Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.036 min, m/z=512.1; 1H NMR (CDCl3) 1.49 (d, 3H), 1.60-1.70 (m, 1H), 1.84 (m, 1H), 1.89-1.99 (m, 2H), 2.10-2.20 (m, 2H), 2.25 (m, 1H), 2.74 (s, 3H), 3.01 (m, 2H), 4.22 (m, 1H), 5.64 (m, 1H), 6.97 (m, 4H), 7.16 (m, 3H), 7.58 (d, 1H), 7.70 (m, 3H), 8.60 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(a) from 4-acetoxy-7-cyano-1-(3-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25](OCC)=[O:26])=[C:18]2[OH:30].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:19]2[CH:20]=[N:21][C:22]3[C:17]([C:18]=2[OH:30])=[CH:16][C:15]([F:14])=[CH:24][CH:23]=3)=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(F)cc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.52 mL) in 5 mL of toluene is added 2.13 mL of a 2.0 M solution of trimethylaluminum in tolune. The solution is stirred for 5 min at 0° C. and then a suspension of 0.50 g of ethyl 6-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 69, 371 (1947)) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 18 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of a large excess of 3 M hydrochloric acid and ice. After stirring the mixture vigorously for 30 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several hours at 5° C. Filtration of this mixture gives the desired amide as 390 mg of a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]I.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-hydroxy-3-methyl-butyric acid (1.0 g, 4.29 mmol) was dissolved in THF (14 mL) and cooled to 0° C. in an external ice/brine bath. MeI (2.13 mL, 34.3 mmol) was added at 0° C. Solid NaH (60% dispersion in mineral oil, 0.514 g, 12.87 mmol) was added slowly at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was diluted in ethyl acetate and water was added slowly with stirring. The quenched mixture was concentrated in vacuo and partitioned between diethyl ether and water. The ether layer was extracted with sodium bicarbonate twice. The combined bicarbonate layers were acidified with aqueous citric acid to pH 3 and extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water, sodium thiosulfate, water, dried with sodium sulfate and concentrated to yield 2-tert-Butoxycarbonylamino-3-methoxy-3-methyl-butyric acid (0.99 g, 94%) as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][C:15]=2[O:28][CH:29]([CH3:31])[CH3:30])[NH:10][C:9]=1[CH3:32])=[O:7])[CH3:4].O.ClCCl>C(O)C1C=CC=CC=1>[CH2:3]([O:5][C:6]([C:8]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][C:15]=2[O:28][CH:29]([CH3:31])[CH3:30])[NH:10][C:9]=1[CH3:32])=[O:7])[C:4]1[CH:16]=[CH:17][CH:8]=[CH:9][CH:32]=1
Reactant: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500-mL four-necked round-bottom flask equipped with a stirrer, dropping funnel, reflux condenser with gas lead-off, a thermometer and a gas inlet are placed 100 mL benzyl alcohol and 0.937 g (0.0312 mole) sodium hydride (80% in oil) is introduced while flushing with a protective gas. The resulting suspension is then subsequently stirred for 30 minutes. Thereafter, a solution of 52.55 g (0.124 mole) (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid ethyl ester in 200 mL benzyl alcohol is allowed to run in, followed by stirring for 15 hours at 120° C. After cooling to ambient temperature, the reaction mixture is stirred with 1 L of water and 400 mL dichloromethane. After separating the phases, the aqueous phase is again stirred with 300 mL dichloromethane. The dichloromethane phases are combined and washed twice with 300 mL amounts of water. The dichloromethane phase is dried over anhydrous sodium sulfate. After filtering, the dichloromethane is distilled off on a rotary evaporator and subsequently the benzyl alcohol is distilled off under oil pump vacuum (54°-65° C./3-5 mm Hg). The distillation residue is dissolved in 600 mL hot cyclohexane and the solution is cooled to 0° C. while stirring. The precipitate obtained is filtered off with suction and subsequently washed with 100 mL n-hexane. The filter cake is then dried at 80° C. Yield: 43.9 g (72.8% of theory); mp 131° C. with a purity of 99.4 relative %.
