Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](CCCO)=[C:20]([O:23][CH2:24][C:25]4C=CC=C[CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[O:23][CH2:24][CH2:25][CH2:26]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(OCc4ccccc4)c(CCCO)c3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)CCCO4)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 2.0 g (4.1 mmole) of [(2R)-7-(benzyloxy)-8-(3-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 100 mL of methanol was added to a slurry of 0.30 g of 10% palladium on carbon in 30 mL of methanol in 500 mL Parr hydrogenation bottle. The mixture was treated with 50 psi of hydrogen on a Parr shaker for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to 1.6 g of a colorless oil. The oil was dissolved in 100 mL of benzene, 2.1 g (8.0 mmole) of triphenylphosphine and 1.6 g (8.0 mmole) of diisopropylazodicarboxylate added and the mixture stirred at room temperature for 5 days. The solvent was then removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant to give 1.2 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.35 δ (2H); doublet 6.6 δ (1H); doublet 6.35 δ (1H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); triplet 4.1 δ (2H); doublet of doublets 4.0 δ (1H); multiplet 2.55 δ (2H); singlet 2.45 δ (3H); multiplet 1.9 δ (2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:28]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[C:12]([CH:15]=[O:16])[C:11]=2[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[C:12]([CH:15]=[O:16])[C:11]=2[CH:17]=1
Reactant: COc1ccc2scc(C=O)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1csc2ccc(O)cc12

Procedure:
A solution of BBr3 (0.07 mol) in 15 ml CH2Cl2 is added at 0° to a solution of 0.014 mol 5-methoxy-benzothiophene-3-carboxaldehyde in 80 ml CH2Cl2. After 4 hours 2 N Na2CO3 is added until pH=7. The organic solvent is evaporated and the suspension is filtered. The solid is washed with water to yield crude title compound which is recrystallized from CH3OH/H2O. M.p.=200°.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[C:19](=O)([O-])O.[Na+]>CO>[CH3:19][O:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=1)=[O:3]
Reactant: O=C([O-])O
Reactant: Cc1cc2cc(C(=O)O)ccc2o1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2oc(C)cc2c1
Yield: 81 %

Procedure:
5-Carboxy-2-methylbenzo[b]furan (1.9 g, 10.7 mmol) was suspended in methanol (50 ml) and concentrated sulfuric acid (0.1 ml) was added, which was followed by reflux under heating for 14 hr. After cooling, a saturated aqueous sodium hydrogencarbonate solution was added. Methanol was evaporated under reduced pressure, and the residue was extracted with methyl t-butyl ether. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to give the objective compound (1.66 g, 81%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2.[OH-].[Na+].[CH2:19]([OH:21])[CH3:20]>O>[CH2:19]([O:21][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2)[CH3:20]
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc2nc3ccccc3c(=O)n2n1
Reaction time: 2 h

Procedure:
To 1.2 g of 2-chloro-10H-pyridazino[3,2-b]quinazolin-10-one dissolved in ethanol, there was added a solution of sodium hydroxide (2.0 g) in water (8 ml), and stirring was continued at 40° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation, followed by addition of an aqueous solution of acetic acid. The precipitates were collected by filtration and recrystallized from a mixture of methanol and water to give 1.0 g of 2-ethoxy-10H-pyridazino[3,2-b]quinazolin-10-one (Compound No. 2). M.P., 159.5°-160.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.O1CCCC1>O>[NH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1-n1cccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(Cl)cc1-n1cccc1

Procedure:
A stirred solution of 42.4 g (0.165 mole) of 1-(4,5-dichloro-2-nitrophenyl)pyrrole in 730 ml. of tetrahydrofuran and 365 ml. of water is treated according to the manipulative procedure described above in Example 13(b) to give 1-(2-amino-4,5-dichlorophenyl)pyrrole, m.p. 57°-58° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C)C=O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:12]=1[C:13]#[N:14]
Reactant: OCc1ccsc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-thiophenemethanol (1.0 g; 8.76 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.42 g; 10.51 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 600 milligrams of 2-fluoro-6-(thiophen-3-ylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[CH3:1][S:2][CH:3]([S:4]([CH3:6])=[O:5])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSC(Cc1ccccc1)S(C)=O
Reaction time: 1 h
Yield: 64.7 %

