Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:30][S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:42][CH:41]=2)=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)cc1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 4-(methylsulfonyl)benzoic acid (16.09 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 39%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.59 (t, 1H), 8.11-8.18 (m, 2H), 8.00-8.07 (m, 2H), 7.63 (t, 1H), 7.47-7.53 (m, 1H), 7.41-7.45 (m, 1H), 7.36-7.41 (m, 2H), 4.70 (d, 2H), 3.16 (s, 3H). LCMS m/z 494.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>C(O)C>[CH:10]1([CH2:9][S:7][C:3]2[N:2]([CH3:1])[CH:6]=[N:5][N:4]=2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: Cn1cnnc1S
Solvent: CCO
Product: Cn1cnnc1SCC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To 4-methyl-4H-1,2,4-triazole-3-thiol (5.2 g, 45 mmol) in absolute ethanol (30 mL) under nitrogen was added (bromomethyl)cyclopropane (4.50 mL, 46 mmol). The reaction was stirred at room temperature for 24 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and sat aq. Na2CO3 solution. The layers were separated and the aqueous phase further extracted with ethyl acetate (×3). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a colourless oil (4.795 g, 28 mmol). 1H NMR (500 MHz, CDCl3) δ (ppm) 8.14 (1H, s), 3.62 (3H, s), 3.17 (2H, d, J=7.3 Hz), 1.27-1.15 (1H, m), 0.63-0.59 (2H, m), 0.30-0.27 (2H, m); m/z (ES+) 170 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][OH:24].C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][OH:24])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCC[C@H]2CO)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 69.9 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.287 mmol), (S)-(+)-2-pyrrolidinemethanol (Aldrich Chemical Company) (0.14 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL) to give 61.9 mg (70%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. Mp: 255-256° C. 1H NMR (CDCl3; 500 MHz): δ 2.06-2.14 (m, 4), 2.54 (s, 3), 3.76 (d, 1, J=9.23), 3.84 (dd, 1, J=2.0, 11.1), 3.96-3.98 (m, 1), 4.11 (q, 1, J=7.6, 7.9), 4.55-4.57 (m, 1), 6.68 (s, 1), 7.35-7.45 (m, 3), 7.61 (d, 2, J=7.4), 9.17 (br s, 1). MS m/z: 167 (base), 307 (M−1). Anal. Calcd for C 18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 70.00; H, 6.59; N, 18.11.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH2:22]([N:24]1[CH2:28][CH2:27][C:26]2([CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25]1)[CH3:23]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:30]3[CH2:31][CH2:32][C:26]4([CH2:27][CH2:28][N:24]([CH2:22][CH3:23])[CH2:25]4)[CH2:29]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCN1CCC2(CCNC2)C1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Product: CCN1CCC2(CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(CC)c4c3F)C2)C1

Procedure:
The title compound was prepared according to example 26 by reacting 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 2-ethyl-2,7-diazaspiro[4.4]nonane dihydrochloride, mp 199°-202° C. (dec).
Reaction SMILES: CC1C[O:5][C:4]2([CH2:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([CH3:15])=[CH:7]2)O1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].O.[Li]>CCCCCC>[CH2:16]([C:9]1([OH:14])[C:10]([CH3:12])([CH3:13])[CH2:11][C:4](=[O:5])[CH:7]=[C:8]1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Agent: [Li]
Solvent: CCCCCC
Solvent: O
Product: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 2,7,9,9-tetramethyl-1,4-dioxaspiro[4,5]dec-6-en-8-one (prepared by the method of Example III) in hexane is stirred while a solution of n-butyl lithium in hexane is added dropwise. When no additional exotherm occurs, the addition is stopped and the mixture is stirred for about 15 minutes. Water is added with stirring to hydrolyze the lithium salt. The organic layer is separated, and the hexane is allowed to evaporate leaving oily crystals which are recrystallized from cyclohexane yielding 10 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one, melting point 90-93° C. The compound exhibits the following spectral characteristics:
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][O:10][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br

Procedure:
(S)-3-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propan-1-ol (130 mg), methanesulfonyl chloride (0.073 mL) and triethylamine (0.264 mL) are stirred in 5 mL of dichloromethane at room temperature overnight. The reaction mixture is washed with citric acid saturated aqueous solution and with brine. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound, used in the next step without further purification. Yield: 148 mg.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][C:15](C(OC)=O)([C:16]([O:18]C)=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.FC1C=CC(C(C2N3CCC(C(OC)=O)C3=CC=2)=O)=CC=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: COC(=O)C1CCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCC2C(=O)O
Yield: 80 %

