Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])(=[O:13])=[O:12].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1(C)C=CC=CC=1>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[S:11]([N:6]1[C:7]2[C:3](=[C:2]([CH:23]=[CH2:24])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)(=[O:13])=[O:12]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(Br)cccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1CCN2S(=O)(=O)c1cc(C)ccc1OC
Temperature: 110 °C
Yield: 48.2 %

Procedure:
4-bromo-1-[(2-methoxy-5-methylphenyl)sulfonyl]indoline (tot 721 mg, 1.89 mmol; Intermediate 9), tributyl(vinyl)stannane (tot 1.10 mL, 3.78 mmol) and Pd(PPh3)2OAc2 (tot 142 mg, 0.19 mmol) in dry toluene (tot 12 mL) was distributed into 3 tubes and stirred at 110° C. using a STEM block over weekend (68 h). Still about 30% starting material. The reactions were combined, filtered and concentrated. Redissolved in dry MeCN (8 mL), distributed into 2 Micro wave tubes followed by addition of tributyl(vinyl)stannane (300 μL, 1.03 mmol) and Pd(PPh3)2OAc2 (30 mg, 0.04 mmol) to each tube. The mixtures were irradiated by micro waves 180° C. for 600 s. Filtration and concentration followed by purification by flash (30% hexane in DCM) gave the title compound (300 mg, 48%) as a colorless viscous oil. MS (ESI+) for C18H19NO3S m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:33])[C:7]([CH:30]([CH3:32])[CH3:31])=[CH:8][C@@H:9]1[O:13]C(C)(C)[N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]1[CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:33])[CH:7]([CH:30]([CH3:32])[CH3:31])[CH2:8][C@H:9]([OH:13])[C@@H:10]([NH2:11])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C(C[C@H](O)[C@@H](N)CC(C)C)C(C)C
Yield: 99.9 %

Procedure:
93 mg (Z-isomer) of 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoic acid isobutylamide was dissolved in 0.8 ml of ethanol and then hydrogenated by using palladium black at atmospheric pressure. The reaction mixture was subjected to filtration, the solvent of the filtrate was distilled off under reduced pressure to obtain 58 mg of (2RS,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyl-octanoic acid isobutylamide as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Mg].[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16].S(=O)(=O)(O)O>C(OCC)C>[F:12][C:5]1[CH:4]=[CH:3][C:2]([CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)C=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A Grignard is prepared from 10 g (40 mmol) 5-bromo-2-fluorobenzotrifluoride, dissolved in 50 mL diethyl ether, and 0.97 g (40 mmol) magnesium. Then a solution of 3.63 mL (40 mmol) isobutyraldehyde and 30 mL diethyl ether is added dropwise at ambient temperature and the mixture is left overnight with stirring. The reaction mixture is poured onto ice water, combined with 30 mL 20% sulphuric acid and extracted with diethyl ether. The combined organic phases are washed successively with sodium hydrogen carbonate solution, water and sodium chloride solution, dried with sodium sulphate and evaporated down. The chromatographic purification of the residue yields the target compound in the form of a brown oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1.S(=O)(=O)(O)[OH:15]>O>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([OH:15])=[N:7][CH:8]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
Sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) was added dropwise to a cooled (0° C.) mixture of 2-amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol; Lancaster) in 2:6 M sulfuric acid (70 mL). The mixture was allowed to warm to ambient temperature, stir for 1.5 hours, filtered, and the filtercake was washed with cold water and air dried. The precipitate was dissolved in dichloromethane (100 mL), dried (MgSO4), and concentrated to provide the title compound as a solid (4.2 g, 84%). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:1]1
Reactant: COC(=O)CCCC(C)=O
Reactant: OCC(S)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCC1(C)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercaptopropanol (2.8 g, 0.022 mol), methyl 4-acetylbutyrate (3.2 g, 0.022 mol) and boron trifluoride etherate (0.62 ml) in methylene chloride (70 ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane as eluent to give 0.91 g (16.5%) of product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][CH2:4][CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]([F:21])([F:22])[CH2:3][CH2:4][CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(CCC(F)(F)F)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(CC(CCC(F)(F)F)CC(=O)O)c1
Yield: 97.7 %

Procedure:
Ethyl ester (119) (1.75 g, 5.50 mmol) was saponified with 1 N NaOH in THF and EtOH to give 1.56 g (98%) of the title compound (120) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.60-1.70 (m, 2H), 2.05-2.40 (m, 5H), 2.55-2.70 (m, 2H), 3.80 (s, 3H), 6.70-6.74 (m, 1H), 6.74-6.80 (m, 2H), 7.21 (t, J=7.9 Hz, 1H).
