Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCI
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Product: CCCCOc1ccc(/C=C/C(=O)OCC)cc1OC
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Preparation 116, but using 6.66 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 6.62 g of butyl iodide, 7.00 g of the title compound were obtained as a solid material.
Reaction SMILES: [CH2:1]([C:3]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].Cl.[CH3:31][NH2:32]>>[CH2:1]([C:3]([NH:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)=[O:29])([C:4](=[O:6])[NH:32][CH3:31])[CH2:7][CH3:8])[CH3:2]
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)O
Reactant: CN
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e=432.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([CH3:9])[N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH:26]([C:29]1[CH:30]=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O)([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:13]([O:12][C:10]([N:4]1[C@H:5]([CH3:9])[C@H:6]([CH2:7][OH:8])[C@H:2]([NH:1][CH2:34][C:33]2[CH:36]=[C:29]([CH:26]([CH3:28])[CH3:27])[CH:30]=[CH:31][C:32]=2[O:37][CH3:38])[C@@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(C(C)C)cc1C=O
Reactant: C[C@@H]1[C@@H](CO)[C@H](N)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@@H](CO)[C@@H](C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 148.9 %

Procedure:
To a stirred solution of (2S*,3S*,4S*,5R*)-3-amino-1-benzyloxycarbonyl-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine (0.61 g, 1.79 mmol) in dry CH2Cl2 (14 ml) was added a solution of 5-isopropyl-2-methoxybenzaldehyde (0.40 g, 2.24 mmol) in dry CH2Cl2 (2 ml) at room temperature. To this was then added NaBH(OAc)3 (0.57 g, 2.69 mmol) portionwise at room temperature. The added NaBH(OAc)3 dissolved gradually with stirring at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was basified to pH 10-11 with 10% NaOH aq. solution. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (×3). The combined CH2Cl2 solution was washed with sat. NaCl aq. solution (×1), dried (K2CO3), and concentrated in vacuo to give a yellow oil (1.34 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 20 g). Elution with n-hexane-AcOEt (30:1) followed by CH2Cl2 --MeOH (400:1→200:1) gave title compound (0.70 g, 78%) as a viscous pale yellow oil: IRmax (film): 3330(s), 1700(s), 1610(m), 1500(s), 1250(s), 1110(s), 1030(s), 815(s), 770(s), 738(s), 700(s) cm- ; 1H-NMR δ: 7.45-7.16(m, 9H), 7.05(dd, J=8.4, 1.8 Hz, 1H), 7.02(br.s, 1H), 6.88(d, J=1.8 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 5.33-4.93(m, 3H), 3.97-3.65(m, 3H), 3.81(d, J=12.1 Hz, 1H), 3.72(d,J=12.1 Hz, 1H), 3.67(s, 3H), 3.53-3.35(m, 1H), 3.38(dd,J=11.5, 7.9 Hz), 2.79 (sep, J=7.0 Hz, 1H), 2.17-1.98(m, 1H), 1.56(br.s, 4H), 1.18(d, J=7.0 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[CH2:11]([N:29]=[C:30]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:11]([NH:29][C:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCCCCCCCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCCCN

Procedure:
36 grams (.25 mole) of 1,8 diaminooctane was reacted with 20 gms (0.068 mole) octadecyl isocyanate as in Example 2. Yield: 26.6 gms, melting point 120°-145°-156°C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:14][O:13][C:9](=[O:12])[CH:10]=[CH:11][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Cc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cnc(C)nc1
Temperature: 150 °C
Yield: 16.8 %