Procedure:
590 mg of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice, 171 mg (1.5 equivalents) of sodium hydride was added. The mixture was stirred for 1 hour. 813 mg of benzyl chloride was added, and the mixture was stirred at room temperature for 15 hours. 50 ml of methylene chloride and 1 ml. of water were added, and the reaction mixture was dried with anhydrous sodium sulfate, and the organic layer was concentrated at reduced pressure. The residue was subjected to column chromatography (silica gel, methylene chloride and ethyl acetate) to give 659 mg of methyl 1-methylthio-2-phenylethyl sulfoxide in a conversion yield of 92.2%.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]([NH:24]C(=O)C1C=CC=CC=1)([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C2C=CC=CC=2)=[CH:11][CH:10]=1)[CH:5]=[C:6]=[CH2:7].[OH-].[Na+]>C(Cl)Cl.CCOCC.CO>[NH2:24][C:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)([CH:5]=[C:6]=[CH2:7])[C:3]([OH:33])=[O:2]
Reactant: C=C=CC(Cc1ccc(OC(=O)c2ccccc2)cc1)(NC(=O)c1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: C=C=CC(N)(Cc1ccc(O)cc1)C(=O)O
Reaction time: 8 h

Procedure:
To 1.33 g of 2-(benzoylamino)-2-(4-benzoyloxybenzyl)penta-3,4-dienoic acid methyl ester in 5 ml of dry methylene chloride was added 9 ml of 1.0M solution of Meerwein's reagent triethyloxonium tetrafluoroborate at room temperature with stirring and under argon. The reaction was left at room temperature for five (5) days with stirring under argon. The reaction mixture was then concentrated under vacuum and the residue was taken in 10 ml of tetrahydrofuran and 5 ml of 5% acetic acid and left overnight at room temperature with stirring under argon. The resulting reaction mixture was then diluted with 50 ml of ether and extracted 3 times with 2% hydrochloric acid (15 ml). The aqueous fractions were combined and the pH adjusted to 7.5 in a two-phase system containing methylene chloride. The aqueous extraction was further extracted with 3×30 ml of methylene chloride. The organic fractions were pooled, dried over anhydrous magnesium sulfate, and concentrated to give a residue which was then taken up in 15 ml of methanol and 10 ml of a 2.0N sodium hydroxide solution and left stirring overnight under argon. This mixture was then diluted with 30 ml of ether and extracted with water (3×15 ml). The pH of the aqueous layer was adjusted to 2.5 and the sample desalted by passing the the aqueous solution through an ion exchange column (BioRad Ag 50w×8), eluting with 20% pyridine-water. Appropriate eluant fractions were concentrated under vacuum and the residue taken up in water, the pH adjusted to the pI of tyrosine and absolute ethyl alcohol added. Resulting crystals of the title compound were collected and characterized as follows: mp 270°-275° C. (dec), IR (KBr); 1958 cm-1 (C=C=C), 1HNMR; (delta D2O); 3.05 (AB, 2H, --CH2--), 5.0 (d, 2H, CH2 =C), 5.5 ppm (dd, 1H, CH=C), MH+ 220.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH:21]1[CH2:30][NH2:31]>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:31][CH2:30][CH:21]2[O:20][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH2:22]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCC1COc2ccccc2O1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCC2COc3ccccc3O2)=C(c2ccccc2)S1(=O)=O
Temperature: 100 °C
Yield: 64.9 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and (2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amine (0.083 g, 0.50 mmol) and TEA (0.07 mL, 0.50 mmol) in MeCN (2 mL) was heated in a microwave reactor at 100° C. for 45 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography using a 15-25% EtOAc in petroleum ether mixture as eluant, to give the title compound (0.139 g, 65%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.45 (m, 3H), 6.92-6.82 (m, 4H), 5.65 (t, 1H), 4.12-4.04 (m, 1H), 3.86 (dd, 1H), 3.68 (dd, 1H), 3.17 (t, 2H), 1.75 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.5, 142.9, 142.3, 135.1, 131.7, 130.2, 129.2, 124.8, 122.2, 122.1, 117.7, 117.5, 108.7, 71.4, 65.3, 61.9, 44.1, 27.9; Mass Spectrum: [M+H]+ 429.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH3:31][NH2:32]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:32][CH3:31])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reactant: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 0.04 mmol) and a solution of methanamine (107 μL of 2 M, 0.21 mmol) in THF was heated at 65° C. for 6 h. The reaction mixture was allowed to cool to room temperature and the solvents were evaporated under reduced pressure. The crude material obtained was dissolved in DMF (1 mL), filtered and purified by mass directed reverse phase LC/MS (1-99% ACN/H2O (5 mM HCl)) to yield 1-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (9 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 2H), 8.58 (s, 1H), 8.18 (d, J=7.7 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.63 (s, 2H), 6.66 (s, 1H), 4.30-4.13 (m, 4H), 3.70 (dt, J=16.2, 5.4 Hz, 2H), 2.71 (s, 1H), 2.59 (t, J=5.2 Hz, 4H), 2.41 (dt, J=21.8, 7.3 Hz, 2H), 1.03 (q, J=7.0 Hz, 3H). LC/MS m/z 420.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23][OH:24])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[H-].[Na+].I[CH3:33]>O1CCCC1.O>[CH3:33][O:24][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:1])([F:28])[F:29])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.075 g, 0.18 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodium hydride (0.011 g, 0.28 mmol, 60% dispersion in oil). After 15 min., iodomethane (0.017 mL, 0.27 mmol) was added. The mixture was stirred at 23° C. for 1.75 h. The reaction mixture was diluted with water (20 mL), extracted with diethyl ether (3×15 mL), and washed with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.045 g.) as a clear, colorless oil.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24](Cl)=[O:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:27]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH:27]1([CH2:31][NH:32][C:24]([C:21]2[CH:20]=[CH:19][C:18]3[S:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH:8]([CH3:9])[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[C:23]=3[CH:22]=2)=[O:25])[CH2:30][CH2:29][CH2:28]1
Reactant: NCC1CCC1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NCC3CCC3)cc21
Yield: 48.6 %

