Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[N:3]=1.C(N(CC)CC)C.ClC1C(NC=O)=C([NH:33][C@H:34]2[CH2:38][C@@H:37]([CH2:39][OH:40])[CH:36]=[CH:35]2)N=C(NC(=O)C)N=1.CO>C(O)C>[Cl:11][C@H:6]1[C:7]([NH:8][CH:9]=[O:10])([NH:33][C@@H:34]2[CH2:38][C@H:37]([CH2:39][OH:40])[CH:36]=[CH:35]2)[CH:2]=[N:3][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:5]1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(N[C@@H]2C=C[C@H](CO)C2)n1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CO
Product: CC(=O)NC1=N[C@@H](Cl)C(NC=O)(N[C@H]2C=C[C@@H](CO)C2)C=N1

Procedure:
(1S,4R)-4-Amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate prepared as described in Example 13 (2.76 g, 9.02 mmol) was dissolved in water (20 mL) and applied to a column of 65 mL of Amberlite IA-400 (OH- form) anion exchange resin. The column was washed with water. Basic fractions were combined and evaporated to a residual oil which was dried by evaporation of absolute ethanol and then at 0.5 mm to give (1S,4R)-4-amino-2-cyclopentene-1-methanol (1.2 g) as a pale yellow oil (darkens rapidly in air) which was used immediately. This oil was dissolved in ethanol (5 mL) and added to a solution of N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide (2.07 g, 8.31 mmol), prepared as described in Example 15, and triethylamine (2.50 g, 24.8 mmol). The resulting dark solution was heated (oil bath 75°-80° C.) under nitrogen for 50 minutes. The solution was evaporated to a syrup which was applied to a silica gel column. Title compound was eluted with 3 to 5% methanol-chloroform as a pale yellow solid foam (1.59 g, 54%); 1H-NMR identical with that of crystallized sample. Such a sample was crystallized from ethanol to give white granules, m.p. 194°-195° C.; 1H-NMR (DMSO-d6) identical with that of the title compound of Example 15; [α]D20 +2.7°, [α]578 ° +3.6°, [α]54620 +2.9°, [α]43620 -2.5°, [α]36520 -41.2° (c=0.238, methanol).
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[F:33][CH:34]([F:66])[O:35][C:36]1[CH:41]=[CH:40][C:39](/[CH:42]=[C:43](\[NH:50][C:51](=[O:65])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][C:61]([F:64])([F:63])[F:62])=[CH:54][CH:53]=2)/[C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])=[CH:38][CH:37]=1>>[F:66][CH:34]([F:33])[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([NH:50][C:51](=[O:65])[C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][C:61]([F:62])([F:63])[F:64])=[CH:54][CH:53]=2)[C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])=[CH:38][CH:37]=1
Reactant: O=C(NCCO)/C(=C/c1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(OC(F)F)cc1)C(=O)NCCO)c1ccc(OCCC(F)(F)F)cc1
Yield: 68.3 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using N-((Z)-2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)-4-(3,3,3-trifluoropropoxy)benzamide (204 mg) to give 140 mg of the title compound (white powder).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].C1(C=C(O)C=C(O)C=1)O.[CH2:14]([O:16][C:17](=[O:23])[CH:18](I)[CH:19]([CH3:21])[CH3:20])[CH3:15]>CN(C)C=O>[CH2:14]([O:16][C:17](=[O:23])[CH:18]([N+:1]([O-:3])=[O:2])[CH:19]([CH3:21])[CH3:20])[CH3:15]
Reactant: CCOC(=O)C(I)C(C)C
Reactant: O=N[O-]
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(C)C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To an ice cooled solution of 5.31 g sodium nitrite and 8 g dried phloroglucinol in 70 ml dimethyl formamide is added a solution of 11.3 g 2-iodo-3-methyl-butyric acid ethyl ester in 30 ml dimethyl formamide. The solution is allowed to warm up to room temperature and is stirred over night. The solvent is removed at reduced pressure. The residue is dissolved in ethyl acetate and washed with water. The organic layer is dried and the solvent is removed. The title compound is obtained as an oil. MS: m/z (M+)=176.1
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)c1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.61 mmol) was placed in DMF (20 mL) and Cs2CO3 (627 mg, 1.93 mmol) was added. The reaction was stirred for 5 min and 2-chloro-4-(chloromethyl)pyridine (312 mg, 1.93 mmol) was added. The reaction was stirred at 45° C. overnight and was then partitioned between H2O (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with H2O (2×50 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 10%-100% EtOAc) to afford 5-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow solid (420 mg, 60%). MS (ES+) C18H12ClF3N6O2 requires: 436. found 437 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.42 (d, J=5.1 Hz, 1H), 8.28 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 7.05 (d, J=5.1 Hz, 1H), 5.46 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:7]=1.[OH-].[NH4+:21].[NH4+]>CC(O)C>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:21])[N:10]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1Nc1ccnc(Cl)n1
