Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([N:38]([CH3:39])[CH3:37])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N,-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring until all was dissolved dissolved. The solvent was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 533 (M+H+).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]1[C:19]2=[N:20][NH:21][C:22](=[O:27])[C:23]3[CH:24]=[CH:25][CH:26]=[C:17]([C:18]=32)[NH:16][CH:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH3:13][C:11]1[N:10]=[C:9]([CH:14]2[C:19]3=[N:20][NH:21][C:22](=[O:27])[C:23]4[CH:24]=[CH:25][CH:26]=[C:17]([C:18]=43)[NH:16][CH:15]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:8][CH:12]=1
Reactant: Cc1cn(Cc2ccccc2)c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1c[nH]c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)n1
Yield: 87.4 %

Procedure:
A mixture of 9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (40 mg, 0.09 mmol) and palladium hydroxide on carbon catalyst (40 mg, 20% wt) in anhydrous methanol (15 mL) was purged with hydrogen (1 bar) at room temperature for 12 hr. The mixture was filtered and the filtrate was concentrated to give crude product, which was purified by pre-HPLC to give 9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (27 mg, yield 87%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.22 (dd, 3H), 4.77-4.86 (m, 2H), 7.06 (s, 1H), 7.20 (d, 1H), 7.36 (t, 5H), 7.55 (d, 1H), 7.62 (t, 1H); LC-MS (ESI) m/z: 344 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:21]=1)[NH2:18].CS(O)(=O)=O>O1CCOCC1>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:17]2[CH:19]=[C:20]([B:22]3[O:26][C:25]([CH3:27])([CH3:28])[C:24]([CH3:30])([CH3:29])[O:23]3)[CH:21]=[C:15]([CH3:14])[CH:16]=2)[N:7]=1
Reactant: COCCCOc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: COCCCOc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
The product of Step 1 (107 mg, 0.528 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (123 mg, 0.528 mmol) were dissolved in Dioxane (4 ml), and methanesulfonic acid (0.036 ml, 0.554 mmol) was added. The mixture was heated to 100° C. for 18 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 4-(3-methoxypropoxy)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (165 mg, 78%) as a brown solid. MS ESI: [M+H]+ m/z 400. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=5.8, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.32 (s, 1H), 6.17 (d, J=4.4, 1H), 4.48 (t, J=5.8, 2H), 3.53 (t, J=5.5, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 2.05 (dd, J=3.3, 9.4, 2H), 1.34 (s, 12H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26]>CCO>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]3[NH:11][CH:10]=[N:9][C:8]=3[C:12]=2[F:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: NN
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Yield: 80.3 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8a (0.051 g, 0.135 mmol) is suspended in EtOH (5 mL) and hydrazine hydrate (0.118 g, 2.023 mmol) is added. The reaction mixture is heated at reflux for 16 hours. The reaction mixture is concentrated under reduced pressure and purified by FCC eluted with 97:3 ethyl acetate:MeOH to give 0.041 g (81%) of clean desired product: LC/MS ESI (+) m/z 378, 380 (M+ Br pattern) detected.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:50])[CH:37]([NH:43][C:44](=O)[C:45]([F:48])([F:47])[F:46])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[O:50][C:44]([C:45]([F:46])([F:47])[F:48])=[N:43][C:37]=2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C(NC(=O)C(F)(F)F)C(=O)c1ccc(F)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 0.9 %

Procedure:
Triethylamine (64 mL, 0.46 mmol)) was added to a solution of triphenylphosphine (60 mg, 0.23 mmol) and iodine (58 mg, 0.23 mmol) in dry DCM (0.5 mL) and stirred for 5 min. Then a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-(2,2,2-trifluoroacetamido)propanoate (37 mg, 12 mmol) in dry DCM (0.7 mL) was added and the reaction mixture was stirred for 1 hr. The solvent was removed under reduced pressure, and the residue was purified by SiO2 chromatography on silica gel (isocratic DCM) to yield a white solid (31 mg, 88% yield). 1HNMR (400 MHz, CDCl3): d 8.12 (m, 2H), 7.18 (t, 2H, J=8.8 Hz), 4.43 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz). 19FNMR (400 MHz, CDCl3): d −66.10, −107.21. MS (ESI): m/z MS (ESI): m/z 303.9 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[F:28])[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N3CCOCC3)ccc1F)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(N2CCOCC2)ccc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 35.9 %

Procedure:
A mixture of 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.12 g, 0.29 mmol), lithium hydroxide hydrate (0.12 g, 0.29 mmol), water (2 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (40 mg, 36%) as a white solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.5, observed: 385.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH3:8])[CH:4]=[N:3]1.[CH2:10]([NH2:13])[CH2:11][NH2:12].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([NH:12][CH2:11][CH2:10][NH2:13])[CH3:8])[CH:4]=[N:3]1
Reactant: NCCN
Reactant: CC(=O)c1cnn(C)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCN)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
1-(1-Methyl-1H-pyrazol-4-yl)-ethanone (250 mg) and ethylenediamine (362 mg) were dissolved in methanol (10 ml), the solution was added with acetic acid (1.21 g) and sodium cyanoborohydride (189 mg), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and tetrahydrofuran, the layers were separated, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (163 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:15].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>>[O:15]=[C:2]1[C:3](=[N:23][NH:22][C:21]2[CH:20]=[CH:19][C:18]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:17][CH:16]=2)[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=2)[NH:1]1
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)cc1

