Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: OB(O)c1cc(F)ccc1F
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: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate 66.13B (1.00 g, 2.9 mmol) in DMF (5.8 mL) at 23° C. was added 2,5-difluorophenylboronic acid (0.69 g, 4.4 mmol) (commercially available from Aldrich), and potassium carbonate (1.2 g, 8.8 mmol). Tetrakis(triphenylphosphine)palladium (0.24 g, 0.20 mmol) was then added to the mixture. The mixture was heated to 90° C. and was stirred for 17 hours. The reaction was then cooled to room temperature, diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 83.27A as a colorless oil (0.800 g, 89% yield).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH2:13][C:14]([CH3:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH3:11][N:12]([CH2:13][C:14]([CH3:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNCC(C)(CC=C(C)C)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CCC(C)(CN(C)S(=O)(=O)c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
Benzenesulfonyl chloride (0.280 mL, 388 mg, 2.19 mmol) was added dropwise over 5 min to a solution of N-methyl-(2,5-dimethyl-2-phenylhex-4-en-1-yl)amine (415 mg, 1.91 mmol) and N,N-diisopropylethylamine (0.520 mL, 386 mg, 2.99 mmol) in THF (5.0 mL) at RT. After 16 h, the reaction mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 4% ethyl acetate in hexane, to give 0.59 g of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ7.72 (d, 2H, J=7.5 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.33-7.23 (m, 4H), 7.17 (t, 1H, J=7 Hz), 4.83 (bt, 1H, J=7 Hz), 3.40 (d, 1H, J=13 Hz), 2.9(d, 1H, J=13 Hz), 2.50 (dd, 1H, J=15, 6 Hz), 2.33 (dd, 1H, J=15, 8 Hz), 2.09 (s, 3H), 1.59 (s, 6H), 1.42 (s, 3H). Mass spectrum (NH3/CI): m/z=358 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.CC1N=C([O:42][CH2:43][CH2:44][CH3:45])N=C(C(O)=O)C=1>>[CH3:30][C:28]1[N:27]=[C:26]([O:42][CH2:43][CH2:44][CH3:45])[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:23]=2)[CH:29]=1
Reactant: CCCOc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: CCCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(6-Methyl-2-propoxy-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-propoxy-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.96 min; [M+H]+=472.23.
Reaction SMILES: OCCC[C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:7][CH2:6]1.BrC1C=CN(C)C(=O)C=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:29]1([CH:5]2[O:10][C:9](=[O:11])[NH:8][CH2:7][CH2:6]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cn1ccc(Br)cc1=O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1NCCC(c2ccccc2)O1
Yield: 128.3 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) and 4-bromo-1-methylpyridin-2(1H)-one (30 mg, 0.16 mmol), Pd(Ph3P)2Cl2 (10 mg), and aq. Cs2CO3 solution (4 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-(S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, 51%). 1H NMR (CDCl3): δ=1.35 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.94 (m, 2H), 2.18 (m, 1H), 2.39 (m, 2H), 2.86 (m, 1H), 3.51 (m, 5H), 5.63 (m, 1H), 6.31 (m, 1H), 6.70 (m, 1H), 6.91 (m, 2H), 7.20-7.32 (m, 8H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:24])[O:5][N:4]=1)[CH3:2].O[N:26]1[C:30](=O)CC[C:27]1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:23])[CH2:18][CH2:19][C:20]([N:26]([CH3:30])[CH3:27])=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:24])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 978 mg (0.003 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-γ-oxo-indole-3-butanoic acid in 15 ml of methylene chloride is treated with 345 mg (0.003 mole) of N-hydroxy-succinimide followed by the dropwise addition of 618 mg (0.003 mole) of dicyclohexylcarbodiimide in 10 ml CH2Cl2. The resulting mixture is stirred 5 hours at room temperature. The mixture is then filtered, and the filter cake is washed with CH2Cl2. The combined CH2Cl2 layers are added dropwise to 20 ml of 40% aqueous dimethylamine and 20 ml of CH2Cl. The mixture is stirred overnight; following which water is added and the layers separated. The CH2Cl2 layer is washed with water, brine, dried over MgSO4, filtered and evaporated. The residue is crystallized to give the title compound, m.p. 144.5°-148° C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14]>O.[OH-].[Na+]>[C:1]([S:3][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:4])[CH3:2]
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 75 %