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nccc(Nc2cc(Br)c(F)cc2[N+](=O)[O-])n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution of N-(5-bromo-4-fluoro-2-nitrophenyl)-2-chloropyrimidin-4-amine (1.05 g, 3.02 mmol) in 2-propanol (12 mL) in a pressure vessel was added ammonium hydroxide (12 mL, 303 mmol) carefully at RT. The reaction vessel was sealed and stirred at 90° C. for 15 hr (4 bar). Extra aqueous ammonium (4 mL, 100 mmol) was added and the reaction heated at 90° C. for 1 hr then cooled to 0° C. The resultant orange precipitate was filtered and dried by suction filtration to afford the title compound as an orange solid (713 mg, 63% yield); 1H NMR (500 MHz, DMSO) delta 9.55 (s, 1H), 8.44 (d, J=6.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 6.31 (s, 2H), 6.19 (d, J=5.6 Hz, 1H); LC-MS: m/z+329.80 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[CH2:6][CH2:7][CH3:8].C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][NH:3][O:2][CH3:1]
Reactant: CCCC(C=NOC)c1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC(CNOC)c1ccc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-pentanal O-methyl-oxime (6.0 g, 23 mmol) in acetic acid (50 ml) was treated at 10° C. with sodium cyanoborohydride (2.90 g, 46 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 24° C. for 4 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water and pH was adjusted to 11 with 1M NaOH. The aqueous phase was extracted with dichloromethane (2×50 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent (100 mbar; 45° C.), the residue (6.2 g) was purified by flash chromatography over silica gel (250 g; eluent: c-hexane). 5.15 g (79.0% of theory) of N-[2-(2,4-dichlorophenyl)-pentyl]-O-methyl-hydroxylamine was obtained in form of a clear liquid.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:2][CH3:3])[CH:6]=1
Reactant: Sc1cccc(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The reaction was concentrated in vacuo to give 1-bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](Br)(Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([NH:31][NH2:32])(=[O:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[N:32][NH:31][C:20](=[O:30])[C:21]3[CH:29]=[CH:28][C:27]4[O:26][CH2:25][O:24][C:23]=4[CH:22]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2(Br)Br
Reactant: NNC(=O)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNC(=O)c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 24.2 %

Procedure:
2.0 g. (0.005 moles) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester and 0.9 g. (0.005 moles) of piperonylic acid hydrazide are dissolved in 80 ml. of pyridine. The solution is allowed to stand for two days whereupon the solvent is distilled off in vacuo. To the residue 30 ml. of water are added. After a short standing the crystals are filtered off and recrystallized from methanol. 0.5 g. (24.2%) of 6-methyl-9-(3,4-methylenedioxybenzoylhydrazono)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are obtained, melting at 183° to 185° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:25]([C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:29][C@@H:28]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])#[N:26].N1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:42][C:39]3[CH:38]=[CH:37][C:36]([C@@:27]4([C:25]#[N:26])[CH2:29][C@@H:28]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:41][CH:40]=3)=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc([C@@]4(C#N)C[C@@H]4CCCCCC)cc3)cc2)cc1
Reaction time: 8 h
Yield: 36.8 %

Procedure:
In 8 ml of dichloromethane were dissolved 66 mg of 4-(4-octyloxyphenyl)benzoyl chloride and 36 mg of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane as obtained in Example 11. Thereto was added 0.5 ml of pyridine. The resulting mixture was stirred for 8 hours with refluxing, and then cooled. Thereafter, 50 ml of ether was added to the reaction mixture, and the resulting mixture was washed with diluted hydrochloric acid, water, and saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was separated and purified by silica gel column chromatography (solvent: hexane/ethyl acetate=5/1). Thus, 30 mg of the desired compound was obtained as colorless crystals.
