Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](C(C(OCC)=O)C(OCC)=O)CCC.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]23[O:34][CH2:33][C:30]([CH2:35][CH2:36][CH3:37])([CH2:31][O:32]2)[CH:29]([C:38]([F:41])([F:40])[F:39])[O:28]3)=[CH:23][CH:22]=1>>[CH2:35]([C:30]12[CH2:33][O:34][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][O:17][CH3:16])=[CH:26][CH:25]=3)([O:32][CH2:31]1)[O:28][CH:29]2[C:38]([F:41])([F:39])[F:40])[CH2:36][CH2:37][CH3:1]
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Reactant: CCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F
Product: CCCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F

Procedure:
4-n-Butyl-1-[4-(3-methoxyprop-1-ynyl)phenyl]-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from diethyl n-butyl-malonate in a manner analogous to the synthesis of 1-[4-(3-methoxyprop-1-ynyl)phenyl]-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 81.4 %

Procedure:
7-[2-(2-formamidothiazol-4-yl)-2cyclopentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.7 g.) in methanol (17 ml.) and tetrahydrofuran (5 ml.), and conc. hydrochloric acid (1.5 g.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2cyclopentyloxyiminoacetamido]-3cephem-4-carboxylic acid (syn isomer, 1.3 g.).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]O.[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1>CCOC(C)=O>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([O:15][CH3:5])=[O:14])[C:11]([OH:17])=[C:10]([I:18])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)cc(I)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc(I)c1O

Procedure:
Thionyl chloride (30 mL, 411 mmol) is added dropwise to methanol (100 mL) in an ice bath. The addition is controlled to hold the temperature at 25° C. Upon completion of the addition 6 (25 g, 84 mmol) is added and the reaction heated to reflux for 4 hours. The solids dissolve at first then after 2 hours solids start to come out of solution. After 4 hours TLC (hex:EtOAc; 9:1) shows no starting material. The reaction is cooled in the refrigerator for 12h. The solids formed are filtered washed with water (30 mL), and dried under vacuum at 27° C. to yield methyl 5-chloro-3-iodosalicylate as an off white solid. (mp 143°-145° C.)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:17](=[O:20])[CH:18]=[CH2:19])[CH2:4][CH2:3]1
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A dry round-bottom flask was charged with 1-methylpiperazine (0.15 mL, 1.36 mmol), diisopropylethylamine (0.65 mL, 3.72 mmol) and CH2Cl2 (6 mL) and then the solution was cooled with an ice-water bath. Acryloyl chloride (0.10 mL, 1.24 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. After 3 hours TLC indicated reaction completion. The CH2Cl2 was removed and the residue taken up in EtOAc, washed with NaHCO3 (sat.) (1×), brine (2×) and then dried over MgSO4. The EtOAc was removed in vacuo which yielded after drying, the title compound as an orange-brown oil. (400 MHz, CDCl3) 6.57 (dd, J1=16.8 Hz, J2=10.5 Hz, 1H), 6.29 (d, J=16.8 Hz, 1H), 5.70 (d, J=10.5 Hz, 1H), 3.73 (bs, 2H), 3.60 (bs, 2H), 2.46-2.41 (m, 4H), 2.34 (s, 3H); MS ESI 155.0 [M+H]+, calcd for [C8H14N2O+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1B(O)O)([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc(B(O)O)c(C(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(C)C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 2-isopropyl-4-methoxyphenyl boronic acid (178 mg, 1.0 mmol) to afford after chromatographic purification the title compound (152 mg, 68%). 1H NMR (CDCl3, 300 MHz) δ7.09 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.5 Hz), 6.83 (s, 1H), 6.78 (s, 1H), 6.72 (dd, 1H, J=8.4, 2.9 Hz), 3.80-4.20 (m, 2H), 3.84 (s, 3H), 3.74-3.78 (m, 1H), 3.05-3.50 (m, 7H), 2.84-2.98 (m, 1H), 1.82-1.94 (m, 2H), 1.48 (s, 9H), 1.12-1.17 (m, 6H) ppm. MS-ApCI: 449 [M+H+].
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[C:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([OH:26])=[O:25]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[O:11]=[C:5]1[NH:6][C:7]2[C:3](/[C:4]/1=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[C:2]([C:30]1[CH:31]=[CH:32][C:27]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(C(=O)O)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 112.2 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (151 μL, 0.303 mmol), (Ph3P)2PdCl2 (3 mg, 0.004 mmol) (Aldrich), and 4-carboxyphenylboronic acid (18 mg, 0.108 mmol) (Lancaster) in 4.5 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 40% ethyl acetate-hexanes then 50% ethyl acetate-hexanes with 1% glacial acetic acid elution) to yield pure (Z)-4-[2,3-Dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-benzoic acid (yield: 33 mg, 91%) as an orange solid (mp 315-317° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[C@@H:43]([NH2:47])[CH2:42][C:41]2([CH3:49])[CH3:48].CCOC(C)=O>COCCOC>[Si:22]([O:21][C@@H:20]1[C@H:19]([CH2:15][O:14][Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:47][C@@H:43]3[C:44]4[C:40](=[CH:39][C:38]([Cl:37])=[CH:46][CH:45]=4)[C:41]([CH3:49])([CH3:48])[CH2:42]3)[CH:31]=2)[CH2:16]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC1(C)C[C@H](N)c2ccc(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (3.4 mg, 0.0000052 mol) and potassium tert-butoxide (32.0 mg, 0.000286 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (0.1226 g, 0.0002596 mol) in 1.00 ml DME, followed by (1S)-5-chloro-3,3-dimethylindan-1-amine (0.048 g, 0.00025 mol) in 1 ml DME. The mixture was stirred overnight, and the solution was poured into 50 ml EtOAc, washed with 10 ml water and concentrated. The residue was purified by preparative plate chromatography (70% EtOAc/hexanes) to afford the title compound (28.0 mg, 18.0%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:15][C:4]1[S:3][C:2]2=[N:1][C:20]([CH3:21])=[C:19]([C:18](=[O:23])[C:17]([F:25])([F:24])[F:16])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:5]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc(Cl)cc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
To a stirred solution of 30 mg (0.13 mmol) (2-amino-5-chloro-thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.016 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 70° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CE-CN/H20) afforded 10 mg (23%) 1-(2-chloro-6-methyl-4-phenyl-thieno[2,3-b]pyridin-5-yl)-2,2,2-trifluoro-ethanone as a light brown solid. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]([CH3:18])[CH2:14][C:15](O)=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[N:27]2[CH2:30][C:29](=[CH:31][S:32]([CH2:35][C:36]3[CH:37]=[C:38]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[CH:39]=[CH:40][CH:41]=3)(=[O:34])=[O:33])[CH2:28]2)=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[N:27]2[CH2:28][C:29](=[CH:31][S:32]([CH2:35][C:36]3[CH:37]=[C:38]([N:42]4[CH2:47][CH2:46][N:45]([C:15](=[O:16])[CH2:14][N:13]([CH3:18])[CH3:12])[CH2:44][CH2:43]4)[CH:39]=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH2:30]2)=[CH:24][CH:25]=1
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 24 h
Yield: 84.8 %

