Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(O)[C@H]1CC(O)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To 10 g (76.30 mmol) of 4-hydroxy-D-proline in 75 ml of water was added 17.45 g (91.6 mmol) of 4-toluenesulfonyl chloride and 17 g (160.2 mmol) of sodium carbonate and the mixture was allowed to stir for 24 hours at room temperature. The reaction was then acidified to pH 1 by the careful addition of 10% aqueous HCl solution and the product was isolated by filtration. After drying at high vaccum, 18.5 g of product was isolated (85% yield). M.P.=145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]([OH:21])[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C=O)c(-c3cccc(F)c3)c(=O)n12
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring suspension of 3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine-2-carbaldehyde (1.3567 g, 4.806 mmol) in THF (48.06 mL) was added methylmagnesium bromide 3 M in Et2O (2.403 mL, 7.210 mmol) dropwise at 0° C. and the mixture was allowed to warm to rt and stirred at rt. After 5 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give a dark red syrup. The dark red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min, then 50% isocratic of EtOAc in hexane for 10 min, 50 to 100% gradient of EtOAc in hexane over 10 min, and then 100% isocratic of EtOAc for 10 min as eluent to give 3-(3-fluorophenyl)-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (1 H, dd, J=8.8, 6.8 Hz), 7.41-7.52 (2 H, m), 7.12-7.24 (3 H, m), 6.88-6.96 (1 H, m), 4.98 (1 H, d, J=6.3 Hz), 4.42-4.51 (1 H, m), 2.89 (3 H, s), 1.26 (3 H, d, J=6.3 Hz); Mass Spectrum (ESI) m/e=298.9 (M+1).
Reaction SMILES: [C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].CC(C)=O.O=C(C1C=CC=CC=1)C[O:19][C:20](=[O:48])[C@H:21]([OH:47])[CH2:22][N:23]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)=[CH:36][CH:35]=1)[NH:24][C:25]([C:27]1[O:31][N:30]=[C:29]([OH:32])[CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].CCN(C(C)C)C(C)C.CC(O)=O>[Zn]>[Cl:46][C:42]1[CH:41]=[C:40]([C:37]2[CH:36]=[CH:35][C:34]([CH2:33][N:23]([CH2:22][C@@H:21]([OH:47])[C:20]([OH:48])=[O:19])[NH:24][C:25]([C:27]3[O:31][N:30]=[C:29]([O:32][CH2:3][O:2][C:1]([O:5][CH:6]([CH3:8])[CH3:7])=[O:9])[CH:28]=3)=[O:26])=[CH:39][CH:38]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Reactant: CC(C)OC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)OC(=O)OCOc1cc(C(=O)NN(Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 65 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A mixture of chloromethyl isopropyl carbonate (15.6 mg, 102 μmol) and NaI (15.3 mg, 102 μmol) in acetone (0.7 mL, 10 mmol) was stirred at 65° C. for 1 hour, then added (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) that had been dissolved in acetone (0.4 mL, 5 mmol) at room temperature and treated with cesium carbonate (13.0 mg, 40 μmol). The resulting mixture was then heated at 40° C. for 1 hour. DIPEA (0.2 mL, 1 mmol) was added and heating continued for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was partitioned between EtOAc (10.0 mL) and water (2.0 mL). The organic layer was washed with saturated aqueous NaHCO3 (3.0 mL), saturated aqueous NaCl (3.0 mL), dried over Na2SO4, filtered, and concentrated. Zinc 90.8 mg, 1.4 mmol) and AcOH (0.5 mL, 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The solids were washed with AcOH (1.0 mL) then filtered. The filtrates were combined and purified by reverse phase preparative HPLC to yield the title compound (3.8 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O9, 548.14. found 548.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-trifiuoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 inmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24](Cl)[CH:23]=3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].[F-].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O.O.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.O>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([C:22]3[CH:23]=[C:24]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=4)[CH:25]=[CH:26][CH:27]=3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N1CC[C@@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2cccc([C@@H]3CN(S(=O)(=O)c4ccccc4)CC[C@H]3c3ccccc3)c2)c1
Yield: 26.3 %

