Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:49][CH:48]([C:50]([N:52]2[CH2:58][CH2:57][CH2:56][N:55]([CH:59]3[CH2:62][CH2:61][CH2:60]3)[CH2:54][CH2:53]2)=[O:51])[CH2:47]1>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH:59]1([N:55]2[CH2:56][CH2:57][CH2:58][N:52]([C:50]([CH:48]3[CH2:47][N:46]([C:9]([CH:6]4[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]4)=[O:11])[CH2:49]3)=[O:51])[CH2:53][CH2:54]2)[CH2:62][CH2:61][CH2:60]1
Reactant: COC1CCC(C(=O)O)CC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1CCC(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To a stirred solution of 4-methoxycyclohexane carboxylic acid (20 mg, 0.13 mmol) in DMF/DCM (1:1) (2 ml) was added HOBt (38 mg, 0.28 mmol) and HBTU (96 mg, 0.25 mmol) and the reaction mixture stirred for 15 mins at RT. 1-(Azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (30 mg, 0.13 mmol) in DCM (1 ml) was added and the reaction mixture stirred at RT for 16 hrs. Upon completion, the reaction mixture was evaporated at reduced pressure and purified by silica gel FCC (using DCM/MeOH/NH3; 95:5:0.5 to 90:10:1 as eluent) to give the title compound as colourless oil and as a 1:1 mixture of diastereoisomers by 1H NMR spectroscopy (5.2 mg, 11% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(O[C:43](N(C)C)=[N+:44](C)[CH3:45])C2C=CC=CC=2N=N1.CNC>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][CH:22]([C:25]([N:44]([CH3:45])[CH3:43])=[O:27])[CH2:23][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)N(C)C)CC4)nc23)c1

Procedure:
Prepared from compound 46 of Example 1 by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and dimethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([CH2:38][N:39]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:35]=1[O:36][CH3:37])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)=[O:23])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22](=[O:23])[C:21]2[CH:33]=[C:34]([CH2:38][N:39]([CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:35]([O:36][CH3:37])=[C:19]([CH2:18][N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:20]=2)=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: COc1c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1c(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc(C(=O)c2ccc(N)cc2)cc1CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C

Procedure:
Nitrotetraester 4 (3.0 g, 3.9 mmol) was reduced in 50 mL CH3OH with 100 mg 10% Pd/C in a Parr shaker with an initial hydrogen pressure of 50 psi for 2.5 hours. TLC indicated quantitative reduction. The mixture was filtered through diatomaceous earth and evaporated to leave a yellow oil which was purified by gel permeation chromatography by the method used for compound 4. The yellow glass thus obtained had the correct NMR, IR and field desorption mass spectroscopic behavior.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCCCO1>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccc(C)c(Cl)c1
Reactant: Cc1ccccc1B(O)O
Agent: C1CCOOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccc(C)c(-c2ccccc2C)c1
Yield: 80.2 %

Procedure:
2-Chloro-p-xylene (56 mg, 0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 2.5/5.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and Cs2CO3 (391 mg, 1.20 mmol) in 1,2-dioxane at 100° C. to give the title compound (63 mg, 80%): 1H-NMR (300 MHz, CDCl3): δ 7.12-7.18 (m, 6H), 6.97 (s, 1H), 2.37 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 141.74, 141.45, 135.77, 134.86, 132.60, 129.94, 129.72, 129.65, 129.26, 127.81, 127.02, 125.47, 20.92, 19.81, 19.28. GC/MS(EI): m/z 196 (M+).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5]([CH3:7])[CH3:6].CO.[Li+].[OH-].Cl>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:3]([OH:38])=[O:2]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 330 (150 mg, 0.293 mmol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (61.58 mg, 1.46 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[C:16]([CH2:20]OS(C(F)(F)F)(=O)=O)([F:19])([F:18])[F:17]>CN(C=O)C>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:20][C:16]([F:19])([F:18])[F:17]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1ccc2[nH]c(=O)ccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccc(=O)n2CC(F)(F)F)c1Br
Reaction time: 2 h

