Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:26])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:26])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of zinc chloride (21.2 g, 0.156 mol) in diethyl ether (200 ml) was added sodium borohydride (13.1 g, 0.31 mol) and the mixture was stirred at room temperature for 2 hrs. The insoluble material was removed by filtration. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-(4-methoxybenzyl)propionate (25.7 g, 77.8 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction solution under ice-cooling to terminate the reaction. Water (200 ml) and ethyl acetate (200 ml) were added to the mixture and the mixture was extracted. The extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-3:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionate (23.3 g, 90%) as a colorless oil.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[C:20]1([CH:26]2[CH2:31]CNC[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:20]1([CH:26]2[CH2:31][CH2:18][N:16]([CH2:15][C:4]3[C:5]4[CH2:6][CH2:7][C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[C:10]=4[NH:2][N:3]=3)[CH2:19][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C2CCN(Cc3n[nH]c4c3CCc3ccccc3-4)CC2)cc1

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.30 g), 4-phenylpiperidine (0.15 g) and diisopropylethylamine (0.30 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 24 hours. The mixture was cooled, poured into water (25 cm3) and extracted with 50% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated to give the title compound as a brown oil. This was crystallised as the half-oxalate salt from DMF-ethanol-ethyl acetate (0.045 g; 12%), m.p. 128°-230° C. (from DMF-EtOH-EtOAc); Found: C, 73.85; H, 6.8; N, 10.8. C23H25N3.0.5(CO2H)2.0.1(H2O) requires C, 73.9; H, 6.8; N, 10.8%. δH (360 MHz; d6 -DMSO; 353K) 1.70-1.92 (4H, m, 2 x NCH2CH2), 2.40-2.56 (2H, m, 2 x NCHAHBCH2 ; partially obscured by DMSO peak), 2.58-2.64 (1H, m, NCH2CH2CH), 2.78 (2H, t, J 7.5, --CH2 --), 2.90 (2H, t, J 7.5, --CH2 --), 3.16 (2H, broad d, J 11, 2 x NCHA HBCH2), 3.82 (2H, s, --CH2N), 7.15-7.30 (8H, m, 8 of ArH) and 7.66 (1H, d, J 7.7, 1 of ArH); m/z (CI+ ; NH3) 344 (MH+ ; 5%), 235 (5), 185 (18) and 162 (100).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C@H:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=1)[C@H:10]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:11][OH:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](COC(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CO)[C@H](COC(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
(2S,3S)-3-(Tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(4-(trifluoromethyl)phenyl)butyl pivalate (2.2 g, 4.0 mmol) was taken up in 40 mL of THF and chilled to 0° C. TBAF, 1 M in THF (6.0 mL, 6.0 mmol) was added slowly. After 20 minutes, the mixture was warmed to room temperature and stirred for 1 hour. 0.5 mL of additional TBAF was added, and the mixture was stirred for 20 minutes. The mixture was quenched with 20 mL of aq NH4Cl. The mixture was then diluted with 40 mL of water and extracted twice with 50 mL of EtOAc. The combined organic extracts were washed with 50 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 40% EtOAc/hexanes) afforded (2S,3S)-3-(tert-butoxycarbonyl)-4-hydroxy-2-(4-(trifluoromethyl)phenyl)butyl pivalate (1.5 g, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.22 Hz, 2H) 7.37 (d, J=8.02 Hz, 2H) 4.57 (d, J=6.4 Hz, 1H) 4.45-4.35 (m, 2H) 4.06 (s, 1H) 3.70 (s, 2H) 3.51-3,41 (m, 1H), 1.75 (broad s, 1H) 1.33 (s, 9H) 1.08 (s, 9H).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[OH-].[Na+].[C:14]12([C:24]([CH2:26]Br)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1>[C:14]12([C:24]([CH2:26][CH:2]([C:3]([O:5][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:4])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC(=O)C12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To tert-butyl malonate was added, in THF, an equimolar amount of sodium hydroxide. To this mixture was added bromomethyl adamantyl ketone, and the mixture was stirred for 3 hours. The salt precipitated was filtered off, and the filtrate was concentrated to obtain di-tert-butyl 2-((1-adamantyl)carbonyl-methyl)malonate (ADTB).
