Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[F:24]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[F:24]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.21 (2H, s), 5.72 (1H, d, J=1.6 Hz), 7.15 (1H, d, J=8.0 Hz), 7.28 (1H, dd, J=1.6 Hz, J=9.6 Hz), 7.40-7.44 (2H, m), 7.57 (1H, d, J=2.08 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[C:6]3[C:22]([CH3:23])=[N:21][O:20][C:7]=3[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10](=[O:11])[C:4]=2[C:3]=1[CH3:25].S1C=[CH:29][CH:28]=[CH:27]1.IC(C)C>C1(C)C=CC=CC=1.[Ag]=O>[CH:28]([O:11][C:10]1[C:4]2[C:3]([CH3:25])=[C:2]([CH3:1])[S:24][C:5]=2[C:6]2[C:22]([CH3:23])=[N:21][O:20][C:7]=2[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)([CH3:29])[CH3:27]
Reactant: c1ccsc1
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Agent: O=[Ag]
Solvent: CC(C)I
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(OC(C)C)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate (17 wherein ring A is thiophene; 100 mg, 0.276 mmol), silver oxide (70 mg, 0.304 mmol) and 2-iodopropane (61 mg, 0.359 mmol) in toluene (5 mL) was heated to 90° C., and stirred overnight. After cooling to room temperature, the reaction mixture was evaporated to dryness and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give tert-butyl 2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate as a yellow solid (80 mg, 72% yield). LC/MS m/z 404 [M+1-1]+; 1H NMR (300 MHz, CDCl3) δ 5.30-5.03 (m, 1H), 4.51 (t, J=6 Hz, 1H), 3.11-3.08 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.46 (s, 9H), 1.30 (d, J=6 Hz, 3H), 1.20 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=S)[NH:7][NH2:8])([CH3:4])[CH3:3].Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[S]>Cl>[CH3:1][C:2]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[NH:8][N:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [S]
Product: CCOC(=O)c1c(NC(C)(C)C)n[nH]c1C
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A solution of 25 g (0.17 mole) of 4-(1,1-dimethylethyl)-3-thiosemicarbazide in 85 mL of 2N ethanolic hydrogen chloride was cooled to 0° C. with an ice bath and while stirring under nitrogen atmosphere, 28 g (0.17 mole) of ethyl 2-chloroacetoacetate was added dropwise. The reaction mixture was allowed to come to room temperature while stirring for 16 hr. The pale yellow solution was then refluxed for 2 hr during which a film of sulfur deposited on the sides of the flask. The reaction mixture was cooled to room temperature and the sulfur removed by filtration. The filtrate was concentrated in vacuo to give 39 g of pale yellow oil which was dissolved in ligroin and, after standing at ~7°-10° C. for ~60 hr, yielded 20.5 g of large crystals, mp 118°-119° C. An additional 6.1 g of crude material was obtained by reworking the residues.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=1)[CH2:11][N:12]1[C:24]2[CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH2:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([C:31](=[S:33])[NH2:32])[CH:17]=2.[CH3:37]N(C=O)C>O>[F:7][C:8]1[CH:9]=[C:10]([CH:34]=[CH:35][CH:36]=1)[CH2:11][N:12]1[C:24]2[CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH2:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH:31]1[N:32]([CH3:37])[C:2]([CH3:6])=[CH:3][S:33]1)[CH:17]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1
Reactant: CC(=O)C(C)Br
Reactant: CN(C)C=O
Solvent: O
Product: CC1=CSC(c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C(C)C)C2)N1C