Procedure:
511 mg of supported EDCI (2.5 mM), 11.5 mg of N,N-dimethylglycine and then 5 cm3 of dichloromethane are successively added, at a temperature close to 20° C., to 54 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 24 hours at a temperature close to 20° C., 35 mg of N,N-dimethylglycine are added. After stirring for 96 hours at a temperature close to 20° C., the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 2.5 cm3 of dichloromethane. The combined filtrates are washed with 10 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 20° C. 53 mg of 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone are thus obtained in the form of a beige foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.20 (s, 6H), 2.94 (s, 3H), 3.12 (s, 2H), 3.16 (mt, 4H), 3.58 (mt, 2H), 3.68 (mt, 2H), 3.80 (mt, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.81 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3ccncc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol), potassium carbonate (79 mg, 0.573 mmol) and water (1 mL). The reaction mixture was heated at 100° C. in a microwave for 15 min (×2) and then for 30 min (×1). Another portion of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58.7 mg, 0.286 mmol) and additional bis(triphenylphosphine)palladium(II) chloride (13.40 mg, 0.019 mmol) were added and heating continued, at 100° C. in a microwave, for another 15 min. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (30 mL) and washed with water (30 mL). The aqueous phase was re-extracted with ethyl acetate (30 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (37 mg). LCMS (A) m/z: 520 [M−1]−, Rt 1.22 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl: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[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=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:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[Cl:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2Cl)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2Cl)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-chloro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-3) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=415.2 [M+H]+, 417.1 [M+2+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: Fc1ccccc1I
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccccc1F

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-2-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 12 mg of (8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3cccs3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 14 mg (0.11 mmol) 2-thiophenesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:40][C:41]([F:54])([F:53])[O:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[CH:50]C=O)=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:50]=[CH:49][C:46]4[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:53])[F:54])=[CH:48][CH:47]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)CC1
Reactant: O=CC=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(CN2CCN(C3CCN(CC=Cc4ccc(OC(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
Tert-butyl (S)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]piperidine-1-carboxylate (750 mg, 1.66 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated. To the residue, methylene chloride (5 ml) and triethylamine (5 ml) were added, and the mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in 1,2-dichloroethane (20 ml), 3-(4-trifluoromethoxyphenyl)propenal (396 mg, 1.83 mmol) and sodium triacetoxyborohydride (564 mg, 2.66 mmol) were added followed by stirring at room temperature for 3.5 hours. The reaction solution was washed with a saturated sodium hydrogencarbonate solution (15 ml), water (20 ml), and a saturated saline solution (20 ml) in this order, and then dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) and then recrystallized from methanol/water to obtain (S)-2-methyl-6-nitro-2-[4-{1-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperidin-4-yl}piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (446 mg, 49%) as a light yellow powder.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[O:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12
Reactant: BrBr
Reactant: c1ccc(-c2cc3n(n2)CCCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1c(-c2ccccc2)nn2c1OCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (6.3 g, 0.031 mol) in 60 mL chloroform is added a solution of bromine (1 eq, 5.03 g, 0.031 mol) in 40 mL chloroform over a period of 25 min at room temperature. The resulting suspension is stirred for 4 h at room temperature. Thereafter the reaction mixture is treated with aqueous sodium thiosulfate, the phases are separated and the organic phase is washed with water and dried over sodium sulfate. The volatiles are evaporated and the crude product is purified by filtration over silica using a 1:1 mixture of ethyl acetate/cyclohexane as eluent. After evaporation of the solvent 7.0 g (90%) of 3-bromo-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained as solid.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[NH:33][C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[N:33]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:24])([CH3:25])[O:18]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2Cc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-2-{(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl}-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide (170 mg, 0.37 mmol) and 4-chlorobenzaldehyde (104 mg, 0.74 mmol) and acetic acid (44 mg, 41 μL, 0.74 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 30 minutes and then treated with sodium triacetoxyborohydride (196 mg, 0.93 mmol). After 24 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phase was collected, dried over MgSO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-{(1R,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide as a pale yellow oil which was used immediately in the next step; m/z for C32H51BClN3O4 expected 587.4. found 589.7 (M+H(37Cl))+, 588.0 (M+H(35Cl))+,