Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27](=[S:29])[NH2:28])[CH2:26][CH2:25]1>CN(C)C=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27]2[S:29][C:2]([CH3:15])=[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=3[Cl:14])[N:28]=2)[CH2:26][CH2:25]1
Reactant: COc1cc(Cl)c(C(=O)C(C)Br)cc1C
Reactant: NC(=S)C1(c2c(F)cccc2Cl)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-c2nc(C3(c4c(F)cccc4Cl)CC3)sc2C)cc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromo-1-(2-chloro-4-methoxy-5-methly-phenyl)-propan-1-one (254 mg, 0.87 mmol) and 1-(2-Chloro-6-fluoro-phenyl) cyclopropane carbothioic acid amide (200 mg, 0.87) mmol) were dissolved in dimethlyformamide (DMF) (2.9 mL). The reaction was heated with stirring to 80° C. overnight. The mixture was then cooled, diluted with ethyl acetate and washed three times with water and once with brine. The organic layer was separated, dried with sodium sulfate and concentrated in vacuo. The crude product was then chromatographed on silica using an ethyl acetate/hexane gradient resulting in a pale green-yellow solid. Yield: 110 mg (18%). [MH]+422.0. 1H NMR (300 MHz, CDCl3) •1.54 (m, cyclopropyl, 2H), 2.11 (m, cyclopropyl, 2H), 2.27 (s, CH3, 3H), 2.28 (s, CH3, 3H), 3.93 (s, —OCH3, 3H), 6.97 (s, Ar, 1H), 7.15 (m, Ar, 1H), 7.35 (s, Ar, 1H), 7.37 (m, Ar, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC[C@H](O)CO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Yield: 53 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (S)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (53% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Cl.[C:12]1(Cl)[C:18](=O)C(Cl)=C(Cl)[C:14](=O)[C:13]=1Cl.C(=O)/C=C/C>C(O)CCC.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]2[C:3]=1[N:4]=[C:13]([CH3:14])[CH:12]=[CH:18]2
Reactant: COc1ccc(Cl)c(N)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCCCO
Solvent: C1CCOC1
Product: COc1ccc(Cl)c2nc(C)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 214.5 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with 2-chloro-5-methoxyaniline (50 g, 317 mmol), n-butanol (120 mL), concentrated hydrochloric acid (37%, 90 mL), and chloranil (tetrachloro-1,4-benzoquinone) (78 g, 317 mmol). The resulting solution stirred for 1 h at 100° C. in an oil bath. A solution of (E)-crotonaldehyde (28.9 mL, 349 mmol) in n-butanol (50 mL) was added dropwise over 1 h. The resulting solution stirred for 1 h at 100° C. in an oil bath and was then cooled to 70° C. Tetrahydrofuran (650 mL) was added, and the reaction mixture stirred for 1 h at 70° C. and was then cooled to 0° C. The resulting precipitate was held at 0-5° C. for 1 h. The mixture was filtered, the solids were washed with cold (ca. 0° C.) THF (2×350 mL), and then dried in an oven to afford 8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as a yellow solid. MS (ES, m/z): 208 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]3[C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=[C:22]4[NH:30][CH:31]=[CH:32][C:21]=34)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]3[C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=[C:22]4[NH:30][CH:31]=[CH:32][C:21]=34)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cnc2[nH]ccc2c1N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2[nH]ccc2c1N[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 80 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
To a solution of (R)-methyl 4-((1-(2-((3,5-dichlorophenyl)amino)acetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (173 mg, 0.36 mmol, 1.0 eq) in CH3OH (20 mL) and water (10 mL) was added NaOH (73 mg, 1.82 mmol, 5.0 eq). The mixture was stirred at 80° C. for 10 h, cooled to rt, adjusted pH to 6 with HCl (1N) the aqueous layer was extracted with EtOAc (50 mL×3). The organic layer was separated and concentrated in vacuo to afford the title compound as a yellow solid which was used to next step without further purification (120 mg, yield: 71%) to use next step. 1H NMR (400 MHz, CD3OD) δ: 8.6˜88.63 (m, 1H), 7.37˜7.32 (m, 1H), 7.02˜6.95 (m, 1H), 6.6˜06.57 (m, 2H), 6.34 (s, 1H), 4.57˜4.41 (m, 1H), 4.10˜3.75 (m, 5H), 3.65˜0.362 (m, 1H), 2.22˜2.21 (m, 1H), 2.04˜1.79 (m, 3H). ESI-MS: 462.1 (M+H)
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:31]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:39]2[C:38]2[CH:40]=[CH:41][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Yield: 50.2 %