Reaction SMILES: O[CH2:2][C@H:3]1[N:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)=[O:9])[CH2:6][C@H:5]([CH3:22])[O:4]1.CS(Cl)(=O)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)=[N:33][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)(Cl)Cl.O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:39]=[N:38][N:37]([CH2:2][C@H:3]3[N:7]([C:8]([C:10]4[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=4[N:17]4[N:18]=[CH:19][CH:20]=[N:21]4)=[O:9])[CH2:6][C@H:5]([CH3:22])[O:4]3)[CH:36]=2)=[N:33][CH:34]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C)O[C@H]2CO)c1
Reactant: Fc1ccc(-c2cn[nH]c2)nc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C)O[C@H]2Cn2cc(-c3ccc(F)cn3)cn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
By using ethyl(2RS,5S)-5-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate obtained in Reference Example 5 (0.11 g, 0.33 mmol) as the raw material, the same procedure as in Reference Example 2 was carried out to obtain the diastereomer mixture of [2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). The obtained diastereomer mixture was purified by thin layer chromatography (1 mm, hexane/EtOAc=50/50) to obtain [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). To a solution of the obtained [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (30.2 mg, 0.10 mmol) and TEA (0.021 mL, 0.15 mmol) in CHCl3 (0.8 mL), MsCl (0.011 mL, 0.15 mmol) were added under cooling with ice water and the resulting mixture was stirred for 1 hour. Water was added to the reaction mixture under cooling with ice water, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. 5-Fluoro-2-(1H-pyrazol-4-yl)pyridine (0.033 g, 0.20 mmol) and Cs2CO3 (0.065 g, 0.20 mmol) were added to a solution of the obtained residue (0.5 mL). The resulting mixture was reacted for 1 hour at 120° C. under irradiation of microwave. The reaction mixture was allowed to cool, water was added thereto, followed by extraction with CHCl3, the extract was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.020 g) (colorless oil).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C1COCC1.O>[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC1=O
Temperature: -72 °C
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
A mixture of oxalyl chloride (6.47 mL, 74.5 mmol) in THF (166 mL) is cooled to −72° C. under nitrogen and treated dropwise with DMSO (10.59 mL, 149.1 mmol). The mixture is stirred for 5 min, whereupon tert-butyl (1S,2S)-2-hydroxycyclopentylcarbamate (10.0 g, 49.7 mmol) is added. Stirring is continued at −75° C. for 45 min. Triethylamine (37.4 mL, 268.3 mmol) is added slowly keeping the temperature below −68° C. After the addition is complete the reaction is allowed to warm slowly to room temperature overnight. The reaction is combined with the reaction mixture from a pilot reaction (200 mg scale) completed earlier. Water (100 mL) is added and the reaction is concentrated in vacuo to remove THF. The mixture is extracted with EtOAc (3×150 mL). The combined organic portions are dried over sodium sulfate, filtered, and concentrated to give 12.41 g of crude product as a yellow oil. The material is purified on silica gel (330 g, 10-40% EtOAc/hexanes) to give the title compound (9.17 g, 93%). 1H-NMR (400 MHz, CDCl3) δ 5.04-5.02 (m, 1H), 3.98-3.96 (m, 1H), 2.65-2.63 (m, 1H), 2.44-2.39 (m, 1H), 2.21-2.11 (m, 1H), 2.04 (s, 1H), 1.89-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.44 (s, 9H). GC-MS m/z 199 (M+). [a]D20=+96.9° (c 1.0, CHCl3) [literature (Aube, J.; Wolfe, M. S.; Yantiss, R. K.; Cook, S. M.; Takusagawa, F. Synthetic Communications 1992, 22, 3003-3012) [a]D25=+125° (c 0.2, CHCl3)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[CH:37][C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:38]=[CH:37][C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: O=c1[nH]c2ccc(Oc3cc(Cl)ncn3)cc2o1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.34 mmol) 6-(6-chloropyrimidin-4-yloxy)benzo[d]oxazol-2(3H)-one and 0.07 mL (0.41 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>C(#N)C>[CH3:26][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1)=[O:38])[CH3:25]