Procedure:
5-Bromo-6-methylquinolin-2(1H)-one (103.5 mg, 0.435 mmol) was suspended into DMF (3 mL). To the suspension, was added NaH (17.4 mg 60% in mineral oil) at room temperature. After 2 h stirring, CF3CH2OTf (201.8 mg, 0.869 mmol) was added into the mixture at room temperature. The reaction mixture was stirred for 2 h at the same temperature. The reaction mixture was quenched with water (30 mL). The whole was extracted with AcOEt (30 mL×3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. Gilson PHPLC purification gave 5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one.
Reaction SMILES: [OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26].[OH:32]OS([O-])=O.[K+].Cl>O1CCCC1.O>[OH:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10](=[O:18])(=[O:17])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:25]([N:27]1[CH2:31][CH2:30][S:29](=[O:32])[CH2:28]1)=[O:26]
Reactant: O=S([O-])OO
Reactant: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCSC1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
3-[4-hydroxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (67 mg) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and oxone (45 mg) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (46 mg) as a colorless crystal.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27](O)=[O:28])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][C:27]([NH:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[O:28])[C:17](=[O:30])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Reactant: NCCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21)NCCc1ccccn1
Reaction time: 8 h

Procedure:
20 mg (0.042 mmol) of [4-(4-chlorobenzoyl)-2-oxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl]acetic acid trifluoroacetate was dissolved in 2 ml of dichloromethane. 7 mg (0.05 5 mmol) of 2-aminoethylpyridine, 11 mg (0.05 5 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.018 ml (0.126 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11](=[O:17])[N:10]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:14][C:12]1[C:11](=[O:17])[N:10]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9](=[O:23])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1
Reactant: [H][H]
Reactant: COC(=O)Cn1c(=O)c([N+](=O)[O-])cn(Cc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(=O)c(N)cn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
EX-1B) A solution of 1-Benzyl-3-methoxycarbonylmethyl-5-nitro-2,4(1H,3H) pyrimidinedione (EX-1A; 6.30 g, 19.74 mmol) in 100.0 mL methanol was degassed with hydrogen gas. The solution was then added 5% Pd/C (0.737 g) and allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The oil was purified by MPLC (60% Ethyl acetate/hexanes) to give pure 5-amino-1-Benzyl-3-methoxycarbonylmethyl-2,4(1H,3H)-pyrimidinedione (EX-1B) in 63% yield as a tan solid: 1H NMR (300 MHz, DMSO) δ7.41-7.28 (m, 5H), 6.93 (s, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for C14H16N3O4 290.1141, found 290.1138.
Reaction SMILES: [OH-].[K+].C(O)C.[Br:6][C:7]1[CH:33]=[CH:32][C:10]2[S:11][C:12]([CH2:14][C:15]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)C([O-])=O)=[CH:13][C:9]=2[CH:8]=1.Cl>O>[Br:6][C:7]1[CH:33]=[CH:32][C:10]2[S:11][C:12]([CH2:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)C(Cc1cc2cc(Br)ccc2s1)(C(=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2cc(Br)ccc2s1)c1ccc(OC)cc1
Reaction time: 96 h
Yield: 91.1 %