Procedure:
A sealed mixture of 5-Bromo-2-methyl-pyrimidine (2.6 g, 15.03 mmol, 1 eq), methyl acrylate (1.40 eq, 1.89 ml), palladium(II)-acetate (0.013 eq, 44 mg), triphenylphosphine (0.024 eq, 95 mg), and triethylamine (1.21 eq, 2.54 ml) was heated at 150° C. (temperature on display of heating device) for 16 hours. The mixture was cooled to ambient temperature and was poured into 200 ml of water. Organic substances were extracted with EtOAc (twice, 200 ml was used in total). The gathered EtOAc layers were filtered over celite pad, were dried and the solvent was evaporated. The resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and EtOAc/cyclohexane solvent system (gradient 30-80% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-Methyl-pyrimidin-5-yl)-acrylic acid methyl ester (450 mg, yield=16.80%, purity=95%). MS: [M+H]+=179.13 1H NMR (300 MHz; CDCl3) δ/ppm 2.74 (s, 3H), 3.81 (s, 3H), 6.52 (d, J=16.60 Hz, 1H), 7.58 (d, J=16.60 Hz, 1H), 8.75 (s, 2H)
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=1)[S:27]([CH3:30])(=[O:29])=[O:28])#[N:19]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:41][C:36]1[CH:35]=[C:34](/[CH:33]=[CH:32]/[CH2:31][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]2[NH:19][N:7]=[N:6][N:5]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:39]=[C:38]([Cl:40])[CH:37]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCc1nnn[nH]1
Yield: 53.4 %

Procedure:
Trimethylsilylazide (0.136 mL, 1.026 mmol) and dibutyltinoxide (38 mg, 0.15 mmol) were added to a solution of trans-N-(6-cyano-hexyl)-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (59A) (199 mg, 0.52 mmol) in toluene (4 mL). The reaction was heated at reflux ovemight. The reaction was diluted with CH2Cl2 and the organic solution was washed sequentially with HCl (1×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified via radial chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (120 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.50 (d, 1H), 6.22 (m, 1H), 4.00 (m, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.90 (s, 3H), 1.83 (t, 2H), 1.62 (t, 2H), 1.38 (m, 4H); MS 132 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][CH:3]=1>CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8](=[O:10])[C:7]=12
Reactant: Cc1ccnc(-c2ccccc2)c1C(=O)O
Solvent: CCCCCC
Product: Cc1ccnc2c1C(=O)c1ccccc1-2
Yield: 91 %

Procedure:
To a stirred, cooled (0°) solution of ethyl benzoylacetate (200 g) and concentrated ammonia in ethanol (1 L) was added crotonaldehyde (110 g) at a rate 2.5 ml/min while the temperature was kept below 10°. The mixture was warmed to room temperature overnight and concentrated in vacuo to give a yellow oily residue (260 g). The residue was treated with a mixture of con H2SO4 (100 ml), con HNO3 (130 ml) and water (580 ml) and the mixture cautiously heated on a steam bath until the evolution of NO2 had subsided, then heated for another 30 min. After cooling, the supernatant was basified with con NH4OH and extracted with diethyl ether (300 ml×10). The combined ether extracts were concentrated to leave a dark brown oily residue (38 g). Purification of the residue by silica gel column chromatography (70 - 230 mesh, 400 g, 42×5 cm, three times) using n-hexaneethyl acetate (2:1) as eluent afforded 15 g of ethyl-4-methyl-2-phenylnicotinate. Hydrolysis of ethyl-4-methyl-2-phenylnicotinate (15 g) with refluxing ethanolic KOH, followed by work-up afforded 4-methyl-2-phenylnicotinic acid (9 g) as colorless prisms, mp 210°-212°. Treatment of 4-methyl-2-phenylnicotinic acid (9 g) with polyphosphoric acid (166.7 g) at 130° for 3 hr., afforded 1-methyl-4-azafluoren-9-one, onychine, (7.5 g) as yellow prisms from n-hexane, mp 130°-131° C.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(O)(=O)C.O[C:9]([C:12]1[S:13][CH:14]=[C:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH2:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]=12)[CH3:11]
Reactant: CC(C)(C)OC(=O)N1Cc2csc(C(C)(C)O)c2C1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: C=C(C)c1scc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 102.8 %