Reaction SMILES: BrC1C2C(=CC(F)=CC=2)C(=O)NC=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.FC1C=C2C(C(B3OC(C)(C)C(C)(C)O3)=CN(C)C2=O)=CC=1.ClC1C(OCC2CC2)=CN=C(S(C)(=O)=O)N=1.[CH:70]1([CH2:73][O:74][C:75]2[C:76]([C:85]3[C:94]4[C:89](=[CH:90][C:91]([F:95])=[CH:92][CH:93]=4)[C:88](=[O:96])[N:87]([CH3:97])[CH:86]=3)=[N:77][C:78](S(C)(=O)=O)=[N:79][CH:80]=2)[CH2:72][CH2:71]1.[CH2:98]([S:100]([NH2:103])(=[O:102])=[O:101])[CH3:99]>>[CH:70]1([CH2:73][O:74][C:75]2[C:76]([C:85]3[C:94]4[C:89](=[CH:90][C:91]([F:95])=[CH:92][CH:93]=4)[C:88](=[O:96])[N:87]([CH3:97])[CH:86]=3)=[N:77][C:78]([NH:103][S:100]([CH2:98][CH3:99])(=[O:102])=[O:101])=[N:79][CH:80]=2)[CH2:71][CH2:72]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccc(F)cc2c1=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(F)cc2c1=O
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3cc(F)ccc23)n1

Procedure:
The title compound of Example 58, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-one was treated with with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3 400 MHz) δ 8.53 (dd, J1=8.8 Hz, J2=6.0 Hz, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J=8.8 Hz, 1H), 7.27-7.23 (m, 1H), 3.88 (d, J=6.8 Hz, 2H), 3.69 (s, 3H), 3.60 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.16-1.13 (m, 1H), 0.62-0.56 (m, 2H), 0.27-0.26 (m, 2H). LCMS: 433.2 (M+1)+
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1.[CH3:17]I>C1COCC1>[F:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[N:9]([CH3:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1
Reactant: CI
Reactant: CC1(C)NC(=O)c2ccc(F)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(F)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% dispersion in oil) (112 mg, 2.82 mmol) was added to a solution of 7-fluoro-2,2-dimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (0.5 g, 2.56 mmol) in THF (10 mL) at 0° C., under argon then the mixture allowed to warm to RT and methyl iodide (0.18 mL, 2.82 mmol) added. The reaction was stirred at RT for 24 hours, poured into ice/water (50 mL) and extracted into ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 30-60% ethyl acetate in isohexane, to give the desired compound as a colourless oil (0.36 g). 1H NMR δ (CDCl3): 1.65 (s, 6H), 3.08 (s, 3H), 6.61 (dd, 1H), 6.75-6.80 (m, 1H), 7.93-7.96 (m, 1H); m/z 210 (M+H)+
Reaction SMILES: [NH2:1][C@:2]([CH3:13])([CH2:5][CH2:6][C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:15].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cn1cccc1CC[C@@](C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1cccc1CC[C@]1(C)COC(=O)N1
Yield: 53.1 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 D-(−)tartrate (41.4 mg, 0.16 mmol) obtained above in dichloromethane (1.6 ml) was added successively di-t-butyl dicarbonate (0.1758 g, 0.81 mmol), triethylamine (0.225 ml, 1.62 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2-2:1) as the eluent to afford (4R)-4-methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.7 mg, yield: 53%).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:16]([CH3:28])[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[C:30]([Si:33]([CH3:35])([CH3:34])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH2:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[C:16]([CH3:28])[CH:15]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=1[CH3:13])([CH3:32])([CH3:31])[CH3:29]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Yield: 90.2 %

Procedure:
