Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1
Yield: 95.4 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(4-chloro-3-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-116, 0.400 g, 0.890 mmol), KOH (0.099 g, 1.78 mmol), water (2 mL) and THF (4.0 mL) to afford 0.300 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.CO[C:26](OC)([N:28](C)C)[CH3:27].C1(C)C=CC=CC=1.[NH2:40]N>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)=[C:26]([CH3:27])[NH:28][N:40]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: NN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1[nH]nc(-c2ccc(F)cc2F)c1-c1ccc2nnc(C(C)C)n2n1
Temperature: 95 °C
Yield: 2.8 %

Procedure:
A solution of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.26 g, 0.82 mmol; Preparation #K.1), N,N-dimethylacetamide dimethyl acetal (0.22 g, 1.64 mmol) and toluene (5 mL) was heated at about 110° C. in an oil bath for about 45 min. The reaction mixture was cooled and then concentrated under reduced pressure. 1,4-Dioxane (5.0 mL) and hydrazine (0.055 g, 1.64 mmol) were added to the mixture and it was then heated at about 95° C. in an oil bath for about 1 h. The mixture was concentrated under reduced pressure and then acetic acid was added and the material was purified by RP-HPLC (Table 1, Method d). The appropriate fractions were concentrated under reduced pressure to give a solid which was collected by filtration and dried to give the title compound (0.008 g, 3%): LC/MS (Table 1, Method a) Rt=1.99 min; MS m/z: 355.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=[O:23])[NH:13][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH3:15].[CH:24]([O-])([O-])OCC.O>CN(C=O)C>[O:23]=[C:12]1[C:3]2[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[N:1]=[CH:24][N:13]1[C:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: CCOC([O-])[O-]
Reactant: COC(=O)c1ccc(N)c(C(=O)NC(C)(C)c2ccccc2)c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ncn(C(C)(C)c3ccccc3)c(=O)c2c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of methyl 4-amino-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.13 g, 0.42 mmol) in DMF (2.5 mL) was added ethyl orthoformate (3.0 mL, 18 mmol) followed by one scoop of 3 Å molecular sieves. The reaction mixture was heated to 150° C. and stirred for 1 d. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-oxo-3-(2-phenylpropan-2-yl)-3,4-dihydroquinazoline-6-carboxylate (0.11 g, 84%). LC-MS: (FA) ES+ 323.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Br)c1)N(CCO)CCO
Temperature: 20 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 3-bromobenzene sulfonyl chloride (0.25 mL, 1.73 mmol) in dioxane (2.0 mL) was added dropwise a solution of diethanolamine (0.547 g, 5.20 mmol) in dioxane (1.0 mL) over 1 min. The reaction mixture was stirred at room temperature (20° C.) for 16 h. After this time the mixture was poured onto brine (30 mL) and extracted with ethyl acetate (25 mL). The organic liquor was concentrated in vacuo to afford the title compound, (0.495 g, 88%). No further purification was required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>ClCCCl>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1
Reaction time: 0.17 h

Procedure:
5-Chloro-2-aminopyridine (450 grams; 3.5 moles) and 5000 ml. of 1,2-dichloroethane were slurried together. The flask was then purged with nitrogen and a cold water bath applied, resulting in a lowering of the temperature to 20° C. 2,6-Dichlorobenzoyl isocyanate (912 grams; 4.2 moles) was added dropwise over one hour, holding the temperature at <30° C. The reaction mixture was stirred for 10 minutes, the cold water bath was removed, and a hot tap water bath (about 55° C.) was applied. The flask temperature rose to 42° C. and was held at 40° C. for 30 minutes. TLC showed that all starting material had been reacted. Solvent was removed on a rotary evaporator, and the solid residue was slurried with 1 liter of methanol, chilled and filtered. Yield was 1177 grams. m.p. 219°-222° C. Identity of the product was confirmed by NMR and IR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Br:9][CH2:10][C:11](=O)[CH3:12]>C(O)C>[BrH:9].[Cl:8][C:4]1[N:3]2[CH:10]=[C:11]([CH3:12])[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CBr
Reactant: Nc1cccc(Cl)n1
Solvent: CCO
Product: Br
Product: Cc1cn2c(Cl)cccc2n1

Procedure:
To a solution of 19.28 g (150 mmol) of 2-amino-6-chloropyridine in 150 ml of ethanol, 25 g (180 mmol) of bromoacetone was added at room temperature, followed by refluxing for 64 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was purified by recrystallization (solvent: ethanol-ethyl acetate) to yield 20.22 g (54.5%, light brown crystal) of the desired product.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]=[C:7]=[O:8])(=[O:3])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)CCN=C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)CCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 5 h