Procedure:
5 g of calcium chloride and 0.17 ml (3 mmol) of acetic acid are added to a solution of 0.81 g (2.86 mmol) of 1-(2-hydroxy-2-propyl)-5-(1,1-dimethyl-ethoxy) carbonyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 60 ml of chloroform. The mixture is heated at reflux for 24 hours, filtered, washed with a 5% sodium bicarbonate solution, then dried over sodium sulphate and evaporated to dryness. 0.78 g of an oily product is obtained.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31]([CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:2])[S:26][CH:27]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCOC(=O)Cc1csc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)n1
Yield: 14.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethy 2-aminothiazole-4-acetate (63.3 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethoxycarbonylmethylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (11.2 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([O:38]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([N:3]([CH3:4])[CH3:2])=[O:38])[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl amine hydrochloride (150 mg) was added to a solution of N,N-diisopropylethylamine (DIPEA, 0.50 ml) and tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 250 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:17])(=[O:3])[CH3:2].[Br:18]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:14])[F:15])[C:9]([Br:18])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:17])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(Br)c(C(F)(F)F)c2CC1C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
To a solution of 1-acetyl-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.100 g, 0.45 mmol; step A above) in acetic acid (1.0 mL) at rt was added bromine (0.035 mL; 0.68 mmol). More bromine (0.020 mL, 0.39 mmol) was added after 14 h. After another 5 h, the mixture was slowly added to sat'd NaHCO3 and extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.090 g of the title compound as a white solid: MS (ES) m/z 324 (M+2 isomer).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[N:9]([CH:10]=1)[CH2:8][CH2:7][S:6]2(=[O:12])=[O:11]>C(#N)C.[O-2].[O-2].[Mn+4]>[S:6]1(=[O:12])(=[O:11])[CH2:7][CH2:8][N:9]2[CH:10]=[C:3]([CH:2]=[O:1])[N:4]=[C:5]12
Reactant: O=S1(=O)CCn2cc(CO)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: O=Cc1cn2c(n1)S(=O)(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-Dihydro-6-hydroxymethylimidazo[2,1-b]thiazole- 1,1-dioxide (207 mg, 1.1 mmol) was dissolved in acetonitrile (minimum volume) and treated with manganese dioxide (621 mg, 3 wt. equivalents) and the mixture stirred vigorously at ambient temperature. After 1 h, more manganese dioxide (621 mg) was added and the mixture sitrred for a further 18 h. The mixture was filtered through Celite, the filter bed washed with acetonitrile, the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was triturated under dichloromethane and the resulting solid collected by filtration, washed with dichloromethane and dried in air (108 mg, 53%) (Found: M+ 186.0103. C6H6N2O3S requires M 186.0099); νmax (Nujol) 1691, 1320 and 1132 cm-1 ; δH [250 MHz; (CD3)2SO]4.25 (2H, t, J 7 Hz), 4.68 (2H, t, J7 Hz), 8.32 (1H, s), 9.81 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH:23]([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[C:19]([N+:32]([O-:34])=[O:33])=[C:18]([F:35])[CH:17]=2)[CH2:11][S:10](=[O:37])(=[O:36])[CH2:9]1)(C)(C)C.[ClH:39]>C1COCC1.O1CCOCC1>[ClH:39].[NH2:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH:23]([C:24]([F:27])([F:26])[F:25])[C:28]([F:31])([F:29])[F:30])[C:19]([N+:32]([O-:34])=[O:33])=[C:18]([F:35])[CH:17]=2)[CH2:11][S:10](=[O:36])(=[O:37])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OC(C(F)(F)F)C(F)(F)F)c2)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(OC(C(F)(F)F)C(F)(F)F)c2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(3R,4S,5S)-5-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-benzyl]-4-hydroxy-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-3-yl}-carbamic acid tert-butyl ester (3.42 g, 5.85 mmol) in THF (5 mL) was added 4N HCl in dioxane (20 mL) and the reaction mixture was stirred for 2 h at 25° C. After evaporation the residue was stirred with Et2O, filtered and dried to provide the title compound as a beige solid: TLC (EtOAc-MeOH 9:1) Rf=0.12; HPLC RtA=1.76 min; ESIMS [M+H]+=485; 1H NMR (400 MHz, CD3OD): δ 7.24 (s, 1H), 7.18 (d, 1H), 6.29 (m, 1H), 3.3-3.7 (m, 5H), 3.21 (dd, 1H), 2.97 (m, 1H), 2.70 (dd, 1H), 2.42 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=S)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 76.9 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-chlorophenyl isothiocyanate (0.024 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 71 (0.048 g, 0.10 mmol, 80%) as a solid film. LCMS m/z (%)=451 (M+H79Br35Cl, 85), 453 (M+H81Br35Cl, 100), 455 (M+H81Br37Cl, 35). 1H NMR (400 MHz, CDCl3) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J=2.7, 8.8 Hz, 1H), 7.37 (s, 4H), 7.30 (d, J=2.7 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:13]([S:16][CH3:17])=[CH:14][CH:15]=1)[CH:11]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:10]([CH:11]=[CH2:1])[C:9]=1[O:18][CH3:19]
Reactant: COc1c(Br)ccc(SC)c1C=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(SC)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
At 0° C., potassium tert-butoxide (6.2 g, 55.4 mmol) was added to a solution of methyltriphenylphosphonium bromide (19.7 g, 55.4 mmol) in THF (180 ml). At from −10 to −5° C., 3-bromo-2-methoxy-6-methylsulfanylbenzaldehyde (12 g, 46 mmol) dissolved in THF (180 ml) was then added, and the mixture was stirred overnight at RT for 7 h. The mixture was filtered, and the solution was admixed with H2O (200 ml) and MTBE (200 ml) and then extracted with MTBE (200 ml). The combined organic phases were dried over MgSO4 and concentrated. Chromatography (cyclohexanez→cyclohexane/EtOAc 9:1) gave 1-bromo-2-methoxy-4-methylsulfanyl-3-vinylbenzene.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])[OH:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32](=[O:50])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)=[CH2:34]>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:50])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)[CH2:34][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C=C(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CCOP(O)C(NC(=O)OCc1ccccc1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)-2-methylpropyl-phosphonous acid ethyl ester (6.2 g 20.7 mmol) in 150 ml CH2Cl2 was added DIEA (6.5 mL, 47.5 mmol). The mixture solution was cooled down to 0° C. over an ice-water bath. TMSCI (5.5 mL, 42.0 mmol) was added dropwise under N2. The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0° C. again. A solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-propenoic acid methyl ester (6.7 g, 23.0 mmol) in 15 mL CH2Cl2 was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by 10 mL MeOH, then concentrated in vacuo, and the residue was taken up into 300 mL ethyl acetate. The organic phase was washed with 2 N NaHSO4, water, and brine. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel to afford 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (10.7 g, 18.1 mmol, 81%) as white solid.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1
Yield: 50.8 %