Procedure:
Thioacetic acid (9.3 cc) and potassium carbonate (7.5 g) in water (150 cc) are added under nitrogen atmosphere to a solution of (R)-2-bromo-3-phenylpropanoic acid (25 g) in 1M sodium hydroxide (110 cc). The solution is stirred for 15 hours at a temperature close to 20° C. After evaporation under reduced pressure, the residue is taken up with water and ethyl acetate. The aqueous phase is separated, acidified to pH=2 and then extracted with ethyl acetate. After washing, the organic phase is dried over sodium sulphate. After filtration and concentration under reduced pressure, (S)-2-acetylthio-3-phenylpropanoic acid (18.5 g) is obtained with a yield of 75% in the form of an oil having the following characteristics: Rf =0.49 [hexane/ethyl acetate/acetic acid (6:4:0.5 by volume)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[C:31](O)=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([C:37]([F:38])([F:39])[F:40])=[C:28]([C:27]([F:26])([F:41])[F:42])[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cccc(NC(=O)c3ccc(C(F)(F)F)c(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.285 mmol) produced in Example 3(vi), 3,4-bis(trifluoromethyl)benzoic acid (88 mg, 0.340 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (129 mg, 0.340 mmol) and pyridine (3 mL) was stirred at 60° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (119 mg, 71%) as a white powder.
Reaction SMILES: [CH3:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[CH2:6][C:5]2[CH:11]=[C:12]([C:15]([O:17]CCCC)=O)[CH:13]=[CH:14][C:4]=2[NH:3]1.FC(F)(F)C(O)=O.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][NH:40][CH3:41].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][N:40]([CH3:41])[C:15]([C:12]1[CH:13]=[CH:14][C:4]2[NH:3][C@H:2]([CH3:1])[C:8](=[O:9])[N:7]([CH3:10])[CH2:6][C:5]=2[CH:11]=1)=[O:17]
Reactant: CCCCOC(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](C)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1Nc2ccc(C(=O)N(C)Cc3cc4ccccc4n3C)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a stirred solution of ten-butyl (2R)-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.6 mmole) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20 mL). After stirring at RT for 45 min the reaction was concentrated on the rotavap. The residue was redissolved in 4 N HCl in dioxane (50 mL), and the solution was concentrated to dryness. Trituration with Et2O, filtration, and drying under vacuo gave the crude carboxylic acid-hydrochloride salt as a white solid. To a stirred solution of this material in 1:1 DMF/CH2Cl2 (50 mL) was added 1-methyl-2-(methylaminomethyl)indole (0.42 g, 2.6 mmole), Et3N (0.73 mL, 5.2 mmole), HOBt.H2O (0.35 g, 2.6 mmole), and EDC HCl (0.5 g, 2.6 mmole). After stirring for 18 h the reaction was concentrated on the rotavap, and the residue was taken up in EtOAc (50 mL). The solution was washed sequentially with H2O (50 mL), 1.0 N Na2CO3 (50 mL), and brine (50 mL), then was dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (EtOAc) gave the title compound (0.87 g, 86%) as a white solid: MS (ES) m/e 391.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[C:24](=[O:26])[CH3:25])=[CH:13][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(C)=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Nc2ccc(O)cc2)c(C(C)=O)c1
Yield: 80.3 %