Procedure:
A solution of 7.3 g of potassium hydroxide dissolved in 20 ml of water was added to 200 ml of an ethanol solution containing 24.2 g of 3-(5-bromobenzo[b]thien-2-yl)-2-ethoxycarbonyl-2-(4-methoxyphenyl)propionate obtained in the above step a), and the thus prepared mixture was stirred for 4 days. The resulting reaction solution was poured into cooled dilute hydrochloric acid to collect precipitated crystals by filtration. The thus collected crystals were dissolved in ethyl acetate, and then dried. After distilling off the solvent, the resulting residue was dissolved in 200 ml of ethanol, mixed with 3 ml of concentrated sulfuric acid, and then refluxed under heating for 2 hours. After cooling, the resulting reaction solution was concentrated, mixed with chloroform, washed with water, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 20 g of ethyl 3-(5-bromobenzo[b]thien-2-yl)-2-(4-methoxyphenyl)propionate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.Cl[CH:30]([CH3:34])[C:31](=[O:33])[CH3:32].C(OCC)(=O)C>CN(C=O)C.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([O:28][CH:30]([CH3:34])[C:31](=[O:33])[CH3:32])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: CC(=O)C(C)Cl
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)OC(C)C(C)=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
IPEA (2.1 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1 g) and 3-chloro-2-butanone (0.39 mL) in DMF (10 mL), and the reaction solution was stirred at room temperature for 19 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 1.3 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:19](Cl)(=O)/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[N:4]1[C:3]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:2]=2[N:1]=[C:19]1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-amino-N-(2-pyridyl)-4-trifluoromethylaniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 365.36; mp: 144.5-145.0° C.; 1H-NMR (CDCl3) δ: 8.82-8.79 (1H, m), 8.12-8.00 (3H, m), 7.57-7.49 (6H, m), 7.41-7.31 (3H, m), 7.11 (1H, d, J=16.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)C.N1CCCCC1.[F:20][C:21]([F:26])([F:25])[C:22]([CH3:24])=[O:23]>O1CCCC1.C(OCC)(=O)C>[F:20][C:21]([F:26])([F:25])[C:22](=[O:23])/[CH:24]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(=O)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(O)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of 4-hydroxybenzaldehyde (5.0 g, 40.9 mmol) in tetrahydrofuran (165 ml) was treated with acetic acid (3.5 ml) and piperidine (3.5 ml). Then 1,1,1-trifluoroacetone (8 ml) was added dropwise. After 2 h at 22° C., another portion of 1,1,1-trifluoroacetone (8 ml) was added and the mixture was stirred for another 3 h. The reaction mixture was then diluted with ethyl acetate, washed with water, saturated ammonium chloride, saturated sodium bicarbonate, and brine. The organic phase was dried (magnesium sulfate), concentrated under reduced pressure and chromatographed on silica gel. Elution with a gradient of ethyl acetate (0-5%) in toluene gave 4.16 g (47%) of title material as yellow needles after crystallization from ether-hexane: mp 106-107° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12](SC)[N:13]=[CH:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].C(O)(=O)C.[O-]Cl.[Na+].[CH3:29][NH2:30].C1COCC1>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[C:18]([CH3:19])=[N:17][C:10]2[N:11]=[C:12]([NH:30][CH3:29])[N:13]=[CH:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: CN
Reactant: CSc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Heat a mixture 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (28.6 g, 84 mmol), dimethylformamide (74 mL) and glacial acetic acid (9.61 mL, 169 mmol) to 45° C. and then add 6.15% aqueous NaOCl (bleach, 612 g, 506 mmol) dropwise over 2 h. Heat at 45-50° C. for 2 h, cool to RT, collect the solids by filtration and wash with water (300 mL). Add DCM (200 mL) to the solids, cool the suspension in an ice-water bath and treat with a solution of 2.0 M N-methylamine in THF (126 mL, 253 mmol). Allow the mixture to slowly warm to RT and stir for 2 h. Remove the solvent under reduced pressure, treat with methanol (MeOH) (50 mL) and stir at RT for 30 min. Collect the solid by filtration and wash with MeOH. Treat the solid with EtOAc (30 mL) and stir at RT for 30 min. Collect the solid by filtration and wash with EtOAc to obtain the title compound (19.82 g, 73% yield). MS (m/z): 323.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](O)=[O:13].C(OC(=O)C)(=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:12]=[O:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
4-Methyl-2-nitroaniline, 30 g (197 mmols), was dissolved in 500 ml of methylene chloride and a liquid mixture of 52 ml (1.378 mol) of formic acid and 31 ml (328 mmols) of acetic anhydride was added dropwise to the solution. The mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure. The resulting crystals were washed with ether to give 34.7 g (97.7%) of N-(4-methyl-2-nitrophenyl)formamide.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)C.[CH3:16][Si:17]([CH3:24])([CH3:23])[C:18]#[C:19]C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1(C)C=CC=CC=1>[CH3:15][O:14][C:10]1[CH:9]=[C:8](/[CH:7]=[CH:6]/[CH2:5][C:19]#[C:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)C#CC(=O)O
Reactant: COc1cccc(C=CCOC(C)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/CC#C[Si](C)(C)C)c1
Temperature: 75 °C
Yield: 41.9 %