Reactant: CCCCN(CCCC)Cc1cc(N)n(Cc2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Product: CCCCN(CCCC)Cc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 5-amino-3-[(dibutylamino)methyl]-1-(phenylmethyl)-1H-pyrazole (0.70 g, 2.2 mmol), 2,6-diisopropylphenylisocyanate (0.48 mL, 2.2 mmol), and cuprous iodide (cat) in acetonitrile was heated to reflux for 16 hours. The resulting solution was cooled (25° C.), concentrated in vacuo, and chromatographed on silica (90:10 hexane:ethyl acetate). The product containing fractions were combined and concentrated in vacuo. The resulting oil was crystallized from hexane to yield 0.40 g (34.7%) of the title compound as a white powder, m.p. 149°-151.5° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Cl[C:31]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]3[O:48][C:47]([C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)=[C:46]([C:56](=[O:59])[NH:57][CH3:58])[C:45]=3[CH:60]=2)=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1B(O)O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[Cl:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[C:31]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]([C:41]2[CH:42]=[CH:43][C:44]3[O:48][C:47]([C:49]4[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=4)=[C:46]([C:56](=[O:59])[NH:57][CH3:58])[C:45]=3[CH:60]=2)=[CH:39][CH:40]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(Cl)c(C(=O)OC)c3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4Cl)c(C(=O)OC)c3)cc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
To a microwave vial was added dioxane (6 mL), water (0.600 mL), dicyclohexyl(2′,6′-dimethoxy biphenyl-2-yl)phosphine (S-Phos, 16.42 mg, 0.040 mmol), methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methyl carbamoyl)benzofuran-5-yl)benzoate (87.6 mg, 0.2 mmol), tribasic potassium phosphate (0.170 g, 0.800 mmol), palladium(II) acetate (8.98 mg, 0.040 mmol), and 2-chlorophenylboronic acid (0.094 g, 0.600 mmol). The vial was capped, degassed, flushed with N2 and heated in the microwave for 10 minutes at 130° C. The solvent was removed and the crude reaction mixture was taken up in 4 mL of acetonitrile and purified using a Shimadzu preparative HPLC employing acetonitrile/water/trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25 mL/min. over 20 minutes with a 10 minute hold. The solvent was removed to give 43.8 mgs (80% yield) of methyl 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 2.92-2.97 (m, 3H), 3.60-3.62 (m, 3H), 7.19-7.26 (m, 2H), 7.27-7.34 (m, 3H), 7.37 (d, J=8.03 Hz, 1H), 7.41-7.45 (m, 1H), 7.46-7.52 (m, 1H), 7.62-7.67 (m, 1H), 7.68-7.73 (m, 1H), 7.92 (dd, J=7.91, 2.13 Hz, 1H), 8.05 (d, J=1.25 Hz, 1H), 8.12-8.19 (m, 2H), 8.29 (d, J=2.01 Hz, 1H). LCMS m/z 514.2 (M+H), Rt=3.908 min., 93% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]=[C:18]([NH:20][NH2:21])[CH2:17][S:16][CH:15]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:14]=3[CH:29]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[N:31]([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]4[N:31]=[N:21][N:20]=[C:18]4[CH2:17][S:16][CH:15]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:14]=3[CH:29]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NNC1=Nc2ccc(C(=O)c3ccc(Cl)cc3)cc2C(c2cccc(Cl)c2)SC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: 5 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
Intermediate (30) (0.01125 mol) was cooled on an ice bath. Hydrochloric acid (90 ml) was added. Then a solution of sodium nitrite (0.013 mol) in water (18 ml) was added quickly dropwise. The mixture was stirred at 5° C. for 30 min and at room temperature for 2 hours. Water was added. The mixture was basified with K2CO3 10% and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DCM/DIPE. The precipitate was filtered off and dried, yielding 1 g (19.6%) of (4-chlorophenyl)[6-(3-chlorophenyl)-4H,6H-tetrazolo[1,5-a][4,1]benzothiazepin-8-yl]-methanone (intermediate 31), mp. 212° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH3:19][N:20]([CH3:40])[C:21]([C@@H:23]1[C@H:28]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH2:37])[C:31]=2[NH2:38])[C@@H:27]2[CH2:39][C@H:24]1[CH:25]=[CH:26]2)=[O:22].C([O-])(=O)C.[NH4+]>>[CH3:19][N:20]([CH3:40])[C:21]([C@@H:23]1[C@H:28]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]3[NH:37][C:15]([C:14]4[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][CH:13]=4)=[N:38][C:31]=23)[C@@H:27]2[CH2:39][C@H:24]1[CH:25]=[CH:26]2)=[O:22]
