Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:13]=[C:12]([C:19](OC)=[O:20])[CH:11]=2)[CH:9]=1)[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:23])=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]=[C:12]([CH:19]=[O:20])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2cc(C(=O)OC)nc(C(C)C)c2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(C(C)C)c2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carboxylate (which may be prepared as described in Description 115) (0.72 g, 2.27 mmol) in THF (20 mL) was cooled to −78° C. under nitrogen and was treated dropwise with 1M DIBAL in toluene (4.54 mL, 4.54 mmol) over 10 minutes. The mixture was stirred at −78° C. for 2 hrs. The mixture was quenched with satd. aq. NH4Cl solution (5 ml) and the mixture was allowed to reach room temperature and stirred for 30 mins. Celite was added to the mixture and the mixture was stirred for 10 minutes and then filtered through Celite and concentrated to give 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbaldehyde (D116) (0.57 g);
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([OH:32])[CH:31]=1>C1COCC1>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[CH3:33]
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Cc1ccc(N)cc1O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (42.03 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 73% (100 mg, 0.225 mmol) of the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:40])[NH2:39])[CH:34]=2)[CH:29]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38](=[NH:39])[NH2:40])[CH:34]=2)[CH:29]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CC(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)CC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 1.8 g of isovaleric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with a small volume of pyridine, then with acetone, and dissolved in methanol at room temperature. The insolubles were collected by filtration and washed with a small volume of methanol. The filtrate and the washings were concentrated under reduced pressure and admixed with ethyl ether. The precipitated crystals were recrystallized from an ethanol-methanol (9:1) mixture to yield 2.0 g of colorless flaky crystals of 6-amidino-2-naphthyl isovalerate methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11]Br)=[CH:7][N:6]=1)=[O:4].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:23])[F:24])[CH:17]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cnc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 88.1 %

Procedure:
A solution of 5-bromomethyl-pyrazine-2-carboxylic acid methyl ester (0.305 g, 1.314 mmol) in DMF (6 mL) was treated with 3-trifluoromethoxyphenol (0.280 g, 1.577 mmol) and potassium carbonate (0.400 g, 2.89 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel to give 0.380 g of pure 5-(3-Trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid methyl ester. LCMS: 330 (M+2)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:35])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: CC(=CBr)c1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (79 mg, 0.36 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.0362 mmol), L-proline (8 mg, 0.072 mmol), and K3PO4 (154 mg, 0.724 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (100 mg, 0.434 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 85 mg of 6-chloro-9-(2-(4-chlorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CDCl3) FREE BASE 7.53-7.44 (m, 2H), 7.43-7.38 (m, 2H), 7.18-7.03 (m, 2H), 6.93 (d, 1H), 6.84 (s, 1H), 3.63-3.58 (m, 2H), 3.32-3.26 (m, 1H), 2.88 (s, 3H), 2.83-2.80 (m, 1H), 2.60 (s, 2H), 1.99 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26](O)=[O:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2].[NH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][N:37]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]([CH3:34])[CH3:33])[C:6]2[O:10][C:9]([C:11]3[CH:30]=[CH:29][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26](=[O:27])[NH:35][C:36]5[CH:41]=[C:40]([C:42]([F:44])([F:43])[F:45])[CH:39]=[CH:38][N:37]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)O)CC4)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)Nc5cc(C(F)(F)F)ccn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from [trans-4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)cyclohexyl]acetic acid and 2-amino-4-(trifluoromethyl)pyridine as described in EXAMPLE 1. Mass spectrum (ESI) 604.1 (M+1). 1H NMR (500 MHz, CD3OD): δ 8.50 (d, J=5.0 Hz, 1H), 8.44 (s, 1H), 8.35 (d, J=8.0 Hz, 2H); 8.02 (d, J=8.5 Hz, 2H), 8.02 (d, J=1.5 Hz, 1H); 7.65 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 3.50 (septet, J=7.0 Hz, 1H), 3.26 (d, J=7.0 Hz, 2H), 2.35 (d, J=6.5 Hz, 2H), 185-1.70 (m, 5H), 1.65 (m, 1H), 1.47 (d, J=7.0 Hz, 6H), 1.08-1.18 (m, 4H).
Reaction SMILES: [OH-].[Na+].[NH:3]1CCC[C@H]1C(O)=O.[N-]=[N+]=[N-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30](Br)=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O.[Cu]I.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[C:30]([NH2:3])=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][CH:33]=[CH:32]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Agent: [Cu]I
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2N)CC1
Temperature: 95 °C
Yield: 101.9 %