Reaction SMILES: CO[C:3]1[CH:11]=CC([N+]([O-])=O)=C2[C:4]=1CN(C)C2=O.[OH:17][C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]2[C:19]=1[CH2:20][N:21]([CH3:31])[C:22]2=[O:30].C(I)(C)C>>[CH3:31][N:21]1[CH2:20][C:19]2[C:23](=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=2[O:17][CH:3]([CH3:11])[CH3:4])[C:22]1=[O:30]
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Solvent: CC(C)I
Product: CC(C)Oc1ccc([N+](=O)[O-])c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205B) using 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one and 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205C, 50.0 mg, 0.240 mmol) and isopropyl iodide. 1H NMR (400 MHz, CD3OD) δ=1.40 (d, J=6.1 Hz, 6H), 3.15 (s, 3H), 4.37 (s, 2H), 4.80-4.87 (m, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H). MS (ES+): m/z 237.18 (100) [MH+]; HPLC: tR=0.94 min (UPLC, Analytical).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:24]([O:28][C:29](=[O:30])[NH:31][C@H:32]([C:33](=[O:34])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=1)[CH3:36])([CH3:25])([CH3:26])[CH3:27]
Reactant: N#Cc1cccc(Nc2ccccc2N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
Triethylamine (0.35 mL, 2.59 mmol) was added to a mixture of 3-(2-aminophenylamino)benzonitrile (177 mg, 0.85 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (190 mg, 1.02 mmol), HOAt (140 mg, 1.02 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (190 mg, 1.02 mmol) in anhydrous DCM (10 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) to afford the title compound as a yellow oil (290 mg, 90%). Material still impure, taken forward in the next step without further purification. LCMS (Method J): RT 3.54 min [M+H]+ 380.8
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 54.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and benzyl bromide (52 μL, 0.44 mmol) in N,N-dimethylformamide (4.5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-benzyl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (71.5 mg, 55%) as an off-white solid. APCI-MS (M+H) 297.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:13]#[CH:14])[CH:3]=1.Br[C:16]1[CH:31]=[CH:30][C:19]2[C:20](=[O:29])[N:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[S:22](=[O:24])(=[O:23])[C:18]=2[CH:17]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.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>[C:25]([N:21]1[C:20](=[O:29])[C:19]2[CH:30]=[CH:31][C:16]([C:14]#[C:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=3[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:17][C:18]=2[S:22]1(=[O:23])=[O:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)O
Reactant: CC(C)(C)N1C(=O)c2ccc(Br)cc2S1(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)O)cc2S1(=O)=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (4-chloro-2-ethynylphenoxy)acetic acid (Intermediate 238; 211 mg; 1.00 mmol), 6-bromo-2-tert-butyl-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (prepared as described in Tetrahedron, 2006, 62, 7902-7910, 382 mg; 1.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (70 mg; 0.10 mmol) and cuprous iodide (9.5 mg; 0.05 mmol) in anhydrous THF (4 ml) was degassed for 10 minutes then treated with triethylamine (1.00 ml; 7.21 mmol) and the mixture stirred at 60° C. for 16 h. EtOAc was added and the organic phase washed with a sat. NH4Cl solution then brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1)(=[O:33])=[O:32]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(N)cc2C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(NS(C)(=O)=O)cc2C1=O
Reaction time: 20 h

Procedure:
0.5 g of methyl 7-amino-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is dissolved under an inert atmosphere in 5 cm3 of dichloromethane at a temperature close to 20° C. 0.142 cm3 of pyridine is poured into the reaction mixture which is then cooled to a temperature close to 5° C. 0.122 cm3 of methanesulfonyl chloride is introduced over 30 min. The stirring is continued for 20 h while gradually allowing it to climb back up to a temperature close to 20° C. 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate and 5 cm3 of water are added to the reaction mixture. Stirring is continued for 1 h at a temperature close to 20° C. The aqueous phase is extracted with 10 cm3 of dichloromethane. After decanting, the organic phase is dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by trituration in 10 cm3 of hot diisopropyl ether. After filtering at a temperature close to 20° C., washing with 2 lots of 5 cm3 of diisopropyl ether and drying under vacuum, 0.6 g of methyl 7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate is obtained in the form of pink crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C(OCC)(=O)C.C1COCC1>[O:42]=[C:33]1[C:34]2[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](=[O:37])[N:32]1[O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=1