Procedure:
To a solution of trans-1-benzenesulfonyl-3-(3-chloro-phenyl)-4-phenyl-piperidine (150 mg) and (3-methylsulfonylphenyl)boronic acid (109 mg) in a mixture of DMA/water (2.1 mL, 20:1) was added potassium fluoride (42.3 mg), tetrakis(triphenylphosphine)palladium(0) (50.5 mg) and triphenylphoshine (22.9 mg). The reaction mixture was irradiated with microwave at 160° C. at intervals up to 80 min. Water was added, the phases were separated, and the inorganic one was extracted with diethylether (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 1:1) yielded trans-1-benzenesulfonyl-3-(3′-methanesulfonyl-biphenyl-3-yl)-4-phenyl-piperidine (51 mg, 26%) as a white foam, MS: 531.5 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[NH:12].C[O:15][C:16](=O)/[C:17](/[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[C:18](\O)/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C[O-].[Na+]>CO>[C:22]([O:21][C:19]([C:18]1[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:16]([OH:15])[N:13]=[C:11]([CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[N:12]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)Cc1cccc(Cl)c1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2-(2,3-dichlorophenyl)-acetamidine hydrochloride salt (129) (10 g, 41.84 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (19.33 g, 62.76 mmol) in methanol (300 mL) was added sodium methoxide (6.7 g, 125.52 mmol) at 0° C. Then the reaction mixture was allowed to warm to room temperature, and was stirred for 16 h. After completion of the reaction, it was quenched with 1N HCl, the methanol was evaporated and water was added. The mixture was extracted with ethyl acetate and the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get a crude product, which was purified by a normal silica column using 30% ethyl acetate in hexane to get 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130) (10 g, 57.8%) as a brown solid.
Reaction SMILES: [OH2:1].[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>S(=O)(=O)(O)O.CC(C)=O>[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:1])=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCCCCCCCCCCCCC1CCCCC1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCCCC1CCCCC1
Yield: 58.7 %

Procedure:
CrO3 (VI) (3.204 g, 32.04 mM) was dissolved in sulfuric acid (2.76 ml), followed by stirring for a time, and then water (4.8 ml) was added to yield a solution. This solution was added drop by drop to a solution of 12-cyclohexyldodecanol (5.36 g, 20 mM) in acetone (300 ml) under ice cooling conditions, followed by stirring for 1 hour. To the mixture, iso-prapanol (about 2 ml) was added and then concentrated to dryness under reduced pressure. To the resulting residue, water (50 ml) and chloroform (50 ml) were added, followed by vigorous stirring, after which the chloroform layer was separated. The chloroform layer was dryed over anhydrous sodium sulfate, purified by silica gel colum (50 g) (methanol-chloroform (1:49)) to yield the title compound (5.3 g, yield 58.7%) as a colorless powder.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:15][C:14]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][NH:18]2
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c2cc[nH]c2c1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-[(E)-2-(dimethylamino)ethenyl]-3,5-dinitrobenzoate (19.3 g) in ethyl acetate (200 mL) was added 5% palladium on carbon (1.5 g). The mixture was placed under 45 PSI H2 and shaken overnight. The mixture was filtered through celite and concentrated. The residue was dissolved in CH2Cl2 to which was added ((1:1) H2O:conc. HCl (250 mL)). The resulting solids were collected by filtration, dissolved in ethyl acetate and washed with 2N NaOH. The ethyl acetate layer with anhydrous magnesium sulfate, filtered and concentrated to give 7.4 g if the title compound: 1H NMR (CDCl3) δ 3.91, 4.01, 6.51, 7.09, 7.27, 8.40.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][C:3]=1[N+:14]([O-])=O.[Sn].Cl>>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=1[NH2:14]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Sn]
Product: Nc1cc(N)c(Cl)c(N)c1

Procedure:
The nitro groups of 2-chloro-1,3,5-trinitrobenzene (1) are reduced by reaction with tin and hydrochloric acid to yield 2-chloro-1,3,5-triaminobenzene (2).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[CH2:21][O:20][CH2:19][CH2:18][NH:17]2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[CH2:21][O:20][CH2:19][CH2:18][N:17]2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([C:71]([F:74])([F:73])[F:72])[CH:66]=2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)C1COCCN1)c1cccc2ccccc12
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@@H](NC(=O)C1COCCN1c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 110 °C
Yield: 33.3 %

Procedure:
To a mixture solution of N-((R)-1-(naphthalen-1-yl)ethyl)morpholine-3-carboxamide (Intermediate-1) (400 mg, 1.4 mmol) in toluene (10 mL), bis(tri-tert-butylphosphine palladium(0) (19.3 mg, 0.021 mmol), xantphos (36.67 mg, 0.047 mmol), 1-bromo-3-(trifluoromethyl)benzene (244 μL, 1.69 mmol) and Cs2CO3 (688 mg, 2.11 mmol) were added. The reaction mass was heated to 110° C. and further maintained for 20 h under nitrogen atmosphere. After reaction completion the mixture was diluted with diethylether, filtered through celite, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluent to afford the title compound (200 mg), m/z 429.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:13][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1.CC1C=CC(S([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Br:56])[CH:51]=2)[N+:48]#[C-:49])(=O)=O)=CC=1>>[Br:56][C:52]1[CH:51]=[C:50]([C:47]2[N:48]=[CH:49][N:13]([CH3:14])[C:12]=2[C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=3[CH:11]=2)[CH:55]=[CH:54][CH:53]=1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Reactant: [C-]#[N+]C(c1cccc(Br)c1)S(=O)(=O)c1ccc(C)cc1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: CSc1ncnc2sc(-c3c(-c4cccc(Br)c4)ncn3C)cc12

