Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]([CH:9]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=2)=[N:5][N:4]=[CH:3]1.Cl.N([O-])=O.[Na+]>CCO.O>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH:9]([NH:24][C:25]([CH:27]2[CH2:28][CH2:29][CH2:30]2)=[O:26])[C:6]2[C:7](=[O:8])[NH:2][CH:3]=[N:4][N:5]=2)[CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nn1cnnc(C(NC(=O)C2CCC2)c2cccc(OCc3ccccc3)c2)c1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclobutanecarboxylic acid [(4-amino-5-oxo-4,5-dihydro-[1,2,4]triazin-6-yl)-(3-benzyloxy-phenyl)-methyl]-amide (315 mg, 0.777 mmol) and concentrated HCl (344 μL) in anhydrous EtOH (16 mL) was dropwise added a solution of sodium nitrite (120 mg, 1.72 mmol) in H2O (4 mL) at 0° C. and stirred for 30 min and warmed to rt for an additional 1.5 h. The reaction mixture was concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 3% MeOH in CHCl3] to obtain the title compound as an off-white foam solid. 1H NMR (CDCl3, 400 MHz) δ 1.78-1.93 (m, 1H), 1.93-2.04 (m, 1H), 2.12-2.2.36 (m, 4H), 3.13 (quint, J=8.4 Hz, 1H), 4.97 (s, 2H), 6.35 (d, J=8.8 Hz, 1H), 6.85 (dd, J=2.4, 8.4 Hz, 1H), 6.96-7.05 (m, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.27-7.41 (m, 4H), 7.61 (brs, 1H), 8.46 (s, 1H); MS (ES+): m/z 391.04 (100) [MH+]; HPLC: tR=2.87 min (MicromassZQ, polar—5 min).
Reaction SMILES: [F:1][C@@:2]12[C:29]3([CH3:30])[C:24](=[CH:25][C:26](=[O:31])[CH:27]=[CH:28]3)[C@@H:23]([F:32])[CH2:22][CH:3]1[CH:4]1[C:13]([CH3:17])([CH2:14][CH:15]2[OH:16])[C@:7]2([C:18](=[O:21])[CH2:19][OH:20])[O:8]C(C)(C)[O:10][C@@H:6]2[CH2:5]1>B(F)(F)F.F.O>[F:32][C@@H:23]1[C:24]2[C@:29]([CH3:30])([CH:28]=[CH:27][C:26](=[O:31])[CH:25]=2)[C@:2]2([F:1])[C@H:3]([C@H:4]3[C@:13]([CH3:17])([CH2:14][C@@H:15]2[OH:16])[C@@:7]([OH:8])([C:18](=[O:21])[CH2:19][OH:20])[C@H:6]([OH:10])[CH2:5]3)[CH2:22]1
Reactant: CC1(C)O[C@@H]2CC3C4C[C@H](F)C5=CC(=O)C=CC5(C)[C@@]4(F)C(O)CC3(C)[C@]2(C(=O)CO)O1
Agent: F
Agent: FB(F)F
Solvent: O
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
(4bR,6bS,9aR,12S)-4b,12-Difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-2-one (10.3 g, 22.76 mmol—commercially available) was suspended in 48% aqueous hydrofluoroboric acid (100 mL) and the resulting suspension stirred at ambient temperature under an atmosphere of nitrogen for 7 hours. The suspension was then diluted with water (200 mL), filtered and the solid washed with water (500 mL). The solid cake was suspended in methanol (200 mL) and concentrated in vacuo. The resulting solid was suspended in tert-butyl-methyl ether (150 mL), filtered and washed with tert-butyl methyl ether (200 mL) to yield the title compound as a white solid, 95% yield, 8.9 g.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>>[N+:1]([CH:4]=[C:5]([NH:19][CH3:18])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Reactant: CN
Product: CNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with methylamine according to the process of Example 8(ii) yielded the title compound, m.p. 103°-104°. (from ethanol ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].COC(=O)[C:21](Cl)([F:23])[F:22].O>CN(C=O)C>[F:22][CH:21]([F:23])[O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of 5-fluoro-2-nitrophenol (3.1 g, 20 mmol) in DMF (40 mL), potassium carbonate (4.2 g, 30 mmol) and chlorodifluoroacetic acid methyl ester (3.2 mL, 30 mmol) were successively added at room temperature. Subsequently, the temperature of the mixture was raised to 100° C., and the mixture was stirred for 2 hours. The mixture was cooled to room temperature, and water (100 mL) was added to the reaction mixture, followed by extraction with diethyl ether (200 mL) once. The organic layer was successively washed with water (100 mL) and a saturated aqueous sodium chloride solution (100 mL), and after it was dried with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (3.1 g, yield: 75%).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CO.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>[C:22]1([C:2]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)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: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
A mixture of dimethyl 2-iodoterephthalate (22.8 g, 71.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.14 g, 3.38 mmol) in toluene (120 mL) was stirred for 10 minutes. Aqueous sodium carbonate (2 M, 160 mL) and a solution in methanol (40 mL) of phenylboronic acid (10.4 g, 85.3 mmol) were then added and the reaction mixture was stirred at reflux for 15 hours. The reaction mixture was cooled to ambient temperature and extracted with ether. The organic phase was washed with water (2×) and brine, dried, and concentrated in vacuo to give dimethyl 2-phenylterephthalate as a dark brown oil (18.4 g) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[NH2:23])=[CH:5][CH:4]=1)#[N:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[NH:23][S:36]([C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)(=[O:38])=[O:37])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C#N)cc3)c2)cc1
Yield: 68 %

