Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:21])[O:20][C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1.[CH:22]([O-])([O-])OC.CO>C(OCC)(=O)C>[CH3:12][C:13]1([CH3:21])[O:20][C:18](=[O:19])[C:17](=[CH:22][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[C:15](=[O:16])[O:14]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: COC([O-])[O-]
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 68.5 %

Procedure:
A mixture of 4-amino-3-methylbenzoic acid (7.3 g), Meldrum's acid (7.3 g), methyl orthoformate (5.6 g) and methanol (30 mL) was heated under stirring in an oil bath at 60° C. for 5 hours. The reaction mixture was returned to room temperature, diluted with ethyl acetate and the precipitate was collected by filtration to obtain 4-{[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl]amino}-3-methylbenzoic acid (10.1 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C@H:11]([NH:16]C(=O)OCC1C=CC=CC=1)[CH2:10]2.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:16][C@@H:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=3)[CH:8]=2)[CH2:12]1
Reactant: [H][H]
Reactant: O=C(N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To (S)-benzyl 5-(3-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-ylcarbamate (2.94 mmol, 1.34 g) in Ethanol (35.4 mL) was added palladium hydroxide (2.51 mmol, 0.353 g). The reaction was placed under 2 bar of hydrogen gas and allowed to stir at room temp for 30 mins. The reaction mix was filtered through a dicalite cartridge before washing with EtOH. The solvent was removed before purifying further by SCX (20 g cartridge, 1:1 MeOH/DCM wash, 2M NH3 MeOH elution). The solvent was removed to give the product as a clear gum (810 mg, 86%). MS (ESI): m/z [M+H]+ 322.2
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH2:19]([N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n(Cc3ccccc3)c2cc1Cl
Reaction time: 48 h
Yield: 96.3 %

Procedure:
2,5,6-Trichlorobenzimidazole (5, 50 mg, 0.0002 moles) was dissolved in 15 ml of CH3CN, and K2CO3 (33 mg, 0.0002 moles) was added. The mixture was stirred at room temperature for one hour, at which time benzyl bromide (0.024 ml, 0.0002 moles) was added. The mixture was then stirred for two days. TLC analysis showed the formation of a new compound with a higher Rf than starting material. The mixture was then concentrated and a liquid-liquid extraction was done using CHCl3, and H2O . The CHCl3 layer was kept, dried with MgSO4, filtered, and then concentrated. Column chromotograpy was then performed using 2% MeOH/CHCl3 to elute the compounds. The fractions were collected and those containing the compound were concentrated. The compound was recrystallized from MeOH, giving 60 mg of 1-benzyl-2,5,6-trichlorobenzimidazole (181) (96.2%). 1H NMR (CDCl3): d 3.49 ppm (s, 3H), 7.13 (m, 2H), 7.32 (m, 4H), 7.78 (s, 1H). 13C NMR (CDCl3): d 43.20 ppm, 106.25, 115.78, 121.62, 122.24, 122.66, 123.50, 124.15, 129.05, 129.16, 135.97, 137.86. GC-MS: m/e 310, 273, 239, 221, 197, 170, 158, 138, 120, 100, 91.7, 65, 51, 39. m.p: 175°-176° C. Elemental Analysis: (C14H9Cl3 N2): Calculated: C, 53.85; H. 2.88; N. 8.97. Found: C, 53.92; H, 2.85; N. 8.89. UV Imax nm (e×104): (pH 7) 263 (0.080), 290 (0.102), 299 (0.154); (pH 1) 224 (0.412), 258 (0.157), 299 (0.166).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH3:33]>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH3:33])=[CH:25][C:24]([F:23])=[CH:32][CH:31]=3)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: Cc1c[nH]c2ccc(F)cc12
Product: Cc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as colorless solid. MS: 426.1 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16]([O:20][C:21](Cl)=[O:22])[CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:21](=[O:22])([O:20][CH2:16][CH2:17][CH2:18][CH3:19])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: CCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted 0.328 g. of chloroformic acid n-butyl ester as in Example 1. The 0.579 g. of colorless oil obtained according to the procedure described in Example 1 crystallizes after trituration. The crystals are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of colorless crystals which are recrystallized from ether/hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-butyl carbonate obtained melts at 64.8°-65.7° and is liquid crystalline (monotrope) upon cooling to 64.3°. UV (EtOH): ε270 = 26,300.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[O:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A mixture solution of dibenzo[b,d]furan-4-yl boronic acid (2.5 g, 11.79 mmol), bis(3-bromo-phenyl)diphenylsilane (14.57 g, 29.5 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and K2CO3 (3.26 g, 23.58 mmol) in 150 mL of toluene and 50 mL water was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was separated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]furan-4-yl)phenyl)diphenylsilane (4.4 g, 64%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[NH:4][N:3]=1.S([O-])(O)=O.[Na+].O.[CH3:15][C:16]1([CH3:29])[C:25]2[C:20](=[CH:21][C:22]([NH2:27])=[C:23]([NH2:26])[CH:24]=2)[NH:19][C:18](=[O:28])[CH2:17]1>C(O)C>[CH3:15][C:16]1([CH3:29])[C:25]2[CH:24]=[C:23]3[NH:26][C:7]([C:5]4[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=4)=[N:27][C:22]3=[CH:21][C:20]=2[NH:19][C:18](=[O:28])[CH2:17]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: Cc1cc(C=O)[nH]n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)[nH]n1