Procedure:
The product from Example 39C (10.86 g, 20.79 mmol), DMF (65 mL) and 4-tert-butylaniline (26.5 mL, 166 mmol) was reacted according to the procedure in Example 39D to provide the title compound (5.0 g, 50%, yellow solid) as a mixture of cis and trans pyrrolidine stereoisomers.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:5][CH2:4][CH2:3][S:2][CH3:1])=[O:20])=[CH:16][CH:17]=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:10]1([CH3:30])[CH3:29])(=[O:8])[CH3:7]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CSCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCCNC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Condensation of 2-(methylthio)ethylamine (4.1 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 l) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([C:9]#[N:10])=[C:7](F)[C:6]=1[F:16].O>C(O)C>[Br:4][C:5]1[C:6]([F:16])=[C:7]2[C:8]([C:9]([NH2:10])=[N:2][NH:3]2)=[C:11]([F:14])[C:12]=1[F:13]
Reactant: N#Cc1c(F)c(F)c(Br)c(F)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12

Procedure:
1.14 cm3 of hydrazine monohydrate are added to 2.0 g of 4-bromo-2,3,5,6-tetrafluorobenzonitrile in 40 cm3 of absolute ethanol. The mixture is refluxed for 18 hours, 30 cm3 of distilled water are then added and the reaction medium is concentrated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 10 cm3 of water, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 40° C.), 2.1 g of 6-bromo-4,5,7-trifluoro-1H-indazole-3-amine are obtained in the form of a beige-coloured solid.
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.[H][H]>C(O)(C)C.[C].[Pd]>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(-c2cccnc2)nc1C
Reactant: [H][H]
Agent: [Pd]
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCCNC2)nc1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 19.6 %

Procedure:
Benzyl bromide in an amount of 1.06 g was added to a solution of 1 g of 5,6-dimethyl-2,3′-bipyridine in 15 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. to finish the reaction. To the reaction solution, 0.18 g of 10% palladium carbon and 0.59 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 400 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 1.70 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 0.20 g of the entitled compound as light yellow crystals. Yield rate: 20%, EI-MS: (m/z) 188 (M+), melting point: 102-104° C.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][CH:11]=1.O1CCOCC1>C(OCC)(=O)C>[CH3:19][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:17])=[CH:12][CH:11]=1
Reactant: CCOC(O)C(F)(F)F
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 500 mL round-bottom flask was charged with trifluoroacetaldehyde ethyl hemiacetal (12.3 g, 85.0 mmol), p-toluamide (10.0 g, 74.0 mmol), and dioxane (150 mL). The thick white slurry was stirred at ambient temperature for 3 hours, then heated at reflux for 44 hours. The homogeneous solution was cooled and concentrated in vacuo to provide a white solid. The crude material was dissolved in ethyl acetate (50 mL), adsorbed onto silica gel (50 g), and eluted through a medium porosity fritted filter funnel (elution with 25% ethyl acetate/hexanes, then ethyl acetate) to provide 14.1 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[CH:23])=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1.I[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>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)I>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([CH:21]([OH:24])[C:22]#[C:23][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[CH:14][C:15]=3[C:16]([CH3:20])([CH3:19])[CH2:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(N(C)C)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1ccc(C2=CCC(C)(C)c3cc(C(O)C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 16b, by reacting 0.81 g (2.4 mmol) of 1-[5-(4-dimethylaminophenyl)-8,8-dimethyl-7,8-dihydro-2-naphthyl]prop-2-yn-1-ol with 0.496 g (2 mmol) of 4-iodobenzoic acid, 0.035 g (0.05 mmol) of trans-dichlorobis(triphenyl-phosphine)palladium and 0.019 g (0.1 mmol) of copper iodide, a beige-colored solid is obtained (0.65 g; yield=72%; m.p.=91° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a mixture of 3-methoxyphenol (20 g, 161.3 mmol) and Cs2CO3 (52.4 g, 161.3 mmol) in DMF (200 mL), methyl bromoacetate (24.5 g, 161.3 mmol) was added. The reaction mixture was stirred at room temperature under argon overnight. The inorganic precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and CH2Cl2 (200 mL×3). The combined organic solution was dried over Na2SO4 and evaporated to give (28 g, 90%) product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=O)[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[NH2:33][OH:34]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[N:33][OH:34])[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: NO
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=NO)cc2OC)cn1
Temperature: 25 °C
Reaction time: 64 h
Yield: 96.3 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one (5.48 g, 19.07 mmol) and potassium carbonate (10.54 g, 76.29 mmol) in methanol (100 mL) and water (10 mL) was added hydroxylamine sulfate (4.70 g, 28.61 mmol). The resulting mixture was heated to reflux. After 64 h, the mixture was allowed to cool to room temperature and was diluted with water (250 mL). The resulting suspension was filtered, and the filtercake was washed with water (50 mL) and dried to provide 5.55 g (96%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oxime as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.[F-].[K+].Cl>CN(C)C=O.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:17][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)C2
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1

