Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]2[CH2:10][O:11][C:12]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:7]2=[CH:6][CH:5]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]>CN(C=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]2([C:40]([F:43])([F:42])[F:41])[O:1][N:2]=[C:3]([C:4]3[N:9]=[C:8]4[CH2:10][O:11][C:12]5([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]5)[C:7]4=[CH:6][CH:5]=3)[CH2:39]2)[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=NO)ccc12
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of tert-butyl 2′-((hydroxyimino)methyl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-carboxylate (0.520 g, 1.705 mmol, 1 eq) in DMF (12 mL) was added NCS (0.272 g, 2.046 mmol, 1.2 eq) at room temperature in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 45° C. for 1 hour. After chloro intermediate formation, 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (0.530 g, 2.046 mmol, 1.2 eq) was added followed by addition of KHCO3 (0.255 g, 2.557 mmol, 1.5 eq). Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere. After complete consumption of chloro intermediate, reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×100 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (1.2 g, Crude). Crude compound was purified by column chromatography in 100-200 mesh size silica gel. Desired compound was eluted in 10% ethylacetate in hexanes to afford title compound as white semisolid (0.800 g, impure). Impure compound was used as such for next reaction. 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.84 (d, J=18.2 Hz, 1H), 4.10 (dd, J1=2.54 Hz, J2=9.5 Hz, 2H), 4.22 (d, J=18.16 Hz, 1H), 4.33 (dd, J1=3 Hz, J2=9.44 Hz, 2H), 5.02-5.10 (m, 2H), 7.56 (d, J=6 Hz, 2H), 7.84 (d, J=8.04 Hz, 1H), 8.03 (d, J=8.04 Hz, 1H). LC-MS (m/z): 59.6 (M−H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[CH2:11](CN)[OH:12]>>[OH:12][CH2:11][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:10]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: NCCO
Product: Cc1c(O)c(=O)ccn1CCO

Procedure:
A reaction analogous to that used for the synthesis of 3-hydroxy-1,2-dimethyl-4- pyridinone was employed, starting with ethanolamine (0.44 g). No precipitate was observed after concentration. Recrystallization from ethanol and diethyl ether resulted in a white powder (0.53 g). Proton NMR (D20): 7.82 (d, 1H), 6.89 (d, 1H), 4.27 (t, 2H), 3.74 (t, 2H), 2.36 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:26])([CH3:25])[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:25][C:8]1([CH3:26])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]1=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(C)(C)c2nccnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of tert-butyl 4-(2-(3-chloropyrazin-2-yl)-2-methylpropanamido)piperidine-1-carboxylate (2.8 g, 7.31 mmol) and cesium carbonate (7.15 g, 21.94 mmol) in DMSO (25 mL) was stirred at RT overnight. H2O was added, extracted with EtOAc (3×). The extracts were dried over MgSO4, concentrated, purified by ISCO (30% EtOAc/Hexanes) to give the title compound (2.15 g, 85%). MS (M+1): 347.1
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:42])[CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-4-fluoro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example M38) (375 mg, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (115 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:26]([F:29])([F:28])[F:27])=[N:19][C:20]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[CH3:24][N:22]([CH3:23])[C:21]([C:20]1[N:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:13][C:14]=12)=[O:25]
Reactant: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 98 %

Procedure:
(R)-[3-(1-Dimethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (0.138 g, 0.245 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid dimethylamide hydrochloride 9 (0.12 g, yield 98%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH2:20]([OH:23])[C:21]#[CH:22].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11]([C:22]#[C:21][CH2:20][OH:23])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCO)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate (1.38 g, 3.95 mmol) obtained in Example 47 (c) was dissolved in dimethylformamide (20 ml), and then propargylalcohol (0.69 ml, 11.9 mmol), triethylamine (5.60 ml, 40.1 mmol), copper(I) iodide (76 mg, 0.40 mmol), and dichlorobis(triphenylphosphine)palladium (276 mg, 0.39 mmol) were added thereto followed by stirring for 1 hour at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and after the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:3) to afford the title compound (685 mg, 54% yield) as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13]1([CH3:21])[CH2:18][CH:17]([CH:19]=O)[CH2:16][CH2:15][O:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:19]([CH:17]1[CH2:16][CH2:15][O:14][C:13]([CH3:21])([CH3:12])[CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1(C)CC(C=O)CCO1
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(C2CC(=O)c3cc(Br)ccc3O2)CCO1
Yield: 76.2 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (13.5 g, 62.78 mmol), 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (9.40 g, 62.78 mmol) and pyrrolidine (5.22 mL, 62.78 mmol) in MeOH (125 mL) was heated to reflux for 3 h. The mixture was allowed to reach r.t. and then concentrated. The residue was dissolved in EtOAc (100 mL) and washed with 1M NaOH (60 mL), 1M HCl (60 mL), and brine (60 mL) successively. The organic phase was concentrated and the residue was purified by flash chromatography with a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to give the title compound (16.22 g, 76% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (m, 6H), 1.26 (m, 2H), 1.52 (m, 1H), 1.76 (m, 1H), 2.12 (ddd, 1H), 2.65 (m, 1H), 2.83 (m, 1H), 3.57 (m, 1H), 3.66 (m, 1H), 4.32 (ddd, 1H), 7.05 (dd, 1H), 7.70 (dd, 1H), 7.78 (d, 1H); MS (ES−) m/z 337 [M−H].
