Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5]NN=1.COC(=O)C1C=CC(OCC2CC2)=C(Cl)C=1.[CH3:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28]C)=O.[H-].[Na+].C(#N)CC>C1(C)C=CC=CC=1.O>[CH3:5][CH:6]([C:26](=[O:28])[C:25]1[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=1[CH3:23])[C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccccc1C
Agent: COC(=O)c1ccc(OCC2CC2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)C(C)C#N
Temperature: 80 °C
Yield: 88 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1). The mixture of methyl 2-methylbenzoate (3.0 mL, 20.0 mmol, 1.0 eq) and NaH (1.6 g, 40.0 mmol, 2.0 eq) in dry toluene (20 mL) was heated at 80° C. and then propionitrile (6.7 mL, 94.4 mmol. 4.7 eq) was added dropwise; the reaction was heated for 18 hours. The crude product was dissolved in water and extracted with DCM, and it was used in the following step without further purification (3.04 g, yield: 88%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[Cl:19])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:26][C:22]1[N:21]=[C:20]([CH:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[Cl:19])[CH2:9][OH:8])[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(F)cc1Cl)c1ccnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1nccc(C(CO)Oc2ccc(F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58.8 %

Procedure:
To a solution of 4-(2-(tert-butyldimethylsilyloxy)-1-(2-chloro-4-fluorophenoxy)ethyl)pyrimidin-2-amine (20a) (830 mg) in tetrahydrofuran (15 mL) was added tetrabutyl-ammonium fluoride (1 g) and the mixture was stirred at room temperature for 5 days. The mixture was concentrated and purified by column chromatography using 0 to 10% methanol in dichloromethane to give the title compound (348 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[C:5](=O)[NH:6][C:7]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][N:2]([CH3:16])[C:3]12[CH2:13][CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:4]2[CH2:5][NH:6][CH2:7]1
Reactant: CN(C)C12C=CC(CC1)C1C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)C12C=CC(CC1)C1CNCC12

Procedure:
12 g (54.5 mmol) of 1-dimethylamino-4-azatricyclo-[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with LiAlH4 as described under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1.[OH:24]OS([O-])=O.[K+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>CC(C)=O.O>[ClH:1].[ClH:1].[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([S:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1
Reactant: O=S([O-])OO
Reactant: CNCc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC(C)=O
Product: CNCc1cn(-c2ccccc2)c(S(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
To a solution of N-methyl-1-[1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanamine dihydrochloride (70 mg) in acetone (20 mL) and water (10 mL) was added dropwise a solution of oxone (176 mg) in water (10 mL), and the mixture was stirred at room temperature for 5 hr. Sodium thiosulfate pentahydrate (1 g) was added to the reaction mixture and the mixture was stirred for 1 hr. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with a mixed solution of ethyl acetate-tetrahydrofuran (1:1). The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→7:3) and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in a mixed solution of methanol-tetrahydrofuran, and ethyl acetate was added. The precipitated insoluble materials were collected by filtration to give the title compound as a colorless powder (yield 34 mg, yield 47%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[OH-].[K+]>C(O)C.O>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)Cc1ccc(CNS(C)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(CC(=O)O)cc1