Procedure:
Combine 3-bromo-2-butanone (0.224 g, 1.48 mmol) and (R)-N-(9-(3-fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 22) (0.209 g, 0.493 mmol) and heat in DMF at 80° C. under nitrogen for 2 h. Upon cooling, dilute the mixture with water and collect the precipitate by filtration. Recrystallize from absolute EtOH to give yellow crystals: MS (ES): m/z 476 (M+1); HPLC: Rt=3.87 min (100%).
Reaction SMILES: O1CCOCC1.Cl.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:23]#[C:24][NH2:25].O>CCOCC>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([NH:19][C:24]([NH2:25])=[NH:23])[CH:20]=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A 4 N HCl dioxane suspension of 3-benzyloxyaniline (1.0 equivalent) and cyanamide (1.0 equivalent) was stirred at 100° C. overnight. To the reaction mixture was added water and ether. The aqueous layer was washed with ether twice. The aqueous layer was adjusted to a pH greater 10 with 1M NaOH, and the desired guanidine was extracted to methylene chloride, precipitated and filtered. The filtration cake was N-(3-benzyloxy-phenyl)-guanidine (greater than 80% yield).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+].O>COCCOCCO.[Cu]>[C:13]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:22])=[O:21]
Reactant: Nc1ccccc1C(=O)O
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCO
Product: CSc1ccc(Nc2ccccc2C(=O)O)c(C(=O)O)c1
Yield: 30.1 %

Procedure:
A mixture of 2-chloro-5-(methylthio)benzoic acid (10 g), anthranilic acid (7 g), potassium carbonate (14 g) and copper (1 g) in 2-(2-methoxyethoxy)ethanol (100 ml) was heated at 180° for 24 h. Water (400 ml) was then added, and the catalyst was filtered off. The filtrate was acidified with dilute hydrochloric acid. The resulting precipitate was filtered off, washed with water, dried, and crystallised from methanol to give the title compound (4.5 g) as crystals. IR includes peaks at 3300 cm-1 (NH) and 1700 cm-1 (CO2H).
Reaction SMILES: Br.[CH2:2]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:3].[C:16](=[O:19])(O)[O-].[Na+].[C:21](O[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(OC(C)(C)C)=O>O.C1COCC1>[CH3:21][O:14][C:9]1[CH:8]=[C:7]([CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[CH3:15])[CH:12]=[CH:11][C:10]=1[O:19][CH3:16].[C:32]([O:31][C:29](=[O:30])[N:4]([CH:5]([CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[CH2:2][CH3:3])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCNC(C)Cc1ccc(O)c(O)c1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc(O)c(O)c1
Product: CCNC(C)Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To all of 2B from the above reaction mixture was added 30 mL of 50% THF in water. To the reaction mixture 1.1 g of sodium bicarbonate was added as a solid followed by 1.35 g (6.18 mmol) of di-t-butyl dicarbonate in 7 mL of THF dropwise over a period of 30 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours, then concentrated under reduced pressure. This was diluted with 50 mL of water and the pH of the solution was adjusted to 5. The aqueous layer was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried (anhydrous Na2SO4) and concentrated to dryness. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane to give 764 mg (2.58 mmol, 53% from 2A) of 2C as a clear gum (M+Na, 318).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]([C:16]1[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][C:19]([C:28]([O:30][CH3:31])=[O:29])([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)[CH3:15]>>[C:35]([O:34][C:32]([N:17]1[CH2:18][C:19]([C:28]([O:30][CH3:31])=[O:29])([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[C:16]1[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:15])=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)N)=N1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline (Example J), the title compound was prepared as an amorphous solid. The reaction was monitored by tlc (Rf=0.34 in 2:1 hexanes/EtOAc) and the product was purified by flash column chromatography.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[N:12]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c2c(=O)n(C)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2c(=O)n(C)ccc12
Yield: 69.3 %

