Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([CH:10]=[O:11])=[N:8][CH:9]=1>CCO>[F:3][C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: Cc1cc(F)cnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(F)cnc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
Sodium borohydride (125 mg, 3.3 mmol) was added to a solution of 5-fluoro-3-methylpyridine-2-carbaldehyde (417 mg, 3.0 mmol) in EtOH (10 mL) and stirred at rt for 3 h. The reaction was quenched by dropwise addition of saturated aqueous NH4Cl solution (10 mL) and stirred for 15 h. The reaction mixture was extracted twice with DCM and the combined organic phases were concentrated in vacuo. Purification by gradient column chromatography, eluting with 10-60% EtOAc in iso-hexane to yield the title compound (218 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a mixture of 2-(3-bromophenyl)ethanol (3.40 g, 16.9 mmol), tert-butyl 2-bromoacetate (26.0 g, 133 mmol, 8.0 equiv.), tetra-n-butylammonium hydrogen sulfate (4.52 g, 13.3 mmol, 0.80 equiv.), and 84 mL of toluene was added 267 mL of 5N aqueous NaOH solution. The reaction mixture was stirred at room temperature for 3 h. The aqueous layer was then extracted with four portions of EtOAc, dried (MgSO4), and evaporated. The residue was purified by CC on silica gel with EtOAc/petroleum ether 1:40 to afford the title compound (4.8 g, 90%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.42 (s, 1H), 7.35-7.39 (m, 1H), 7.18-7.20 (m, 2H), 3.98 (s, 2H), 3.76 (t, 2H, J=6.9 Hz), 2.94 (t, 2H, J=7.2 Hz), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2Cl)[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[NH3:22]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:22])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Reactant: N
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Yield: 61 %

Procedure:
3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W) (8.2 g, 21 mmol), conc. ammonia (100 mL) and dioxan (100 mL) were heated in a Parr pressure vessel at 120° C. for 20 hrs. The solvents were evaporated and the residue partioned between EtOAc and water. The EtOAc layer was dried over Na2SO4, filtered and evaporated to leave 3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a solid (4.7 g, 61%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 8.21 (1H, s), 4.71 (1H, m), 3.90 (4H, m), 2.11(2H, m), 1.72-1.88 (6H, m ) HPLC: Tr=11.84 mins, 92.1%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].C(O)(=O)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C([O-])(=O)C.[Na+]>O>[Cl:18][CH2:19][C:20]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)CCl
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a stirred and cooled (about 10° C.) solution of 11.7 parts of 2-methoxy-5-(trifluoromethyl)benzenamine in 50 parts of acetic acid were added dropwise 7.7 parts of chloroacetyl chloride at a temperature below 20° C. After stirring for 30 minutes, there was added dropwise a solution of 24.8 parts of sodium acetate in 62 parts of water (exothermic reaction). Upon completion, stirring was continued for 30 minutes at room temperature. The precipitated product was filtered off, washed with a lot of water and dried, yielding 15.5 parts (93.3%) of 2-chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]-acetamide; mp. 94.7° C. (intermediate 62).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:40])=[N:14][C:15]([CH3:39])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCC(C)(C)C)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCC(C)(C)C)cc1
