Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24])([CH3:20])([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:24][C:14](=[O:16])[C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A solution of N-benzyl-L-pyroglutamic acid (J. Am. Chem. Soc. 106:4539 (1984), 10.00 g, 45.62 mmol), L-tyrosine tert-butyl ester (11.91 g, 50.17 mmol) and BOP (22.19 g, 50.17 mmol) in DMF (250.0 mL) was charged to a 500 mL round bottom flask equipped with a stir bar and nitrogen inlet. Triethylamine (7.00 mL, 50.17 mmol) was added dropwise and the resulting solution was stirred at 25° C. for 16 h. The solution was transferred to a 1.0 L separatory funnel with ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (300 mL×2), brine (300 mL×2), dried (MgSO4) and the solvent removed to give 18.63 g (93%) of N-(benzyl)-L-pyroglutamyl-L-tyrosine tert-butyl ester as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:20][OH:21])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH2:18]C)=[C:11]([O:14][CH2:15]C)[CH:12]=2)[CH2:7][CH2:6][N:5]=1>C1C=CC=CC=1>[OH:1][CH2:2][CH:3]([CH2:20][OH:21])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: CCOc1cc2c(cc1OCC)C(C(CO)CO)=NCC2
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)NCC2

Procedure:
The 6,7-diethoxy analogue of the above compound can be prepared in an analogous manner, starting from 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-3,4-dihydroisoquinoline; melting point: 127° to 128 C.° (benzene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH2:11][N:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13](=[O:26])[CH2:14][N:15]2C(=O)C3=CC=CC=C3[C:16]2=[O:25])=[CH:5][CH:4]=1.O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=C=O)[CH:41]=[CH:42][CH:43]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:33])[CH2:11][N:12]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13](=[O:26])[CH2:14][NH:15][C:16]([NH:44][C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1ccc(NC(=O)CN(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc2)cc1
Agent: NN
Solvent: O
Product: COc1ccc(NC(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 9.9 %

Procedure:
The procedure is analogous to that described in Example 23, but 1.2 g of N-(4-methoxyphenyl)-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.28 g of hydrazine hydrate and 0.38 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 25 g of silica (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride/ethyl acetate (80-20 by volume)], collecting 25 cm3 fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 0.12 g of N-(4-methoxyphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 194° C. is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=O.C1(C)C=CC=CC=1>O>[O:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[CH:1]=[C:6]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1ccccc1C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2ccccc2o1
Temperature: 111 °C

Procedure:
The crude product 2 was placed into a 5-liter 3-necked round-bottomed flask equipped with a mechanical stirrer and a water trap. Toluene (1,900 ml) was added and the solution heated at reflux temperature (111° C.) until all water had been removed. Diazabicyclounde-7-ene (DBU) (65 g) was then added and the mixture was stirred at 111° C., without the water trap, until the starting material was no longer present, i.e., was not detectable by TLC monitoring. Most of the solvent (90%) was then distilled off. The residue was cooled to 25° C., and ethyl acetate (1,000 ml) was added. The mixture was transferred to a separatory funnel and the organic solution washed with 2N HCl (2×1,000 ml), then with water (1,000 ml). Drying was done over magnesium sulfate. The crude product (326.56 g) was a dark oil and was used directly in the next step. A small sample was purified for the purpose of structure elucidation: the crude material (2 g) was dissolved in ethyl ether and washed with 1N KOH. Drying was done over magnesium sulfate, the material was filtered, and the solvent evaporated. The oily residue was crystallized from isopropanol. The melting range is 53.8°-54° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][C@H:12]1[CH2:22][C:23](=[O:30])[CH2:24][C:25](OCC)=O)=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1CC(=O)CC(OCC)=O)=O)C1C=CC=CC=1>>[C:16]1([C@@H:14]2[CH2:15][N:11]3[C@H:12]([CH2:22][C:23](=[O:30])[CH2:24][CH2:25]3)[CH2:13]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)C[C@@H]1C[C@H](c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Product: O=C1CCN2C[C@@H](c3ccccc3)C[C@H]2C1
Yield: 27 %