Procedure:
1,5-Bis-(4-cyano-phenoxy)-2-aminobenzene 0.175 g (0.54 mmol), 2-naphthalene-sulfonyl chloride 0.148 g (0.65 mmol) and N,N-diisopropylethylamine (DIPEA) 0.85 g (0.65 mmol) were dissolved in 5 ml of dry toluene and refluxed for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate after the pH was adjusted to 2 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 (5×100 ml) and saturated brine solution. The solution was dried over sodium sulphate and concentrated to afford an oily residue, which was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.190 g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 8.10 (2H, d), 8.35 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:24]C(OC(C)(C)C)=O)[C:11]([O:13][C@H:14]([CH3:23])[C@H:15]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]>Cl.O1CCOCC1>[NH2:24][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][C@H:14]([CH3:23])[C@H:15]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:16])=[O:12]
Reactant: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
(1R,2R)-1-Methyl-2-(2-methylpropanoyloxy)propyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (18) (6.7 g, 15 mmol) was dissolved in 20 ml of 4M HCl in 1,4-dioxane. The resulting mixture was stirred at room temperature for 60 min. dioxane and then evaporated completely under reduced pressure. The residue was dissolved in acetonitrile (20 mL). The solution was stirred at room temperature. The product was crystallized as hydrogen chloride salt, which was collected by filtration and dried under vacuum to give the title compound (9) (4.1 g, 75% yield). m.p.: 164.7-166.2° C. 1H NMR (400 MHz, CD3OD): δ 1.15 (d, 3H, J=6.8 Hz), 1.16 (d, 3H, J=6.8 Hz), 1.18 (d, 3H, J=6.8 Hz), 1.19 (d, 3H, J=6.4 Hz), 2.55 (m, 1H, J=6.8 Hz), 3.03 (dd, 1H, J=12.4, 6.8 Hz), 3.07 (dd, 1H, J=14.4, 6.8 Hz), 4.20 (t, 1H, J=6.8 Hz), 4.96 (m, 1H), 5.05 (m, 1H), 6.57 (dd, 1H, J=2, 8 Hz), 6.67 (d, 1H, J=2 Hz), 6.74 (d, 1H, J=8 Hz). MS (ESI) m/z 340.1 (M+H)+ and 338.1 (M−H), de>98% (by HPLC on Chiralpak column).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH2:8][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:10][CH2:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]2[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=2[Cl:31])=[CH:15][CH:14]=1)=[O:6].Cl>C1COCC1>[C:35]([O:34][C:32]([N:9]1[CH2:10][CH2:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:15][CH:14]=2)=[C:7]([C:5]([OH:6])=[O:4])[CH2:8]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)CN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
Aq. 1M LiOH (11.1 mL, 11.1 mmol) was added to a sol. of compound C3 (1.50 g, 2.72 mmol) in THF (10 mL). The mixture was stirred at 60° C. for 3 days. The mixture was allowed to cool to rt, and aq. 1M HCl was added, until the mixture was acidic. The mixture was extracted with EtOAc. The org. extracts were washed with aq. 1M HCl and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 1:2) yielded the title compound mixed with 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester (1.41 g, 99%). LC-MS: tR=1.10 min; ES+: 522.30.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])C>C(O)C>[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[C:8]([C:6]([OH:7])=[O:5])=[CH:16]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2c(C(=O)O)cc3cc(Cl)ccc32)c1
Temperature: 45 °C
Yield: 96.9 %