Procedure:
To the above solution of 2-acetylethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for further 5 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-acetylethyl)carbamoyl]-5-fluorouracil (439 mg.).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](Cl)(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[O-:15][C:16]#[N:17].[Na+].N1C=CC=CC=1.Br.[NH2:26][C:27]1[S:28][C:29]([Br:32])=[CH:30][N:31]=1>C(#N)C>[Br:32][C:29]1[S:28][C:27]([NH:26][C:16]([NH:17][S:9]([C:7]2[S:6][C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)(=[O:11])=[O:10])=[O:15])=[N:31][CH:30]=1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1ncc(Br)s1
Reactant: N#C[O-]
Agent: Br
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc2sc(S(=O)(=O)NC(=O)Nc3ncc(Br)s3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a suspension of 5-methyl-benzo[b]thiophenesulfonyl chloride (Maybridge, CAS: 90273-30-6, 0.37 g) in acetonitrile (5.0 mL) were added sodium cyanate (0.163 g) in one portion and pyridine (0.60 mL). The reaction mixture was stirred at rt for 3 h, then 2-amino-5-bromothiazole hydrobromide (0.286 g) was added in one portion. The mixture was stirred at rt for 4 h and quenched with 70% acetic acid (2.4 mL) and water (4.0 mL). The suspension was filtered, washed with waterlethanol and water, dried over P2O5 under high vacuum to obtain the desired compound (0.372 g) as a creamy solid. MS (ISN): m/e 430.1, 432.0 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([CH:12]1[N:20](C(OC(C)(C)C)=O)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([CH:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.2 g, 533 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol, Eq: 48.7) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (3×10 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as an off-white solid (0.15 g), m/z=276 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][NH2:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>C(O)C.O>[CH:1](=[N:21][NH:20][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzaldehyde (1.48 g) in ethanol (10 ml) was added to a stirred suspension of 5-chloro-2-hydrazinobenzoic acid hydrochloride (described in U.S. Pat. No. 4,105,766; 5.2 g) in water (100 ml). Stirring was continued for 1 hour. The mixture was then left unstirred for 16 hours and then extracted with ether. The extracts were dried (MgSO4) and evaporated to give 2-(benzylidenehydrazino)-5-chlorobenzoic acid (3.5 g) which was used without purification.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:21][NH:22][CH3:23].[CH2:24]=O>C(O)(=O)C>[CH3:21][N:22]([CH2:24][C:2]1[O:1][C:9]2[CH2:8][CH2:7][N:6]([C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:5][C:4]=2[CH:3]=1)[CH3:23]
Reactant: C=O
Reactant: CNC
Reactant: O=C(CCCc1ccccc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)CCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.160 g (0.594 mmol) of 1-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-4-phenylbutan-1-one in 20 ml of acetic acid, 0.080 ml (0.88 mmol) of 50% aqueous dimethylamine and 0.072 ml (0.88 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:28].CN1CCCC1=O>CO>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:29][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)[CH:3]=1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A mixture of 6-chloro-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (60 mg, 0.183 mmol), cis-cyclohexane-1,2-diamine (125 mg, 1.1 mmol) and N-methyl-2-pyrrolidinone (2 mL) was heated to 150° C. After 18 h, the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (spherical silica 20-45 uM, 23 g, Versaflash Supelco, 0 to 5% MeOH containing 10% NH4OH in CH2Cl2, 20 min) gave a solid residue. This residue was dissolved in MeOH and CH2Cl2, then precipitated by addition of cyclohexane. The solid formed was obtained by decantation of the mother liquor, then dried to give 6-(cis-2-aminocyclohexylamino)-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxamide (19 mg, 45.6 μmol, 25%) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.21 (s, 1H) 8.73 (d, J=2.27 Hz, 1H) 8.48 (br. s., 1H) 8.16 (s, 1H) 8.12 (dd, J=8.69, 2.64 Hz, 1H) 7.75 (br. s., 1H) 7.14 (d, J=8.69 Hz, 1H) 7.03 (d, J=7.93 Hz, 1H) 4.06 (br. s., 1H) 3.26 (s, 3H) 3.09 (br. s., 1H) 1.24-1.78 (m, 10H). LCMS (EI/CI) m/z: 406 [M+H].
Reaction SMILES: O.[Br:2][C:3]1[N:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:6]([C:13](OC)=[O:14])=[C:5]([CH:17]([OH:22])[CH2:18][N+:19]([O-])=O)[N:4]=1.C(O)(=O)C>C(O)C.[Fe]>[Br:2][C:3]1[N:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:6]2[C:13](=[O:14])[NH:19][CH2:18][CH:17]([OH:22])[C:5]=2[N:4]=1
Reactant: COC(=O)c1c(C(O)C[N+](=O)[O-])nc(Br)n1CC=C(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)=CCn1c(Br)nc2c1C(=O)NCC2O