Procedure:
Under argon atmosphere 600 μL (0.6 mmol) of 1N NaOH, 13.8 mg (0.12 mmol) L-proline, 7.6 mg (0.04 mmol) of CuI and 52 mg (0.8 mmol) of NaN3 were added to a solution of 163 mg (0.4 mmol) 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11) in 0.6 mL of water. The mixture was heated to 95° C. for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through Celite, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 42 mg of compound 18 (containing some 11 as impurity).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH3:2]>CCOC(C)=O.[Pt]>[CH2:1]([C:3]1[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:24][CH2:25]3)[CH2:16][CH2:15]2)=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A mixture of 1-{1-[2-ethyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.12 g, 2.63 mmol) and sulfided platinum on carbon (0.410 g, 0.105 mmol) in EtOAc (40 mL) was sealed in a round bottom flask with a rubber septum. The reaction mixture was purged with N2 gas and then a balloon of H2 gas was connected and the vessel was flushed with the H2 gas. The reaction was stirred at rt for 2 d. TLC analysis showed the complete consumption of the starting nitro compound so the reaction mixture was filtered through celite to remove the catalyst. The filtrate was concentrated onto silica gel and purified by flash chromatography to afford 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.479 g, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.60 (s, 1H), 6.46 (s, 1H), 4.35 (br. s., 2H), 3.71 (s, 3H), 3.03-3.16 (m, 4H), 2.81-2.93 (m, 5H), 2.56-2.68 (m, 6H), 2.29-2.42 (m, 1H), 1.72-1.89 (m, 2H), 1.44-1.62 (m, 2H), 1.09 (t, J=7.51 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7]([NH2:11])[CH:8]([CH3:10])[CH3:9]>CCO>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][CH2:5][NH:11][CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: C=CC(=O)NC
Reactant: CC(C)CN
Solvent: CCO
Product: CNC(=O)CCNCC(C)C
Temperature: 25 °C

Procedure:
N-methylacrylamide (ABCR; 1 g, 11.75 mmol) was dissolved in EtOH (5 mL). Isobutylamine (Aldrich; 2.33 mL, 23.5 mmol) was added and stirred at ambient temperature in a stoppered flask over the weekend. The reaction was then transferred to a microwave reactor vessel and heated in a microwave for 10 minutes at 140° C. Solvents were evaporated in vacuo to give the title compound as a colourless liquid. (1.78 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:14])[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:14])[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(CO)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
33.11 ml (33.11 mmol, 1 M in THF) of a borane-tetrahydrofuran complex solution was added dropwise at 0° C. to a solution of 3.10 g (13.24 mmol) 2-(3,4-dichloro-phenylamino)-propionic acid (synthesized in analogy to intermediate 11, with 3,4-dichloroiodobenzene, D-alanine and copper(I) iodide, 2-hydroxybenzaldehyde phenylhydrazone and tri-potassium phosphate in N,N-dimethylformamide; enantiomeric ratio 71:29) in 50 ml THF, then after 10 min the ice bath was removed and the solution stirred for 2 h at RT. After cooling, 22 ml of MeOH and 1.1 ml of H2SO4 were added, and after 30 min at RT and 1 h at reflux the reaction mixture was concentrated in vacuo. The residue was partitioned between NaCl sat. 1 M aq. sodium hydroxide solution and EtOAc (3×). The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. Flash silica gel column (CH2Cl2/MeOH 99:1→98:2) afforded 2.90 g (99%) of the title compound as a 71:29 mixture of the (R) and (S) stereoisomers. Yellow oil, MS: 220.0 (MH+, 2Cl)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.O>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[Cl:8][C:6]1[CH:7]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=[C:4]([Cl:20])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(c1c(Cl)cc(-c2cccnc2)cc1Cl)n1ccc2cnccc21