Procedure:
A solution of 4M aqueous sodium hydroxide (0.29 ml) was added to a solution of 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid ethyl ester (2.90 g, 8.85 mmol) in ethanol (30 ml) and the reaction heated at 45° C. for 3 h. After concentrating the mixture to 5 ml, a solution of 2M aqueous HCl (2 ml) was added to precipitate the product as a pale solid which was filtered, washed with water (3×30 ml) and dried under vacuum, to afford 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (2.57 g, 89%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH-].[K+].N#N.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH2:11][CH3:12]>C(O)(C)C>[CH3:12][CH2:11][CH:10]([OH:13])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)c1ccccc1
Agent: N#N
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Product: CCC(O)c1ccccc1
Reaction time: 4 h

Procedure:
12.2 mg (2×10-5 moles) of [Ir(PPEI)COD]+ClO4- (+) were suspended in 50 ml of isopropanol and oxidized with air for 4 hours. The yellow limpid solution so obtained was degasified for 20 minutes at reflux under a nitrogen stream and then treated with 2.7 ml of a deaerated isopropanol solution of KOH (2 mg of KOH). The solution was preliminarily reduced for 30 minutes in a N2 stream at reflux and then treated with 2.56 ml of deaerated propiophenone. After 60 minutes the reaction was stopped, obtaining a conversion to phenylpropanol (+) of 57.3% with an e.e. of 30%. Ratios:
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3]([C@H:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:28]2[C:7]3[CH2:6][C@@H:5]([C:3]([N:2]([CH3:40])[CH3:1])=[O:4])[N:10]([C:11](=[O:25])[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:9][C:8]=3[N:26]=[CH:27]2)=[CH:31][C:32]=1[CH3:39]
Reactant: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1N
Yield: 100.1 %

Procedure:
(S)-N,N-dimethyl-5-diphenylacetyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxamide (III-2) (2.3636 g, 0.00440 mol) was dissolved in a mixture of 28 ml of ethyl acetate and 5 ml of methanol, followed by addition of tin chloride dihydrate (4.9580 g, 0.0220 mol) and agitation of the solution on an 80° C. oil bath in a stream of nitrogen for 30 minutes. The reaction mixture was cooled, neutralized by adding a 5% sodium carbonate solution, and concentrated. The residue was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and then concentrated to obtain a light-yellow foamy material (2.2368 g). This material was purified by silica gel column chromatography (Kieselgel 60, 120 g, chloroform methanol=50/1) to obtain the objective compound (II-2) (2.0077 g; yield: 90.0%) as a white foamy material. MS (EI): 508 (M+1).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4NC(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:47]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:48][C:49]4[N:54]([CH2:55][CH:56]5[CH2:59][CH2:58][CH2:57]5)[C:53](=[O:60])[CH2:52][O:51][C:50]=4[N:61]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:47]([C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[CH:48][C:49]4[N:54]([CH2:55][CH:56]5[CH2:59][CH2:58][CH2:57]5)[C:53](=[O:60])[CH2:52][O:51][C:50]=4[N:61]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CCC3)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC3CCC3)C(=O)CO4)cc2)CCC1
Yield: 91 %