Yield: 83.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.02 g, 0.036 mmol) and LiOH (8.66 mg, 0.362 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 4 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0158 g, 0.030 mmol, 83% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.12-7.16 (m, 1H), 7.06 (d, J=7.7 Hz, 1H), 6.96-7.00 (m, 2H), 5.92 (br. s., 1H), 4.06-4.15 (m, 2H), 3.46-3.81 (m, 1H), 2.90 (br. s., 1H), 2.69 (br. s., 3H), 2.27-2.42 (m, 1H), 2.25 (s, 3H), 1.95-2.17 (m, 1H), 1.79 (t, J=7.3 Hz, 2H), 1.50-1.64 (m, 1H), 1.27-1.40 (m, 3H), 1.25 (s, 9H), 1.04 (s, 9H), 0.81 (br.s., 6H). LCMS (M+H)=525.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]1[CH2:31][NH:30][CH2:29][C@H:28]1[OH:32]>C(O)CCC>[NH2:26][C@H:27]1[CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:29][C@H:28]1[OH:32]
Reactant: N[C@H]1CNC[C@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@@H](N)C3)c2c1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (740 mg, 2.0 mmol, prepared in analogy to the one in Example 2-1) and cis-4-aminopyrrolidin-3-ol (600 mg, 6.0 mmol) in n-butanol (0.2 mL) was heated at 180° C. for 3 days. After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (dd, J=7.83, 1.26 Hz, 1 H), 8.02 (s, 1 H), 7.87 (d, J=7.07 Hz, 1 H), 7.82-7.71 (m, 2 H), 7.67-7.57 (m, 2 H), 5.93 (s, 1 H), 5.33 (s, 2 H), 4.66 (d, J=2.02 Hz, 1 H), 4.56 (brs, 2 H), 4.28-4.17 (m, 2 H), 4.13-3.99 (m, 2 H), 3.91 (s, 1 H), 3.76 (brs, 2 H), 3.37 (s, 3 H), 2.50 (s, 3 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.BrCC1C=C(C=CC=1)C=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].O>CC(C)=O>[C:21]([S:23][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: O=Cc1ccc(CBr)cc1
Agent: O=Cc1cccc(CBr)c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (Hsung et al. (1995) Organometallics, 14: 4808–4815; Bookser and Bruice (1991) Am. Chem. Soc. 113: 4208–4218; Wagner et al. (1997) Tetrahedron 53: 6755–6790 for the synthesis of 3-(bromomethyl)benzaldehyde) (0.43 g, 2.2 mmol) in acetone (10 mL) was added potassium thioacetate (280 mg, 2.5 mmol) under stirring at rt, then the mixture was refluxed. A precipitate formed after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (3.5 h). Water (25 mL) was added, the mixture was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried (Na2SO4) and evaporated. Column chromatography over flash silica gel (ethyl ether/hexanes, 1:1) gave 359 mg (85% yield) of a brown oil which darkened upon standing (nonetheless elementary analysis four weeks after exposure to air at rt indicated a high level of purity as listed below). IR (neat): {tilde over (v)} 3052, 2923, 2830, 2737, 1694, 1606, 1576; 1H NMR δ 2.36 (s, 3H), 4.15 (s, 2H), 7.45, 7.81 (AA′BB′, 2×2H), 9.97 (s, 1H); 13C NMR (APT) δ 30.1 (−), 32.9 (+), 129.3 (−), 129.9 (−), 135.2 (+), 144.7 (+), 191.5 (−), 194.3 (+); GC-MS (EI) obsd 194, 152, 119, 91, 43; Anal. Calcd for C10H10O2S: C, 61.83; H, 5.19; S, 16.51; Found: C, 61.97; H, 5.20; S, 16.60.
Reaction SMILES: [C:1]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O.NN>C(O)CO>[CH2:1]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCCc1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 2-butyrylfluorene (11.3 g.), powdered potassium hydroxide (4.16 g.) and 100% hydrazine hydrate (9 ml.) in ethylene glycol (104 ml.) was refluxed for one hour with stirring. The mixture was then slowly distilled until the boiling-point reached 185° and then heated to reflux for 3 hours. The cooled mixture was treated with water (ca. 300 ml.) and the produce was isolated with ether in the usual manner. Recrystallisation from methanol gave 2-butyfluorene, m.p. 65°-66.5° .