Procedure:
The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid amide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ7.04 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.26 (s, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.70 (dd, J=8.2, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.98 (d, J=1.6 Hz, 1H), 11.43 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 395 (M)−. Anal. Calcd for C14H13N5O5S2.0.5H2O: C, 41.58; H, 3.49; N, 17.32; S, 15.86. Found: C, 41.67; H, 3.46; N, 17.26; S, 15.78.
Reaction SMILES: OP([O-])([O-])=O.[K+].[K+].[F:8][C:9]1[C:10]([CH3:28])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16](B1OC(C)(C)C(C)(C)O1)[CH:15]=[CH:14][CH:13]=2.Br[C:30]1[NH:34][C:33]2[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=2[CH:31]=1>CN(C=O)C.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:8][C:9]1[C:10]([CH3:28])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16]([C:30]1[NH:34][C:33]3[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=3[CH:31]=1)[CH:15]=[CH:14][CH:13]=2
Reactant: C[C@H]1NC(=O)c2cc(Br)[nH]c21
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1F
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1F
Yield: 42.6 %

Procedure:
Argon was bubbled into a slurry of potassium phosphate dibasic (Aldrich; 0.164 g, 0.944 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Aldrich; 0.019 g, 0.027 mmol), 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (618) (0.155 g, 0.539 mmol), (R)-2-bromo-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (287) (0.058 g, 0.270 mmol) in 1.5 mL DMF and 0.5 mL water for 1 min. The reaction was sealed and placed in a 70° C. oil bath for 45 min. Additional 1 equiv boronic ester and 5 mg catalyst added, and the reaction was heated 30 min additional. The reaction was partitioned between water and EtOAc. The aq. layer was extracted 1× EtOAc, and the combined organic layers were washed with water 2 times, saturated aq. NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (R)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (287f; 0.034 g, 0.115 mmol, 42% yield) as a orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, s), 8.07 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=8.2 Hz), 7.78-7.88 (1H, m), 7.69 (1H, s), 7.01 (1H, d, J=1.6 Hz), 4.58 (1H, q, J=6.7 Hz), 2.71 (3H, s), 1.41 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 297.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].Br[C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:26]=[CH:25][C:19]([O:20]CC(O)=O)=[C:18]([CH3:27])[CH:17]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1.[C:28]1([CH2:34][C:35]#C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:6])[CH2:5][O:20][C:19]1[CH:25]=[CH:26][C:16]([S:15][C:10]2[CH:9]=[C:8]([C:35]#[C:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=[C:12]([OH:14])[CH:11]=2)=[CH:17][C:18]=1[CH3:27])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Sc2cc(O)cc(Br)c2)ccc1OCC(=O)O
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (3 g; 7.55 mmol), 3-phenyl-1-propyn (2.63 g; 22.65 mmol), bis(triphenylphosphine)palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.086 g; 0.45 mmol) were dissolved in a mixture of triethylamine (3 mL) and DMF (6 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 11 h. The reaction mixture was evaporated to dryness, and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by preparative HPLC method A. Yield: 1.4 g. HPLC-MS: m/z: 433.3 (M+); Rt: min.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:12][CH:13]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH2:15])(=[O:11])[CH3:10].[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](N)=[NH:27].CN(C)C=O>O>[ClH:24].[C:9]([O:12][CH:13]([CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][NH:15][C:26](=[NH:27])[C:25]([Cl:30])([Cl:29])[Cl:24])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(CN)COc1ccccc1
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(CNC(=N)C(Cl)(Cl)Cl)COc1ccccc1
Temperature: 60 °C

Procedure:
Triethylamine (0.50 g., 5.0 mmoles) is added in small portions over 10 minutes to a well stirred mixture of 1.23 g. (5.0 mmoles) of 2-acetoxy-3-phenoxy-propylamine hydrochloride and 1.61 g. (10 mmoles) of trichloroacetamidine in 5 ml. of dimethylformamide. The reaction mixture is heated at 60° C. for 2 hours, diluted with water and extracted with benzene. The benzene extract is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in benzene and treated with an excess of ethanolic hydrogen chloride. Concentration to dryness affords N-(2-acetoxy-3-phenoxypropyl) trichloroacetamidine hydrochloride with a m.p. of 70° to 77° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O.O>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 50 %