Procedure:
To a dried 40 mL scintillation vial fitted with a Teflon coated cap is added 3-methoxycinnamyl acetate (619 mg, 3.0 mmol), toluene (20 mL), 3-(trimethylsilyl)propiolic acid (512 mg, 3.6 mmol), cesium carbonate (1.17 g, 3.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (346 mg, 0.3 mmol, 10 mol %). The vessel is evacuated and back-filled with Argon and then heated to 75° C. for 18 h. Upon cooling to room temperature, the reaction mixture is quenched with H2O (5 mL) and extracted with diethyl ether (2×10 mL). The combined organics are washed with brine, dried over MgSO4, filtered, and concentrated. The crude oil is purified by flash chromatography (12 g RediSep flash cartridge, hexanes to 1.5% ethyl acetate/hexanes) to give 307 mg (42%) of ((E)-5-(3-methoxyphenyl)pent-4-en-1-ynyl)trimethylsilane as an oil. 1H NMR (acetone-d6, 400 MHz) δ 7.23 (d, J=8.1 Hz, 1H), 6.99-6.97 (m, 2H), 6.80 (m, 1H), 6.65 (dt, J=15.7, 1.7 Hz, 1H), 6.26 (dt, J=15.7, 5.7 Hz, 1H), 3.8 (s, 3H), 3.19 (dd, J=5.7, 1.8 Hz, 2H), 0.16 (s, 9H). Reference: Tunge, J. A.; rayabarapu, D. K. J. Am. Chem. Soc. 2005, 127, 13510-13511.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]([C:13]3[CH:23]=[CH:22][C:16]4[O:17][CH2:18][C:19](=[O:21])[NH:20][C:15]=4[CH:14]=3)=[O:12])[CH:9]([CH2:24][C:25]([OH:27])=O)[CH2:8][O:7][C:6]=2[CH:28]=1.[CH3:29][NH2:30].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]([C:13]3[CH:23]=[CH:22][C:16]4[O:17][CH2:18][C:19](=[O:21])[NH:20][C:15]=4[CH:14]=3)=[O:12])[CH:9]([CH2:24][C:25]([NH:30][CH3:29])=[O:27])[CH2:8][O:7][C:6]=2[CH:28]=1
Reactant: CN
Reactant: O=C(O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
A mixture of 2-(7-chloro-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)acetic acid (Intermediate 22, 38 mg, 0.09 mmol), methanamine (0.236 mL, 0.47 mmol) (2 M solution in THF), and TEA (0.039 mL, 0.28 mmol) in EtOAc (2 mL) was treated with T3P (50 wt. % in EtOAc, 0.112 mL, 0.19 mmol) at rt. The reaction mixture was stirred at rt over night and concentrated. The crude product was purified by preparative HPLC (Kromasil C8 column (10 μm 250×20 ID mm), using a gradient of 20-60% ACN in H2O/ACN/FA 95/5/0.2 buffer, over 20 min with a flow of 19 mL/min, UV detection at 240 nm). Freeze-drying gave the title compound (24 mg, 61%) as a white powder.