Procedure:
A mixture of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (0.05 g, 0.135 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.011 g, 0.0135 mmol), potassium carbonate (0.055 g, 0.40 mmol), pyridine-3-boronic acid (1.1 equiv) and water (0.5 mL) in acetonitrile (2.5 mL) was heated in a sealed vial under microwave irradiation at 110° C. for 25 minutes. Acetonitrile was removed under vacuum and the residue was diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give crude product which was purified by silica gel column chromatography using ethyl acetate and hexane as eluent to yield [2,6-dichloro-4-(pyridin-3-yl)phenyl](1H-pyrrolo[3,2-c]pyridin-1-yl)methanone.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([NH2:11])=O)[CH:4]=1)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]#[N:11])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(N)=O)nn1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(C#N)nn1C
Yield: 79.3 %

Procedure:
5-Ethyl-1-methyl-1H-pyrazole-3-carboxamide (3.8 g, 25 mmol) was treated with phosphorous oxychloride (18 mL, 0.19 mol) according to the method described in Part C of Example 8 to provide 2.68 g of 5-ethyl-1-methyl-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:19])([CH3:18])[CH:12]([OH:17])[CH2:13][N+:14]([O-:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[CH2:13][N+:14]([O-:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)C(O)C[N+](=O)[O-])cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C(=O)C[N+](=O)[O-])cc1OC
Reaction time: 48 h
Yield: 72.2 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-ol (700 mg, 2.60 mmol) in DCM (30 mL) were added PCC (3.36 g, 15.60 mmol) and Celite (3.36 g). After stirring 48 h, additional PCC (3.36 g, 15.60 mmol) and Celite (3.36 g) were added. After stirring further for 24 h, the mixture was diluted with Et2O and filtered. The filtrate was concentrated and purified by flash chromatography to afford 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-one (502 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 6.91-6.84 (m, 2H), 6.69 (s, 1H), 5.13 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:55]=[CH:54][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH2:40][C@H:41]5[CH2:46][CH2:45][C@H:44]([C:47]([O:49]C)=[O:48])[CH2:43][CH2:42]5)=[C:35]([N+:51]([O-:53])=[O:52])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:56][C:57]4[CH:58]=[C:59]5[CH:65]=[CH:64][NH:63][C:60]5=[N:61][CH:62]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCCC1.CO.ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:55]=[CH:54][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH2:40][C@H:41]5[CH2:42][CH2:43][C@H:44]([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]5)=[C:35]([N+:51]([O-:53])=[O:52])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:56][C:57]4[CH:58]=[C:59]5[CH:65]=[CH:64][NH:63][C:60]5=[N:61][CH:62]=4)[CH:24]=3)[CH2:21][CH2:22]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC[C@H]5CC[C@H](C(=O)O)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 50 °C

Procedure:
To a solution of EXAMPLE 379B (0.162 g) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was added 1.0 M aqueous LiOH (0.596 mL) and the reaction heated to 50° C. for 1 hour. The reaction was cooled, diluted with dichloromethane (30 mL) and water (5 mL), and quenched with aqueous HCl (1.0 M, 0.6 mL). The aqueous layer was diluted with saturated NH4Cl solution (5 mL) and removed. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 0.5% to 5% methanol/dichloromethane over 30 minutes (flow=40 mL/minute) provided the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12.00 (s, 1H), 11.68 (s, 1H), 11.38 (s, 1H), 8.55 (d, 2H), 8.04 (d, 1H), 7.79 (dd, 1H), 7.59-7.43 (m, 3H), 7.34 (d, 2H), 7.05 (t, 3H), 6.68 (dd, 1H), 6.39 (dd, 1H), 6.19 (d, 1H), 3.25 (s, 2H), 3.07 (s, 4H), 2.75 (s, 2H), 2.17 (d, 7H), 1.95 (s, 6H), 1.62 (s, 1H), 1.38 (s, 4H), 1.03 (dd, 2H), 0.92 (s, 6H).
Reaction SMILES: [C:1]12[C:7](=[N:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[NH:13]([CH2:15]C(O)=O)[CH3:14]>CS(C)=O>[CH3:14][N:13]1[C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[N:8][C:7]=2[NH:6][C:5](=[O:12])[CH2:15]1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ncccc2C1=O