Procedure:
A solution of ethyl 4-[[(methylsulphonyl)amino]methyl]benzeneacetate (3.1 g) and 1M KOH (22 ml) in ethanol (50 ml) was stirred at room temperature for 3 h and evaporated in vacuo to leave an off-white solid. This solid was dissolved in water (50 ml) and washed with EA (2×50 ml). The organic extract was discarded and the aqueous layer was acidified (pH1) with 5M hydrochloric acid (about 10 ml) to precipitate the title compound (2.54 g) as a white solid m.p. 167°-169°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([NH2:21])=[N:18][C:17]=1[CH3:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([NH:21][C:1](=[O:4])[CH2:2][CH3:3])=[N:18][C:17]=1[CH3:22])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use propionyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 31% yield; m. p. 175-176° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.15, (s, 1H), 8.51 (t, J=6.0 Hz, 1H), 7.32-7.16 (m, 5H), 4.34 (d, J=6.0 Hz, 2H), 2.65-2.22 (m, 5H), 1.07 (t, J=7.5 Hz, 3H); MS (ES+) m/z 304.3 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:31][CH3:32])[C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][C:22]([CH3:28])=[CH:23][C:24]2=4)[NH:19][C:18]=3[CH3:29])[N:14]([CH3:30])[CH2:13]1)=O)[CH3:7].CCOC([S-])=[S:37].[K+].N>ClCCl.C(#N)C>[CH2:6]([N:8]([CH2:31][CH3:32])[C:9]([NH:11][C@H:12]1[CH2:26][C@H:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][C:22]([CH3:28])=[CH:23][C:24]2=4)[NH:19][C:18]=3[CH3:29])[N:14]([CH3:30])[CH2:13]1)=[S:37])[CH3:7]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Reactant: CCOC(=S)[S-]
Agent: N
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3cc(C)cc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
0.5 M1 of freshly distilled phosphorus oxychloride (5.6 mmol) and 368 mg of 1,1-diethyl-3-(2,6,13-trimethyl-8alpha- ergolinyl)-urea (1 mmol) are dissolved in 20 ml of dichloromethane at -20° C. and the mixture is allowed to stir overnight at room temperature. The volatile portions are now drawn off in a vacuum, the residue is dissolved in 40 ml of acetonitrile and mixed with a solution of 0.8 g of potassium xanthate (5.6 mmol) in 80 ml of acetonitrile. It is stirred for 2 hours at room temperature, then ice and conc. ammonia solution are added and shaken out with dichloromethane. The organic phases are dried with sodium sulfate and concentrated by evaporation, the residue is chromatographed on silica gel with ethyl acetate and crystallized from ethyl acetate/diisopropyl ether, yield 43%.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[S:16][CH:15]=[C:14]([CH2:17][C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[C:11]=3[S:12][CH:13]=2)=[CH:4]1.[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>C1COCC1>[S:20]1[CH:21]=[CH:22][C:18]([C:17]([C:14]2[C:11]3[S:12][CH:13]=[C:9]([C:8]([C:5]4[CH:6]=[CH:7][S:3][CH:4]=4)([CH2:7][CH2:6][CH2:5][CH2:8][CH2:9][CH2:10][CH2:11][CH3:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]=3[S:16][CH:15]=2)([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19]1
Reactant: c1cc(Cc2csc3c(Cc4ccsc4)csc23)cs1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCCCC)(c1ccsc1)c1csc2c(C(CCCCCCCC)(CCCCCCCC)c3ccsc3)csc12

Procedure:
To a suspension of sodium hydride in THF is added a THF solution of 3,6-bis(thiophen-3-ylmethyl)thieno[3,2-b]thiophene. Octyl bromide is then added and the mixture is refluxed until reaction completion, as determined by TLC. The reaction is then poured into cold water, extracted with MTBE and combined organic phases are washed with water. After drying the organic phase with magnesium sulfate and filtering through Buchner the solvent is evaporated. The resulting product can be purified by column chromatography.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].C([O:14][C@@H:15]1[C@H:19]([O:20]C(=O)C2C=CC=CC=2)[C@@H:18]([CH2:29][O:30]C(=O)C2C=CC=CC=2)[O:17][C@H:16]1[N:39]1[CH:47]=[N:46][C:45]2[C:40]1=[N:41][C:42]([Cl:49])=[N:43][C:44]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:49][C:42]1[N:43]=[C:44]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:45]2[N:46]=[CH:47][N:39]([C:40]=2[N:41]=1)[C@@H:16]1[O:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:15]1[OH:14]
Reactant: C[C@@H](N)CO
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](CO)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 200 h
Yield: 51.5 %

Procedure:
(R)-2-Amino-1-propanol (0.23 g, 3.0 mmol), 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.7 g, 2.7 mmol) and triethylamine (0.30 g, 3.0 mmol) were dissolved in dioxan (20 ml) and stirred for 200 h at room temperature. Following purification by column chromatography, the resultant 2',3',5'-tri- O-benzoyl-2-chloro- N-[(R)-1-hydroxy-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-chloro- N-[(R)-1-hydroxy-2-propyl]adenosine as an amorphous foam (0.5 g, 54%), 1H NMR (DMSO-d6)δ 1.17 (3H, d, --CH3), 3.35-3.72 (4H, m, H-5'a, H-5'b and --CH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, dd, H-2'), 5.08 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.83 (1H, d, H-1'), 8.0 (1H, d, N--H) 8.40 (1H, s, H-8).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:18])[CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+:20]>CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:18])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH2:3][CH2:2]1.[Na+:20]
Reactant: COC(=O)c1ccc(CC(=O)NCC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1ccc(C(=O)[O-])cc1)NCC1CC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 126.6 %