Reactant: NC(=O)c1ccc(CO)nc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(CON2C(=O)c3ccccc3C2=O)nc1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg of triphenylphosphine, 503 mg of N-hydroxyphthalimide, and 4.7 ml of THF was added dropwise 0.53 ml of diisopropyl azodicarboxylate, followed by stirring overnight. After concentration, the solid thus produced was suspended in water, and ethyl acetate was added thereto. After stirring for 30 minutes, the solid was collected by filtration to obtain 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)oxy]methyl}nicotinamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-fluoroaniline to yield 2-[(4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:29]([N:36]1[C:44]([CH3:45])=[C:43]2[C:38]([CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42]2)=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[CH2:29]([N:36]1[C:44]([CH3:45])=[C:43]2[C:38]([CH:39]=[C:40]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH:14]5[CH2:17][NH:18][CH2:19][CH2:20][N:13]5[CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:41]=[CH:42]2)=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2nn1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(Br)c4c(N)ncnn34)OCC2C1
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: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c2ccc(-c3cc(C4CN5CCNCC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a stirred solution of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (300 mg, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.099 mmol) in degassed 1,4-dioxane (5 mL) and DMF (5 mL) were added 2-benzyl-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (345 mg, 0.99 mmol), K2CO3 (274 mg, 1.99 mmol), and H2O (1.0 mL). The reaction was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The crude residue was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The solution was allowed to stir for 30 minutes and concentrated. The mixture was partitioned between ethyl acetate (75 mL) and H2O (50 mL). The layers were separated and the organic phase was washed with 1N HCl (50 mL). The combined aqueous phase was transferred to a stirring mixture of ethyl acetate and pH 14 brine and allowed to stir for 30 minutes, keeping the pH above 12 with additional NaOH pellets as needed. The layers were partitioned and aqueous layer was extracted 2× with ethyl acetate (75 mL ea.). The combined organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 135 mg (42%) of the desired product. 1H NMR (300 MHz, DMSO-d6) 7.91 (s, 1 H), 7.78 (d, 1 H), 7.52 (s, 1 H), 7.34-7.19 (m, 5 H), 7.21 (dd, 1H), 6.72 (s, 1H), 5.63 (s, 2H), 5.12 (dd, 1H), 3.73 (dd, 1H), 3.30-3.23 (m, 1H), 2.92 (dd, 1H), 2.75-2.64 (m, 4H), 2.61 (s, 3H), 2.41 (t, 1H), 2.25-2.06 (m, 4H); LC-MS [M+H]+=495, RT=2.17 min.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+:20]([O-])=O)([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[NH2:20]
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Yield: 97.6 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g of dinitroanthraquinone (a mixture of 1,5-isomer and 1,8-isomer), 50 g of a 4% aqueous solution of sodium hydroxide, 50 g of toluene and 0.25 g of 5% palladium-carbon, and the dinitroanthraquinone was hydrogenated with stirring at a pressure of 40 to 30 Kg/cm2.G and a temperature of 40° to 50° C. The reaction was stopped in 5 hours with the absorption of 0.1169 mole of hydrogen. 50 g of a 4% aqueous solution of sodium hydroxide was added, and the reaction mixture was filtered in a stream of nitrogen to separate the catalyst. The filtrate was separated into an aqueous pahse and a toluene phase. The aqueous phase was oxidized with air with stirring at 20° to 30° C. for 2 hours. The crystals precipitated were filtered and dried to afford 3.9 g of diaminoanthraquinone in a yield of 97.5%.
Reaction SMILES: O[CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.O1CCOCC1.CCN(S(F)(F)[F:30])CC>O>[F:30][CH:2]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:3][N:4]1[CH:8]=[N:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: COCCOCC(O)Cn1cnc([N+](=O)[O-])n1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: COCCOCC(F)Cn1cnc([N+](=O)[O-])n1
Yield: 44.8 %

Procedure:
To 1.1 g (4.5 mmol) of 1-[2'-hydroxy-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole, 10 ml of 1,4-dioxane was added and then 1.0 g (6.2 mmol) of DAST was dropwise added. Then, the mixture was reacted for a day at room temperature with stirring. After the reaction, to the reaction solution, 2 ml of water was added to decompose excess DAST. The solution was concentrated and partitioned between chloroform and water. The chloroform phase was washed with water, dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel column chromatography to give 500 mg of 1-[2'-fluoro-3'-(2"-methoxyethoxy)-propyl]-3-nitro-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([Br:26])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc2scc(-c3ccc(F)c(Cl)c3)c12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
To the solution of 4-amino-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (240 mg, 0.86 mmol) in 10 ml of THF cooled at 0° C. was added NBS (153 mg, 0.86 mmol) and the reaction mixture was stirred for 1 hour at 0° C. The resultant mixture was poured into 10% Na2SO3 and ethyl acetate, the organic phase was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (333 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.97 (s, 1H), 7.73 (dd, J=2.1, 7.2 Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J=8.8 Hz, 1H), 7.48 (ddd, J=2.2, 4.7, 8.4 Hz, 1H), 5.66 (s, 2H). MS: m/z 357, 359, 361 (M+H)+.