Procedure:
In a similar manner to that described in Preparative Example 1(iii)′ above, a reaction was conducted, using (2S,4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-phenylpyrrolidine [obtained as described in Preparative Example 6(iv)′ above] instead of (2S,4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methoxypyrrolidine, to give the title compound as a pale yellow oil (yield: 27%).
Reaction SMILES: Cl.B.[Na].[CH2:4]([N:11]1[C:15](=O)[CH2:14][C@H:13]([OH:17])[C:12]1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO>COCCOC>[CH2:4]([N:11]1[CH2:15][CH2:14][C@H:13]([OH:17])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1C[C@H](O)C(=O)N1Cc1ccccc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
173 g of a solution of hydrogen chloride in DME (content 21.1% w/w=36.5 g (1.0 mole) HCl) were added dropwise to a suspension of 37.8 g (1.0 mole) sodium boron hydride and 51.3 g (0.25 mole) (S)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (IIa) in 300 ml DME within 2 h at 15°-20° C. The mixture was heated to 70° C. and, after addition of another 100 ml DME, agitated 3 h at 70° C. After cooling off, 80 ml MeOH were added dropwise and the batch was evaporated to dryness. The residue was taken up in 240 ml water and, after addition of 60 ml conc. hydrochloric acid, agitated at room temperature until the end of the development of gas. 300 ml toluene were added and the mixture was alkalized with 100 ml 30% sodium hydroxide solution. The toluene phase was separated off at 70° C., compounded with 100 ml water and 300 ml conc. hydrochloric acid and agitated overnight at room temperature. The mixture was then alkalized again with 50 ml 30% sodium hydroxide solution and the toluene phase separated off at 70° C. After filtration, the toluene phase was evaporated to dryness to yield 44.8 g (practically quantitative) (S)-1-benzyl-3-hydroxypyrrolidine (IIIa) as almost colourless oil. The structure of IIIa was corroborated by an NMR spectrum.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:25])[N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15].CN(CCN(C)C)C.[I:34]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([I:34])=[C:10]2[C:6]=1[CH:7]([OH:25])[N:8]([C:16]([CH3:17])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:24])[C:9]2=[O:15]
Reactant: COCOc1c(C)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 59.7 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-5-methyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.94 g, 8.61 mmol) was dissolved in THF (110 mL), and the solution was treated with TMEDA (4.20 mL, 27.8 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 29.0 mL, 27.6 mmol) and iodine (2.62 g, 10.3 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=4/1 to 7/3 to 6/4). The obtained solid was purified by slurry using hexane to obtain 4-methoxymethoxy-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (2.40 g, yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[N:18]([CH2:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
To an ice cooled solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2.5 g, 8.1 mmol) in anhydrous N,N-dimethylformamide (25 ml), sodium hydride (60% emulsion in paraffin oil, 500 mg, 12 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was again cooled to 0° C. and (2-bromoethyl)benzene (1.5 ml, 8.9 mmol) was added. The solution was then heated to 90° C. for 2 hours. The reaction was monitored by TLC and LCMS, and on completion of reaction, it was cooled to room temperature and ice cooled water (75 ml) was added. The reaction mixture was then extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2 g, 60%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.65 (s, 1H), 7.15-7.3 (m, 7H), 6.85 (d, 2H), 5.77 (s, 2H), 3.85 (t, 2H), 3.70 (s, 3H), 2.95 (t, 2H); LCMS: [M+H] 413. Trifluoroacetic acid (20 ml) was added to 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 2.1 mmol) at 0° C., and then stirred at 100° C. for 5 hours. The reaction was monitored by TLC, and on completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure and the residue was basified using aqueous ammonia to form a solid precipitate. The solid was filtered over a sintered funnel. The solid was washed with hexane and dried under reduced pressure to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (500 mg, 80%). The compound was used next without further purification. 1HNMR (400 MHz, DMSO-d6) δ: 14.50 (s, 1H), 9.00 (s, 1H), 8.50 (s, 1H), 7.05-7.15 (m, 5H), 3.95 (t, 2H), 2.95 (t, 2H); LCMS: [M+H] 293.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][Br:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccnc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CBr)Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-2-hydroxy-1-pyridin-3-ylmethyl-ethyl)-carbamic acid tert-butyl ester (0.43, 1.70 mmol) in dichloromethane (10 ml) is added carbon tetrabromide (0.33 g), 2.04 mmol) and triphenylphosphine (0.23 g, 1.70 mmol). The reaction mixture is stirred at ambient temperature for 2 hours, filtered, and the filtrate partioned between ethylacetate and hydrochloric acid (1M). The aqueous phase is separated, neutralised with saturated sodium bicarbonate solution and extracted into dichloromethane. The dichloromethane is dried over magnesium sulphate and evaporated to afford ((R)-2-bromo-1-pyridin-3-ylmethyl-ethyl)-carbamic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 1.29 (s 9H), 3.05 (dd J 14.3 9.8 1H), 3.18 (dd J 14.3 4.9 1H), 3.51 (d J 4.9 2H) 4.07-4.16 (m 1H) 7.84 (dd J 7.9 5.9 1H), 8.35 (d J 7.9 1H), 8.65 (d, J 5.4 1H), 8.86 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([NH2:29])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>ClCCl>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([F:16])[CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: ClCCl
Product: Cc1cn(-c2ccc(Nc3nc(C)cc(Cc4ccccc4)n3)cc2F)cn1
Yield: 86.2 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) and 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (88 mg, 0.57 mmol) using in analogous manner the procedure described in example 43b). Column chromatography (15 g silica, dichloromethane+3.7% methanol v/v) afforded the title compound (148 mg, 86%) as a white solid. MS ISP (m/e): 374.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.98 (dd, 1H), 7.65 (s, 1H), 7.26 (m, 8H), 6.92 (s, 1H), 6.53 (s, 1H), 3.98 (s, 2H), 2.38 8s, 3H), 2.31 (s, 3H). Mp 155-158° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:14]2[CH2:19][CH2:18][N:17]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Clc1ncccn1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CN(c1ncccn1)CC2)C(C)(C)C
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
Compound 2 (15 mg, 35 umol) was dissolved in DMF (3 mL). DIPEA was added followed by the 2-chloropyrimidine. The reaction was subjected to microwave irradiation and heated at 160° C. for 15 minutes and then for a further 5 minutes under the same conditions to drive to completion. The reaction was quenched by the addition of 2 mL of saturated aqueous NaHCO3 and extracted of DCM (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and evaporated. The residue was purified by preparative LC/MS using a 10 minute gradient from 70% water/acetonitrile to 10% water/acetonitrile with 0.1% formic acid as a modifier. The desired product, Compound 298, was isolated as a clear oil (11 mg, 68% yield). LCMS (+ESI) m/z 448.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([N+:11]([O-])=O)[C:3]=1[CH3:14].O.O.Cl[Sn]Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([NH2:11])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc(N)c1N
Temperature: 80 °C
Yield: 90.4 %

