Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[N:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 4.00 g of 1-(4-ethylphenyliminomethyl)-2-nitroiminoimidazolidine, 3.00 g of 2-chloro-5-chloromethylpyridine, 4.20 g of potassium carbonate, and 10 ml of DMSO was agitated at 60° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to give an oily residue, followed by purification with column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to obtain 2.70 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(4-ethylphenyliminomethyl)imidazolidine.
Reaction SMILES: C(N(CC)CC)C.CC1C=CC([C:13]([NH:15][C:16]2[CH:21]=[C:20]([N:22]3[CH:26]=[CH:25][N:24]=[C:23]3[CH3:27])[CH:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=2)=[O:14])=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:64]([OH:68])([CH3:67])([CH3:66])[CH3:65]>>[CH3:27][C:23]1[N:22]([C:20]2[CH:21]=[C:16]([NH:15][C:13](=[O:14])[O:68][C:64]([CH3:67])([CH3:66])[CH3:65])[CH:17]=[C:18]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC(C)(C)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Triethylamine (5.23 mL, 37.5 mmol) is added to a stirred suspension of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 91 b; 6.8 g, 25 mmol) in t-butanol (200 mL). Diphenylphosphorylazide (7.6 g, 27.5 mmol) is added to the resulting solution and the mixture is heated 80° C. for 16 h. The solvent is evaporated off under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts are washed with brine (100 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 2% ethanol in ethyl acetate) and recrystallised from ether-hexane to afford the title compound as a colourless crystalline solid, m.p. 203–208° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CN(C=O)C>[Br:1][C:2]1[C:9]([O:10][CH3:13])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Br)c1OC
Temperature: -10 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A stirred suspension of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (commercially available, 24 g, 104 mmol) and K2CO3 (29.4 g, 213 mmol) in DMF (125 ml) was cooled to −10° C. Dimethylsulfate (9.6 ml, 102 mmol) was added, the reaction was warmed to room temperature and stirred overnight. The resulting solution was quenched with water (375 ml) and the resulting suspension stirred overnight. The resulting suspension was filtered and the solid dried in vacuo at 50° C. to give 23.1 g of the subtitle product (91%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH:16]3[CH2:21][CH2:20][C:19]4([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=O.O1CCCC1.[AlH4-].[Li+]>>[CH2:20]1[C:19]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17][CH:16]([O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13]3)[CH2:21]1
Reactant: COC(=O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(Spiro[5.5]undec-3-yloxy)-naphthalene-2-carboxylic acid methyl ester (0.374 g, 0.00106 mol) in tetrahydrofuran (10 mL, 0.1 mol) was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (3.18 mL, 0.00318 mol) at 0° C. The reaction was then allowed to warm to room temperature while stirring for 2 h, Rochele's salt was then added and stirred the resulting mixture was stirred at room temperature for 1 h. After extraction with ethyl acetate, and solvent removal under vacuum, (6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methanol was obtained as a white solid (0.28 g, 83%). ESI-MS: 307.5 (M+H)+. 100%). 1H NMR (400 MHz, CDCl3) δ 7.74-7.70 (m, 3H), 7.44 (d, J=10.0 Hz, 1H), 7.16 (m, 2H), 4.81 (s, 2H), 4.40 (m, 1H), 1.94-1.26 (m, 18H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1)[CH:10]=2)=[O:5]>CO.O1CCCC1>[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)[CH:10]=2)=[O:5]
Reactant: NC(=O)Nc1[nH]c2cc(-c3cccc(C=O)c3)ccc2c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1[nH]c2cc(-c3cccc(CO)c3)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Sodium borohydride (0.23 g, 6.2 mmol) was added to a solution mixture of 2-aminocarbonylamino-6-(3-formylphenyl)indole-3-carboxamide (Compound 4-69, 1.0 g, 3.1 mmol) in anhydrous methanol and anhydrous tetrahydrofuran (methanol/tetrahydrofuran=1/1, 60 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with water (30 mL), ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (0.59 g) as a brown solid (yield 58%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]([C:18](=[O:36])[N:19]1[C@H:24]([C:25](=[O:35])[NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22][CH2:21][NH:20]1)[CH2:13][CH2:14][C:15](O)=[O:16].CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl>C1COCC1>[CH2:27]([NH:26][C:25]([C@H:24]1[N:19]2[C:18](=[O:36])[C@@H:12]([N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[CH2:13][CH2:14][C:15](=[O:16])[N:20]2[CH2:21][CH2:22][CH2:23]1)=[O:35])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CC[C@@H](C(=O)N1NCCC[C@H]1C(=O)NCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.6 %