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:18].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C([O-])(=O)C>[NH2:3][C:4]1[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([Br:1])[N:8]2[CH3:18]
Reactant: BrBr
Reactant: Cn1cnc2c(N)nc(CCCCO)nc21
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: C1COCCO1
Product: Cn1c(Br)nc2c(N)nc(CCCCO)nc21
Reaction time: 0.17 h

Procedure:
Bromine (0.4 ml, 6.8 mmol) was added dropwise, at −14° C., to 4-(6-amino-9-methyl-9H-purin-2-yl)butan-1-ol (250 mg, 1.13 mmol) dissolved in a mixture of dioxane (5 ml) and acetate buffer pH 4 (2.5 ml) (obtained by dissolving 4 g of sodium acetate in 100 ml of water and by adjusting to pH 4 with glacial acetic acid). The reaction was stirred at this temperature for 10 minutes and then at RT for 15 minutes. Excess of bromine was eliminated with sodium metabisulphite and the reaction brought to pH 8 by addition of saturated solution of Na2CO3. The aqueous phase was extracted with DCM (6×10). The organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure, to give a residue that was used for the following reaction without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:33]1([C:39]2[S:40][CH:41]=[C:42]([C:44]3[N:52]=[CH:51][CH:50]=[CH:49][C:45]=3[C:46]([OH:48])=O)[N:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[CH2:54]([O:56][C:57](=[O:69])[CH:58]([OH:68])[CH:59]([NH3+:67])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH3:55]>ClCCl>[OH:68][CH:58]([CH:59]([NH:67][C:46](=[O:48])[C:45]1[CH:49]=[CH:50][CH:51]=[N:52][C:44]=1[C:42]1[N:43]=[C:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:40][CH:41]=1)[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:57]([O:56][CH2:54][CH3:55])=[O:69]
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)c1cccnc1-c1csc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (700 mg, 3.65 mmol), 1-hydroxybenzotriazole hydrate (550 mg, 3.59 mmol) and N,N-diisopropylethylamine (DIPEA) (1.2 ml, 6.87 mmol) were successively added to a solution of (2-phenylthiazol-4-yl)nicotinic acid (820 mg, 2.90 mmol) and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride (800 mg, 3.08 mmol) in dichloromethane (70 ml) at 5° C., and the mixture stirred at 5° C. for about 5 minutes. A pH of 8 was adjusted by adding 0.6 ml of DIPEA, the mixture stirred for 1 hour at 5° C. and then overnight at room temperature. The mixture then was concentrated under reduced pressure, poured into 200 ml of water, the precipitate formed was filtered off with suction and dried in vacuo to give 1.33 g of the title product as white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[N:66]1([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:69]3[CH2:68][CH2:67][N:66]([CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])[CH2:71][CH2:70]3)=[O:17])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)c3s2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydrous tetrahydrofuran (10 ml) was heated at 60° C. for 10 minutes, followed by addition of ethyl piperazinoacetate (57 mg, 0.33 mmol). Heating was continued at 60° C. for 30 minutes and the mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate as white solid. Yield: 73 mg, 54%.
Reaction SMILES: C(O[CH:4]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1)[C:5]([F:8])([F:7])[F:6])C.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[H-].[Na+].Cl>O1CCCC1.CCOC(C)=O.O>[F:8][C:5]([F:6])([F:7])[CH:4]([CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1
Reactant: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 83.2 %

Procedure:
To a solution of 318 (470 mg, 1.01 mmol) and diethyl malonate (0.17 mL, 1.11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added sodium hydride (60% in oil, 89 mg, 2.22 mmol). The mixture was heated to reflux for 2 h, cooled, diluted with EtOAc and water and acidified to pH 3 using a 1N HCl solution. The organic layer was separated and the aqueous layer extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 20:80) to afford 319 (490 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.2 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.24 (t, J=9.2 Hz, 1H), 6.98 (dd, J=13.6, 2.8 Hz, 1H), 6.72 (dd, J=9.2, 2.8 Hz, 1H), 6.62 (d, J=10.0 Hz, 1H), 6.46 (d, J=5.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.23-4.07 (m, 4H), 3.91 (d, J=9.2 Hz, 1H), 3.72 (s, 3H), 1.18 (t, J=7.0 Hz, 3H), 1.11 (t, J=7.0 Hz, 3H). LRMS (M+1) 581.0 (100%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:24]1>CS(C)=O>[CH3:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:4][CH2:37]2)[CH2:24]1
Reactant: C=C(CO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1)C(=O)OCC
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(CO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At room temperature, 12 mg of a 60 percent strength sodium hydride suspension are added to a suspension of 55 mg of trimethylsulfonium iodide in 2 ml of DMSO, and the mixture is stirred at room temperature for 20 min. At 10° C. 100 mg of ethyl (1R,3S)-2-[3-(5-methyl-2-m-tolyloxazol4-ylmethoxy)cyclohexyloxymethyl]acrylate, dissolved in 2 ml of DMSO, are then added, and the mixture is stirred at room temperature for 90 min. The mixture is poured into ice-water and extracted with methyl tert-butyl ether. The organic phase is dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=2:1). This gives ethyl (1R,3S)-1-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]cyclo-propanecarboxylate as a colorless oil. C25H33NO5 (427.55), MS (ESI): 428 (M+H+).