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[C:2]([NH2:4])=[S:3].Br[CH:15]([CH:18]=O)[CH:16]=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH:16]([C:15]1[S:3][C:2]([NH:1][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=2)=[N:4][CH:18]=1)=[O:17]
Reactant: NC(=S)Nc1ccc(C(=O)O)cn1
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cnc(Nc2ccc(C(=O)O)cn2)s1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
A mixture of 6-thioureido-nicotinic acid (197 mg, 1 mmol), 2-bromomalonaldehyde (166 mg, 1.1 mmol) and sodium acetate (100 mg) in acetic acid (2 mL) was stirred at 100° C. for 20 min. The mixture was then cooled to RT, diluted with water and the precipitates were collected. The solid was washed with water, then methanol and dried in vacuo to afford 6-(5-formyl-thiazol-2-ylamino)-nicotinic acid, (240 mg, 96%). MS m/z 250 (M+H)+. 1H NMR (DMSO-d6) δ 12.7 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.24 (d, 1H, J=5.6 Hz), 7.21 (d, 1H, J=5.6 Hz). 13C NMR (DMSO-d6) δ 183.5, 166.0, 165.1, 153.3, 151.5, 148.8, 139.1, 131.2, 120.3, 110.0.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2.CC([O-])(C)C.[K+].Br[CH:32]([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[CH2:13][CH:5]1[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=2[C:2](=[O:1])[N:8]([CH2:38][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]1=2)([CH3:19])([CH3:20])[CH3:18]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2NC(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCN1C(=O)c2ccccc2C(CC(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
tert-Butyl (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate 4 (2 g, 6.18 mmol) was dissolved in 25 ml of dry DMF and, at 10° C., 2.1 eq. of KOtBu (1.5 g) were added, and the mixture was stirred for about 20 min. Then, at RT 2.5 g of ethyl bromopropionate were added dropwise and, after stirring at RT for 1 h, further KOtBu (0.2 g) and ethyl bromopropionate (0.8 g) were added. After a further 2 h, the mixture was diluted with CH2Cl2, washed with H2O, dried and concentrated. Chromatography on silica gel (CH2Cl2CH3OH 1 to 25%) afforded 1.2 g of the required product and 2.0 g of nonreacted precursor.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:15][O:14][C:13]([CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([CH:16]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:32])[CH3:33])=[CH:27][CH:28]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[O:14][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C1=NC(C(=O)OCc2ccccc2)CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)c1nc(C(=O)OCc2ccccc2)co1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of methyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazolin-2-yl]-4-[4-(triisopropylsilyloxy)phenyl]butanoate (4.45 g, 8.03 mmole) in CH2Cl2 (40 mL) at 0° C. was added DBU (1.4 mL, 9.64 mmole), followed by bromotrichloromethane (0.95 mL, 9.64 mmole). The mixture was allowed to warm to RT as the bath warmed. After 18 hr the mixture was concentrated. The residue was chromatographed on silica gel (20% EtOAc/hexanes) to give the title compound (2.23 g, 50%) as a clear oil: MS (ES) m/e 552 (M+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=2[F:27])[CH2:16][N:15]2[C:28]([C:31]([O:33]C)=O)=[CH:29][N:30]=[C:14]12)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:27][C:21]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=1[C@H:17]1[CH2:16][N:15]2[C:28]([C:31]3([OH:33])[CH2:2][CH2:1]3)=[CH:29][N:30]=[C:14]2[C@H:13]([NH:12][C:10](=[O:11])[O:9][C:5]([CH3:7])([CH3:8])[CH3:6])[CH2:19][CH2:18]1
Reactant: COC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(O)CC3)cnc21
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
Ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) was added dropwise over 15 min to a solution of titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and methyl (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylate (54 mg, 0.13 mmol) in ether (0.9 mL) at 0° C. After 1.5 h, additional titanium(IV) isopropoxide (0.08 mL, 0.26 mmol) and ethylmagnesium bromide (3 M in ether; 0.17 mL, 0.51 mmol) were added. After 1.5 h, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed with saturated brine, dried with magnesium sulfate, filtered, and concentrated. Purification by reverse phase HPLC (C-18, 80% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 420.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH:34]C(=O)CCl)[S:32][CH:33]=1)[C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[Na+].NC(N)=S.Cl>O>[CH2:1]([O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH:16]([S:18][C:19]3[NH:20][N:21]=[N:22][N:23]=3)[CH3:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: NC(N)=S
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a solution of 3.90 g of sodium 7β-{α-ethoxyimino[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate in 50 ml of water is added 1.52 g of thiourea. The mixture is stirred at room temperature for 3 hours and adjusted to pH 2.0 with 1N hydrochloric acid. The resulting precipitates are filtered, washed with water and dried to obtain 2.40 g of 7β-[α-ethoxyimino-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH2:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[C:11]#[C:12][CH3:13]>>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:10][C:11]#[C:12][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22])[CH3:8])[CH3:3]
Reactant: CCOC(=O)C(C)N
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C)C(=O)OCC)cc1
Yield: 57.6 %

Procedure:
According to the procedure of Example 20, 1.00 g (6.51 mmol) of D,L-alanine ethyl ester hydrochloride reacted with 1.75 g (7.16 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride to provide 1.22 g (58%) of the sulfonamide as a white solid. Electrospray Mass Spec: 325.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8].[F:17][C:18]([F:35])([C:23]1[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32](Cl)=[O:33])[NH:25][N:24]=1)[C:19]([F:22])([F:21])[F:20]>ClCCl.[Ag]C#N>[Cl:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32]([C:26]2[NH:25][N:24]=[C:23]([C:18]([F:17])([F:35])[C:19]([F:20])([F:21])[F:22])[C:27]=2[C:28]([F:31])([F:29])[F:30])=[O:33])=[CH:15][C:6]=1[C:7](=[O:8])[NH:9][CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Reactant: O=C(Cl)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Agent: N#C[Ag]