Procedure:
Ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 17.6 g.), mp 122° to 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:19])[CH:11]=[C:12]([C:16]([OH:18])=O)[N:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:55]1([CH2:60][CH2:61][NH2:62])[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:19])[CH:11]=[C:12]([C:16]([NH:62][CH2:61][CH2:60][N:55]3[CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:18])[N:13]([CH3:15])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(COc2cn(C)c(C(=O)O)cc2=O)cc1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c(C(=O)NCCN3CCCC3)cc2=O)cc1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A mixture of 5-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1.21 g, 4.18 mmol), HATU (1.908 g, 5.02 mmol), diisopropylethyl amine (1.5 ml, 8.59 mmol) in N,N-dimethylformamide (15.0 ml) was stirred at room temperature for 30 min. at which time 2-(pyrrolidin-1-yl)ethanamine (0.58 ml, 4.61 mmol) was added and the reaction was allowed to stir for 3 h. The reaction was concentrated under vacuum, the residue was triturated with dichloromethane. The solid material was filtered and further washed with dichloromethane. The supernatant was collected, concentrated under reduced pressure and the residue was purified on silica gel eluting with methanol/dichloromethane/ammonium hydroxide. The fractions containing the desired product were concentrated, the residue was dissolved in dichloromethane, and washed with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to give 5-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydropyridine-2-carboxamide (1.32 g, 3.42 mmol, 82% yield) as nearly white solid. LCMS: (M+H)+: 386.2