Procedure:
By working in a manner similar to that described below in Example 103, but starting with 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (3.4 g) in dichloromethane (100 cc) and with cyclobutylmethylamine (4.5 g), N-(cyclobutylmethyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (1.7 g) is obtained, after recrystallization in isopropyl ether, in the form of white crystals, m.p. 133° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH:15]=O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>O1CCCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][C:2]1[C:3]([C:12]2([CH:15]=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
0.72 g of 1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbaldehyde (step 2) was dissolved in 13 ml of tetrahydrofuran, then 1.32 g of titanium(IV)ethoxide and 355 mg of 2-methyl-propane-2-sulfinic acid amide were added to the solution. The reaction mixture was stirred at ambient temperature for 24 hours, then poured into brine. The resulting suspension was filtered, the filtrate extracted with ethyl acetate, the organic phase dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (95:5) as eluent. Thus, 0.73 g of 2-methyl-propane-2-sulfinic acid 1-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-methylideneamide was obtained as a pale yellow solid. 1H-NMR (CDCl3): 8.73 ppm (s, 1H), 7.95 ppm (s, 1H), 7.65 ppm (s, 1H), 1.70 ppm (m, 4H), 1.12 ppm (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](=[O:42])[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]3=4)=[O:25])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43].O1CCOCC1>>[ClH:43].[CH3:36][N:31]1[C:30]2[NH:29][C:28]3[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]=3[N:26]([C:24]([CH:21]3[CH2:20][CH2:19][CH:18]([CH2:17][NH:16][C:15](=[O:42])[CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:23][CH2:22]3)=[O:25])[CH2:35][C:34]=2[CH:33]=[N:32]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Yield: 93 %

Procedure:
A solution of 4-({[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamoyl}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound Number 228)(259 mg, 0.45 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (230 mg, 93%).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH2:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(=O)OC(C)(C)C
Reactant: Clc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
Toluene (60 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-chlorothiazole (2.00 g, 16.73 mmol) and tert-butyl acetate (2.137 g, 18.40 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 61.3 mL, 36.8 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h. The orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography on silica (0-25% ethyl acetate in hexanes) afforded tert-butyl (1,3-thiazol-2-yl)acetate (770 mg, 23%) as a pale yellow oil. MS ESI: [M t-Bu]+ m/z 144.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]1=[O:14].CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:12][O:13][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:7]1=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C=C(CO)CCN1Cc1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1=CC(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-(3-chloro-4-fluorobenzyl)-4-hydroxymethyl-5,6-dihydropyridin-2(1H)-one (3.1 g, 11 mmol) from the previous step and DIEA (2.8 mL, 16 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. with stirring. Methanesulfonyl chloride (1.4 g, 12 mmol) was added and the mixture was stirred at 0° C. for 30 min and then at ambient temperature for 1 hour. The reaction mixture was diluted with CH2Cl2 (75 mL) and extracted with water (2×30 mL). The CH2Cl2 layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a gum. 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J=6.9, 2.9 Hz, 1H), 7.1-7.2 (m, 2H), 4.64 (d, J=15 Hz, 1H), 4.44 (d, J=15 Hz, 1H), 4.13 (ABX, J=6, 15 Hz, 2H), 3.28 (m, 2H), 3.04 (s, 3H), 2.64 (m, 1H), 2.34 (m, 1H), 2.23 (dd, J=6, 16 Hz, 1H), 2.02 (m, 1H), 1.61 (m, 1H); HPLC RT=2.99 min (Method A); ES MS M+1=350.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To 0.838 g of L-valine methyl ester hydrochloride in 15 mL of dichloromethane, cooled in an ice bath, 1.34 g of 4-bromobenzenesulfonyl chloride was added followed by 2.79 mL of triethylamine. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 1.77 g of methyl N-[(4-bromophenyl)sulfonyl]-L-valinate as a colorless solid. Yield ˜100%. m.p. 88-90° C.; MS: 348.2 (M−H)−.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:16].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:11]([F:16])=[O:13])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-alanine, 24c, (189.2 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in CH2Cl2, and precipitated with hexane to afford 163.5 mg of a mixture of 24c and 25c as white crystals. FTIR (film) 1842 cm−1.