Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL of THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was then partitioned between 0.05N HCl and ethyl acetate. The organic layer was washed with water (2×), and brine (1×), and was then dried over anhydrous magnesium sulfate, filtered and then was concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline product (470 mg, 78%). LCMS (M+H)+: m/z=306, 308.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32]>C(NCC)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCN1CCOCC1
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN1CCOCC1
Yield: 38.5 %

Procedure:
Operating analogously to what described in example 74 starting from trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, 4-prop-2-ynyl-morpholine (640 mg, 5.12 mmoles), prepared as described in example 137, diethylamine (40 ml), bis(triphenylphosphine)PdCl2 (60 mg, 0.0854 mmole) and Cul (16 mg, 0.0854 mmole), 728 mg of the title compound were obtained (yield: 38.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1
Yield: 99.3 %

Procedure:
A solution of methyl indole-6-carboxylate (15.0 g) in 2-butanone (214 ml) was treated with 4-methylbenzenesulfonylchloride (33 g) and potassium carbonate (47.0 g) and heated to reflux under a nitrogen atmosphere for 18 hours. The hot reaction mixture was filtered, and the filtrate was evaporated to give a solid which was triturated with ether to give methyl 1-(4-methylphenylsulfonyl)indole-6-carboxylate (28.0 g, 99%) as an ivory solid NMR (80 MHz, CDC3): 2.33(s, 3H, ArCH3), 3.95(s, 3H, OCH3), 6.67(dd, 1H, H3-indole), 7.16-7.98(7H, m, Ar), 8.7(m, 1H, H7 -indole)
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH2:22][CH2:21][NH:20]1>O1CCCC1>[CH2:1]([O:8][C:9]([N:20]1[CH2:21][CH2:22][C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:30][C:31]=2[CH2:19]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(benzyloxycarbonyloxy)succinimide (9.61 g, 38.6 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a suspension of 2,3,4,9-tetrahydro-1H-β-carboline (4.43 g, 25.7 mmol) and 4-N,N-dimethylaminopyridine (266 mg) in anhydrous tetrahydrofuran (30 ml), while cooling with ice. The suspension was stirred at room temperature for 16 h and the tetrahydrofuran was then removed i. vac. The residue was dissolved in ethyl acetate (20 ml) and the solution was washed with water (2×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (11.0 g) was purified by flash chromatography with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: B(F)(F)F.CCOCC.[N+:10](=[CH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N-].[Cl:19][CH2:20][C:21]#N>>[Cl:19][CH2:20][C:21]1[O:18][C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:10]=1
Reactant: CC(C)(C)C(=O)C=[N+]=[N-]
Reactant: N#CCCl
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of chloroacetonitrile (40 mL) and boron trifluoride etherate (20 mL, 0.16 mmol) at 0° C. was added 1-diazo-3,3-dimethyl-2-butanone in chloroacetonitrile (40 mL) dropwise over a period of 20 minutes. After addition was complete, the mixture was stirred at 0° C. for one hour and then partitioned between saturated NaHCO3 solution (700 mL) and CH2Cl2 (500 mL). The aqueous solution was. extracted with CH2Cl2 (500 mL) and the combined organic layers were washed with brine (400 mL) and dried over MgSO4. After filtration, the solution was concentrated and then distilled under vacuum using an oil bath temperature of 40° C. The 2-(chloromethyl)-5-t-butyloxazole (9.2 g, 44% overall from the acid chloride, C8H12CINO, MS m/e 174 (M+H)+) was obtained as a light yellow oil.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].S(=O)(=O)(O)O.O.[OH-].[Na+].C(#[N:22])C>>[NH2:22][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 0 °C

Procedure:
Trans-1,2-indandiol (1.5 g) was dissolved in acetonitrile (25 mL) cooled to 0° C., and concentrated sulfuric acid (1.1 mL) was added. The mixture was gradually warmed to 20° C. and aged to 3 hours. Water (2 mL) was added and the mixture heated to reflux. Concentrated aqueous sodium hydroxide was added to adjust the pH to 12. The resulting solid was removed by filtration to provide an aqueous acetonitrile solution of cis-1-amino-2-indanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[H-].[Na+].[CH3:14]I.CO>C1COCC1.C(Cl)Cl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCc1cccc(NC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cccc(N(C)C#N)c1
Yield: 82.4 %

