Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[C:7]=2[CH:37]=1)#[N:2].Cl[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[O:50][CH3:51].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:39][C:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[CH:43]=[CH:42][C:41]=3[O:50][CH3:51])[C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[C:7]=2[CH:37]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CCl
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 127 μmol) in DMF (316 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (31.4 mg, 152 μmol), cesium carbonate (53.6 mg, 165 μmol), and sodium iodide (24.7 mg, 165 μmol). The reaction was stirred at rt for 1 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (75 mg, 87%) as a white solid. MS m/z 706 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=O)[CH3:9].CC([O-])=O.[Na+].Cl.[NH2:30][OH:31]>CCO>[F:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=[N:30][OH:31])[CH3:9]
Reactant: NO
Reactant: CC(=O)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1F
Temperature: 60 °C
Yield: 0.1 %

Procedure:
A mixture of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (0.7 g, 2.118 mmol), NaOAc (1.73 g, 21.1 mmol), and hydroxylamine hydrochloride (0.735 g, 10.55 mmol) in EtOH (20 mL) was heated at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure, water (200 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined extracts were concentrated under reduced pressure to afford 0.66 mg (90%) of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime as a white solid. MS (ESI): m/z=348.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)CCOc4ccccc4C)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCCOc4ccccc4C)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-3-(2-methylphenoxy)propaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 445 (M++1)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)([OH:8])[CH3:7])C.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O.C(OCC)(=O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:6]([OH:8])([CH3:7])[CH2:5][CH2:4][OH:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 32 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester in 300 ml. of absolute THF is added dropwise, under nitrogen, to a suspension of 4.6 g. of LiAlH4 in 200 ml. of THF and the mixture is heated under reflux for one hour. After cooling, ethyl acetate, water and 32% sodium hydroxide solution are added and the mixture is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=[N:12]2)[C:3]([OH:25])=[O:2])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)n1ncc(OCC2CCCC2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (702.6 g, 2.01 mmol) in methanol (1.3 mL, 1.55M) was treated with a 4N aqueous sodium hydroxide solution (0.55 mL, 2.22 mmol) and stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo. The resulting solids were then taken up in water (30 mL) and a 1N aqueous sodium hydroxide solution (20 mL) and extracted with methylene chloride (1×30 mL). The aqueous layer was then acidified with a 3N aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration and dried in vacuo. The initial organics were treated with a 1N aqueous sodium hydroxide solution (50 mL), concentrated in vacuo, and then acidified with a 3N aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration and dried in vacuo. The combined solids afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (490.5 mg, 73%) as a white solid; ES+-HRMS m/e calcd for C18H26N2O4 [M+H+] 335.1966, found 335.1964. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.18 (m, 2H), 1.24-1.82 (m, 15H), 1.94 (ddd, J=13.6, 9.0, 4.0 Hz, 1H), 2.16 (ddd, J=13.8, 11.1, 5.1 Hz, 1H), 2.25-2.36 (m, 1H), 3.90 (d, J=7.0 Hz, 2H), 5.31 (dd, J=11.1, 4.0 Hz, 1H), 6.29 (d, J=2.8 Hz, 1H), 7.81 (d, J=2.8 Hz, 1H), 12.92 (br s, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]12[O:37][CH:8]1[C@@H:9]1[C@H:13]([CH2:14]2)[C@H:12](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:11]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:10]1)(=O)=O.C1C2C(=CC=CC=2)C=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:37][CH:8]1[C:7](=[CH2:6])[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][C@@H:11]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[C@H:12]2/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H]2CC3(COS(C)(=O)=O)OC3[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: c1ccc2ccccc2c1
Solvent: CCCCCC