Procedure:
A solution of the mixture of dimethyl 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate and methyl 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (0.200 g) in methanol (5 ml) and water (3 ml) containing potassium hydroxide (0.5 g) was heated at reflux temperature for 1 hour. The solvent was removed in vacuo, water was added to the residue and the solution waas made acidic with 10% hydrochloric acid solution. The product was extracted into ethyl acetate, the extract was dried and evaporated. The solid residue on crystallization from ethyl acetate-hexane gave 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (0.124 g, 80%) m.p. 163°. A mixed m.p. with an authentic specimen (m.p. 170°) had m.p. 165°. The IR spectrum was identical to that of the authentic sample.
Reaction SMILES: O1CCOCC1.Cl.C(OC([NH:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1>O1CCOCC1>[NH2:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: COc1ccccc1
Product: NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 0.5 h

Procedure:
An HCl dioxane solution (4N, anhydrous, 0.27 mL) was added to 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole (54) (50.0 mg, 0.11 mmol), anisole (59 ml, 0.55 mmol), and dioxane (4 mL) in one portion. After 30 min at 23° C., the reaction was concentrated with a stream of nitrogen in a hood. The residue was diluted with saturated bicarbonate (30 mL), extracted with ethyl acetate (3×50 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate: methanol 19:1) to afford 6-(2′-amino-1-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (55): Mass Spectrum (CI) 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:27])[C:5]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:20])[C:11]([C@H:14]([NH:16]C(=O)C)[CH3:15])=[N:12][CH:13]=2)[CH:7]=1.Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:27])[C:5]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:20])[C:11]([C@H:14]([NH2:16])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1
Reactant: CC(=O)N[C@H](C)c1ncc(-c2cc(Cl)cc(F)c2-c2noc(C)n2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)N)c(F)c2)no1
Temperature: 75 °C

Procedure:
A suspension of N—((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-acetamide (195 mg, 0.496 mmol, step A) in 2N HCl (2.5 ml, 5.00 mmol) was heated to 75° C. overnight. The colorless solution was cooled to room temperature, diluted with water and the pH was adjusted to 12 by addition of 1N NaOH. The mixture was then extracted three times with EtOAc and the combined organic layers were washed with brine (pH adjusted to 12 with 1N NaOH), dried with Na2SO4 and evaporated. The crude title compound (167 mg, 96%, light yellow gum) was used in the next reaction step without further purification. MS: 351.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][OH:20].C(O)(C)C>CC(OC)(C)C>[CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: CCOc1cc2ccc(=O)oc2cc1O
Reactant: OCCCCl
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CCOc1cc2ccc(=O)oc2cc1OCCCO
Yield: 69 %

Procedure:
Method K; starting materials: 6-ethoxy-7-hydroxy-2H-1-benzopyran-2-one and 3-chloro-1-propanol; yield 69%; fusion point 96°-98° C. (from isopropanol and TBME).
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O>C(Cl)Cl>[CH2:1]([C@@H:8]([C@@H:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:12])[CH:9]=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CO[C@@H](C)[C@@H](CO)Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H](C)[C@@H](C=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3((4-methoxybenzyl)oxy)butan-1-ol (5.38 g, 17.91 mmol) in CH2Cl2 (90 mL) in a nitrogen flushed 250 mL round bottomed flask was added DMSO (17.9 mL, 25.24 mmol) and TEA (12.5 mL, 90 mmol) via syringe followed by sulfur trioxode-pyridine complex (8.55 g, 53.7 mmol) in three equal portions at 0° C. under N2. The reaction was removed from the cold bath and allowed to warm to room temperature, and stirred for 2 h. The reaction was diluted with ice cold 0.5 N HCl (100 mL) and EtOAc (150 mL). The phases were separated and the organic phase was washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL). The solution was dried over magnesium sulfate (MgSO4), filtered, and concentrated to afford the title compound (5.3 g, 96%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.78 (d, J=2.8 Hz, 1H), 7.29-7.09 (m, 7H), 6.89 (d, J=8.7 Hz, 2H), 4.56 (d, J=11.3 Hz, 1H), 4.34 (d, J=11.3 Hz, 1H), 3.82 (s, 3H), 3.03 (dd, J=14.0, 8.2 Hz, 1H), 2.87 (dd, J=14.0, 6.4 Hz, 2H), 2.78-2.55 (m, 1H), 1.29 (d, J=6.4 Hz, 3H); ESIMS m/z 321.3 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][CH2:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[N:22]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cccc(CNc2cccc(OCc3ccccc3)c2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 3-benzyloxyaniline (0.70 g, 3.51 mmol) in 1,2-dichloroethane (10 ml) were added 6-bromo-pyridine-2-carboxaldehyde (0.65 g, 3.51 mmol), sodium triacetoxyborohydride (1.49 g, 7.03 mmol) and acetic acid (0.80 ml, 14.1 mmol). The reaction mixture was shaken at 40° C. overnight. For work-up dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=3:1) to yield an orange oil (1.03 g, 80%); MS (ISP): 371.1 ([81Br M+H]+), 369.1 ([79Br M+H]+).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25](=[O:40])[CH2:26][C:27]2[NH:28][C:29](=[O:39])[CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:32]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25](=[O:40])[CH2:26][C:27]2[NH:28][C:29](=[O:39])[CH:30]=[C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:32]=2)=[C:17]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(F)ccc2NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.7 %