Procedure:
Methyl 4-(2-(cyclopropylmethylamino)-2-oxoethyl)benzoate (5.26 mmol, 1.3 g), and sodium hydroxide (5.26 mmol, 0.210 g) were combined in methanol (15 mL) and the reaction mixture was stirred and refluxed at 65° C. After 4 hours, an additional equivalent of sodium hydroxide (5.26 mmol, 0.210 g) was added and reaction mixture stirred and refluxed at 65° C. overnight. The reaction mixture was concentrated under vacuum to afford the title compound (1.7 g). MS (ESI) m/z 234.0 [M+H]+
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)cc(F)c1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc(F)c2c(c1)O[C@@H](C)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3nc(cn13)-c1cccc-2c1
Yield: 41 %

Procedure:
Prepared in 41% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=7.3 Hz, 1H), 6.86 (s, 1H), 6.71 (d, J=10.6 Hz, 1H), 5.90 (br. s., 1H), 4.66 (br. s., 1H), 3.87 (br. s., 1H), 3.63 (br. s., 1H), 3.49-3.42 (m, 2H), 3.12 (br. s., 1H), 2.64 (d, J=10.6 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.93-1.51 (m, 10H), 1.20 (s, 3H), 1.18 (s, 9H), 1.10 (d, J=5.9 Hz, 3H) LCMS (ESI, M): 657.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C@@H:21]([CH:29]([CH3:31])[CH3:30])[CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C@H:11]([CH2:20][C@@H:21]([CH:29]([CH3:30])[CH3:31])[CH:22]=[CH:23][C:24]([OH:26])=[O:25])[O:10][C:9]1([CH3:32])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@@H](C=CC(=O)O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
1.7 g (3.7 mmol) of ethyl (S)-5-[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]-4-isopropyl-2-pentenoate are dissolved in 10 ml of methanol, treated with 2 ml (18 mmol) of 28% sodium hydroxide solution and stirred at room temperature for 16 hours. Thereafter, the reaction mixture is poured into ice-water, the pH value is adjusted to 5 with acetic acid and the mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on 20 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 1.2 g of (S)-5-[(4S,5S)-3-(t-butoxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinyl]-4-isopropyl-2-pentenoic acid as an oil, MS: 422 (M-CH3)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([OH:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:6]=2[CH:30]=1.[OH-].[Na+:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O-:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:6]=2[CH:30]=1.[Na+:32]
Reactant: COc1ccccc1[C@H]1O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1[C@H]1O[C@H](CC(=O)[O-])C(=O)N(CC(C)(C)C)c2ccc(Cl)cc21

Procedure:
To a suspension of (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (12 g) in methanol (200 ml) was added 1N aqueous sodium hydroxide (27.7 ml). After the acid was dissolved completely, the mixture was concentrated in vacuo. To the residue was added ethyl acetate (200 ml) and the mixture was concentrated in vacuo. The deposited crystals were collected to give sodium (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (11.8 g) as colorless crystals (mp>300° C.).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:10](O)=[O:11])[S:7][C:8]=1[CH3:9])#[N:2]>C1COCC1>[OH:11][CH2:10][C:6]1[S:7][C:8]([CH3:9])=[C:4]([CH2:3][C:1]#[N:2])[CH:5]=1
Reactant: Cc1sc(C(=O)O)cc1CC#N
Solvent: C1CCOC1
Product: Cc1sc(CO)cc1CC#N
Yield: 41.4 %