Procedure:
To a solution of (S)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-5-((S)-6-phenethylcarbamoyl-tetrahydro-pyridazin-1-yl)-pentanoic acid (0.74 g, 1.5 mmol) and N-methylmorpholine (0.6 g, 6.0 mmol) in THF (20 mL) at 0° C., is added PCl5 (470 mg, 2.25 mmol) in one portion. After stirring at 0° C. for 3 hours, the reaction mixture is concentrated and purified by chromatography (CH2Cl2/MeOH:97/3) to yield (1S,9S)-9-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid phenethyl-amide (310 mg, 43.6%) as white solid. (NMR and MS data confirmed, U-3133-65).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23]Cl)[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3,4-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 58 mg (41%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.41 (m, 2H), 7.55 (t, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.25 (d, J=6 Hz, 1H), 10.08 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])[C:6](=[O:12])[NH:7]2)[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[NH:7][C:6](=[O:22])[O:12][C:5](=[O:13])[C:4]=12)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 g (0.114 mol) of 4-ethylisatin are suspended in 75 ml of 100 percent acetic acid, treated portionwise with 26 g (0.137 mol) of m-chloroperbenzoic acid, the temperature not rising above 50°, and then the mixture is stirred at this temperature for a further 15 minutes. The mixture is poured into ice-water and filtered. The crude product obtained is taken up in ethyl acetate and extracted cautiously with a mixture of 2 N sodium hydroxide and ice. The ethyl acetate phase is dried over magnesium sulphate and concentrated to give crude 6-ethylisatoic acid anhydride which melts at 202°-204° after recrystallization from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C1C(=O)N([Br:29])C(=O)C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:29])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cccnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Yield: 97.7 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (1.37 g, 5.85 mmole) in. CH2Cl2 (30 μL) was added glacial HOAc (3.4 mL, 58.5 mmole) and NBS (1.09 g, 6.14 mmole). After 72 hr the mixture was washed with 2.0 M NaOH, H2O. and brine. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.79 g, 98%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 8.35 (s,1H), 7.51 (s, 1 H), 3.77 (m, 2 H), 2.75 (t,J=6.5 Hz, 2 H), 1.93 (m, 2 H), 1.54 (s, 9 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1Cl)[C:4]#[N:5].[OH:19]S(O)(=O)=O>O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH:3]([CH:2]([CH3:18])[CH3:1])[C:4]([NH2:5])=[O:19])=[CH:8][CH:9]=1
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3.63 g (0.015 mol) of the above nitrile, 10 ml of conc. H2SO4 and 0.5 ml of water, under nitrogen, is allowed to stand at room temperature for about 24 hours. The mixture is poured onto about 40 g of ice and extracted with ether. The ether extracts are washed with water and brine, dried over sodium sulfate and solvent removed to give 2-(4-trifluoromethylphenylamino)-3-methylbutyramide (VI; R is hydrogen), which can be recrystallized from ether/hexane, m.p. 93°-94°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:19])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Yield: 94.8 %

Procedure:
(±)-2-(4-Cyano-3-fluoro-phenoxy)-propionic acid tert-butyl ester (1.77 g, 6.7 mmol) was shaken on a Parr shaker under 40 psi hydrogen for 30 min, using palladium hydroxide on carbon (1 g, 30% Pd by wt) in 200 mL anhydrous methanol. The reaction mixture was filtered through sintered glass, and solvents removed in vacuo to afford 1.71 g colorless oil (95% yield).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.C([C:12]1[C:25]2[C:16](=[CH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=C.C1(C=O)C2C(=CC3C(C=2)=CC=CC=3)C=CC=1>>[CH:15]1[C:16]2[C:25](=[CH:24][C:23]3[C:18]([CH:17]=2)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1cccc2cc3ccccc3cc12
Agent: O=Cc1cccc2cc3ccccc3cc12
Solvent: Cc1cc(C)cc(C)c1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 150 °C

Procedure:
Approximately 10 mmol mesitylene solution of vinylanthracene (VA) or anthraldehyde (AnA) was put in a round bottom flask and bubbled with nitrogen or argon gas for at least 30 min. A piece of the H-terminated silicon substrate was then immersed in the solution and allowed to react with VA or AnA for about 12 h under reflux at about 150° C. in an oil bath. During the reaction, the solution was also purged with nitrogen (or argon) to eliminate dissolved oxygen and to prevent the substrate from being oxidized. After the reaction, the substrate derivatized with VA or AnA was rinsed with dichloromethane, acetonitrile and methanol, and dried under a stream of nitrogen gas. The derivatization of the H-terminated surface with anthracene moieties as described in Example 3 is illustrated in FIG. 6.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=S)[CH:9]2C)=[O:5])[CH3:2].C([OH:20])C>[Ni]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=[O:20])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c2c(c1)C(C)C(=S)N2
Reactant: CCO
Agent: [Ni]
Product: CCOC(=O)c1cc(C)c2c(c1)CC(=O)N2
Yield: 67 %

Procedure:
An 0.80 g (3.01 mmol) portion of the 5-ethoxycarbonyl-7-methyl-3-methylthio-2-oxindole in 130 ml of absolute ethanol was treated with Raney Nickel by the above described procedure to give 0.44 g (2.01 mmol, 67% yield) of 5-ethoxycarbonyl-7-methyl-2-oxindole, m.p. 238°241°;
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C)C=O.O>[CH3:13][S:14]([N:6]([C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a cooled (0° C.) solution of 2-nitroaniline (1 g, 7.25 mmol) in dimethylformamide (DMF, 10 mL) was added sodium hydride (608 mg, 25 mmol). After addition was complete methanesulfonyl chloride (1.69 mL, 21.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. The reaction was then diluted with water and the product extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to provide N-(methylsulfonyl)-N-(2-nitrophenyl)methanesulfonamide (1.5 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.89 (m, 1H), 7.80 (m, 2H), 3.58 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>CCO.N1CCCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)ccc1F
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)ccc1F

