Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].C([O-])([O-])=O.[Na+].[Na+].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21]>O>[F:24][C:18]1[CH:17]=[CH:16][C:15]([NH:14][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
Propane-1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was dissolved in 10% Na2CO3 (1.65 mL, 1.55 mmol) at room temperature. 5-Amino-2-fluorobenzoic acid (0.100 g, 0.645 mmol) was added and heated to 60° C. overnight. Propane-1-sulfonyl chloride (0.0871 mL, 0.774 mmol) was added again, and the reaction mixture was heated at 60° C. for another hour. The reaction mixture was cooled to room temperature, diluted with water, taken to a pH of 10 with 10% Na2CO3 and extracted with DCM (2×). The reaction mixture was then taken to a pH of 2 with 1N HCl, extracted with DCM (3×) and concentrated to a solid, 2-fluoro-5-(propylsulfonamido)benzoic acid (29%).
Reaction SMILES: [C:1]1([C:7]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Cl:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl>CN(C)C=O.C(OCC)(=O)C.C(OCC)C.O>[ClH:22].[N:25]1([CH2:24][CH2:23][O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: ON=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(C(=NOCCN2CCOCC2)c2cc3ccncc3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone oxime (Example 39) (100 mg, 0.42 mmol) and sodium hydride (17 mg of 60% in mineral oil, 0.43 mmol) in N,N-dimethyl formamide (2 mL) was stirred under a nitrogen atmosphere for 0.5 h. A mixture of N-(2-chloroethyl)morpholine hydrochloride (80 mg, 0.43 mmol) and sodium hydride (17 mg of 60% in mineral oil, 0.43 mmol) in N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 38 h. The reaction mixture was poured into stirring cold water (25 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. Purification by Biotage chromatography (1 to 10% methanol in methylene chloride) produced an oil. The oil was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (0.45 mL of a 1 M solution in diethyl ether) was added. The reaction mixture was stirred for 1 h and the precipitate formed. The solvent was decanted and the solid was dried to give phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-[2-(4-morpholinyl)ethyl]oxime hydrochloride, a mixture of isomers, as a pale yellow solid: ESI MS m/z 351 [C20H22N4O2+H]+; HPLC (Method A) >99% (AUC), tR=13.3 and 13.7 min.
Reaction SMILES: CC([O:5][C:6](=[O:18])[CH2:7][S:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][CH:10]=1)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:15]([NH:14][C:12]1[S:13][C:9]([S:8][CH2:7][C:6]([OH:18])=[O:5])=[CH:10][N:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ncc(SCC(=O)OC(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ncc(SCC(=O)O)s1
Yield: 97 %

Procedure:
A solution of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) was stirred at rt overnight and concentrated in vacuo. To the residue was added ethyl ether (50 mL). The precipitated solid was collected, washed with ethyl ether and dried to afford the desired product (3.38 g, 97%) as a solid, mp 210° C. 1H NMR (CD3OD) δ7.48 (s, 1 H), 3.47 (s, 2 H), 2.20 (s, 3 H) ppm; MS m/e 231 (M-H)- ; HPLC (Column: Zorbax Rapid resolution C-18; flow rate: 2.5 mL/min; solvent system: 0-100% B in 8 min. Solvent A: 10% MeOH-90% water-0.2%H3PO4 ; Solvent B: 90% MeOH-10% Water-0.2% H3PO4 ; UV: 254 nm): retention time 4.32 min.
Reaction SMILES: O[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(OC(=O)C)(=O)C>>[CH:10]1[C:6]2[C:7](=[O:9])[O:8][C:2]3[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=3[O:4][C:5]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Oc2ccccc2Oc2ccccc21
Reaction time: 8 h

Procedure:
5.06 g of 2-(2-hydroxyphenoxy) benzoic acid were suspended in 35 ml of newly distilled acetic anhydride, then the mixture was refluxed for 3 hours while the reaction is controlled from time to time by analyzing a sample of the mixture by gas chromatography. The excess of acetic anhydride was then removed by distillation under reduced pressure and the oily residue crystallized at rest. The crystals were left overnight in a refrigerator; then they were taken up with some ml of ether. The crystalline mass was filtered off, squeezed out, rinsed with some ml of ether and dried under vacuum. The obtained dibenzo (b,e) dioxepinone was purified on fractional distillation under reduced pressure. The pure product distills over at 0.01 mmHg, and melts at 62°-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[C:13]([N:15]1CCCC1)C.O.NN>CO.C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:15]2
Reactant: CC(=Cc1c(Br)cc(F)cc1[N+](=O)[O-])N1CCCC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100° C. for 3 h. The mixture was cooled to RT and concentrated in vacuo to give 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-1-methyl vinyl]-pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney®-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0° C. and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@@H:23]([O:41]C=O)[C@H:24]([CH2:28][CH2:29][N:30]3[C:38](=[O:39])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:40])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:11]=[C:12]([F:14])[CH:13]=1>CO>[F:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C@@H:23]([OH:41])[C@H:24]([CH2:28][CH2:29][N:30]3[C:31](=[O:40])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]3=[O:39])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:9]=[C:8]([F:7])[CH:13]=1
Reactant: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)[C@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.06 g) was added to a solution of the compound obtained from step e above (0.12 g) in methanol (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified with preparatory thin layer chromatography using 10% methanol in ethyl acetate as eluent to get the title compound (0.025 gm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41]C)=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=[O:40])=[CH:35][CH:34]=2)=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Br)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2Oc2ccc(C(=O)O)cc2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-methoxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 50c(0.8 g, 1.2 mmol) in tetrahydrofuran (20 mL) was added an aqueous solution (1 M) of NaOH (10 mL, 10 mmol) and methanol (10 mL). The reaction mixture was stirred at room temperature for 18 h, then acidified to “pH” 2 with concentrated aqueous HCl solution. The mixture was concentrated, partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(4-hydroxycarbonyl-phenoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.6 g, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[OH:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[CH:21][CH2:20][CH2:19][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: OCCC=Cc1ccccc1OCc1ccccc1
Yield: 89.3 %