Procedure:
1-[2-(4-Benzyloxyphenylamino)-5-methoxyphenyl]ethanone (9 g, 0.0258 mole) in 810 ml of ethanol and 90 ml of acetic acid was hydrogenated in a Parr apparatus in the presence of 900 mg of 10% palladium-on-carbon catalyst. After the required amount of hydrogen had been consumed, the reaction mixture was filtered and the solvents removed in vacuo. The residue was partitioned between ether and 10% aqueous sodium bicarbonate. The ether extracts were dried (MgSO4), the solvent removed, and the residue chromatographed on silica gel using chloroform as the eluant. There was obtained 5.33 g of 1-[2-(4-hydroxyphenylamino)-5-methoxyphenyl]ethanone, orange solid, m.p. 118°-119° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]([F:42])([F:41])[F:40])[CH:33]=3)[N:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO.N1C=CC=CC=1>[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[N:2][OH:3])[C:39]([F:40])([F:41])[F:42])[CH:33]=3)[N:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Hydroxylamine hydrochloride (0.08 g, 1.2 mmol) was added to methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 33) (0.285 g, 0.515 mmol) in MeOH (4.00 mL) and pyridine (0.666 mL) to give a yellow solution. After heating at 60° C. 5 days, the mixture was concentrated to dryness and the residue was dissolved into DCM (75 mL) and MeOH (15 mL) and this solution was washed with sat. NaHCO3 (20 mL). The aqueous layer was extracted two time with a mixture of CH2Cl2 (50 mL) and MeOH (10 mL) and the combined organic layers were dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (293 mg, 100% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H) 1.44-1.56 (m, 4H) 1.76-1.87 (m, 2H) 2.23-2.44 (m, 6H) 3.57-3.67 (m, 2H) 3.88 (s, 3H) 4.04-4.12 (m, 2H) 7.25-7.33 (m, 1H) 7.34-7.46 (m, 2H) 7.50 (m, J=7.6, 4.1 Hz, 1H) 7.55 (d, J=7.4 Hz, 1H) 7.81 (dd, J=8.2, 1.2 Hz, 1H) 7.99 (d, J=1.2 Hz, 1H) 8.36 (d, J=8.2 Hz, 1H) 12.07 (d, J=3.5 Hz, 1H); MS m/z 569.2 (M+H)+; HPLC >95%, RT=1.88 minutes.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:1]1([CH2:7][CH2:8][NH:20][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2ccccc12
Reactant: OCCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CCNc2cccc3ccccc23)cc1
Temperature: 210 °C
Yield: 85 %

Procedure:
122 parts of phenylethyl alcohol, 250 parts of α-naphthylamine and 10 parts of triphenyl phosphite are mixed and heated to 210° C. The elimination of water commences at this temperature. The mixture is heated to an internal temperature of 245° C in the course of 12 hours, after which the elimination of water has ended (33 parts of water). After removing excess amine and alcohol under reduced pressure, the N-(2'-phenylethyl)-1-naphthylamine distils at 225° - 230° C/5 mm Hg. 210 parts of N-(2'-phenylethyl)-1-naphthylamine (85% of theory) are obtained.
Reaction SMILES: [Br-].[CH3:2][CH:3]([P+:6]1([CH:29]([CH3:32])[CH2:30][CH3:31])[CH2:12][C:11]2[CH:13]=[CH:14][C:15]3[C:20]([C:10]=2[C:9]2[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=[CH:28][C:8]=2[CH2:7]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C(C)=CC=CC=1>[CH3:2][CH:3]([P:6]([CH2:7][C:8]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]=1[C:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]=1[CH3:12])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH2:4][CH3:5]
Reactant: CCC(C)[P+]1(C(C)CC)Cc2ccc3ccccc3c2-c2c(ccc3ccccc23)C1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1C
Product: CCC(C)P(Cc1ccc2ccccc2c1-c1c(C)ccc2ccccc12)C(C)CC

Procedure:
4 g (7.9 mmol) of 4,4-di(1'-methylpropyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]phosphepinium bromide are suspended in 70 ml of absolute xylene and reacted with 400 mg (10.5 mmol) of lithium aluminum hydride using a method analogous to Example 5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[C:12]([OH:31])=[C:13]([CH:28]=[CH:29][CH:30]=1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([O:23]C(C)(C)C)=[O:22])=[O:15])[CH3:2].C(OCC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[C:12]([OH:31])=[C:13]([CH:28]=[CH:29][CH:30]=1)[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])[CH3:2]
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)c2O)c(=O)c1=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)O)c2O)c(=O)c1=O
Yield: 86 %

Procedure:
1.00 g (2.32 mmol) of tert-butyl (R)-1-[3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-benzoyl]pyrrolidine-2-carboxylate were dissolved in 5 ml of trifluoroacetic acid. 25 min later, the reaction medium was concentrated to dryness and was taken up in toluene before being again concentrated. A pink foam was obtained. This foam was taken up with diethyl ether, with stirring, and then filtered. 0.75 g was obtained in the form of a beige solid. Yield=86%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[C:18](\[C:22]#[N:23])/[C:19]([NH2:21])=[O:20])=[C:9]1OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-]>CO>[NH2:23][C:22]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[N:27]=1
Reactant: CCOc1c(/C=C(\C#N)C(N)=O)c2ccccc2n1Cc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 2.00 g, 5.79 mmol) in MeOH (150 mL) was added NH4OH (30% weight solution of NH3 in water, 100 mL). The reaction was stirred at RT overnight. The reaction was concentrated under reduced pressure and the crude solid was triturated with H2O. The solid was filtered and triturated again with ether. A yellow solid was collected by suction filtration to yield 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide (vii-a, 1.23 g, 63%). NH4OAc standard conditions. DAD Retention time =7.25 min. M+H=317. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.62 (br s, 2H), 7.40 (d, J=7.7 Hz, 1H), 7.31-7.16 (m, 9H), 5.52 (s, 2H).
Reaction SMILES: [CH2:1]([N:3](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>[NH4+].[Cl-]>[CH2:1]([NH:3][CH2:4][C@@H:5]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1
Yield: 21 %