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2C1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of the (1S,2RS,3RS,5S,6S,7R)-3-methanesulfonyloxymethyl-2,3-epoxy-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy) bicyclo[3.3.0]octane (781 mg, 1.40 mmoles) in 3 ml of tetrahydrofuran was added to an anion radical solution prepared by reacting naphthalene (1.28 g, 10 mmoles) and sodium (207 mg, 9 mmoles) in 30 ml of tetrahydrofuran at room temperature for 1 hour. The mixture was stirred at room temperature for 10 minutes. To the reaction solution was addded 3.0 g of ammonium chloride, and thereafter, a saturated aqueous solution of ammonium chloride was added. The mixture was worked up and extracted with ethyl acetate. The organic layer was washed with sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (silica gel 50 g; hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane (520 mg, 1.12 mmoles, 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A solution of (S)-piperidine-3-carboxylic acid (XXXI) (10.0 g, 77.4 mmol) in a mixture of 80 ml of THF and 50 ml of water was cooled to 0° C. and sodium bicarbonate (13.0 g, 15.5 mmol) and benzyl chloroformate (15.8 g, 92.9 mmol) were added simultaneously. The reaction mixture was stirred at 0° C. for 6 hours and concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether to remove excess of benzyl chloroformate, then it was acidified with 1 M HCl solution to pH 6 followed by extraction with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to provide (S)-piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (10.0 g, 49%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12]C)=[O:11])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:6]=[C:5]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:4]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[C:8]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[C:7]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[N:6]=[C:5]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[N:4]=1)[CH3:2]
Reactant: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(CC)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 74.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-ethyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.085 g; 0.215 mmol), sodium hydroxide 10N (0.15 mL; 1.50 mmol) in methanol (1.5 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.061 g (74%)of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@H:3]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:12][CH:13]=1)=[O:6])[NH2:4].C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH3:1][C:2]([C@H:3]1[NH:4][C:34](=[O:36])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:12][CH:13]=2)[C:5]1=[O:6])([CH3:25])[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C(C)(C)C)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-methyl-N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-valinamide (Intermediate 97, 5.2 mg) was dissolved in dry dichloromethane (0.5 mL). The reaction mixture was cooled down in an ice bath. Triethylamine (12.6 μl, 0.091 mmol) was added at 0° C. Then 0.5 mL of a solution of triphosgene in dry dichloromethane (2.47 mg, 0.0083 mmol) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. Some water was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 60/40 during 15 min and 60/40 during 10 min. This afforded the title compound (5.9 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[N:4][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[C:18]1([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C>[CH2:10]([O:9][CH2:8][C:5]1[N:4]=[C:3]([OH:17])[C:2]([NH:1][C:25](=[O:26])[CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][N:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cnc(COCc2ccccc2)nc1O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc(COCc2ccccc2)nc1O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A mixture of compound 3-e (1.6 g, 6.9 mmol), 2,2-diphenylacetic acid (1.47 g, 6.9 mmol), DIEA (1.8 g, 13.8 mmol), and TBTU (2.7 g, 8.28 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was added with sat. NH4Cl (50 mL), extracted with DCM (100 mL), washed with water (50 mL) and brine ((50 mL). The organic layer was concentrated and purified by column chromatography to afford the product as a white solid, 3-f (2.2 g, 76%). 1H NMR (300 MHz, CDCl3) δ 4.45 (s, 2H), 4.63 (s, 2H), 5.07 (s, 1H), 7.27-7.40 (m, 16H), LC-MS (M+H)+ 426.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:14]1[C:27]2[C:26](=O)[C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:26]3[C:25](=[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:27]4=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NCC(N)c1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1cccc(-c2cnc3c4ccccc4c4ccccc4c3n2)c1

Procedure:
First, into a 500-mL three-neck flask were put 2.5 g of 1-(3-bromophenyl)ethane-1,2-diamine, 0.62 g of potassium hydroxide, and 200 mL of dry ethanol, and the atmosphere in the flask was replaced with nitrogen. A reaction container was heated, the reacted solution was refluxed for two hours, 2.1 g of 9,10-phenanthrenequinone was added thereto, and the mixture was refluxed for nine hours. Then, the obtained mixture was subjected to suction filtration, and washed with ethanol, thereby obtaining 2-(3-bromophenyl)dibenzo[f,h]quinoxaline (a yellow white solid, a collection rate of 70%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])([OH:21])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:28]([CH3:36])([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO>[OH:21][C:15]1([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:14]2[C:9]([OH:8])=[CH:10][C:11]([C:28]([CH3:35])([CH3:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:12][C:13]=2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16]1