Procedure:
90 ml of water and 5.40 g iron powder are added to 4.15 g methyl 2-bromo-5-(1-hydroxy-2-nitro-ethyl)-3-(3-methyl-2-buten-1-yl)-3H-imidazole-4-carboxylate in 270 ml of ethanol. The mixture is refluxed, combined with 36 ml glacial acetic acid and stirred for one and a half hours at reflux temperature. The cooled reaction solution is filtered through Celite. The filtrate is evaporated down, combined with ethanol and made basic with solid potassium carbonate. The mixture is stirred for three hours at 60° C. Then the ethanol is distilled off, the flask residue is combined with water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (1:1 to 7:1) as eluant.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH3:35])([CH3:34])[O:32][B:31]([OH:36])[C:30]=2[CH:37]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:36][B:31]1[C:30]2[CH:37]=[C:26]([NH:25][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[CH:27]=[CH:28][C:29]=2[C:33]([CH3:35])([CH3:34])[O:32]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: CC1(C)OB(O)c2cc(N)ccc21
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: CC(C)(C)OC(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a suspension of (R)-2-(tert-butoxycarbonylamino)-4-(4-(trifluoromethyl)phenyl)butanoic acid (LXXI) (1 g, 2.88 mmol) and 6-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (XCVIII) (0.615 g, 2.88 mmol) in dry DCM (10 mL) was added DIPEA (1.47 mL, 8.64 mmol). To this solution was added HATU (1.09 g, 2.88 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine, dried over MgSO4 and evaporated under vacuum to give (R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (1.44 g, 2.84 mmol, 99% yield). ESIMS found for C25H30BF3N2O5 m/z 507.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N+:20]([O-])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Yield: 94.5 %

Procedure:
A solution of 2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine (4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cube (2.0 mL·min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo. The crude product was subjected to SCX capture and release and the solvent was removed in vacuo to give 2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine, (3.82 g, 94%) as a purple solid: m/z 266 (M+H)+ (ES+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:20]([O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:11]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: OC1CCN(c2ccc3cc[nH]c3c2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc3cc[nH]c3c2)C1
Yield: 91.8 %

Procedure:
A homogeneous, colorless solution of 1-(1H-indol-6-yl)pyrrolidin-3-ol (0.1036 g, 0.512 mmol), tert-butylchlorodimethylsilane (0.093 g, 0.615 mmol) and imidazole (0.087 g, 1.281 mmol) in DMF (2.56 mL) was stirred overnight. The mixture was diluted with EtOAc (75 mL), washed with water (4×25 mL) and brine (25 mL) successively, dried over MgSO4, and concentrated in vacuo. The residue was triturated with hexanes to give the desired product (0.1600 g, 0.470 mmol, 92%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:18][OH:19])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:19][CH2:18][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(F)cc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(F)cc2)CC1
Yield: 96 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(4-fluorophenyl)cyclopropane (Example 12) (0.2 g), benzene (12 ml) and pyridine to yield the title compound (0.23 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]([C:15]3[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[N:9]2[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CC=CCC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A mixture of 2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine (30.2 mg, 0.108 mmol), 2-(4-bromo-butyl)-isoindole-1,3-dione (33.5 mg, 0.119 mmol), DMF (3 mL), DIPEA (0.3 mL), and KI (4 mg) were heated to 110° C. for 4 h and overnight at 90° C. The solvent was removed and CH2Cl2 (20 mL) was added to the residue. It was washed with saturated NaHCO3 (10 mL). The aqueous layer was extracted two more times with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 2:1 hexanes:EtOAc) provided 13.3 mg of 2-{4-[2,7-bis-(3-methyl-pyridin-2-yl)-2,3,6,7-tetrahydro-azepin-1-yl]-butyl}-isoindole-1,3-dione as a film. 1H NMR(CDCl3) δ 0.53-0.59 (m, 1H), 0.65-1.00 (m, 3H), 2.36 (s, 6H), 2.36-2.41 (m, 1H), 2.47-2.50 (m, 2H), 3.02-3.24 (m, 5H), 4.72 (dd, 2H, J=9.6, 1.8 Hz), 5.80-5.83 (m, 2H), 6.90 (dd, 2H, J=7.5, 4.2 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.67-7.73 (m, 2H), 7.76-7.86 (m, 2H), 8.35 (d, 2H, J=4.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[N:18]1([CH2:24][CH2:25][C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(N=C=NC2CCCCC2)CCCCC1>>[N:18]1([CH2:24][CH2:25][C:26]([O:1][C:2]2[C:7]3[C:8]4[CH2:16][CH2:15][S:14][C:9]=4[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
Following the procedure similar to that described in Example 8 hereinabove, 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran is reacted with methyl magnesium bromide to give 1,2-dihydro-9-hydroxy-4,4,7-trimethyl-4H-thieno-[2,3-c][1]benzopyran. The benzopyran is then reacted with β-piperidinopropionic acid and dicyclohexylcarbodiimide to yield the desired ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O>C(O)C>[C:24]1([C:22]2[N:1]=[C:2]3[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]4[C:17](=[O:18])[CH2:16][S:15][C:14]4=[O:19])=[CH:6][CH:5]=[CH:4][N:3]3[CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ncccc1OCCCCN1C(=O)CSC1=O
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: O=C1CSC(=O)N1CCCCOc1cccn2cc(-c3ccccc3)nc12

Procedure:
To a solution of 5.69 g (20 mmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]thiazolidine-2,4-dione in 40 ml of ethanol, 3.98 g (20 mmol) of bromoacetophenone was added at room temperature, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 5.24 g (68.7%, light orange crystal) of the desired product.