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1cc(NC(=O)c2[nH]nc(C(F)(F)C(F)(F)F)c2C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A suspension of 212 mg (0.84 mmol) of 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)benzamide and 168 mg (1.26 mmol) of silver(I) cyanide in 5.0 ml of dichloromethane is admixed with a solution of 265 mg (0.84 mmol) of 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride in 3.0 ml of dichloromethane and stirred for 16 h at room temperature. The suspension is then filtered over silica gel and the product is eluted with a mixture of dichloromethane and methanol (1:1). The solvents are removed under reduced pressure on a rotary evaporator and the resulting crude product is taken up in ethyl acetate. The organic phase is washed successively twice with 1M hydrochloric acid and once with saturated sodium chloride solution. The organic phase is then dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure on a rotary evaporator. The crude product is then triturated with a mixture of dichloromethane, methyl tert-butyl ether and cyclohexane (1:1:1). The crude product obtained from the mother liquor is then purified by means of preparative HPLC. In this way, 49 mg of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (11%) were obtained as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].CCN(CC)CC>CN(C=O)C.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(N)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A mixture of commercially available 2-amino-5-bromopyridine (25 g, 144 mmol), 2-methyl-3-butyn-2-ol (21.2 mL, 217 mmol), Et3N (30.2 mL, 217 mmol), PdCl2(PPh3)2 (507 mg, 0.5 mol %) and PPh3 (95 mg, 0.25 mol %) in DMF (140 mL) was purged for 10 min with argon. Then CuI (83 mg, 0.3 mol %) was added and the reaction mixture was heated up to 90° C., stirring was continued at 90° C. for 16 h. Cooled to 23° C., the reaction mixture was concentrated in vacuum to remove all volatiles left a dark brown residue which was purified by flash chromatography with n-heptane and ethyl acetate to give the title compound as a brown solid (24 g, 94%, contains residual DMF). MS (ISP) 177.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=S)[NH:10][C:4]=2[CH:3]=1.O.[NH2:21][NH2:22]>C1C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[N:21][NH2:22])[NH:10][C:4]=2[CH:3]=1
Reactant: NN
Reactant: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Solvent: c1ccccc1
Solvent: O
Product: NN=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reaction time: 8 h
Yield: 59.5 %

Procedure:
9-Bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-thione (4 g), hydrazine hydrate (4 ml) and benzene (150 ml) were combined and refluxed overnight. The reaction mixture was concentrated to approximately 50 ml and, after standing overnight, the precipitate was filtered. Recrystallization of the filter cake from chloroform/ether gave 2.35 g (59.5%) of product, mp 260° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:10]2[C:11]3[CH2:12][CH2:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=4[C:6]=3[CH2:7][CH2:8][CH2:9]2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.0 g (0.06 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline are dissolved in 150 ml of methylene chloride, treated With 6.68 g (0.066 mol) of triethylamine and 11.2 g (0.066 mol) of p-methoxybenzoyl chloride in 50 ml of methylene chloride are added dropwise thereto at 0°. After stirring at room temperature for 1 hour, the mixture is extracted with water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Crystallization (methylene chloride-ether) gives 4-(p-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo-[f]quinoline as white crystals with melting point 182-183°.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]1([S:30]([NH:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]2[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
224.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 207 mg of benzenesulfonyl chloride and 303 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 98 mg. MS (ES+): m/e=464.1 (M+H)+; 408.1.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([Cl:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[S:28][C:29]([CH3:32])=[CH:30][N:31]=1)[CH3:16]
Reactant: Cc1cnc(C(=O)c2cc(Cl)cc(Br)c2)s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
a suspension of NaH (60%, 1.77 g, 44.2 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (10.12 g, 44.2 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of 14 g (44.2 mmol) (3-Bromo-5-chloro-phenyl)-(5-methyl-thiazol-2-yl)-methanone in THF (10 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc mixtures to afford (Z)-3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-acrylic acid ethyl ester as an gel (18 g, yield=106%) The material is used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH2:30]([O:29][C:27]([CH2:26][O:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COC[C@@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
Tert-butyl (S)-1-(3-fluorophenyl)-2-hydroxyethylcarbamate (256 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL) and treated with cesium carbonate (391 mg, 1.2 mmol) and ethyl bromoacetate (0.14 mL, 1.25 mmol). The mixture was heated to 100° C. for 30 min, then cooled to room temperature, acidified, and extracted with ethyl acetate. Purification on silica gel (15%-40% ethyl acetate/hexanes) gave 69 mg of tert-butyl (S)-2-((ethoxycarbonyl)methoxy)-1-(3-fluorophenyl)ethylcarbamate as a colorless glass. HPLC-MS calculated for C17H24FNO5 (M+H+) 342.2, found 342.1.