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([OH:34])=[O:33].Cl>C1COCC1.CCCCCC.O>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:1])[C:32]([OH:34])=[O:33]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccccc1Cl
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of diisopropylamine (1.6 mL, 12 mmole) in 20 mL of THF at −78° was treated with n-BuLi (7.5 mL of a 1.6N solution in hexane, 12 mmole). The solution was stirred 10 minutes, and then treated with HMPA (2.16 mL, 12 mmole), and stirred an additional 2 minutes. A solution of o-chlorophenylacetic acid (850 mg, 5 mmole) in 4 mL of THF was added, the reaction was warmed to 23°, stirred 45 minutes, warmed to 50° and stirred for 5 minutes, and then cooled to 0°. Mel (1 mL) was added, the reaction was warmed to 23°, and stirred for 30 minutes. The reaction was diluted with H2O, acidified with HCl, and extracted with Et2O. The extracts were washed with 0.1N HCl, H2O, aqueous NaHSO3, dried, and the solvent removed, and gave the titled compounds as a white crystalline solid, 603 mg (66% yield). MS (ESI) 185 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH2:14]O)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:43])C(=O)C1>C(Cl)Cl>[Cl:43][CH2:14][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([N:2]([CH3:16])[CH3:1])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(CO)cc(N(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CCl)cc(N(C)C)c1
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a solution of Compound 2 (3.45 g, 15.452 mmol) and PPh3 (6.14 g, 23.17 mmol) in 70 mL of DCM was added NCS (3.19 g, 23.178 mmol) at 0° C. The reaction mixture was stirred for 1.5 hours. After removal of solvent under reduced pressure, the residue was dissolved in Et2O. The solution was washed with brine and dried with MgSO4. The solution was filtered and concentrated. The residue was subjected to chromatography over silica gel (Hexanes/EtOAc=9.5/0.5) to give Compound 3 (3.585 g, 96%). 1H-NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (s, 1H), 6.89 (s, 1H), 4.57 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.00 (s, 6H), 1.39 (t, J=7.1 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 166.73, 150.63, 138.35, 131.59, 117.31, 116.20, 113.22, 60.95, 46.40, 40.43, 14.31; ESI-MS: m/z (MH+): 242.0942 (calc'd), 242.0944 (found).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:16])[C@@H:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:14][O:13][CH2:12][O:11][C:10]=2[CH:15]=1)[OH:5].CCN(C(C)C)C(C)C.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1COCC1>[O:11]1[C:10]2[CH:15]=[C:6]([C@H:4]3[O:5][C:31](=[O:32])[NH:2][C@H:3]3[CH3:16])[CH:7]=[CH:8][C:9]=2[CH2:14][O:13][CH2:12]1
Reactant: C[C@H](N)[C@H](O)c1ccc2c(c1)OCOC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccc2c(c1)OCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated by evaporation, the residual material was partitioned between EtOAc and water, the organic phase was washed with 10% NaHSO4, dried over MgSO4, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:15])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O>CC(O)C.CO>[CH3:15][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CN(C)CCC(O)c1ccccc1
Reaction time: 2 h
Yield: 97 %

Procedure:
Sodium borohydride (6.7 g) was slowly added to a solution of 3-dimethylaminopropiophenone (15.5 g) in 2-propanol (125 ml) and methanol (25 ml). After two hrs, the reaction mixture was stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 15.2 g (97%) of 3-dimethylamino-1-phenyl-1-propanol, as an oil. A solution of 3-dimethylamino-1-phenyl-1-propanol (15 g) in dimethylformamide (75 ml) was slowly added to a suspension of sodium hydride (60% oil-dispersion, washed with hexane, 5.5 g) in dimethylformamide (20 ml). A solution of 4-fluorobenzotrifluoride (18 g) in dimethylformamide (20 ml) was added. After two hrs, the reaction mixture was stirred with ice-water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to provide 27 g (100%) of N,N-dimethyl-3-[ 4-(trifluoromethyl)phenoxy]benzenepropanamine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:12][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:31][CH:30]=3)=[O:28])=[CH:22][CH:23]=2)[NH:18][CH2:17]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:14][N:13]([CH2:15][CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([NH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][CH:34]=3)=[O:28])=[CH:22][CH:23]=2)[N:18]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17]1)[CH3:12]
Reactant: CN(C)CC1CNc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CC1Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.02 ml) was added to pyridine solution (1 ml) of N-[3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydro-7-quinolinyl]-4-biphenylcarboxamide (80 mg) under ice-cooling, which was stirred at room temperature for 1 hour. Further, methanesulfonyl chloride (0.02 ml) was added to the reaction mixture under ice-cooling, which was stirred at room temperature for 12 hours. 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized using THF-IPE to give the titled compound (64 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1.[C:14](OC(OC(C)(C)C)=O)([O:16]C(C)(C)C)=[O:15]>CC#N>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:3]2[O:4][CH2:5][CH2:6][N:1]([C:14]([OH:16])=[O:15])[CH2:2]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(C2CNCCO2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Product: O=C(O)N1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-morpholin-2-yl-phenol (0.99 g; 5.41 mmol) and di-tert-butyl dicarbonate (1.18 g; 5.41 mmol) in CH3CN (50 mL) was stirred at RT for 3 days. Subsequently, the resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, CH2Cl2:CH3OH 97:3) to afford 2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tort-butyl ester (1.15 g).