Procedure:
To a stirred solution of ethyl 2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 6.4 mmol) in N,N-dimethylformamide (50 mL) was added (1-bromoethyl)-benzene (1.5 g, 7.9 mmol) and cesium carbonate (3.14 g, 9.6 mmol). The resultant solution was stirred at 80° C. for 12 hours. Once starting material was consumed, the reaction mixture was quenched with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 69%) as a yellow solid. LRMS (M+H+) m/z: calcd 338.16. found 338.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:13]=1[CH2:14][CH3:15])(C)(C)C.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:13]1[CH:12]=[C:11]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[N:10]=[CH:9][C:8]=1[CH2:7][C:6]([OH:21])=[O:5])[CH3:15]
Reactant: CCc1cc(-n2cnnn2)ncc1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CCc1cc(-n2cnnn2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl[4-ethyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (165 mg, 0.570 mmol) in DCM containing thioanisole (0.405 ml, 3.42 mmol) was added TFA (0.879 ml, 11.41 mmol) at 0° C. The mixture was stirred at RT overnight, concentrated. The residue was triturated with ether:hexane (1:1) to give [4-ethyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid: LC-MS: [(M+1]+=234.17.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26]C(O)=O.[N:30]1[CH:35]=CC=CC=1>>[CH:18]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[CH2:25][CH2:26][N:30]=[C:35]=[O:8]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: O=C(O)CCC1CC2CCC1C2
Product: O=C=NCCC1CC2CCC1C2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Diphenylphosphoryl azide (6.05 g.) was added dropwise to a solution of 3-(2-norbornyl)propionic acid (3.36 g.) in dry pyridine (20 ml.) and stirred at 80° C. for 30 minutes to give 2-(2-norbornyl)ethyl isocyanate (I.R. 2260 cm-1).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si](C)(C)[N-][Si](C)(C)C.[Na+].[F:17][CH:18]([F:34])[C:19](=[O:33])[CH2:20][C:21]([CH3:32])([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])[CH3:22]>CS(C)=O.C1COCC1.CCCCCC>[F:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:21]([CH3:22])([CH3:32])[CH2:20][C:19]2([CH:18]([F:17])[F:34])[CH2:7][O:33]2)[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Reaction time: 0.25 h

Procedure:
To suspension of trimethylsulfoxonium iodide (0.22 g) in DMSO (0.5 mL) and THF (0.5 mL) stirred under nitrogen and cooled on ice was added sodium hexamethyldisilazide (1.0 mL, 1.0M in THF) dropwise over 5 minutes. After 15 minutes, a solution of 1,1,-difluoro-4-methyl-4-(2-methoxy-5-fluorophenyl)pentan-2-one (0.23 g) in THF (0.6 mL) was added dropwise and the mixture was allowed to come to room temperature over 2 hours. The mixture was diluted with hexane, washed with water, dried, filtered, and evaporated in vacuo to give 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane as an oil (0.25 g).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[C:19]1([CH:25]2[CH2:26][CH2:27][N:28]([C:2]([Cl:1])=[O:4])[CH2:29][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.68 g (2.26 mmol) triphosgene in 6,8 mL dichloromethane at −80° C. is added 0.52 mL (6.5 mmol) pyridine. Then 1.05 g 4-phenylpiperidine (6.5 mmol) is added over a period of 10 minutes. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. 4.5 mL 1N hydrochloric acid is added for hydrolization. The organic phase is separated, washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After evaporation of the solvent the crude product is purified via column chromatography on silica gel using dichloromethane as eluent
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: N#C/N=C1\CC(C2CCOCC2)Oc2ccc(Br)cc21
Reactant: C[O-]
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(C3CCOCC3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a solution of methylhydroxylamine HCl salt (25.08 mg, 0.3 mmol) in anhydrous MeOH (5 mL) was added NaOMe (25% in MeOH (Wt. %), 0.06 mL, 0.27 mmol), followed by (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (100 mg, 0.3 mmol). After stirring 10 min, the solvent was removed in vacuo. The resulting residue was redissolved in DCM (10 mL), The mixture was filtered and the solvent was removed to give the residue, which was purified by column chromatography to give compound 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 40%).
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: OCc1ccccn1
Solvent: CCO
Product: c1ccc(B(OCc2ccccn2)C(OC(B(OCc2ccccn2)c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (34 mg) was obtained by allowing 59 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 59 mg of 2-hydroxymethylpyridine to act in 0.7 mL of ethanol at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[N:45]=[CH:44][CH:43]=[CH:42][C:31]=2[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])[CH:25]=[CH:26][C:27]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+].BrC1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:28][C:27]4[CH:26]=[CH:25][C:24]([NH:29][C:30]5[N:45]=[CH:44][CH:43]=[CH:42][C:31]=5[C:32]([NH:34][C:35]5[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=5)=[O:33])=[CH:23][C:22]=4[F:21])=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Reactant: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 160 °C
Yield: 79.4 %