Procedure:
To a 40-mL vial with magnetic stirbar at 25° C. under a nitrogen atmosphere was added 4-{(S)-2-[Ethyl-(4-nitro-benzenesulfonyl)-amino]-1-phenyl-ethylamino}-quinazoline-8-carboxylic acid amide (0.45 g, 0.86 mmol, 1 eq.) and anhydrous acetonitrile (25 mL). The Cesium carbonate (0.84 g, 2.6 mmol, 3 eq.) was added followed by the thiophenol (0.14 g, 1.3 mmol, 0.13 mL, 1.5 eq.). Stirring was continued at 25° C.×16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution (40 mL) and extracted with EtOAc (30 mL)×3. The combined organics were washed with brine (20 mL), dried (e.g., Na2SO4), filtered and concentrated. The resulting residue was purified by column chromatography (ISCO CombiFlash) using a 0-100% gradient (10% MeOH in EtOAc/EtOAc) to afford 58.3 mg (21% yield). LCMS (ESI) 336.2 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH:8]1[NH:12][CH2:11][CH2:10][O:9]1)(=[O:4])[CH:2]=[CH2:3].[C:13](OCCN1CCOC1(C)CCC)(=O)C(C)=C.C(OCCOCCN1CCOC1)(=O)C=C.C(OCCOCCN1CCOC1)(=O)C(C)=C.C(OCCOCCN1CC(C)OC1)(=O)C(C)=C.C(OCCOCCN1CC(C)OC1)(=O)C=C.CC1(C)NCCO1.C(OCCOCCN1CCOC1C1C=CC=CC=1)(=O)C(C)=C.C(C1OCCN=1)(C)=C>>[C:1]([O:5][CH2:6][CH2:7][CH:8]1[NH:12][CH2:11][CH2:10][O:9]1)(=[O:4])[C:2]([CH3:13])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN1CCOC1(C)CCC
Reactant: C=CC(=O)OCCC1NCCO1
Agent: C=C(C)C(=O)OCCOCCN1CCOC1
Agent: C=C(C)C(=O)OCCOCCN1CCOC1c1ccccc1
Agent: C=C(C)C(=O)OCCOCCN1COC(C)C1
Product: C=C(C)C(=O)OCCC1NCCO1

Procedure:
oxazolidinylethyl acrylate; 3-(gamma-methacryl-oxypropyl)-tetrahydro-1,3-oxazine; 3-(beta -methacryloxyethyl)-2,2-penta-methylene-oxazolidine; 3-(beta-methacryloxyethyl-2-methyl-2-propyloxazolidine; N-2-(2-acryloxyethoxy)ethyl-oxazolidine; N-2-(2-methacryloxyethoxy)ethyl-oxazolidine; N-2-(2-methacryloxyethoxy)ethyl-5-methyl-oxazolidine; N-2-(2-acryloxyethoxy)ethyl-5-methyl-oxazolidine; 3-[2-(2-methacryloxyethoxy)ethyl)]-2,2-penta-methylene-oxazolidine; 3-[2-(2-methacryloxyethoxy)ethyl)]-2,2-dimethyloxazolidine; 3-[2-(methacryloxyethoxy)ethyl]-2-phenyl-oxazolidine; 2-isopropenyl-2-oxazoline.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[I:1][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:10]([NH2:9])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(OC)cc1N
Product: COC(=O)c1cc(I)c(OC)cc1N

Procedure:
Synthesized according to the method of reagent preparation 1 by N-iodosuccinimide iodination of methyl 2-amino-4-methoxybenzoate to give methyl 5-iodo-2-amino-4-methoxybenzoate then proceeding with step 1. 1H NMR (400 MHz, CDCl3): 8.97, (s, 1H), 8.75, 7.31 (s, 1H), 4.08 (s, 3H). GC-MS for C9H6ClIN2O: 319 (M+).