Procedure:
6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg), 2-chloro-5-nitropyridine (21 mg) and potassium fluoride (23 mg) in dry dimethylformamide were heated at 120° C. until disappearance of the starting material. Water and 1 N HCl were added and the mixture extracted with ethyl acetate. Ethyl acetate was washed with brine and water, dried and evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[NH:41][N:40]=[N:39][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1SC[C@H](/C=C/C(O)Cc2ccccc2)N1CCCCCCc1nnn[nH]1
Yield: 62.3 %

Procedure:
To a solution of 4-4 (70 mg, 0.2 mmol) in 0.2 mL toluene was added tributyltin azide (0.27 mL, 1.0 mmol) and the resulting solution was stirred at reflux for 4 hours. Ethyl acetate (100 mL) was added and the solution was quenched with 5% aqueous KF (30 mL) and 1N HCl (30 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 0–5% MeOH/CH2Cl2 to yield 50 mg of 4-5 as a colorless oil. 1H NMR (400 MHz, CD3OD): δ7.29–7.17 (m, 5H), 5.81 (dd, 1H), 5.53 (dd, 1H), 4.38 (q, 1H), 4.33 (q, 1H), 3.45 (dd, 1H), 3.33 (m, 1H), 2.97 (m, 4H), 2.78 (m, 1H), 2.68 (m, 1H), 1.83–1.21 (m, 8H); MS (−ESI): m/z 400.2 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+].[O:34]1CCCC1>CO>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:34]
Reactant: N#Cc1ccc(N2CCOCC2)cc1F
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 68 %

Procedure:
To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82 g, 13.7 mmol) in tetrahydrofuran (27 ml) under a nitrogen atmosphere was added dropwise a 1.5 M solution of DIBAL-H in toluene (18.3 ml, 27.3 mmol) during 13 minutes and the resulting mixture stirred for 23.5 hr at room temperature. The mixture was cooled to −50° C. and the excess DIBAL-H deastoyed by careful addition of methanol (27 ml). The mixture was then stirred at room temperature for 10 mins, saturated ammonium chloride (27 ml) added and the resulting mixture stirred at room temperature for 40 mins., and then evaporated under reduced pressure to a yellow solid. This solid was partitioned between dichloromethane (120 ml) and water (120 ml) and solid potassium carbonate added until the aqueous phase was pH10. The phases were separate via a hyrophobic frit and the organic phase evaporated and the residue purified by a Biotage™ column (40 g, silica) eluting with cyclohexane:ethyl acetate: (7:3) to give 2-fluoro-4-(morpholino)-benzaldehyde (1.96 g, 68%) as a white solid.
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24]=1[CH3:32]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ncccc12
Reaction time: 0.5 h

Procedure:
BEMP (182 μL, 0.63 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester prepared as described in U.S. Pat. No. 3,320,268 (80 mg, 0.39 mmol) in DMF (2.4 mL). After 30 minutes, benzyl bromide (75 μL, 0.63 mmol) is added and the reaction stirred for 3 days, before partitioning between water and 1:1 EtOAc/ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (3:1 iso-hexane/EtOAc elution) to furnish (1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester; MH+=295.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:41])[CH2:10][C:11]1[C:16]2[C:17](I)=[N:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]=2[CH:14]=[C:13]([Cl:40])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:43]([O-:46])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O>[Cl:40][C:13]1[CH:14]=[C:15]2[NH:19][N:18]=[C:17]3[C:16]2=[C:11]([CH2:10][CH:9]([CH3:41])[N:8]3[CH2:1][C:2]2[CH:7]=[CH:6][C:5]([O:46][CH3:43])=[CH:4][CH:3]=2)[N:12]=1
Reactant: CC(Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)NCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2c3n[nH]c4cc(Cl)nc(c34)CC2C)cc1
Temperature: 55 °C

Procedure:
N-benzyl-1-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine (670 mg, 0.958 mmol) and RuPhos pre-catalyst (70 mg, 0.096 mmol) were charged in a 2 dram vial, evacuated and backfilled with nitrogen and taken in toluene (4.8 mL). A solution of 2M NaOtBu in THF (1.2 ml, 2.4 mmol) was added and the reaction mixture was heated to 55° C. for 12 hours. The reaction mixture was cooled and diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C35H30ClIN4 [M+H]+ 572. found 572.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C([O:11][C:12]([CH:14]([C:28](=O)[CH3:29])[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=O)C>CO>[NH2:7][C:6]1[N:8]=[C:12]([OH:11])[C:14]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:28]([CH3:29])[N:5]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1OC)C(C)=O
Agent: O=C(O)O
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
Guanidine carbonate (8.73 g) was added in one portion to a solution of the product from step (i) (14.7 g) in MeOH (200 mL). The resulting mixture was stirred at 65° C. for 16 h and allowed to cool. The precipitate was collected by filtration and suspended in water (50 mL). The solid was collected by filtration, washed with MeOH (20 mL) and EtOAc (20 mL) to give the subtitle compound as a colourless solid 8.60 g that was used without further purification.