Procedure:
10.0 g (60.6 mmoles) of L-phenylalanine was dissolved in 16 ml concentrated H2SO4 (95-98%, D. 1.84 g/ml) at 0° C. 3.0 ml of HNO3 (90%, D. 1.5 g/ml) was added dropwise to the stirring solution keeping temperature at about 0° C. After all of the HNO3 has been added, the solution was allowed to stir 10-15 minutes. Reaction solution was then poured over about 200 ml of ice and then diluted to about 700 ml with additional H2O. This solution was then heated to a boil, and neutralized with PbCO3, about 80 g. The resulting precipitate was filtered and the supernatant was treated with H2S(g) to precipitate remaining Pb++, and then filtered. The resulting filtrate was reduced to 1/3 its volume. The solid which formed was filtered and washed with 95% ethanol. Yield was 50-55% of p-nitrophenylalanine when recrystallized from boiling H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:36]([OH:38])=O)[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH:10]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][OH:27])[CH:10]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])=[N:6][CH:5]=[C:4]([C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH:3]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)O)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCOCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
A solution 5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylic acid (0.15 g, 0.267 mmol), morpholine (0.07 mL, 0.803 mmol), HATU (0.213 g, 0.560 mmol) and DIPEA (0.15 mL, 0.861 mmol) in DMF (7 mL) was stirred at RT for 2 days. Water (20 mL) was added and the solution extracted with ethyl acetate (50 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 1% methanol in ethyl acetate. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual solid taken up in methanol (5 mL) and allowed to stir at RT for 20 minutes. The solution was neutralised with saturated sodium bicarbonate solution and the methanol removed in vaccuo and the residual solution partitioned between water (20 mL) and ethyl acetate. The ethyl acetate layer was separated and washed with brine, dried (MgSO4) and evaporated to give the desired product (34 mg). 1H NMR δ (d6-DMSO): 1.28 (d, 3H), 3.58 (m, 10H), 3.81 (s, 3H), 4.61 (sextet, 1H), 4.89 (t, 1H), 6.60 (d, 1H), 7.03 (t, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 7.63 (d, 1H), 8.20 (q, 2H), 10.84 (s, 1H). m/z 516 (M+H)+
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24](OC)=[O:25])=[CH:6][CH:5]=2.[ClH:28].[NH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33]>C(=O)([O-])O.[Na+]>[ClH:28].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]([NH:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[O:25])=[CH:6][CH:5]=2
Reactant: CS(=O)(=O)CCN
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)CCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Yield: 36 %

Procedure:
Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and 2-aminoethylmethylsulfone hydrochloride, but the reaction mixture was after cooling diluted with a saturated sodium hydrogen carbonate solution (10 mL) and concentrated in vacuo. The residue was suspended in methanol/dichloromethane (1:1) and silica gel (˜2 g) was added. The mixture was re-concentrated in vacuo, resulting in a fine yellow powder that was purified on a silica gel column using dichloromethane/methanol/aqueous NH3, (100:10:1), as the eluent to afford the title compound as a base in 36% yield: 1H NMR (DMSO-d6, 300 MHz) δ 14.70 (br s, 1H), 11.42 (br s, 1H), 10.71 (s, 1H), 8.73 (br s, 1H), 8.22 (s, 1H), 8.06 (d, J=9.3 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.25 (s, 2H), 3.98-3.92 (m, 2H), 3.85-3.67 (m, 4H), 3.44-3.29 (m, 4H), 3.12-3.00 (m, 5H); MS (ES) m/z 459 (M++1). The base was converted to the hydrochloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[C:10]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1>O1CCCC1>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[O:22])[C:19]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])=[C:10]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)C(=O)Cl)c2ccccc21
Reactant: CC1CCNCC1
Solvent: C1CCOC1
Product: CC1CCN(C(=O)C(=O)c2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4-methylpiperidine (0.490 ml, 0.411 g, 4.14 mmol) was dissolved in 3.0 ml of dry tetrahydrofuran in a round bottom flask over an ice bath. To this reaction mixture was added 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-chloro-1,2-ethanedionyl]-1H-indole (0.500 g, 1.39 mmol) and the resulting mixture was stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: C([O:4][C:5](=[CH:7][C:8]([CH3:10])=[CH2:9])[CH3:6])(=O)C.[CH3:11][C:12]([CH3:16])=[CH:13][CH2:14]O.CC(C)=CC(O)=O>C(O)(=O)C>[CH3:6][C:5]([CH2:4][CH2:14][CH:13]=[C:12]([CH3:16])[CH3:11])=[CH:7][C:8](=[O:9])[CH3:10]
Reactant: C=C(C)C=C(C)OC(C)=O
Reactant: CC(C)=CCO
Agent: CC(C)=CC(=O)O
Solvent: CC(=O)O
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 86 %

Procedure:
110 parts of 4-methyl-2,4-pentadien-2-yl acetate and 60 parts of prenol are heated with 1.4 parts of 3,3-dimethylacrylic acid at about 180°C for 4 hours in a small pressure column at a pressure of 2 atmospheres, the acetic acid formed being distilled off continuously. Fractional distillation of the reaction product gives 61.8 parts of 4,8-dimethyl-3,7-nonadien-2-one (yield 86% of theory, conversion 62% based on prenol).