Procedure:
Following the procedure for 14(1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-(cyclobutylmethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (8 mg, 0.02 mmol) was reacted to afford the title compound (8 mg, 97%). LCMS (Method A): RT=4.65 min, M-16=423. 1H NMR (500 MHz, MeOD): 7.56 (1H,s), 7.42-7.37 (4H,m), 7.32-7.30 (3H, m), 7.23-7.21 (2H, m), 4.97 (1H, s), 4.59 (2H, s), 4.14 (2H, d), 2.80-2.72 (3H, m), 2.59-2.53 (2H, m), 2.24-2.20 (1H, m), 2.10-2.06 (2H, m), 1.98-1.87 (5H, m).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:11](=O)[C@@H:12]([NH:16][C:17](=O)OC(C)(C)C)[CH2:13][CH2:14][CH3:15])[CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>C1COCC1>[N:7]1([CH2:11][C@@H:12]([NH:16][CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:10][CH2:9][CH2:8]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H](CN1CCC1)NC
Temperature: 55 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a 1M solution of LAH in THF (31.2 mL, 31.2 mmol) was (S)-tert-butyl 1-(azetidin-1-yl)-1-oxopentan-2-ylcarbamate (Compound E) (2.0 g, 7.80 mmol) dropwise added (over approximately 60 min) as a solution in THF (40 mL) under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 55° C. over night. The reaction mixture was cooled to 0° C. Water (1.5 mL) was slowly added, followed by THF (10 mL), 15% aq. NaOH (1.5 mL) and additional water (4 mL). The reaction mixture was warmed to rt and stirred for 1 h. The mixture was filtered and the solid was washed with THF. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (1.22 g, quant. yield). The obtained crude product was used without further purification. 1H NMR (400 MHz, CH3OD) δ 0.90, 1.13-1.41, 2.04, 2.23-2.43, 3.08-3.24. Total no of protons: 19. LCMS (M+H)+: 157.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=2[N+:19]([O-:21])=[O:20])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (900 mg, 2.83 mmol, prepared as described in the Example 1) in DMF (5 mL), K2CO3 (1.90 g, 14.0 mmol) was added followed by addition of morpholine (0.240 mL, 2.80 mmol). The resulting mixture was stirred at 80° C. overnight. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting residue was purified on silica 0:100-50:50 EtOAc/hexanes to yield 4-morpholin-4-yl-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine. Mass Spectrum (LCMS, ESI pos.) Calculated For Mass Spectrum (LCMS, ESI pos.) Calculated For C16H15F3N4O3: 369.1 (M+H), Measured: 369.1.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[N:29]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.[OH-].[Na+]>O1CCCC1.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>[CH:1]1[C:14]2[CH:13]=[C:12]([C:19]3[CH:20]=[C:21]([C:26]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)[N:29]=[C:28]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)[N:27]=4)[CH:22]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4cc5ccccc5c5ccccc45)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Yield: 44 %

Procedure:
In a stream of argon, 1.29 g (5.81 mmol) of 9-phenanthreneboronic acid, 1.20 g (2.42 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine and 67.9 mg (0.097 mmol) of dichlorobis(triphenylphosphine)palladium were suspended in 108 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 4.53 mL (18.2 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 2 hours. Further, 0.11 g (0.50 mmol) of 9-phenanthreneboronic acid was added, and the obtained mixture was distilled under reflux for 2 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene to give 0.74 g of the target 2-[3,5-di(9-phenanthryl)-phenyl]-4,6-di-p-tolyl-1,3,5-triazine as grayish white solid (yield: 44%).
Reaction SMILES: C([NH:9][C:10](=[S:32])[NH:11][C:12]1[C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]([Br:31])=[CH:14][N:13]=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:31][C:15]1[CH:16]=[C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[Cl:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]([NH:11][C:10]([NH2:9])=[S:32])=[N:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(=S)NC(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(N)=S)c1
Yield: 26.1 %

Procedure:
Ethyl 3-(2-(3-benzoylthioureido)-5-bromopyridin-3-yloxy)-4-chlorobenzoate (8.05 g, 15.1 mmol) and K2CO3 (10.4 g, 75.3 mmol) were placed in ethanol (150 mL) and heated to reflux for 2 days and then cooled. The reaction mixture was filtered and the filtrate was concentrated, triturated with water, and dried. The remaining solid was dissolved in CH2Cl2 and purified by silica gel chromatography to give ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.70 g, 26.2% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1OC

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and corresponding 3,4-dimethoxyphenyl boronic acid (182 mg, 1.0 mmol) to afford after chromatographic purification the title compound (92 mg, 42%). 1H NMR (CDCl3, 300 MHz) δ 7.15 (s, 1H), 7.11(s, 1H), 7.01–7.04 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 4.02–4.10 (m, 1H), 3.92 (d, 6H, J=8.1 Hz), 3.64–3.78 (m, 1H), 2.82–3.52 (m, 8H), 1.82–1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 437 [M+H+].