Procedure:
A suspension of 3-ethylphenylcyanamide (4.65 g, 31.8 mmol) and sodium hydride (2.55 g of 80% NaH in mineral oil suspension, 63.6 mmol of NaH) in dried THF was heated at reflux for 3 hours. The reaction mixture was cooled in an ice bath and methyl iodide (11.28 g, 79.5 mmol) was added dropwise with stirring to the mixture. The reaction mixture was then allowed to stir for 15 hours, followed by the successive addition of MeOH (10 mL). The reaction mixture was then concentrated to dryness to give the crude product. Distilled water (40 mL) was added to this crude product and the aqueous mixture was extracted with CH2Cl2 (4×40 mL). The combined organic extracts were washed with water (3×30 mL) and then dried over MgSO4. The solvent was removed to afford the crude product as an amber syrup. Flash chromatography (SiO2, CH2Cl2) of the crude product afforded 4.2 g (75% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C1(C)C(C)=CC=CC=1.P.[OH-].[Na+]>Cl[Pd]Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:10]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: P
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(Cl)c(N)c1

Procedure:
A degassed solution of 40 mmol of 4-chloro-3-nitrobenzonitrile (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml).2.5 mmol of BINAS (in the form of 14.4 g of an aqueous solution containing 0.173 mol of BINAS/kg of solution) as phosphine and 2.4 g (60 mmol) of NaOH, 23.8 ml of H2O and 1.0 mmol of PdCl2 are added. The pH isfrom 10.5 to 11.0.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetontrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (15.0 mg, 0.0359 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (13.6 mg, 0.0430 mmol) (Peak I), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.8 mg, 0.0022 mmol) and potassium phosphate (22.8 mg, 0.108 mmol) in 1,4-dioxane (0.48 mL) and water (0.24 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=482.1.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].[CH3:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:17][CH2:16][O:15][CH3:14])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (1.62 g, 8.80 mmol, prepared using procedure in WO9849166), 2-bromoethyl methyl ether (1.23 g, 8.85 mmol) and cesium carbonate (2.90 g, 8.92 mmol) in N,N-dimethylformamide (20 ml) was stirred at 20° C. for 20 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (125 ml) and brine (100 ml). The phases were separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc/MeOH, 97:3) to afford the title compound of preparation 4 (831 mg, 3.43 mmol, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].B>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-5-hydroxybenzoic acid (2.96 g, 17.2 mmol, Apin) in THF (60 ml) under nitrogen was slowly added 1 M borane in THF (30 ml, 30.0 mmol). The suspension was stirred for 20 minutes at ambient temperature. The mixture was refluxed at 80° C., under nitrogen for 3 h. The reaction mixture was allowed to cool to ambient temperature then carefully quenched using methanol (20 ml). The mixture was then refluxed for a further 1 h at 80° C. under nitrogen. The solvent was removed in vacuo and left under high pressure vacuum overnight to give the title compound as a cloudy gum (3.38 g); LCMS: (System 4) (M-H)−=157, tRET=1.50 min.
Reaction SMILES: C([O:3][C:4](=[O:48])[C@H:5]([OH:47])[CH2:6][NH:7][C:8](=[O:46])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)C.[OH-]>C(O)C>[F:27][C:26]([F:28])([F:29])[C:24]1[CH:25]=[C:20]([NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:47])[C:4]([OH:48])=[O:3])=[O:46])=[CH:14][CH:13]=2)[C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[CH:21]=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:23]=1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: [OH-]
Solvent: CCO
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
(R)-3-(4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino]-2-hydroxypropionic acid ethyl ester (0.26 g, 0.38 mmol) was dissolved in ethanol (96%, 15 mL) and added solution hydroxide (4 N, 0.57 mL, 2.3 mmol). After stirring at 25° C. for 1 hour the mixture was evaporated in vacuo, and the residue was added water (30 mL) and acidified with hydrochloric acid (4 N, 0.62 mL). The aqueous phase was extracted twice with ethyl acetate (25 mL and 10 mL) and the combined organic phases were washed with saturated sodium chloride:water (1:1), dried (magnesium sulphate) and concentrated in vacuo to afford 0.21 g of the title compound.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:28])C>O>[OH:28][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH:8]([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)C(C)Oc1ccc(C=O)cc1
Reactant: CC(=O)OO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
While stirring a mixture of 25 g of butyl 2-(4-formylphenoxy)propionate and 75 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 2.0 g of water was added, and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and subjected to the same after-treatment as in Example 1, whereby 19.5 g of butyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid by the distillation under reduced pressure. The boiling point was 160° C./1 mmHg.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:37])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:37])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1
