Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (60.0 g, 97 mmol, 1 eq.) in a mixture of THF (750 mL) and MeOH (750 mL) with AcOH (0.279 mL, 4.83 mmol, 0.05 eq.) was added Pd/C (10.3 g, 9.67 mmol, 0.1 eq.). The flask was evacuated and backfilled with argon. Then the reaction was evacuated and backfilled with H2 and stirred at r.t. under atmospheric pressure overnight. The crude product was filtered through a pad of Clarcel and washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified to chromatography on silica gel to afford the expected compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[S:34][C:33]([C:35](=[N:37]O)[NH2:36])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[S:34][C:33]([C:35]2[N:37]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:36]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccc(Cl)s1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)s3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 39 mg (0.22 mmol, 1.1 eq.) of 5-chloro-N′-hydroxythiophene-2-carboximidamide were reacted according to the General Method 1. Yield: 57 mg (53% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:10]1=[O:42].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH:75]1[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([N:75]4[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]4)=[O:25])[CH:21]=3)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:10]1=[O:42]
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Reactant: OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)N5CCC(O)C5)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoic acid (2b) (800 mg, 1.172 mmol) in THF (5 ml) was added EDC.HCl (494 mg, 2.58 mmol), HOBT (395 mg, 2.58 mmol), DIPEA (0.819 ml, 4.69 mmol) and pyrrolidin-3-ol hydrochloride (290 mg, 2.35 mmol). The reaction mixture was stirred at room temperature under N2 atm for 6 h. The reaction mixture was then partitioned between water and ethyl acetate. Organic phase was removed, washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuop to afford crude 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (2c) (550 mg) which was carried forward for the next step without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[S:5][CH:6]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
Under a nitrogen atmosphere, to a mixed solution of the compound (300 mg, 0.95 mmol) obtained in Example 30c and 4-chloro-3-(trifluoromethyl)phenylboronic acid (260 mg, 1.1 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.57 mL, 1.1 mmol) and tetrakistriphenylphosphinepalladium (55 mg, 0.048 mmol), and the mixture was stirred at 100° C. for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (274 mg, 69%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17]>C(N(CC)CC)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:17]#[C:16][CH2:15][N:14]([CH3:18])[CH3:13])=[CH:6][C:5]=1[Cl:11]
Reactant: C#CCN(C)C
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCN(C)C)cc1Cl
Temperature: 60 °C
Yield: 93.6 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 4-bromo-2-chlorobenzoic acid methyl ester (25.13 g, 101 mmol), 1-dimethylamino-2-propyne (16 mL, 150 mmol), bis(triphenylphosphine)palladium(II) chloride (1.0 g) and copper (I) iodide (0.15 g) in 100 mL of triethylamine was heated at 60° C. for 2 hours. The cooled reaction mixture was filtered through Solka floc and the cake was washed with ethyl acetate. The filtrate was partitioned between ethyl acetate and dilute aqueous sodium thiosulfate. The organic layer was washed with water, brine and dried over sodium sulfate. The dark solution was filtered through a plug of Merck-60 silica gel and the filtrate was concentrated in vacuo to give the title compound (23.8 g) as an orange oil, which was used as such in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])=[C:16]3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[N:25]=[N:24][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][C:16]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Solvent: ClCCl
Product: Fc1ccccc1-c1nnn2c1nc(N1CCNCC1)c1ccccc12
Yield: 109.4 %

