Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:10][CH:9]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:19]([Li])CCC.CCCCCC.CI>O1CCCC1>[CH3:19][C:1]1([S:4]([N:7]2[CH2:10][CH:9]([O:11][Si:12]([CH2:15][CH3:16])([CH2:17][CH3:18])[CH2:13][CH3:14])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2CC2)C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2(C)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cyclopropylsulfonyl)-3-[(triethylsilyl)oxy]azetidine (1.0 g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added 2.50 M of n-butyllithium in hexane (1.37 mL, 3.43 mmol) dropwise. After stirring at this temperature for 1 hour, methyl iodide (0.224 mL, 3.60 mmol) was added. After 30 minutes, the reaction temperature was raised to 0° C. and stirred for 50 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate, followed by brine and the product was extracted with ethyl acetate. The extracts were dried over sodium sulfate, decanted and concentrated. Flash column chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes afforded product (890 mg, 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH:5]2[CH3:12].[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]#[N:20]>>[CH3:13][N:14]1[C:18]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH:5]3[CH3:12])=[CH:17][CH:16]=[C:15]1[C:19]#[N:20]
Reactant: CC1CC(=O)c2ccc(Br)cc21
Reactant: Cn1cccc1C#N
Product: CC1CC(=O)c2ccc(-c3ccc(C#N)n3C)cc21
Yield: 76 %

Procedure:
1-Methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile as an orange solid (0.65 g, 76%) was prepared from 5-bromo-3-methyl-indan-1-one and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 2. MS (ES) m/z 251.2; Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.49; H, 5.49; N, 11.10. HRMS: calcd for C16H14N2O+H+, 251.1179; found (ESI, [M+H]+), 251.1179.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na]>CO>[CH2:2]([O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1)[C:10]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 120.8 %

Procedure:
Methyl 4-(3-hydroxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (T) (35.7 g.) was added to a mixture of sodium (2.3 g.) and methanol (200 ml.). The mixture was stirred for 18 hours, and evaporated. The residue was dissolved in N,N-dimethylformamide (100 ml.), cooled to 0° C., and benzyl bromide (15.5 ml.) added. After 18 hours at ambient temperature, ethyl acetate and 1N sodium hydroxide solution were added. The precipitate was isolated by filtration, washed with ether, and chromatographed by HPLC on silica gel, eluting with dichloromethane, to give methyl 4-(3-benzyloxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (CC) (27 g., 60%) as a solid; NMR (250 MHz, DMSO-d6): 3.84(s,3H, OMe); 3.86(s,3H, OMe); 5.38(s,2H, NCH2); 5.65(s,2H, OCH2); 6.95(d,1H); 7.36 (m,3H); 7.46(m,5H); 7.86(m,2H); 8.66(s,1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13](=O)[NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][C:16]=2[NH2:28])=[N:10][NH:11][CH:12]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:22]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]3[NH:14][C:13]([C:9]4[C:8]([NH2:7])=[CH:12][NH:11][N:10]=4)=[N:28][C:16]=3[CH:17]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