Reaction SMILES: CO.[OH-].[Na+].C([O:8][C:9]1[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])=[O:12])(=O)C>C1(C)C=CC=CC=1>[C:34]([C:31]1[CH:32]=[CH:33][C:9]([OH:8])=[C:10]([CH:30]=1)[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])=[O:12])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C(C)(C)C)ccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.7 %

Procedure:
Methanol (2 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.26 mL) were added to the obtained methyl 2-(2-acetoxy-5-tert-butylbenzamido)-4-phenylbenzoate (0.023 g), followed by stirring at room temperature for 15 hours. Toluene was added to the reaction mixture. The aqueous layer was separated and adjusted to a pH of 3.0 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.010 g of 2-(5-tert-butyl-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: COC([N:5]1[CH2:10][CH:9]([CH2:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:13][CH3:14])[C:8](=[O:24])N(C)C1C(C)(C)C)=O.Cl.[O:31]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@H:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[CH2:13][CH3:14])[C:8]([OH:24])=[O:31]
Reactant: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Reactant: C1COCCO1
Agent: Cl
Product: CC[C@@H](Cc1ccc(F)cc1F)C[C@H](CN)C(=O)O
Temperature: 110 °C
Yield: 24 %

Procedure:
A flask was charged with 0.5 g (1.2 mmol) of 2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester, 20 mL dioxane, and 20 mL of conc. HCl solution. The mixture was stirred and heated at 110° C. for 4 days. The solvents were removed under reduced pressure. The residue was taken up in 20 mL of water and 4 drops of conc. HCl solution. The aqueous layer was washed with dichloromethane. The aqueous layer was collected and the water was removed under reduced pressure. The residue was treated with 2 mL of triethylamine, and the excess triethylamine was removed under reduced pressure. The remaining solid was purified by column chromatography (1:8:27 NH4OH, MeOH, dichloromethane eluent). The resulting white solid was washed with acetonitrile and dried under vacuum. This gave 80 mg (24% yield) of the titled compound as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([C:22]([C:24]3[CH:25]=[CH:26][C:27]([NH:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38][CH3:39])=[C:28]([CH:33]=3)[C:29]([O:31]C)=O)=[O:23])[N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH:10]=[CH:11][CH:12]=1)=[O:6]>CO>[O:40]=[C:35]1[N:36]([CH2:37][CH2:38][CH3:39])[C:29](=[O:31])[C:28]2[C:27](=[CH:26][CH:25]=[C:24]([C:22]([C:15]3[N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]4=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[C:5]([OH:4])=[O:6])[N:14]=3)=[O:23])[CH:33]=2)[NH:34]1
Reactant: CCCNC(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Temperature: 70 °C
Yield: 100.6 %

Procedure:
1.31 ml (1.31 mmol) of a 1N aqueous solution of sodium hydroxide are added to 0.27 g (0.52 mmol) of methyl 5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-[(propylcarbamoyl)amino]benzoate in 8 ml of methanol. The reaction medium is heated at 70° C. for 5.5 hours. The methanol is concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is acidified with a 1N aqueous solution of hydrochloric acid, and then extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is taken up in methanol and then filtered, and dried at 50° C. under reduced pressure overnight. 0.245 g of a yellow solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])=[O:4].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([N:30](C2C=CC=CC=2)[C:31](=O)[O-:32])[N:23]=1.N12CCCN=C1CCCCC2.CS(O)(=O)=O>O.C(#N)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]=1[S:10]([NH:13][C:31]([NH:30][C:24]1[N:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[N:25]=1)=[O:32])(=[O:12])=[O:11])=[O:4]
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: COC(=O)c1scc(-c2ccccc2)c1S(N)(=O)=O
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1scc(-c2ccccc2)c1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Yield: 88.8 %

Procedure:
2.4 g (0.008 mol) of 2-methoxycarbonyl-4-phenylthiophen-3-ylsulfonamide, 2.2 g of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate, 1.2 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and 30 ml of acetonitrile are stirred for 16 hours at room temperature. The reaction mixture is then poured into a mixture of ice and water and acidified with methanesulfonic acid. The resultant precipitate is filtered, washed with water and dried, affording 3.4 g (95%) of N-(2-methoxycarbonyl-4-phenylthiophen-3-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl)urea with a melting point of 225°-227° C.