Reactant: COc1c(N2CC3(CC3)C(C)(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Product: COc1c(N2CC(C)(N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
The 7-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid produced in Reference Example 29 (870 mg, 1.676 mmol) was dissolved in concentrated hydrochloric acid (10 mL) in an ice bath, and the mixture was stirred at room temperature for 20 minutes and washed chloroform (20 mL×5). Saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to adjust the pH to 12.0, and the pH was further adjusted to 7.4 by adding hydrochloric acid. The solution was extracted with a mixed solution (chloroform:methanol, 10:1) (200 mL×2), and then, with lower layer of a mixed solution (200 mL) (chloroform:methanol: water, 7:3:1). The organic layers were combined and dried with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue was purified by recrystallization from ethanol, and the crystals were dried under reduced pressure to obtain 644 mg (1.535 mmol, 92%) of the title compound as a pale pink powder.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([O:12]C)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2ccoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(1)-(i) A mixture of 420 mg of methyl benzofuran-7-carboxylate, 5 ml of an aqueous 10% sodium hydroxide solution and 5 ml of methanol is stirred at room temperature for 1 hour. The reaction mixture is evaporated to remove solvent. The residue is dissolved in water and the solution is acidified with 10% hydrochloric acid. The resultant crystals are collected by filtration and dried to give 321 mg of benzofuran-7-carboxylic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].[K+].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.O>CC1C=CC=CC=1C>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:24][CH:21]3[CH2:23][CH2:22]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (100 g), potassium fluoride (41.13 g), cyclopropylamine (80.85 g) were suspended in o-xylene (300 ml) and heated to 130-140° C. in autoclave for 5-9 h. Then the reaction mass was cooled to 25-30° C., diluted with o-xylene (500 ml) and further heated the reaction mass to 70-75° C. Thereafter, DM water (300 ml) added and stirred for 10 min at 70-75° C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (300 ml) at 70-75° C. and organic layer was concentrated at 60-63° C. under reduced pressure up to residue weight attained is approximately 400 g The concentrated mass was cooled to 25-30° C. and stirred for 15 min and further cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (100 ml, 5-10° C.). Dried the obtained solid at 50-60° C. under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.C(O)(=O)C>C1COCC1.[Fe]>[N:10]1([C:7]2[CH:8]=[N:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cn1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(N2CCCCC2)cn1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 6′-Nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (0.25 g) in THF (8 mL) was added iron (0.539 mg) and water (2.5 mL). Then acetic acid (0.35 mL) was added dropwise and the mixture was allowed to stir at 45° C. for 12 hours. TLC analysis confirmed complete consumption of the starting material. The suspension was filtered through celite and the filter cake was washed well with ethyl acetate. The filtrate was concentrated in vacuo prior to addition of 2N NaOH. The aqueous layer was saturated with NaCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and evaporated to give a residue that was purified by flash chromatography on silica gel (gradient of MeOH in DCM containing 0.5% NH4OH). 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine was obtained as a black oil (0.196 g). MS (ESI): 178.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].[OH-].[Na+:27]>C1COCC1>[C:8]([C:7]1[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[Na+:27]
Reactant: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 200 mg (0.583 mmol) (4S)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 6) in THF (6 ml) under argon atmosphere was added 612 μl (0.612 mmol) 1 N aqueous sodium hydroxide solution, and the mixture was stirred under a weak argon stream for 3 days at room temperature. The product was crystallized by stirring the resulting solid in water under a slight argon stream for another 3 days to dryness, yielding 212 mg (100% of th.) of the title compound as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>CN(C=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: COC(=O)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a flask containing methyl 1H-imidazole-4-carboxylate (5 g, 39.7 mmol) in DMF (70 ml), K2CO3 (13.7 g, 99.1 mmol), SEM-Cl (9.3 ml, 51.6 mmol) were added and stirred at 80° C. overnight. The reaction mixture was quenched by the addition of H2O and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.05 (s, 9H), 0.80 (t, 2H), 3.47 (t, 2H), 3.74 (s, 3H), 5.30 (s, 2H), 7.91 (s, 1H), 8.01 (s, 1H). LC-MS: [M+1]=257.27.