Procedure:
A 100 mL sealable tube was charged with 1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (0.250 g, 0.626 mmol Example 84, Step D), 2-(3-fluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)nicotinamide (0.427 g, 1.25 mmol), cesium carbonate (0.408 g, 1.25 mmol), and 1-bromobenzene (6.26 ml, 0.626 mmol). The reaction mixture was heated to 160° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated. The residue was dissolved in EtOAc and washed with brine. The crude material was purified by silica gel (Biotage 40S) eluting with 4:1 Hexane/EtOAc to provide the product (0.35 g, 71%). LRMS M−1 (704.9) observed.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2].C1(C)C=CC=CC=1.[C:44](Cl)([Cl:46])=[O:45]>>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:44]([Cl:46])=[O:45])[CH2:8][C@@H:7]1[CH3:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)Cl)C[C@@H]1C
Yield: 76 %

Procedure:
cis-4-((3,5-Bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (prepared in a manner analogous to the procedures described for Examples 3A-3E) (146 mg, 0.28 mmol) was dissolved in 2 mL of a 1.93M phosgene solution in toluene (3.9 mmol). After heating at reflux for 1.5 h, the sample was concentrated in vacuo to afford the title product (125 mg, 76%). 1H NMR (CDCl3) δ 1.2-1.6 (m, 7H), 2.2-2.4 (m, 1H), 4.2-4.6 (m, 4H), 5.2-5.6 (m, 2H), 7.1 (s, 1H), 7.5-7.9 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH:8]=[CH:9][C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:25])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]([CH:8]=[CH:9][C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:25])[NH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(C=Cc1ccc([N+](=O)[O-])cc1)=NNC(C)C2
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(N)cc1)=NNC(C)C2
Reaction time: 1 h
Yield: 85.6 %

Procedure:
6.95 g (18.9 mmoles) of 1-(4-nitrostyryl)-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine prepared according to Example 25 are suspended in 170 ml of methanol, 0.7 g of dry (corresponding to about 1.4 g of wet) Raney nickel catalyst and 3.3 ml (66 mmoles) of 100% hydrazine hydrate are added to it and the reaction mixture is stirred for 1 hour. A solution is obtained, and in the beginning the inner temperature rises to 40-45° C. The catalyst is filtered off, washed three times with 15 ml each of methanol, the filtrate is evaporated in vacuo, the crude product is conveyed to a filter with 80 ml of water, washed three times with 15 ml each of water and dried. Thus 5.46 g of product are obtained. In order to purify the crude product it is recrystallized from 25 ml of 50% ethanol. Thus 4.21 g (66.0%) of the desired product are obtained. M.p.: 152-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.C(O)(=O)C.O1CCCC1>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 50 °C
Yield: 94.7 %

Procedure:
52.95 g (0.2 mol) of 7-amino-1-(ethoxycarbonylmethyl)quinoxaline-2,3(1H,4H)-dione and a spatula tip of 4-(N,N-dimethyl-amino)pyridine were suspended in a mixture of 500 ml of glacial acetic acid and 300 ml of tetrahydrofuran and heated to 50° C. Then 20.5 g (0.2 mol) of acetic anhydride were added dropwise, and the mixture was heated at 50° C. for 2 h. The precipitate was filtered off with suction. 57.8 g (94%) of the product were obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH2:10][CH2:11][C:12]#[N:13])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[I:14][CH2:15][CH2:16][O:17][CH3:18]>C(#N)C>[I-:14].[C:1]([CH2:3][CH2:4][P+:5]([CH2:10][CH2:11][C:12]#[N:13])([CH2:6][CH2:7][C:8]#[N:9])[CH2:15][CH2:16][O:17][CH3:18])#[N:2]
Reactant: N#CCCP(CCC#N)CCC#N
Reactant: COCCI
Solvent: CC#N
Product: COCC[P+](CCC#N)(CCC#N)CCC#N
Product: [I-]

Procedure:
135.2 g (0.7 mole) of tris-(2-cyanoethyl)-phosphine are dissolved, under nitrogen, in 500 ml of boiling acetonitrile and then 130.2 g (0.7 mole) of 1-iodo-2-methoxyethane are added. The mixture is refluxed for 12 hours. After rapid filtration of the hot solution and cooling, the reaction product crystallises out and is collected by suction filtration and dried in vacuo at 60° C.