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2(O)CC(=O)OCC
Reactant: [H][H]
Solvent: CO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2(O)CC(=O)OC
Yield: 33.3 %

Procedure:
A mixture of 655 mg (1.37 mmole) 5-benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-7(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran, 133 mg 5% palladium-on-calcium carbonate and 50 ml methanol was hydrogenated at 38 psi (2.7 kg/cm2) until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated in vacuo and the residual oil taken up in hexane. Upon cooling, crystals formed which were collected by filtration, 66 mg. The mother liquor was evaporated in vacuo to an oil, pentane added and the mixture refrigerated overnight. Filtration gave an additional 179 mg of product. 1H-NMR (CDCl3) ppm (delta): 3.00 (dd, 2H), 3.20 (s, 2H), 3.70 (s, 3H), 4.90 (s, 1H), 6.35 (m, 2H), 7.65 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3-fluorobenzeneboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[N:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(=O)c2cc([N+](=O)[O-])ccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a pre-dried flask were added 5-nitro-3-oxo-2,3-dihydroindazole-1-carboxylic acid tert-butyl ester (0.65 g, 2.33 mmol), triphenylphosphine (0.92 g, 3.50 mmol), methanol (115 μL, 2.80 mmol) and anhydrous THF (10 mL). The flask was evacuated and purged with N2 then cooled to 0° C. and diisopropylazodicarboxylate (690 μL, 3.50 mmol) added dropwise over 5 min. The mixture was stirred at rt overnight then diluted with EtOAc and partitioned over water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. Purification by column chromatography on silica gel (Jones, 50 g) loading and eluting in DCM revealed the title compound as a white powder. 1H NMR (400 MHz, CDCl3): δ=1.68 (s, 9H), 4.21 (s, 3H), 8.10 (d, J=8.8 Hz, 1H), 8.39 (dd, J=9.2 Hz, 2.4 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H). MS (ES+): m/z 294.3 (20) [MH+]. The N-alkylation product methyl-5-nitro-3-oxo-2,3-dihydroindazole-1-carboxylic acid tert-butyl ester was also isolated. 1H NMR (400 MHz, CDCl3): δ=1.68 (s, 9H), 3.69 (s, 3H), 8.02 (d, J=9.2 Hz, 1H), 8.48 (dd, J=9.2, 2.4 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[H-].[Na+].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].O>C1COCC1>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)=[O:24]
Reactant: OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 0.5 g of 5-(1-hydroxy-2'-trifluoromethylbenzyl)-pyrimidine (produced according to Example 7) in 15 ml THF at room temperature, 0.2 g of NaH (80%) were added. Gas evolution was observed. After 30 minutes, 0.4 g of trimethylacetyl chloride were added to the reaction mixture and gas evolution was again observed. After 3 hours of stirring, the reaction mixture was worked up with water and the organic materials extracted with diethyl ether. The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. Elution on a silica gel column with a 1:1 mixture of diethyl ether and hexane yielded 0.56 g of 5-(1-trimethylacetoxy-2'-trifluoromethylbenzyl)-pyrimidine.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4].[CH:9](OCC)=[O:10]>C(OC(C)C)(C)C>[CH2:7]([O:6][C:3]([CH:4]=[CH:9][O-:10])=[O:5])[CH3:8].[Na+:2]
Reactant: CCOC=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C=C[O-]
Temperature: 45 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in oil) (269 g, 16.7 mol) in isopropyl ether (12 L) was slowly added ethyl acetate (1280 g, 14.2 mol) at such a rate as to maintain an internal temperature of 45° C. Ethyl formate (2232 g, 30.13 mol) then added dropwise at 42° C. and stirred at ambient temperature for 18 h. The mixture was filtered and washed with ethyl ether (2×300 mL), with hexanes (500 mL) and the solid was dried to give sodium 2-ethoxycarbonyl ethenolate as a white solid (1930 g, 99%); 1H NMR (DMSO-d6, 300 MHz) δ1.03 (t.3H), 3.86 (q, 2H), 4.08(d, 1H), 8.03 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-])=O>CCO.O=[Pt]=O>[NH2:21][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:7]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N

Procedure:
A suspension of the above 4-amino-3-nitro-N-quinolin-2-yl-benzamide (5 g, 16.2 mmol) in EtOH (50 mL) was hydrogenated at one atm over PtO2 (250 mg) for 4 h (the suspension will become a clear when the reaction is complete). The catalyst was filtered through Celite and washed with EtOH. The solvent was removed under reduced pressure to give 3,4-diamino-N-quinolin-2-yl-benzamide as a red solid.