Procedure:
4-[3-(2-Fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5-yl]piperazine-1-carboxylic acid tert-butyl ester (0.28 g, 0.63 mmol) was dissolved in dichloromethane (5 ml) and hydrogen chloride bubbled through the reaction (2×10 min). The precipitate was filtered and washed with diethyl ether to give 3-(2-fluorophenyl)-5-(piperazin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline as a white solid (0.24 g, 100%). HCl salt: δH (360 MHz; DMSO) 3.30-3.41 (4H, m), 3.79-3.83 (4H, m), 7.35-7.41 (2H, m), 7.44-7.51 (1H, m), 7.78 (1H, ddd, J=8, 8 and 1), 8.05-8.12 (2H, m), 8.27 (1H, d, J=8), 8.62 (1H, dd, J=8 and 1); m/z (ES+) 349 (M+H+).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]1CCN2C(=NCCC2)CC1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([O:12][CH3:28])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: C1CCC2=NCCCN2CC1
Product: COC1=CC(=O)OC(CCc2ccc(C(C)(C)C#N)c(F)c2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A magnetically stirring solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile (− rotation, 0.15 g, 0.40 mmol) was cooled to 0° C. DBU (0.18 mL, 1.21 mmol) was added followed by Mel (0.076 mL, 1.21 mmol) and reaction was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers of the resulting reaction mixture were separated and the organic layer was washed with brine (1×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (20% EtOAc in Hexanes) to give the desired product as a yellow oil (0.062 g, 41%). 1H NMR (400 MHz, CDCl3): δ 1.18 (d, J=6.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H), 1.50–1.78 (m, 8 H), 1.94–2.05 (m, 2 H), 2.18 (s, 3H), 2.64–2.73 (m, 3 H), 3.75 (s, 2 H), 5.17 (s, 1 H), 6.89–6.97 (m, 2 H), 7.35–7.40 (m, 1 H). MS (ESI): 386 (M+H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.CC(O)=O.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([NH:12][C:9]2[NH:10][N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)n[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) in dry pyridine (10 mL) was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol). The solution was stirred at room temperature under Argon. After 48 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with CH2Cl2. After drying over Na2SO4, the solvent was removed in vacuo to give 0.47 g crude product. The crude product was dissolved in hot HOAc (22 mL), diluted with water (9 mL) and seeded. The product was collected by filtration, washed with water, then EtOH and dried in vacuo to give 361 mg of a granular white solid, mp 245-246° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[CH2:12]([N:14]([CH2:15][CH3:16])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:13]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)Cc1ccc(C(=O)O)cc1
Yield: 63 %

Procedure:
1 g (1 equivalent) of α-chloroparatoluic acid and 1.22 mL (2 equivalents) of diethylamine are placed in solution in 30 mL of acetonitrile. The reaction mixture is taken to reflux for 48 hours. The solvent is evaporated off under vacuum and the residue is purified by chromatography on silica gel column (CH2Cl2/MeOH 60/40 then pure MeOH). The product is obtained in the form of a white powder after precipitation from hexane. (Yield=63%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]([C:25]1[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=1)[CH3:24])=[N+]=[N-].O>C1COCC1>[F:31][C:29]1[CH:30]=[C:25]([C@@H:23]([NH2:20])[CH3:24])[CH:26]=[C:27]([F:33])[C:28]=1[F:32]
Reactant: C[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
Triphenylphosphine (1.23 g) was added to a solution of 5-((S)-1-azidoethyl)-1,2,3-trifluorobenzene (858 mg) in THF (20 ml) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for five minutes. Thereafter, water (2.5 ml) was added to the reaction solution, which was then stirred at 60° C. for 2.5 hours. The reaction solution was returned to room temperature, followed by extraction with 2 N hydrochloric acid (twice). The hydrochloric acid extraction layer was washed with ethyl acetate and then made basic with a 5 N sodium hydroxide solution, followed by extraction with methylene chloride (twice). The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 348 mg of the title compound. Further, the following operation was performed in order to collect the title compound remaining in the ethyl acetate dilution of the reaction solution. Diethyl ether was added to the dilution, followed by extraction with water. The water extraction layer was washed with diethyl ether and then made basic with a 5 N sodium hydroxide solution, followed by extraction with methylene chloride (twice). The methylene chloride layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 413 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17]([O:19][CH:20]([C:24](OC)=[O:25])[C:21]([CH3:23])=[CH2:22])=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O1C2C=CC=CC=2C=CN1.O>C1(C)C=CC=CC=1.C[O-].[Na+]>[F:1][C:2]1[C:15]([N:16]2[C:24](=[O:25])[C:20](=[C:21]([CH3:22])[CH3:23])[O:19][C:17]2=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC(C(=C)C)C(=O)OC)cc21
Agent: C1=Cc2ccccc2ON1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-fluoro-6-(1-methoxycarbonyl-2-methyl-2-propenyloxycarbonylamino)-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (10 g) in toluene (100 g), sodium methoxide was added in an amount of 0.05 equivalent to one equivalent of the benzoxazine. The resulting mixture was refluxed for 3 hours, cooled to room temperature, combined with water and extracted with ethyl acetate. The organic layer was washed with water three times, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate as the eluent to give Compound No. 9 (6.1 g). m.p., 194°-198° C.
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ncnc(O)c12
Product: COC(=O)c1ccc2c(c1)[nH]c1ncnc(Cl)c12
Temperature: 90 °C
Yield: 30.6 %