Procedure:
1.5 ml of 4M hydrochloric acid in dioxane are added to a solution of 223 mg of 4-{5-fluoro-2-[2-(4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetylamino]phenoxymethyl}piperidine-1-carboxylic acid tert-butyl ester in 6 ml of ethanol. After stirring at ambient temperature for 20 h, the reaction medium is concentrated under reduced pressure, taken up with a solution of aqueous ammonia in methanol, and then again concentrated to dryness. After purification by silica column chromatography, eluent: 90/10 CH2Cl2/MeOH, 65 mg of N-[4-fluoro-2-(piperidin-4-ylmethoxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.C(=O)([O-])[O-:26].[Na+].[Na+]>C(O)(=O)C>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=[O:26]
Reactant: CCOC(=O)Cc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetramine are dissolved in 200 ml of 20% acetic acid, heated to 100° C. with stirring and stirred for four hours. The reaction solution is allowed to cool and sufficient sodium carbonate is added until a saturated solution is obtained. This solution is extracted with ether, dried and the ether is then removed. The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CN1C2C(=CC=CC=2)C(C(Cl)=O)=C1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]4[C:30]5[C:35]([CH:36]=[CH:37][C:22]3=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:17][CH:16]=2)=[O:13])=[CH:3]1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: Cn1cc(C(=O)Cl)c2ccccc21
Product: Cn1cc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c2ccccc21
Yield: 14.7 %

Procedure:
1-Methyl-1H-indole-3-carboxylic acid (55 mg, 0.314 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, and 1-methyl-1H-indole-3-carboxylic acid chloride mentioned above, the title compound (11 mg, yield 15%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.[N:50]1([C:56]2[CH:65]=[C:64]3[C:59]([CH2:60][CH2:61][CH2:62][CH:63]3[NH2:66])=[CH:58][CH:57]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[N:50]1([C:56]2[CH:65]=[C:64]3[C:59]([CH2:60][CH2:61][CH2:62][CH:63]3[NH:66][C:32](=[O:34])/[C:31](=[CH:35]/[C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]4)=[C:38]([O:48][CH3:49])[CH:37]=3)/[CH2:30][CH2:29][CH2:28][Cl:27])=[CH:58][CH:57]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: NC1CCCc2ccc(N3CCOCC3)cc21
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(/C=C(\CCCCl)C(=O)NC2CCCc3ccc(N4CCOCC4)cc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
IPEA (330 μL), EDC (181 mg) and HOBT (128 mg) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (276 mg) and 7-morpholin-4-yl-1,2,3,4-tetrahydronaphthalen-1-ylamine (110 mg) in DMF (3.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 213 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11]C(=O)C)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[OH:11])=[O:4]
Reactant: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of example 1 (3.6 g, 9.57 mmol) in MeOH (40 ml) was added K2CO3 (2.7 g, 19.5 mol). The mixture was stirred at room temperature for about 1 hour and then filtered. The filtrate was concentrated into dryness to give the titled product (crude yield 100%) as yellow solid, which was used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1cc(CBr)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCNCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1

Procedure:
A solution of 518.4 mg (1.0 mmole) of the product of Example 279, 0.5 ml (4.8 mmol) of diethylamine and 0.172 ml (2.0 mmol) of pyridine in 10 ml of dichloromethane was stired at room temperature for 18 hr. The resulting mixture washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 2% MeOH/CH2Cl2 as eluant to provide 425 mg (83%). Electrospray Mass Spec 511 (M+H).
Reaction SMILES: C1(S([CH:9]([C:20]2[O:21][C:22]([Br:25])=[CH:23][CH:24]=2)[CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])=O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:25][C:22]1[O:21][C:20](/[CH:9]=[CH:10]/[NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: O=C(NCC(c1ccc(Br)o1)S(=O)c1ccccc1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(N/C=C/c1ccc(Br)o1)c1ccccn1

Procedure:
The mixture of pyridine-2-carboxylic acid [2-benzenesulfinyl-2-(5-bromofuran-2-yl)ethyl]amide (0.11 g, 0.2623 mmol) and Na2CO3 (0.03 g, 0.2623 mmol) in toluene was refluxed in nitrogen atmosphere for 2 h. The toluene solution was washed with 1 M NaOH (25 ml), dried with Na2SO4 and evaporated. The crude product was purified by flash chromatography using heptane-EtOAc as a gradient eluent (90:10-80:20). The E isomer was used in the next step.