[3-(2-Amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (1.350 Kg, 3.24 mol, 1.0 wt) and ethanol (6.75 L, 5.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Conc. aq. hydrochloric acid (1.10 L, 13.2 mol, 0.80 vol) was added at 15 to 30° C. under nitrogen and the contents were then heated to 70 to 80° C. and maintained at this temperature for 16 to 24 hours. A second portion of hydrochloric acid (0.11 L, 1.32 mol, 0.080 vol) was added at 70 to 80° C. and the reaction was heated for a further 4 hours. Reaction completion was determined by HPLC analysis. The reaction mixture was cooled to 10 to 20° C. and potassium carbonate (1.355 Kg, 9.08 mol, 1.0 wt) was charged portionwise at this temperature. The suspension was stirred until gas evolution ceased and was then filtered. The filter-cake was washed with ethanol (1.35 L, 1.0 vol) and the filtrates retained. The filter-cake was slurried with ethanol (4.00 L, 3.0 vol) at 15 to 25° C. for 20 to 40 minutes and the mixture was filtered. The filter-cake was washed with ethanol (1.35 L, 1.0 vol) and the total combined filtrates were concentrated under vacuum at 35 to 45° C. Ethanol (4.00 L, 3.0 vol) was charged to the residue and removed under vacuum at 35 to 45° C. Tetrahydrofuran (5.90 L, 4.4 vol) was added to the residue and stirred for 10 to 20 minutes at 15 to 25° C. The resulting solution was filtered, the filter-cake was washed with tetrahydrofuran (1.35 L, 1.0 vol) and the combined filtrates were concentrated under vacuum at 35 to 45° C. Tetrahydrofuran (5.40 L, 4.0 vol) was charged to the concentrate and removed under vacuum at 35 to 45° C. Tetrahydrofuran (5.40 L, 4.0 vol) was charged to the concentrate and removed under vacuum at 35 to 45° C. to give the desired product, 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.924 Kg, 95.5%, 82.84% by HPLC area) as a purple foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:19])CC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][F:19])[CH:3]=1
Reactant: OCCC#Cc1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution of 1.5 gm (6.67 mmol) of 4-(3-bromophenyl)but-3-yn-1-ol in CH2Cl2 at 0° C. was treated with 2.0 mL (15.3 mmol) of DAST, stirred at 0° C. for 1 h, allowed to warm to room temperature for 1 h, poured into saturated sodium bicarbonate and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the resultant concentrate on silica gel with a gradient of 0% to 24% EtOAc-hexanes gave 1-Bromo-3-(4-fluoro-but-1-ynyl)benzene as a volatile liquid, 0.96 gm (64% yield); 1H NMR (400 MHz, CDCl3) δ: 2.82 (dt, 2H, J=6.6, 19.8 Hz), 4.56 (dt, 2H, J=6.6,46.4 Hz), 7.14 (t, 2H, J=7.9 Hz), 7.31 (m, 1H), 7.41 (m, 1H), 7.55 (t, 1H, J=1.7 Hz).
Reaction SMILES: [CH3:1]N(C)CCCN.CO.C(Cl)(Cl)Cl.[O:14]=[C:15]1[CH:18]([N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:17][N:16]1[CH:30]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[C:31]([O-:33])=[O:32]>C(OCC)(=O)C>[NH2:19][CH:18]1[CH2:17][N:16]([CH:30]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[C:31]([O:33][CH3:1])=[O:32])[C:15]1=[O:14]
Reactant: O=C([O-])C(c1cccs1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(c1cccs1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (1.32 g.) was added to a mixture of methanol (30 ml.) and chloroform (18 ml.) containing 2-(2-oxo-3-phthalimido-1-azetidinyl)-2-(2-thienyl)-acetate (2.22 g.), whereafter the mixture was stirred at ambient temperature overnight. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate. The solution was extracted with three portions of an aqueous solution consisting of 1N hydrochloric acid (6.4 ml.) and water (10 ml.). The combined aqueous extracts were adjusted to pH8 with sodium bicarbonate and then saturated with sodium chloride. The solution was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue (1.57 g.), which was subjected to column chromatography on silica gel (25 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2(3-amino-2-oxo-1-azetidinyl)-2-(2-thienyl)acetate (0.96 g.).