Procedure:
12.0 g (73.1 mmol) of 3-azaisatoic acid anhydride and 6.6 g (73.2 mmol) of sarcosine are stirred at 100° for 2.5 hours in 180 ml of dimethyl sulphoxide. The solvent is removed in a high vacuum and the oily residue is heated to 130° for about 4 hours. After cooling, the crystalline product is suspended in 150 ml of methanol. It is filtered off under suction, washed with methanol and dried. There is obtained 3,4-dihydro-4-methyl-2H-pyrido[2,3-e][1,4]diazepine-2,5(1H)-dione of melting point 245°-247°.
Reaction SMILES: C([C@@:5]1([C:19]([OH:21])=[O:20])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][N:6]1C(OC(C)(C)C)=O)(C)(C)C>ClCCl>[CH3:10][C:8]1([CH3:11])[CH2:7][NH:6][C@H:5]([C:19]([OH:21])=[O:20])[CH2:9]1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)[C@@](C(=O)O)(C(C)(C)C)C1
Solvent: ClCCl
Product: CC1(C)CN[C@H](C(=O)O)C1

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-4,4-dimethylproline in dichloromethane (5 mL) and trifluoroacetic (5 mL) was stirred at room temperature for five hours. The solution was concentrated, dried under high vacuum and taken to the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH:20][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1
Reactant: Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CC1

Procedure:
20 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was dissolved in 3 mL of toluene, and added with 20 μl of triethylamine and 10 μl of cyclopropanecarbonyl chloride at room temperature and stirred all day and night. The reaction solution was added with saturated aqueous sodium hydrogen carbonate, extracted with sodium acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 20 mg of the title compound as a colorless powder.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:31].[K+].Br[C:34]1[CH:43]=[C:42]([Br:44])[CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][CH2:38][C:39]2=[O:45].Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:44][C:42]1[CH:41]=[C:40]2[C:35]([CH2:36][CH2:37][CH2:38][C:39]2=[O:45])=[C:34]([OH:31])[CH:43]=1
Reactant: [OH-]
Reactant: O=C1CCCc2c(Br)cc(Br)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCCc2c(O)cc(Br)cc21
Temperature: 100 °C
Yield: 16.2 %

Procedure:
To a mixture of tris(dibenzylideneacetone)dipalladium(0) (210 mg, 0.23 mmol), di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (403 mg, 0.92 mmol), and potassium hydroxide (1.67 g, 25.32 mmol) were added degassed water (5.25 mL) and a solution of 5,7-dibromo-3,4-dihydro-2H-naphthalen-1-one (3.5 g, 11.51 mmol) in dioxane (7.0 mL) at room temperature under nitrogen. The resulting suspension was heated to 100° C. for 3.5 h. The reaction mixture was then cooled to room temperature, diluted with water (˜10 mL) and acidified with 1N HCl solution. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with brine (200 mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography, using an ISCO (120 g) column (gradient elution with 5-30% ethyl acetate in hexanes) to obtain 7-bromo-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.45 g, 16%) as a white solid: ES(−)-HRMS m/e calcd. (calculated) for C10H9O2Br (M−H)− 238.9713, obsd. (observed) 238.9712. Two other side products were also isolated and characterized as 5-bromo-7-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.3 g, 10%) and 5,7-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (0.191 g, 7%).