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (Intermediate 16) in place of N-(3,4Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) and using ((3-bromophenyl)(isocyano)methyl 4-methylphenyl sulfone (Intermediate 57) in place of PhTosMIC. Foam (1.9 g, 91%);
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Br)(Br)([Br:16])=O.C([O-])(O)=O.[Na+]>>[Br:16][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Br)nc1C
Temperature: 130 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.0 g, 11 mmol) and POBr3 (8.9 g, 31 mmol) were mixed in one 100 mL flask, and the mixture was stirred at 130° C. for 4 hrs. The reaction mixture was cooled to room temperature and 50 g of ice water was added. The mixture was neutralized to pH=9 with aqueous NaHCO3 solution, extracted twice with EtOAc, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.5 g (93% yield) of the desired product. LC-MS found: 244.1 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:21]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(C(F)(F)F)ccn1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
To a mixture of (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.6 g, 3.03 mmol) in DMF (5 mL) was added 2-chloro-4-trifluoromethylpyridine (0.2 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol). The reaction mixture was heated at reflux for 1 hour in a microwave reactor at 80° C. Then the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel with eluent (petroleum ether:ethyl acetate from 50:1 to 10:1) to afford the intermediate (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[BrH:10]>O>[Br-:10].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: Br
Agent: Nc1nc(N)nc(N)n1
Solvent: O
Product: [Br-]

Procedure:
Melamine (63 g) was slowly added to a hot (80° C.) solution of hydrobromic acid (121.5 g) in water (1100 ml) and the solution allowed to cool. The crystals of melamine bromide were filtered off and dried in a vacuum oven at 120°. A yield of 72 g was obtained. The product was compounded into nylon 66 to give a concentration of 5% by weight of melamine bromide. A sample of the extrudate was ignited and was found to extinguish almost immediately the flame was removed.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[OH:29].CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C.Cl[Cu]>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=c1ccn2cc(Oc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 120 °C

Procedure:
To a solution of 7-bromo-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (100 mg, 0.3 mmole) was added 2,4-difluorophenol (0.06 ml, 0.6 mmole), 2,2,6,6-tetramethylheptane-3,5-dione (0.007 ml, 0.03 mmole), CuCl (15 mg, 0.15 mmole) and cesium carbonate (195 mg, 0.6 mmole) in NMP. The mixture was heated to 120° C. until the reaction completed. The mixture was diluted with ethyl acetate, washed with 1N HCl, 1N NaOH, brine, dried over MgSO4, and concentrated to yield crude material. The crude material was purified by silica gel chromatography (CH2Cl2/acetone) to yield the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13]C=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:20]1C2C(=CC=CN=2)C=C1>>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:20]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: C1=C(c2n[nH]c3ccccc23)CCC2(C1)OCCO2
Yield: 68 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 7-azaindole (3.65 g, 31 mmol) in 68% yield (5.42 g) as a white solid: mp 162-165° C.; MS EI m/e 256 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][O:12][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+].[N-:21]=[N+:22]=[N-:23].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:14]1[C@H:9]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:11][O:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCOCC21
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Oxa-7-aza-bicyclo[4.1.0]heptane-7-carboxylic acid tert-butyl ester (intermediate E) (5.2 g, 26 mmol) was dissolved in 100 mL acetonitrile. Lithium perchlorate (23 g, 207 mmol) and sodium azide (6.8 g, 104 mmol) were added and the reaction mixture was stirred at 80° C. overnight. 200 mL Water was added. The mixture was extracted three times with diethylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) yielded the title compound as a colorless oil (3.3 g, 52%), MS: m/e=186 [(M-butene)+].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[CH2:42][NH:41][CH2:40][CH2:39]4)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH:46](=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(O)(=O)C.CO>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[CH2:42][N:41]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:40][CH2:39]4)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1ccc2c(c1)CCNC2
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1ccc2c(c1)CCN(Cc1ccccc1)C2

Procedure:
A suspension of EXAMPLE 133A (20 mg), benzaldehyde (6.58 μL), MP-CNBH3 (100 mg, 2.47 mmol/g), acetic acid (2 μL) in dichloromethane (2 mL)/methanol (2 mL) was shaken at room temperature for 18 hours. The reaction mixture was filtered, washed with methanol/dichloromethane, concentrated and purified by RP HPLC (C8, 30-100% CH3CN/water/0.1% TFA) to provide the title compound.