Reaction SMILES: C([O:5][C:6](=[O:71])[CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:54][CH2:55][C:56]([O:58]C(C)(C)C)=[O:57])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:53])[CH2:28][CH2:29][CH:30]([CH:32]3[C:48]4([CH3:49])[CH:35]([CH:36]5[CH:45]([CH2:46][CH:47]4[OH:50])[C:44]4([CH3:51])[CH:39]([CH2:40][CH:41]([OH:52])[CH2:42][CH2:43]4)[CH2:38][CH2:37]5)[CH2:34][CH2:33]3)[CH3:31])=[CH:22][CH:21]=2)[CH2:13][CH2:12][N:11]([CH2:63][C:64]([O:66]C(C)(C)C)=[O:65])[CH2:10][CH2:9]1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:54][CH2:55][C:56]([OH:58])=[O:57])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:53])[CH2:28][CH2:29][CH:30]([CH:32]3[C:48]4([CH3:49])[CH:35]([CH:36]5[CH:45]([CH2:46][CH:47]4[OH:50])[C:44]4([CH3:51])[CH:39]([CH2:40][CH:41]([OH:52])[CH2:42][CH2:43]4)[CH2:38][CH2:37]5)[CH2:34][CH2:33]3)[CH3:31])=[CH:24][CH:25]=2)[CH2:13][CH2:12][N:11]([CH2:63][C:64]([OH:66])=[O:65])[CH2:10][CH2:9]1)([OH:71])=[O:5]
Reactant: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC2)NCC(=O)OC(C)(C)C)cc1)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)NCC(=O)O)cc1)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 115 %

Procedure:
To a solution of Compound 8 (20 mg, 0.02 mmol) in 1,4 dioxane (1 mL) was dropwise added 4M HCl in 1,4-dioxane (1 mL) at 0-5° C. After the addition, the reaction mixture was gradually increased to room temperature and stirred for 1.8 h. To this solution, ether (30 mL) was added and continuously stirred for 30 min. The resulting mixture was placed in the freezer for 2 h. Solid residue was quickly filtered, washed with ethyl ether (5 mL), and immediately dissolved in DI H2O and lypophilized to provide pure DCA-NE3TA as a light brownish solid (19 mg, 98%). 1H NMR (CD3OD) 0.71 (s, 3H), 0.92-3.90 (m, 55H), 3.97 (s, 1H), 4.09 (s, 1H), 7.28 (d, 2H), 7.57 (d, 2H); 13C NMR (CD3OD) 11.86, 16.39, 22.35, 23.50, 26.09, 27.02, 27.33, 28.53, 29.68, 31.79, 33.43, 33.63, 33.73, 33.91, 35.04, 35.55, 35.79, 36.05, 42.21, 44.44, 46.17, 71.16, 72.65, 120.41, 129.55, 130.54, 167.99, 173.96 HRMS (Positive ion FAB) Calcd for C45H72N5O9 [M+H]+ m/z 826.5330. Found: [M+H]+ m/z 826.5355.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N.CC[N:20](CC)CC>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:20])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Agent: N
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(S(N)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution 1-acetylindoline-5-sulfonyl chloride (Borror, A. L. et al., J. Org. Chem., 53:2047-2052 (1988)) (2.00 g, 7.70 mmol) in CH2Cl2 (5.0 mL) was added NH3 (38.5 mL, 19.3 mmol, 0.5M solution in dioxane) and Et3N (2.2 mL, 15.4 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo, and the residue was triturated with 1N aq. HCl solution (2×) and water (1×) to give the title compound (1.80 g, 97%) as a white solid. 1H NMR (DMSO-d6) δ 8.11 (d, J=8.1 Hz, 1H), 7.64-7.62 (m, 2H), 7.20 (br s, 2H), 4.16 (t, J=8.6 Hz, 2H), 3.19 (t, J=8.5 Hz, 2H), 2.19 (s, 3H); MS(ESI+) m/z 241.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].[C:26]1([CH2:32][CH2:33]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][N:7]2[CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(F)c(F)c(F)c2c1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCc2ccccc2)c2cc(F)c(F)c(F)c2c1=O
Temperature: 90 °C
Reaction time: 27 h
Yield: 33 %

Procedure:
A mixture of ethyl 5,6,7-trifluoro-4-hydroxy-3-quinolinecarboxylate (2.00 g, 7.37 mmol), K2CO3 (3.06 g, 22.1 mmo) and 2-phenylethyl bromide (1.50 mL, 11.1 mmol) in DMF (16 mL) was stirred at 90° C. for 27 h and concentrated in vacuo. After dilution of the residue with CHCl3, the mixture washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (EtOAc: MeOH 10:1) gave ethyl 5,6,7-trifluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (913 mg, 33%) as a pale yellow powder.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Cl)cc12
Yield: 14.3 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-chlorophenylhydrazine hydrochloride (1.03 g, 5.75 mmol) were converted to the title compound (0.230 g, 14%) as a pale brown solid: mp>300° C.; 1H NMR (DMSO-d6,): δ 4.00 (s, 2H), 7.10 (d of d, 1H), 7.46 (d, 1H), 7.51 ( d, 1H), 7.66 (d, 1H), 7.78-7.81 (m, 2H), 11.83 (s, 1H), 13.57 (s, 1H); MS [EI, m/z]: 283 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c([N+](=O)[O-])c4)cc3)c2cc1OC