Procedure:
A mixture of 154 (40 g, 154 mmol), SnCl2.2H2O (208 g, 920 mmol), EtOAc (300 mL) and EtOH (150 mL) was heated to 80° C. for 12 h, cooled to RT, poured into crushed ice (2 Kg) and the pH adjusted to pH 7-8 with solid NaHCO3. The solid was filtered and washed with EtOAc. The filtrate was thrice extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 28 g (91%) of 4-bromo-3-methyl-1,2-benzenediamine (156) as a brown oil: MS (ESI) m/z=202 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C1C2NC3C(=CC=CC=3)[S:32]C=2C=CC=1.[H-].[Na+].Br.NC1N=C(N)C2C(=NC=C(CBr)N=2)N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:32][C:26]4[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Br
Agent: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(CN3c4ccccc4Sc4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopteridin-6-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminopteridin-6-yl; W=CH2 X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:28]([CH3:29])[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methoxypropan-2-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6.82 Hz, 3H) 2.44 (s, 3H) 3.29 (s, 3H) 3.30-3.33 (m, 1H) 3.44 (dd, J=9.47, 6.44 Hz, 1H) 4.15-4.32 (m, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.19 (br. s., 1H) 8.43 (d, J=6.82 Hz, 1H) 8.50 (d, J=7.83 Hz, 2H) 8.87-8.96 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 392.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][CH2:25][CH:26]=[CH2:27].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(OCC)C>[C:16]1([C:9](=[N:8][CH:7]([CH2:27][CH2:26][CH:25]=[CH2:24])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
While under an atmosphere of argon, a solution of N-(diphenylmethylene)glycine tert-butyl ester (6.30 g, 21.33 mmol) and 4-bromo-butene (3.45 g, 25.56 mmol) in freshly distilled THF (50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (23.4 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to room temperature and stirred for 16 h, cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-25% ethyl acetate in heptane over 8 CV) gave product tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate as a colorless oil (7.00 g, 94%). Rf 0.50 (30% ethyl acetate in heptane).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[N+:23]([O-])=O)=[O:12])=[CH:6][CH:5]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[NH2:23])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=O)c2c([N+](=O)[O-])[nH]c3c2C(=O)CCC3)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(NC(=O)c2c(N)[nH]c3c2C(=O)CCC3)cc1
Yield: 32.1 %

Procedure:
N-(4-Ethoxyphenyl)-2-nitro-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (41 mg) was treated with 10% palladium on carbon (5 mg) in ethyl alcohol (10 mL) under hydrogen (50 PSI) in a Parr bottle for 1 hour. The mixture was filtered through Celite, concentrated in vacuo, and purified on Silica gel (5% methyl alcohol/dichloromethane) to afford N-(4-ethoxyphenyl)-2-amino-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 57) (12 mg).
Reaction SMILES: Cl.[C:2]1([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>CO>[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:11]2[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[NH:14][C:10]=12)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(=O)n2c3c([nH]c12)CCCC3
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
250 mg (0.9 mmol) of the compound of Example IX are dissolved in 2 ml Methanol. 50 mg (0.925 mmol) sodium methylate are added at room temperature and the mixture is stirred for 30 min. 75.9 mg (0.9 mmol) methyl propiolate are added and the reaction mixture is stirred for 20 h at room temperature. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: Acetonitrile-Water Gradient) to yield 113 mg (43% of th.) 4-benzoyl-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazol-1(5H)-one.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([CH3:18])[NH:13]1.ClCCl>O>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Temperature: 45 °C
Yield: 103.3 %

Procedure:
A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitro-benzene and 10.91 g (95.5 mmol) of cis-2,6-dimethyl-piperazine is heated at 45° C. for 1 hour. The reaction mixture is cooled and shaken with dichloromethane and water. The organic layer is dried (magnesium sulfate) and concentrated to give 11.62 g (>100%) of the product as a solid.