Procedure:
1.5 g. (13.6 mmole) 3-methyl-1H-pyrazole-5-aldehyde was stirred with 4.5 g. sodium hydrogen sulphite in 9 ml. water for 3 hours at 60° C. The evaporation residue was stirred with 2.79 g. (13.6 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one and 40 ml. ethanol for 3 hours at 60° C. while passing through air. Half of the ethanol was distilled off, water was added and the residue was filtered off with suction and recrystallized from ethyl acetate/methanol to give 3.3 g. (82.5% of theory) of the title compound; m.p. 242°-245° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:27][N:28]1[N:32]=[N:31][C:30]([Sn](CCCC)(CCCC)CCCC)=[N:29]1.O.CCOC(C)=O>CN(C=O)C.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>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[N:31]=[N:32][N:28]([CH3:27])[N:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnc(-c2ccc(S(=O)(=O)C3CCN(CCc4ccc(F)cc4F)CC3)cc2)n1
Temperature: 110 °C
Yield: 57.2 %

Procedure:
A mixture of 4-(4-bromophenylsulphonyl)-1-[2-(2,4-difluorophenyl)ethyl]piperidine (0.38 g, 0.86 mmol), 2-methyl-5-(tributylstannyl)tetrazole (0.64 g, 1.72 mmol) and tetrakis(triphenylphosphine)palladium (100 mg, 0.02 mmol) in DMF was heated at 110° C. for 16 hours while stirring under nitrogen. The solution was poured into water/EtOAc (5/20 ml) and further extracted into EtOAc. The combined organic phase was washed with water, dried (Na2SO4) and evaporated to yield a syrup. Column chromatography (silica, EtOAc) followed by recrystallisation from EtOAc yielded 220 mg of crystalline material. δH (400 MHz, CDCl3) 1.73-1.80 (2H, m), 1.98-2.06 (4H, m), 2.50-2.54 (2H, m), 2.71-2.75 (2H, m), 2.92-2.98 (1H, m), 3.05-3.08 (2H, m), 4.45 (3H, s), 6.71-6.80 (2H, m), 7.09-7.14 (1H, m), 7.99 (1H, d, J 5.2 Hz), 8.34 (1H, d, J 5.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[I:14].C(O)(=O)C.C(N)=[NH:20]>>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:13]([I:14])[CH:12]=2)[N:10]=[CH:9][N:20]=1
Reactant: N=CN
Reactant: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(I)cc12
Temperature: 110 °C
Yield: 91.2 %