Yield: 143.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 4-chloro-3-nitrophenyl isocyanate (224 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 125 mg of the title compound (yield: 75%).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([S:10][CH3:11])[NH:6][CH2:7][CH2:8]Br)([O-:3])=[O:2].[H-].[Na+]>O1CCCC1>[CH3:11][S:10][C:5]1[NH:6][CH2:7][CH2:8][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1=C([N+](=O)[O-])CCN1
Yield: 26 %

Procedure:
(b)(ii) A solution of 1-nitro-2-methylthio-2-(2-bromoethylamino)ethylene (3 g, 0.012 mol) and sodium hydride (50% in oil, 0.62 g, 0.013 mol) in dry tetrahydrofuran (100 ml) was refluxed for 7 hours. The reaction mixture was cooled, and the solvent was removed in vacuo. The residue was extracted with boiling ethyl acetate (2×50 ml), and the extracts were decolourized with charcoal. Concentration of the extracts in vacuo, followed by cooling, resulted in the crystallisation of 2-methylthio-3-nitro-4,5-dihydropyrrole (0.5 g, 26%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O4S [(M+H)+] 714.2642, observed 714.2641.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:34])=[C:15]([C@:17]34[O:25][CH2:24][CH2:23][C@H:22]3[CH2:21][S:20][C:19]([NH:26]C(=O)OC(C)(C)C)=[N:18]4)[CH:16]=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:42]CCl>>[NH2:26][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][CH2:24][O:25][C@:17]2([C:15]2[CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([Cl:42])=[CH:7][N:6]=3)[CH:12]=[CH:13][C:14]=2[F:34])[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (4aR,7aR)-7a-(5-(5-bromopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (45 mg) in dichloromethane (0.44 mL) was added TFA (103 μL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was subjected directly to preparative TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-chloropicolinamide as a white foam (29 mg). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.70 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.5 Hz), 8.06 (1H, dd, J=2.0, 8.06 Hz), 8.0 (1H, m), 7.75 (1H, m), 7.09 (1H, m), 4.13 (2H, m), 3.22 (1H, m), 3.02 (1H, m), 2.89 (1H, m), and 2.22 (2H, q, J=7.5 Hz). MS (M+H)+: 453.3. Retention time: 18.96 chiralcel OJ-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol); Retention time: 11.49 chiralcel OD-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20]C)[N:14]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[S:9][CH3:10].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[S:9][CH3:10])[C:11]([C:13]1[NH:14][C:15](=[O:20])[C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:12]
Reactant: COc1nc(C(=O)c2ccc(SC)c(Cl)c2)ccc1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CSc1ccc(C(=O)c2ccc(C)c(=O)[nH]2)cc1Cl
Temperature: 95 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
48% hydrobromic acid (7 mL) was added to a solution of [3-chloro-4-(methylsulfanyl)phenyl](6-methoxy-5-methylpyridin-2-yl)methanone obtained in Reference Example 1-40 (700 mg) in acetonitrile (7 mL) at room temperature, and the mixture was stirred at 95° C. for one hour. The reaction solution was neutralized with saturated aqueous sodium bicarbonate at room temperature and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to give 6-[3-chloro-4-(methylsulfanyl)benzoyl]-3-methylpyridin-2(1H)-one as a pale yellow solid (632 mg, 95%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][C:14](=[CH2:18])[CH2:15][Mg]Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:6])[CH2:15][C:14]([CH3:18])=[CH2:13]
Reactant: C=C(C)C[Mg]Cl
Reactant: O=C(CCCCl)c1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of compound 4-chloro-1-phenylbutan-1-one (3.64 g, 0.02 mol) in THF (60 mL) was added (2-methylallyl)magnesium chloride (60 mL, 1 mol/L) at −78° C. The mixture was stirred at room temperature for 1 h. TLC showed the disappearance of the starting material. The mixture was quenched with satd aq NH4Cl and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated to give the crude final product, which was purified by chromatography to afford the compound 7-chloro-2-methyl-4-phenylhept-1-en-4-ol (4.2 g, 90%).