]2[NH:1][C:8](=[O:9])[CH2:7][O:6][C:5]=2[CH:11]=1
Reactant: [H][H]
Reactant: O=C(O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 92.8 %

Procedure:
A suspension of 2,4-dinitro-5-fluorophenoxyacetic acid (2.0 g) and 10% palladium-carbon (hydrated) (1.0 g) in ethanol (30 ml) was subjected to catalytic reduction at room temperature under an ordinary pressure until 1000 ml of hydrogen was absorbed. The reaction mixture was filtered, and the filtrate was concentrated to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one (1.3 g; yield, 92.8%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[NH:13][C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:46]=[CH:45][C:39]([CH2:40][O:41][CH2:42][CH2:43]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].P([O-])([O-])([O-])=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[N:13]([CH2:43][CH2:42][O:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(COCCCl)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)Sc1ccccc1
Reaction time: 2 h
Yield: 93.8 %

Procedure:
747 mg (1.97 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone and 398 mg (3.94mmole) of triethylamine were dissolved in 20 ml of methylene chloride. To the solution were added 960 mg (3.94 mmole) of p-nitrobenzyloxyethyl chloride, with ice cooling under a stream of nitrogen. The mixture was stirred for 2 hours and then a 0.1M phosphate buffer solution (pH 7.2) was added to the reaction mixture to complete the reaction. The organic layer was separated and washed with water, after which it was dried. The solvent was distilled off and the resulting residue was purified by column chromatography through 15 g of silica gel, to give 1,032 mg (yield 89%) of the desired product as an oil from the fractions eluted with mixtures of hexane and ethyl acetate in volume ratios from 6:1 to 3:1.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[CH3:12]>>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC(=O)CN
Reaction time: 2 h

Procedure:
From ethanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 2 h. The yield was 1.0 g (85%).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ncc(CN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 34.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg. 0.30 mmol), acetic acid (18 μL, 0.30 mmol), morpholine (78 μL, 0.90 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 42 mg (34%) of the desired product after purification.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.CI>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[C:8]=1[CH3:2]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(Br)ccc(C#N)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DIPA (12.1 g, 0.120 mmol) in 20 mL of dry THF was added 2.5M of n-BuLi (44 mL, 0.11 mmol) dropwise under Ar at −78° C., and then the reaction was allowed to warm to 0° C. After stirring for 1 hour, the solution was added to a solution of 4-bromo-2-fluorobenzonitrile (20 g, 0.1 mmol) in 200 mL of dry THF dropwise at −78° C. under Ar and the mixture was stirred for 3 hours, then MeI (15.6 g, 0.110 mmol) was added at one portion and the mixture was stirred for another 30 minutes. Then the reaction was quenched with aq. NH4Cl and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water, brine, dried and concentrated to brown oil, which was purified by silica gel column to give 4-bromo-2-fluoro-3-methylbenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][Si](C)(C)C)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(NF)(C)(C)C.C1COCC1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[CH:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: C[Si](C)(C)C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: CC(C)(C)NF
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-chloro-2-(4-trifluoromethoxy-benzyl)-5-trimethylsilanylethynyl-2,3-dihydro-isoindol-1-one (0.100 g, 0.22 mmol) in THF (1 mL) was treated with a 1M solution of tertiary-butyl amino fluoride-THF (1 mL). The reaction mixture was stirred at ambient temperature for 2 h. After this time, GC-MS indicated that the reaction was completed. The reaction solution was poured into water (7 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated to afford 7-chloro-5-ethynyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one. The material was used without purification.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Yield: 10 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethylthio)aniline (68.5 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 11.4 mg (45 μmol; 10% yield) of pure desired product. LC-MS (method V): rt=3.09 min; m/z [M+H]+ 315.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[Cl:10].[CH3:11][N:12](C)C=O>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.[C-]#N.[Zn+2].[C-]#N>[Cl:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([CH3:8])=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)c(Cl)cc1F
Temperature: 110 °C
Reaction time: 13 h

Procedure:
Under an argon atmosphere, to a solution (20 mL) of 1-bromo-2-chloro-4-fluoro-5-methylbenzene (4.47 g) in N,N-dimethylformamide were added tetrakis(triphenylphosphine)palladium(0) (0.78 g) and zinc cyanide (1.23 g). The mixture was stirred at 110° C. for 13 hr and partitioned between ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 2.3 g).
Reaction SMILES: [N+:1](=[CH:3][CH2:4][CH3:5])=[N-].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[S:19][C:18](=[S:20])N[C:16](=[O:21])[N:15]=2)=[CH:9][CH:8]=1>CCOCC.O1CCCC1>[CH2:3]([N:1]1[C:16](=[O:21])[N:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[S:19][C:18]1=[S:20])[CH2:4][CH3:5]
Reactant: O=c1nc(Sc2ccc(Cl)cc2)sc(=S)[nH]1
Reactant: CCC=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCn1c(=O)nc(Sc2ccc(Cl)cc2)sc1=S
Yield: 66.4 %

Procedure:
A solution of 7.7 g of diazopropane in ether is added in portions to a solution of 28.8 g of 2,3-dihydro-6-(4-chlorophenylthio)-2-thioxo-4H-1,3,5-thiadiazin-4-one in 250 ml of tetrahydrofuran at 22° C. The solvent is distilled off, the residue is taken up in a small amount of methanol, and the precipitate is filtered off under suction, washed with methanol and dried. 21.9 g of 3-propyl-6-(4-chlorophenylthio)-2-thioxo-1,3,5-thiadiazin-4-one are obtained in the form of yellow crystals of melting point 151°-152° C.