Procedure:
Dimethylfornamide (0.5 litres), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one litre one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 litres of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one litre of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H), 7.49(d, 1H). ESI-MS m/z 291 (M+1).
Reaction SMILES: Br[C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C.[Al]>C1COCC1.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.[Cu]I>[C:6]1(/[CH:5]=[C:2](\[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])/[CH:3]=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(Br)=Cc1ccccc1
Reactant: C#CCCCCC#C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCCC#C/C(C=O)=C\c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of Pd(PPh3)4 (0.55 g, 0.24 mmol) and α-bromocinnamaldehyde Compound 1 (2.08 g, 4.74 mmol) in degassed THF (170 mL) cooled in an ice-water bath was added a solution of 1,7-octadiyne (2.23 g, 9.48 mmol), triethylamine (15 mL), and CuI (0.36 g, 0.95 mmol) in degassed THF (30 mL) via a syringe under a nitrogen atmosphere. The reaction flask was then covered by a sheet of aluminum foil. After stirring at room temperature for 8 hours the reaction was quenched with saturated aqueous NH4Cl (50 mL) and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent EtOAc in hexane) to give 2.13 g (91 percent) of Compound 2: yellow oil; Rf=0.50 (15 percent EtOAc in hexane); IR (neat) 3294, 2944, 2230, 2116, 1692, 1598, 1450, 1324, 1180 cm−1; 1H NMR (300 MHz, CDCl3) δ9.56 (s, 1H), 8.11-8.07 (m, 2H), 7.48-7.43 (m, 3H), 7.43 (s, 1H), 2.60 (t, J=6.65 Hz, 2H), 2.27 (td, J=6.78, 2.64 Hz, 2H), 1.97 (t, J=2.64 Hz, 1H), 1.86-1.69 (m, 4H); 13C NMR (75 MHz, CDCl3) δ192.4, 151.8, 134.9, 132.0, 131.1, 129.4, 124.1, 103.4, 84.6, 75.4, 69.4, 28.2, 28.0, 20.3, 18.7; MS (+FAB) m/z (relative intensity) 237 (M+H+, 100).
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CC(C(=O)c1ccc(F)c(F)c1)N(C)C
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)c1ccc(-c2ccc(F)c(F)c2)nc1C

Procedure:
The title compound was prepared from dimethylamino-(3,4-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.26 (d, 1H), 7.96 (ddd, 1H), 7.79 (m, 1H), 7.57 (d, 1H), 7.20-7.31 (m, 1H), 4.40 (q, 2H), 2.90 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)cc(C(F)(F)F)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(F)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A mixture of 2,3-diamino-5-fluorobenzotrifluoride (148 mg, 0.76 mmol) and oxalic acid dihydrate (96 mg, 0.76 mmol, used as received) in 4N HCl (2 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 120 mg of crude title compound (64%) as a yellow powder. The crude product was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=6, affording 110 mg of pure title compound as a yellow powder. Mp: 300°-2° C. IR (KBr, cm-1): 3408, 3122, 1754, 1721, 1621, 1492. 1H NMR (DMSO-d6): δ 7.178 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz), 7.359 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz); 11.270 (s, 1H); 12.237 (s, 1H). HRMS: calcd for C9H4N2O2 (M+) m/z: 248.0208; found: 248.0220.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=O)[CH:17]=2)[CH:12]=[CH:11][NH:10]1.C(O)(=O)C>CO>[OH:3][NH:2][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][NH:10][C:9]2=[O:8])=[CH:14][CH:15]=1)=[O:21]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NO)c1ccc2cc[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1.0 mL, 1.7 mmol) was added to a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (32.5 mg, 0.16 mmol) in methanol (1 mL). After stirring for 1 h at rt, excess reagent was quenched by the addition of acetic acid (0.20 mL, 3.52 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-1-oxo-1,2-dihydroisoquinoline-7-carboxamide (12 mg, 37%). LC-MS: (FA) ES+ 205; 1H NMR (300 MHz, MeOD) δ 8.67 (d, J=1.5 Hz, 1H), 8.06 (dd, J=8.3, 1.9 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.26 (d, J=7.1 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:10](=O)[CH2:9][C:8]1([CH3:18])[CH3:17].C(O)COCCO.O.NN.[OH-].[K+]>O.CCCCCCC>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]1[C:13]([CH3:14])([CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1([CH3:18])[CH3:17]
Reactant: CC1(C)CCC(=O)CC(C)(C)P1c1ccccc1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Solvent: CCCCCCC
Product: CC1(C)CCCCC(C)(C)P1c1ccccc1-c1ccccc1
Temperature: 210 °C
Reaction time: 7 h
Yield: 51 %