Reaction SMILES: [CH:1]([NH:8][C:9](=[N:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:10][CH2:11][CH:12]=[CH2:13])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].[CH2:23]([N:41]=[C:42]=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[CH:1]([N:8]([C:42](=[O:43])[NH:41][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:9](=[N:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:10][CH2:11][CH:12]=[CH2:13])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: C=CCSC(=NCCCCCCCC)NC(C)CCCCC
Solvent: C1CCOC1
Product: C=CCSC(=NCCCCCCCC)N(C(=O)NCCCCCCCCCCCCCCCCCC)C(C)CCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure and equipment were the same as in Example 26. 1.9 g (0.006 mole) 1-sec-heptyl-3-n-octyl-2-S-allyl isothiourea was mixed with 25 ml of tetrahydrofuran to which 1.77 g (0.006 mole) n-octadecylisocyanate was added to the mixture. The reaction mixture was then stirred at ambient temperature overnight and then vacuum evaporated to produce 3.79 g (100 weight percent of theory yield) of a clear liquid having a nD30 of 1.4769. The product was identified as the title product by IR and NMR spectra analyses. Compound No. 144 in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COCCOC1CCN(c2ccc(N)cc2C#N)CC1
Product: COCCOC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 19.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.13 g) and 5-amino-2-[4-(2-methoxyethoxy)piperidin-1-yl]benzonitrile (0.14 g), the title compound (0.05 g) was obtained, melting point: 180–182° C.
Reaction SMILES: C(Cl)C1C=CC=CC=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[Li+].[N-:27]([S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29].C(OCC)(=O)C>O>[N-:27]([S:28]([C:31]([F:34])([F:32])[F:33])(=[O:30])=[O:29])[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36].[CH2:18]([SH+:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(CSCc2ccc(O)cc2)cc1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: ClCc1ccccc1
Solvent: CCOC(C)=O
Product: Oc1ccc(C[SH+]Cc2ccccc2)cc1
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
30 g (0.11 mol) of benzyl-4-hydroxyphenylmethylsulfonium chloride obtained by reacting benzyl chloride with 4-hydroxyphenylmethyl sulfide was dissolved in 500 mL of water, 33.9 g (0.118 mol) of bis(trifluoromethane sulfonyl)imide lithium and 500 mL of ethyl acetate were added thereto, and then stirred at 5 to 10° C. for two hours. The water layer was removed, the organic layer was dried, and then the reaction solution was concentrated under reduced pressure and dried under vacuum. The resulting oily matter was treated with hexane, and then dried under vacuum again. Then, 44.1 g of benzyl-4-hydroxyphenylmethylsulfonium bis(trifluoromethane sulfonyl)imide was obtained in a white crystal (yield: 76.7%). The melting point was 76 to 80° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C@@H:21]3[C@@H:25]([OH:26])[CH2:24][CH2:23][NH:22]3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].[CH:29](=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C@@H:21]3[C@@H:25]([OH:26])[CH2:24][CH2:23][N:22]3[CH2:29][CH3:30])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@H]3NCC[C@@H]3O)c3ccc(C#N)cc23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1CC[C@H](O)[C@H]1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A solution of [(S)-7-cyano-4-((2R,3S)-3-hydroxy-pyrrolidin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (300 mg, 784.4 μmol) in acetonitrile (20 mL) is treated with acetaldehyde (1.0 mL, 17.80 mmol) and sodium triacetoxyborohydride (520 mg, 2.35 mmol) and stirred at room temperature overnight. The suspension is treated with saturated sodium bicarbonate solution (40 mL) and stirred for 30 min. The resulting suspension is diluted with dichloromethane (100 mL) and washed with water (3×100 mL) and brine. The organic portion is dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by medium pressure liquid chromatography, eluting with methanol:chloroform (5:95). Fractions containing pure product are combined and concentrated to afford 0.1 g (31%) of the title compound. LC-ES/MS m/z 144.2 [M+H]+, TR=1.94 min.