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (3 mL) and 4-Fluoro-3-methoxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-fluoro-3-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl.[N:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([OH:23])=[O:22])[CH:18]=2)[CH2:13]1.C(N(CC)CC)C.Cl[C:32]1[C:33]2[C:40]([CH3:41])=[CH:39][S:38][C:34]=2[N:35]=[CH:36][N:37]=1>C(O)C>[N:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:41][C:40]1[C:33]2[C:32]([NH:11][CH:12]3[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:21]([OH:23])=[O:22])[CH:18]=4)[CH2:13]3)=[N:37][CH:36]=[N:35][C:34]=2[S:38][CH:39]=1
Reactant: NC1Cc2ccc(C(=O)O)cc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(C(=O)O)cc4C3)c12
Yield: 63 %

Procedure:
Using 2-aminoindan-5-carboxylic acid morpholinamide hydrochloride (750 mg, 2.7 mmol), ethanol (23 ml), triethylamine (1.1 ml, 8.2 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (500 mg, 2.7 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to yield a fraction, which was then washed with ether to obtain the title compound (680 mg, 1.7 mmol) having the following physical properties:
Reaction SMILES: [CH:1]1([CH:4]([OH:24])[CH:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N+:35]([O-:37])=[O:36].Cl>CN(C)C=O>[CH:1]1([CH:4]([O:24][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])[CH:5]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)C(C(O)C1CC1)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C(C(Oc1ccc(F)cc1[N+](=O)[O-])C1CC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
1.30 g (4.00 mmol) racemic (2R,3S and 2S,3R)-3-Cyclopropyl-2-dibenzylamino-3-hydroxy-propionic acid in 4 ml dimethylformamide were added at 0° C. to 0.37 g (8.48 mmol) sodium hydride (55%) in 4 ml dimethylformamide. The suspension was stirred for 2 hours and then 0.96 ml (8.8 mmol) 2,5-difluoro-nitrobenzene in 3.4 ml dimethylformamide were added. After stirring overnight the mixture was poured on ice/water. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with diethylether/heptane (25:75 to 100:0) yielded 1.57 g (85%) racemic (2R,3S and 2S,3R)-3-cyclopropyl-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid as light yellow foam, MS m/e (%): 465.0 (M+H+, 100).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C([O-])([O-])=O.[Cs+].[Cs+].[C:11]([N:18]1[C:30]2[C:29]([OH:31])=[C:28]3[N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][C:38]=4[C:27]3=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[C:22]([F:47])[CH:23]=2)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(#N)C>[C:40]([N:32]1[C:28]2[C:29]([O:31][CH2:3][CH2:2][Br:1])=[C:30]3[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:19]4[CH:20]=[CH:21][C:22]([F:47])=[CH:23][C:24]=4[C:25]3=[CH:26][C:27]=2[C:38]2[C:33]1=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=2)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCBr)c21
Yield: 77 %

Procedure:
To a solution of 1,2-dibromoethane (>5 equiv) in acetonitrile was added Cs2CO3 (2 equiv) and 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (1 equiv) under argon. The suspension was refluxed and the reaction was monitored by TLC. After completion of the reaction (1-3 hours), the solid was removed by filtration and washed with dichloromethane. The combined filtrate was concentrated and the residue was subjected to chromatography on silica gel, eluting with 8% ethyl acetate in hexanes to give 5,7-diBOC-2,10-difluoro-6-(2-bromoethoxy)indolo[2,3-b]carbazole (77%). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 8.06 (dd, J=9.0, 4.2 Hz, 2H), 7.68 (dd, J=8.4, 2.8 Hz, 2H), 7.17 (td, J=9.0, 2.8 Hz, 2H), 4.21 (t, J=6.8 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 1.74 (s, 18H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.N12CCCN=C1CCCCC2.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:52]([CH2:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(CN=[N+]=[N-])cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution (7 mL) of the compound (1.3 g, 3.4 mmol) obtained in Example 95c in tetrahydrofuran were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol) and diphenylphosphoryl azide (1.1 g, 4.1 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=85/15) to give the title compound (1.1 g, 80%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CB1OB(C)OB(C)O1>O1CCOCC1>[CH2:1]([C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][C:12]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2
Yield: 99 %

Procedure:
2,7-dibenzyl-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (70 mg, 0.193 mmol) of Preparation 38, Step B, was dissolved in dioxane (5 ml) and Caesium carbonate (251 mg, 0.77 mmol), trimethylboroxine (0.054 ml, 0.385 mmol) and Catalyst 1 (10 mg) were added. The reaction was refluxed under nitrogen for 3 h. The reaction was filtered over arbocel and diluted with ethyl acetate, washed with water, dried over MgSO4 filtered and concentrated in vacuo to afford the title compound as a colourless oil in 99% yield, 66 mg.