Reactant: CN1CCN(CCOc2ccc(C=O)cc2)CC1
Reactant: CN(C)C(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CCN(CCOc2ccc(-c3nc4c(N[C@H]5[C@@H](C(=O)N(C)C)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 28.3 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde (138 mg, 0.222 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid dimethylamide (78.7 mg, 0.244 mmol), and Ammonium acetate (34.3 mg, 0.444 mmol) were reacted to produce 34.61 mg (28%) of the title compound. (300 MHz, DMSO-d6) 12.56 (s, 1H), 8.08 (d, J=8 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.11 (d, J=8 Hz, 1H), 6.42 (m, 2H), 6.32 (s, 1H), 5.35 (m, 1H), 4.15 (m, 2H), 3.49 (m, 1H), 3.07 (d, J=8 Hz, 1H), 3.00 (d, J=8 Hz, 1H), 2.96-2.68 (m, 14H), 2.32 (s, 2H), 2.14 (s, 2H), 1.92 (m, 1H), 1.44 (m, 1H). MS=550 (M+H), HPLC: 1.91 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][N:23]([CH2:25][CH3:26])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH3:26])[N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: CCn1cc(Cl)c(C(=O)O)n1
Product: CCn1cc(Cl)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-ethyl-1H-pyrazole-3-carboxylic acid (CAS512810-20-7) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=416.3 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14])(=O)C.N>>[OH:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14]
Reactant: CC(=O)OCc1cn2c(n1)S(=O)(=O)CC2
Agent: N
Product: O=S1(=O)CCn2cc(CO)nc21
Reaction time: 2.5 h

Procedure:
6-Acetoxymethyl-2,3-dihydroimidazo[2,1-b]thiazole-1,1-dioxide (305 mg, 1.33 mmol) was treated with methanolic ammonia (prepared by saturating methanol (20 ml) with ammonia gas then diluting with more methanol (20 ml)) at room temperature. After 2.5 h, the volatiles were removed under reduced pressure and the residue triturated with diethyl ether and the resulting solid collected by filtration, washed with diethyl ether and dried in air (207 mg, 83%) (Found: M+ 188.0256. C6H8N2O3S requires M 188.0256); νmax (nujol) 3354, 1377, 1325 and 1133 cm-1 ; δH [250 MHz; (CD3)2SO] 4.14 (2H, t, J 6 Hz), 4.40 (2H, d, J 6 Hz), 4.54 (2H, t, J 6 Hz), 5.20 (1H, t, J 6 Hz, exchangeable), 7.36 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:10]([CH2:23][CH2:24]O)[N:9]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][CH2:24][CH2:23][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:9]1
Reactant: O=S(Cl)Cl
Reactant: OCCn1nc(-c2ccccc2Cl)nc1-c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1nc(-c2ccccc2Cl)nn1CCCl

Procedure:
A mixture of 1.1 g of 3-(o-chlorophenyl)-1-(2-hydroxyethyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, 1.09 g of thionyl chloride and 5 ml of toluene is heated at reflux temperature for 4 hours. The reaction mixture is then evaporated, the residue is taken up in diethyl ether, the soluton is washed twice with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated. In this manner there is obtained 1-(2-chloroethyl)-3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 66°-68° C.
Reaction SMILES: CC(C)(O)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[S:19][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+]>C(O)CCC>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[S:19][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)#[CH:3]
Reactant: CCN1CCN(c2cc3cnc(-c4ccc(C#CC(C)(C)O)cc4)cc3s2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: C#Cc1ccc(-c2cc3sc(N4CCN(CC)CC4)cc3cn2)cc1
Yield: 86.1 %

Procedure:
6-[4-(3,3-Dimethyl-3-hydroxy-1-propynyl)phenyl]-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.80 g) was dissolved in 1-butanol (15 ml), followed by the addition of potassium hydroxide (0.47 g), and the mixture was heated under reflux for 20 min. The reaction solution was evaporated, and the resulting residue was partitioned between ethyl acetate and water, and then extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, and the resulting residue was dissolved in ether, and then filtered through NH-silica gel. The resulting filtrate was concentrated, to give 0.59 g of the title compound as a pale yellow oil.