Procedure:
2-Benzyloxybenzaldehyde (8 g; 37 mmole), (3-hydroxypropyl)triphenylphosponium bromide (19.5 g; 47 mmole) and potassium carbonate (6.6 g; 48 mmole) were mixed in isopropanol. The reaction mixture was refluxed over night then filtered and the filtrate was evaporated. Chromatography using ethyl acetate:dichloromethane (up to 5%) as eluant gave 8.4 g (87.6%) of 4-(2-benzyloxyphenyl)-3-buten-1-ol. Both cis and trans 4-(2-benzyloxyphenyl)-3-buten-1-ol were formed according to NMR.
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH:6]=[CH2:7])[CH3:3].[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1>C(#N)C>[N:8]1([CH:2]([O:4][CH2:5][CH:6]=[CH2:7])[CH3:3])[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: c1nc[nH]n1
Reactant: C=CCOC(C)Cl
Solvent: CC#N
Product: C=CCOC(C)n1cncn1

Procedure:
Allyl 1-chloroethyl ether (3.6 g; Black and Lander, J.C.S., 1965, 5525) and 1,2,4-triazole (6.9 g) in acetonitrile (75 ml) were refluxed for 6 hours. The solvent was removed under reduced pressure; the residual solid was heated with water and extracted with diethyl ether. The ethereal phase was washed with water and dried over magnesium sulphate, and the solvent was removed. The residual oil was purified by passing through a column of silica gel, eluting with ethyl acetate to give the title compound as a colourless oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)[N:21]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:70]([C:74]1[CH:79]=[CH:78][C:77]([NH2:80])=[CH:76][CH:75]=1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([C:74]1[CH:75]=[CH:76][C:77]([NH:80][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:20]3[N:21]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])=[CH:10][CH:11]=4)[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=3)[CH:23]=2)=[CH:78][CH:79]=1)([CH3:73])([CH3:71])[CH3:72]
Reactant: O=C(O)c1cccc(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(-c3cn4ccnc4c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoic acid (9) (0.23 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate reagent (0.23 mmol) and N,N′-diisopropylethylamine (0.77 mmol) is stirred under N2 for 15 min. in 1 mL DMF. 4-tert-Butyl-phenylamine (0.37 mmol) is added and the reaction stirred at rt for 8 hrs. The reaction is partitioned between ethyl acetate (15 mL) and water (15 mL) and the ethyl acetate layer washed with water (2×15 mL) and brine (1×15 mL). The organic layer is dried over sodium sulfate and the solvent removed in vacuo. The resulting crude oil is dissolved in 1 ml CH2Cl2 and clean yellow solid is precipitated by slow addition of diethyl ether, yielding the final product, (10) N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:19])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloroquinazolin-4-yl)morpholine (1.0 g, 0.0030 mol—Preparation 1), 3-aminophenylboronic acid pinacol ester (0.657 g, 0.0030 mol), sodium carbonate (0.635 g, 0.0060 mol), toluene (20 mL), ethanol (4 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.105 g, 0.00015 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (40% ethyl acetate in hexane) to provide the title compound (0.65 g, 62%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=1.6 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.66 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.99 (t, J=2.0 Hz, 1H), 6.77 (dd, J′=7.6 Hz, J″=1.2 Hz, 1H), 3.90 (s, 8H), 3.84 (br s, 2H), LC-MS (ESI): Calculated mass. 340.11, Observed mass [M+H]+: 341.1 (RT=0.48 min).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.ClC(Cl)(Cl)[C:40]([N:42]=C=O)=[O:41].C([O-])=O.[Na+].C(Cl)(Cl)Cl>C(OCC)(=O)C.O>[NH2:42][C:40]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:3]1)=[O:41]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(OC(N)=O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
tert-Butyl (E)-3-{2-(3-hydroxypiperidino)-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (138 mg, 0.264 mmol) was dissolved in ethyl acetate (2.6 ml), added with trichloroacetyl isocyanate (62.6 μl, 0.528 mmol) under ice cooling, and then the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated, dissolved in methanol (5.0 ml) and water (0.5 ml), and then added with sodium formate (71.8 mg, 1.06 mmol), and stirred overnight at room temperature. The reaction mixture was further added with chloroform (3.0 ml) and sodium formate (71.8 mg, 1.06 mmol) and stirred overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2, v/v) to obtain the title compound (150 mg, 100%).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:7]([NH:6][CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:4][OH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C)c(OC)c1)NC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(CO)NCc2ccccc2)ccc1C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
55.5 gm (0.16 mol) of N-benzoyl-3-(3'-methoxy-4'-methyl-phenyl)-alanine ethyl ester (m.p. 133° C) were dissolved in 550 ml of absolute tetrahydrofuran, and the resulting solution was slowly added dropwise to a stirred suspension of 37 gm (0.98 mol) of lithium aluminum hydride in 1850 ml of tetrahydrofuran at room temperature in an atmosphere of nitrogen. The resulting mixture was refluxed for five hours, then allowed to stand overnight, and subsequently slowly admixed with water. The inorganic precipitate formed thereby was collected by vacuum filtration, washed with tetrahydrofuran, and the wash solution was combined with the filtrate. The tetrahydrofuran was distilled in vacuo out of the combined solution, the residue was taken up in ether, and the ethereal mixture was extracted with water. The ether phase was dried over sodium sulfate, the ether was distilled off, and the residue was recrystallized from petroleum ether, yielding 45.0 gm (97.5% of theory) of the free base 2-benzylamino-3-(3'-methoxy-4'-methyl-phenyl)-1-propanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH:16]=[CH2:17])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1nc(C(F)(F)F)c(C(=O)OCC)s1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 76.4 %