Procedure:
A round bottom flask was charged with 1-(biphenyl-2-yl)-2,2,7,7-tetramethylphosphepan-4-one (520 mg, 1.54 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (8.0 mL, 85 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (0.680 mL, 7.68 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (431 mg, 7.68 mmol, 5 equiv). The mixture was immersed in an oil bath at 175° C. The temperature of the bath was gradually increased to 210° C. over 30 minutes and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen, and the reaction mixture was diluted with water (10 mL) and heptane (30 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with heptane (2×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was crystallized from a saturated solution of ethanol and isolated by filtration to afford an off-white solid (254 mg, 90 area % by HPLC, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.03-7.95 (m, 1H), 7.47-7.27 (m, 8H), 1.88-1.54 (m, 8H), 1.26 (d, J=4.0 Hz, 6H), 0.96 (s, 3H), 0.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 150.8 (d, J=34 Hz), 143.5 (d, J=7 Hz), 136.3 (d, J=3 Hz), 134.8 (d, J=32 Hz), 130.3 (d, J=4 Hz), 130.2 (d, J=6 Hz), 127.9, 126.7, 125.9, 125.3, 45.1 (d, J=18 Hz), 35.2, 34.9, 32.3, 32.0, 28.1 (d, J=3 Hz), 25.6 (d, J=3 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm 14.4 (s). HRMS (TOF-ESI+) calcd for [M, C22H29P]+ 324.2007. found 324.2004.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:41][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15][N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]=1[Cl:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3cccc(Cl)c32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)c(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-7-chloro-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 25, 60 mg, 0.121 mmol) in DCM (1 mL) was added NBS (23.7 mg, 0.133 mmol) and a few drops of TFA. After stirring at rt for 3 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in ether, washed with sodium thiosulfate, water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the title compound. LC/MS: m/e 574 (M+H)+.
Reaction SMILES: [C:1]1(=[O:15])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([N:18]([CH2:21]C)[CH2:19]C)C>COC(OC)N(C)C>[CH3:16][N:18]([CH:21]=[C:2]1[CH2:3][CH2:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:1]1=[O:15])[CH3:19]
Reactant: O=C1CCCc2nc3ccccc3cc21
Reactant: CCN(CC)CC
Agent: COC(OC)N(C)C
Product: CN(C)C=C1CCc2nc3ccccc3cc2C1=O

Procedure:
3,4-Dihydroacridin-1(2H)-one (19.43 g) was refluxed in N,N-dimethylformamide dimethyl acetal (48.57 ml) and triethylamine (13.76 ml) for 10 hours. The reaction was concentrated and thereafter, triturated first with diethyl ether/pentane and then with diethyl ether, to yield 22.43 g of 2-(dimethylaminomethylene)-3,4-dihydroacridin-1(2H)-one. This was combined with an additional 1.07 g of compound and refluxed in hydrazine (12.68 ml) and ethanol (372 ml) for 2.5 hours. The reaction was cooled, concentrated, and triturated with diethyl ether to yield 20.67 g of a pale orange crystalline solid. A 3.5 g portion was recrystallized from methanol and dried under high vacuum and refluxing xylenes for 30 hours to yield 1.60 g of an off-white crystalline solid, mp 248°-248.5° C.