Procedure:
A solution of 4-cyanomethyl-5-methyl-thiophene-2-carboxylic acid (12.3g, 67.9 mmol) in THF (400 mL) is treated with borane-dimethylsulfide complex (7.5 mL, 10 M, 74.7 mmol) dropwise via syringe. The mixture is heated to a gentle reflux for 2 h. After cooling, the mixture is quenched with water and extracted with dichloromethane (3×). The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography (silica gel, 30-50% ethyl acetate in heptane) to give (5-hydroxymethyl-2-methyl-thiophen-3-yl)-acetonitrile (4.7 g, 41.4%) as a white solid. mp 66-68° C.; 1H NMR (CDCl3, 300 MHz) δ 6.83 (s, 1 H), 4.71 (d, J=6.0 Hz, 2 H), 3.56 (s, 2 H), 2.40 (s, 3 H), 1.75 (t, J=6.0 Hz, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[Br:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[OH-].[Na+]>[Br:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH2:3][CH2:2][Cl:1]
Reactant: Oc1ccc(F)cc1Br
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCCCl)c(Br)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-chloroethyl ester (2.80 g, 11.93 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added 2-bromo-4-fluorophenol (2.73 g, 14.30 mmol), and potassium carbonate (3.30 g, 23.90 mmol). The resulting solution was then heated at 50° C. with stirring for 6 hours. After cooling to room temperature, the reaction mixture was diluted with sodium hydroxide (1M aqueous solution, 30 ml) and tert-butyldimethyl ether (50 ml) was added. The layers were separated and the organic extract was washed with saturated brine solution (30 ml), prior to being dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo. Purification by column chromatography eluting with ethyl acetate:heptane 1:99 to 10:90 afforded the title compound as a colourless oil (1.50 g, 50%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:40]=[O:41]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:9]([S:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:40]=[O:41])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1C(Sc1cc(F)cc(F)c1)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C=O)ncc1C(Sc1cc(F)cc(F)c1)c1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(3,5-difluorophenyl)thio]methyl]-4-methylpyridine (2.35 g, 5.31 mmol) in toluene (60 ml), a hexane solution of n-butyllithium (1.54 M, 4.14 ml, 6.38 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −40° C., and then cooled again to −78° C., and N,N-dimethylformamide (0.494 ml, 6.38 mmol) was added. After completion of dropwise addition, the reaction mixture was Allowed to warm to 0° C., and water was added at the same temperature. Ethyl acetate was added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:1 was concentrated under reduced pressure to obtain the title compound (1.36 g, 3.47 mmol, 65%) as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.[C:18]([O:22][C:23](=[O:37])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CO.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([O:22][C:23](=[O:37])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)[CH2:33][CH2:32]2)=[CH:26][CH:25]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: Brc1ccc2ccccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3ccc4ccccc4c3)CC2)cc1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
Sodium tert-butoxide (0.4 g, 4 mmol) was added to a solution of 2-bromonaphthalene (0.3 g, 1.48 mmol) and 49 (0.4 g, 1.48 mmol) in 5 mL of anhydrous toluene at 25° C. Tris(dibenzylideneacetone)-dipalladium (0) (6 mg, 0.007 mmol) and (+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(±)-BINAP] (12.4 mg, 0.02 mmol) were added sequentially. The reaction mixture was heated to 80° C. and maintained at that temperature for 12 h, then was cooled to 25° C. and diluted with a mixture of CH3OH/CH2Cl2 (150 mL, v/v, 50:50). The diluted mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was partitioned between CH2Cl2 (150 mL) and H2O (150 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give a deep yellow solid residue. Purification of the residue by flash column chromatography (gradient elution 0 to 25% EtOAc in hexanes) provided the title compound (0.35 g, 59%): TLC (Rf =0.80; 40% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.83 (d, 2H, J=8.4), 7.70 (m, 3H), 7.32 (m, 3H), 7.15 (d, 1H, J=2.1), 6.56 (d, 2H, J=8.7), 4.02 (d, 1H, J=7.8), 3.76 (d, 2H, J=12.7), 3.54 (m, 1H), 2.98 (t, 2H, J=12.0), 2.20 (d, 2H, J=10.7), 1.67 (m, 2H), 1.57 (s, 9H); 13C NMR (CDCl3) δ 166.0, 150.4, 149.1, 134.7, 131.5, 128.7, 128.5, 127.4, 126.7, 126.3, 123.4, 120.6, 119.8, 111.9, 110.7, 79.8, 49.6, 48.8, 32.1, 28.4; HRMS (FAB) m/z 402.2321 (M)+ (C26H30N2O2 requires 402.2307).