Procedure:
To a solution of thiazole IV (17.4 g, 57.3 mmol) in toluene (150 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.32 g, 1.14 mmol), tributyl(vinyl)tin (18.4 mL, 63.0 mmol), and 2,6-di-t-butyl-4-methyl phenol (catalytic). This mixture was stirred at 120° C. in a sealed tube for 25 min. The mixture was then allowed to come to 25° C. Ethyl acetate (250 mL) was added and the mixture was washed with 1 N aqueous NaOH (2×150 mL), saturated aqueous NaCl (1×150 mL), dried over MgSO4 and concentrated in vacuo to give a brown oil. Purification by flash chromatography (silica, 0-10% ethyl acetate/hexane) gave the 2-vinyl thiazole III (11.0 g, 76%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 6.88 (dd, J=11.0, 17.6 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.74 (d, J=11.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:11]=1[CH3:12])=[N+:7]([O-])[O:8][N:9]=2.P(OCC)(OCC)OCC>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:9][O:8][N:7]=[C:6]2[C:11]=1[CH3:12]
Reactant: Cc1c(Br)ccc2no[n+]([O-])c12
Agent: CCOP(OCC)OCC
Solvent: CCO
Product: Cc1c(Br)ccc2nonc12
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
The crude 6-bromo-7-methylbenzo[c][1,2,5]oxadiazole 1-oxide (7.0 g, 31 mmol) from the above step was slurried in 100 ml ethanol, treated with triethyl phosphite (6.2 g, 37 mmol) and heated to reflux for 20 h. The volatiles were removed by rotary evaporation, the residue taken up in 100 mL dichloromethane and stirred with 50 mL 5% bleach solution for 20 min. The organic phase was washed with 20 mL saturated NaCl, dried (Na2SO4) and evaporated. The material was purified by flash chromatography with 0-30% ethyl acetate-hexane gradient to give the title compound as an orange solid (3.6 g, 55%): mp 80-83° C.; 1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J=9.3, 1H), 7.50 (d, J=9.4 Hz, 1H), 2.71 (s, 3H). EIMS m/z 212.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH:15]=[C:14]([CH2:16][NH2:17])[O:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH2:16][C:14]2[O:13][CH:12]=[CH:11][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccco1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of 4-chlorobenzoyl chloride (3.2 g, 18.5 mol) in 50 ml dry CH2Cl2 was added over 30 min to a stirred solution of 2-furfurylamine (2 g, 20.6 mol) and iPr2NEt (7 ml, 41 mol) in CH2Cl2 (200 ml) at 0° C. The reaction was allowed to warm to room temperature over 3 h. The mixture was diluted with 200 ml of CH2Cl2, washed twice with HCl aq. (1N) and dried over MgSO4. Evaporation of the solvent afforded 4 g (83%) of the title benzamide as a white solid: 1H NMR: (DMSO-d6) δ 9.05 (t, J=5.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.57 (m, 1H), 7.53 (d, J=8.7 Hz, 2H), 6.40 (dd, J=3.7, 1.1 Hz, 1H), 6.28 (d, J=3.7 Hz, 1H), 4.46 (d, J=5.6 Hz, 2H). M/Z APCI: 236.6 (M+1), 234.8 (M−1).