Using a procedure analogous to Example 13A, 1-{(4-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (Example 1B) (4.91 g, 12.83 mmol) and TBSCl (1.93 g, 12.83 mmol) give the title compound (5.74 g, 11.57 mmol, 90%). 1H NMR (CDCl3), δ 0.21 (s, 6H), 0.60 (t, J=7.5 Hz, 6H), 1.01(s, 9H), 1.26 (s, 9H), 2.01 (q, J=7.5 Hz, 4H), 2.16 (s, 3H), 2.24 (s, 3H), 4.83 (s, 2H), 6.50 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (dd, J=8.4, 2.3 Hz, 1H), 6.87-6.93 (m, 3H). LC/MS (m/z): calcd for C31H52NO3Si (M+NH4)+: 514.8; found: 514.5.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:11]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(pyridin-2-yl)benzoic acid. ESI-MS (m/z): 324 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[C:9](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1.[OH-].[Na+]>CN(C=O)C.O>[CH3:9][N:3]1[C:4]([CH:7]=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc(C=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(C=O)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 16 %

Procedure:
In DMF (10 mL) was dissolved 2-methyl-1H-imidazole-5-carbaldehyde (1.00 g, 9.08 mmol). Potassium carbonate (2.51 g, 18.2 mmol) and methyl p-toluenesulfonate (2.06 mL, 13.6 mmol) were added under ice-cooling and the mixture was stirred at room temperature for 6 hours. A 1 mol/L aqueous sodium hydroxide solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with a 1 mol/L aqueous sodium hydroxide solution and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 1,2-dimethyl-1H-imidazole-5-carbaldehyde (180 mg, 16% yield).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47](=O)[CH3:48])[CH:42]=[C:43]([O:45][CH3:46])[CH:44]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:47]([C:41]2[CH:40]=[C:39]([O:38][CH3:37])[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=2)[CH:48]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 35 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,5-dimethoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (44 mg, 35% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[C:26]([CH3:33])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[C:26]([CH3:33])[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cc(Cl)ccc1N=C=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4C)cc3)c2cc1OC
Yield: 80.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (55 mg) was dissolved in toluene (5 ml) with heat, 4-chloro-2-methylphenyl isocyanate (90 mg) was added, and the admixture was refluxed with heat for 26 minutes. The separated crystals were filtered and then washed with toluene to obtain 69 mg of the title compound (yield: 80%).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:18][CH:17]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>CO>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[C:11]2=[O:33])=[CH:21][CH:20]=1
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N4C(=O)c5ccccc5C4=O)cc3)C2=O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N)cc3)C2=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}isoindol-1,3-dione (E) (654 mg, 1.4 mmol) in MeOH (30 mL) hydrazine hydrate was added as a 0.8 M solution in MeOH (10 mL, 8 mmol) with stirring at RT. The reaction mixture was stirred for 90 min at RT and then H2O (50 mL) was added. The solvent was removed in vacuo and the residue was extracted with EtOAc (3×20 mL). The combined organic phases were dried over Na2SO4 and the solvent again removed in vacuo. There were obtained 430 g (91% of theory) of the desired product 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-imidazolidin-2-one (F).