Procedure:
In a 100 mL round-bottom flask a mixture of methyl 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carboxylate (1.1 g, 4.5 mmol) and phosphorous oxychloride (15 mL, 161 mmol) was heated to 90° C. for 16 hours, cooled down to room temperature and evaporated under reduced pressure. The residue was suspended in dichloromethane (20 mL) and filtered through Celite. Evaporation afforded the title compound as an orange solid (360 mg). LCMS m/z 262.0 (M+H)+, retention time (on analytical HPLC)=2.02 minutes.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (60 mg, 0.213 mmol), DMSO(2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (60.1 mg, 0.319 mmol) HCl salt, N-methylmorpholine (0.093 mL, 0.850 mmol), 1-hydroxy-7-azabenzotriazole (57.9 mg, 0.425 mmol), and EDC (81 mg, 0.425 mmol). The final product was collected as 66 mg (74%). LCMS E-S (M+H)=446.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.0 Hz, 6 H), 2.13 (br. s., 3 H), 2.23 (br. s., 3 H), 4.43 (m, 2 H), 5.37 (m, 1 H), 5.91 (br. s., 1 H), 8.15-8.34 (m, 3 H), 8.44 (s, 1 H), 8.78 (br. s., 2 H), 9.00 (br. s., 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Cl-].[NH4+]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Yield: 47 %

Procedure:
A mixture of 500 mg (1.5 mmol) of 1-benzenesulfonyl-3-bromo-1H-indole, 245 mg (2.0 mmol) of phenylboronic acid, 42 mg (0.04 mmol) of Pd[(Ph3P)]4 in 10 mL of toluene, 5 mL of ethanol, and 3 mL of 2 M aqueous sodium carbonate solution was warmed at reflux overnight. The mixture was then cooled and diluted with 15 mL of saturated aqueous ammonium chloride solution and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of saturated aqueous ammonium chloride solution and 10 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel and chromatographed on silica gel eluting with ethyl acetate-hexanes (2:98) to afford 235 mg (47%) of 1-benzenesulfonyl-3-phenyl-1H-indole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reaction time: 20 h
Yield: 95.6 %

Procedure:
To a suspension of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0.27 g, 1.13 mmol) in methanol (2 mL), ethyl acetate (4 mL) and TEA (0.16 mL) was added 10% Pd/C (60 mg, 0.056 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 20 hr, filtered through Celite and concentrated in vacuo to give desired compound (0.226 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and methyl (S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.4 in 9:1 CHCl3/MeOH).
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]\[CH2:13][O:14]C1CCCCO1)=[CH2:3].O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[CH3:3][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/[CH3:22])=[CH:8]/[CH2:9][CH2:10]/[C:11](/[CH3:21])=[CH:12]\[CH2:13][OH:14])=[CH2:1]
Reactant: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(O)CC/C(C)=C/CC/C(C)=C\CO

Procedure:
A solution of 0.5 g (0.0016 mol) of (6E,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol dissolved in 14.5 ml of tetrahydrofuran and 3.7 ml of water is treated with 167.2 mg (0.4 mol equivalents) of pyridinium p-toluenesulfonate. The solution is boiled at reflux for 17 hours. After cooling 100 ml of water and 300 ml of ether are added thereto. The organic phase is neutralized with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (6E,10Z)-2,6,10-trimethyl-1,6,10-dodecatriene-3,12-diol which has the following bands in the IR spectrum: 3344 cm-1, 1647 cm-1, 1449 cm-1, 1375 cm-1, 997 cm-1.