Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH2:19][N:6]2[CH:7]=[CH:8][C:9]3[C:10]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=3)=[C:5]2[N:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH2:19][N:6]2[CH:7]=[CH:8][C:9]3[C:10]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=3)=[C:5]2[N:4]=1
Reactant: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C=O)=N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(CO)=N3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 8 (40 mg, 0.16 mmol) in dry ethanol (5 mL), under argon, was added NaBH4 (9 mg, 0.24 mmol). The solution was stirred at room temperature for 30 min then the solvent was removed in vacuo. An aqueous saturated Na2CO3 solution (5 mL) was added and the solution was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (MgSO4), filtered and evaporated to give compound 11 (23 mg, 57%); mp 227-229° C.; IR (KBr) 3289, 1685, 1266, 1191 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.38 (t, 3H, J=7 Hz), 4.38 (q, 2H, J=7 Hz), 4.60 (s, 2H), 5.17 (brs, 1H), 7.01 (d, 1H, J=7 Hz), 7.33 (s, 1H), 7.72 (s, 1H), 8.29 (d, 1H, J=7 Hz), 12.50 (brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.3, 58.0, 60.4, 101.1, 106.4, 110.3, 113.1, 124.4, 125.6, 133.1, 140.2, 144.7, 160.5; MS m/z 259 (M+, 60), 213 (52), 212 (100), 184 (22), 57 (25). Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C, 60.13; H, 5.18; N, 16.02.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH:15]=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.N.[Li].C(O)C>C1COCC1>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH2:15][C:16]([O:23][CH3:24])=[CH:17][CH2:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: COc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1=CCC2=C(CC=C3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1
Temperature: -33 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of the arene 1 (1.63 g, 5 mmol) in THF (25 mL) was condensed liquid ammonia (100 mL). Small pieces of freshly cut lithium wire (0.6 g, 86 mmol) were added over a period of 5 min at −50° C. The deep blue solution was stirred at −33° C. for 30 min and ethanol (100%, 10 mL) was added over a period of 10 min. The ammonia was allowed to evaporate and water (20 mL) was added. The biphasic mixture was transferred to a separatory funnel and extracted with ether (3×30 mL). The ether extracts were combined, washed with brine, dried over potassium carbonate and concentrated to afford a shiny white solid which was washed with ether (4×20 mL) to give the enol ether 2 (1.2 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:30]([C:32]1[N:33]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]4)[N:14]3[CH3:29])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 69.5 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (44 mg, 0.10 mmol), 2-ethylbenzimidazole (17 mg, 0.11 mmol), Pd2(dba)3 (2.4 mg, 2.5 mol %), Xphos (5.0 mg, 10 mol %) and Cs2CO3 (51 mg, 0.16 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 20 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-100% EtOAc in cyclohexane) to give 646 (37 mg, 67%) as a yellow solid. LCMS: (Method I): RT 4.34 min, [M+H]+ 533.2 1H NMR (400 MHz, CDCl3d): δ 8.01-7.97 (m, 1 H), 7.78-7.73 (m, 1 H), 7.29-7.22 (m, 2 H), 4.55-4.10 (m, 4 H), 3.86 (t, J=4.67 Hz, 4 H), 3.80 (s, 3 H), 3.80-3.44 (m, 4 H), 3.35 (q, J=7.48 Hz, 2 H), 2.36 (s, 3 H), 1.49 (s, 9 H), 1.44 (t, J=7.48 Hz, 3 H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([OH:27])=[O:26])[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:34](O)=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]>CCOC(C)=O>[F:28][C:29]1[C:34]([O:26][C:25](=[O:27])[C@@H:15]2[CH2:14][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][N:16]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Oc2c(F)c(F)c(F)c(F)c2F)N(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 95 %

Procedure:
trans-4-(N-tert-Butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline (1.96 g, 5.06 mmol) was dissolved in EtOAc (40 mL) and pentafluorophenol (PFP) (1.03 g, 5.6 mmol) was added in one portion. (1,3-)dicyclohexylcarbodiimide (DCC 1.15 g, 5.6 mmol) was pre-dissolved in EtOAc (10 mL) and added dropwise over 1 minute. A white precipitate immediately formed which, upon stirring for 1 hour, 1:5 was filtered and the filtrate was concentrated to dryness to reveal the title compound in 95% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:24][NH:25][S:26](Cl)(=[O:28])=[O:27].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:24][N:25]1[S:26](=[O:28])(=[O:27])[NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[CH:5]=[CH:4][C:3]=2[CH:12]1[C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(C(F)(F)F)nc2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(C(F)(F)F)nc2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 51.5 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(6-trifluoromethyl-pyridin-3-yl)-methanone (Intermediate 371) (100 mg, 0.32 mmol), N-methylsulfamoyl chloride (Intermediate 213) (49 mg, 0.38 mmol) and NaBH4 (12 mg, 0.315 mmol) in pyridine (5 ml) gave the title compound (65 mg, 52%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](I)[CH:18]=1.[CH3:20][S-:21].[Na+]>C1(C)C=CC=CC=1.[Cu](Br)Br>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([S:21][CH3:20])[CH:18]=1
Reactant: C[S-]
Reactant: Brc1cncc(I)c1
Agent: Br[Cu]Br
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1cncc(Br)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 mL, 5.28 mmol) to a solution of 3-bromo-5-iodopyridine (500 mg, 1.76 mmol), (prepared as described in PREPARATION 21), sodium methanethiolate (370 mg, 5.28 mmol) and copper bromide (50.2 mg, 0.35 mmol) in toluene (3 mL). Stir in a sealed flask at 90° C. overnight and then partition between water and ethyl acetate. Separate the organic layer and wash with an aqueous saturated solution of sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with hexane:ethyl acetate, to give the title compound (250 mg, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Yield: 81.3 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and p-aminobenzoic acid (0.18 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.33 g(81%) 145 as a very pale dull yellow powder: mp=331–332° C.; Rf 0.86 (A): Rf 0.92 (C): Rf 0.56 (D): IR(cm−1): 2750–3150 (OH), 3116 (C═CH), 2684 (C—H), 1780 (C═O), 1730 (bs, C═O), 1622 (C═C), 1608 (C═C), 1543 (N═O), 1510 (C═C), 1434 (C═C), 1383 (C—O), 1350 (N═O), 1103 (C—O), 727 (C═CH); MS m/z (rel intensity) 311 (100), 267 (87).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:24]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:14])([O:15][C:16]4[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=4)[C:4]([OH:3])=[O:23])=[CH:8][CH:9]=3)[N:34]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccc(-c5ccccc5)c4)oc3C)cc2)C(=O)O)c1

Procedure:
A mixture of 2-(m-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.095 g, 0.030 mmol), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-(4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-m-tolyloxy-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.18–8.17 (m, 1H), 7.92 (d, 1H, J=7.04 Hz), 7.61–7.57 (m, 3H), 7.45–7.36 (m, 3H), 7.31–7.28 (m, 1H), 7.11 (d, 2H, J=8.60 Hz), 7.05 (t, 1H, J=7.82 Hz), 6.82–6.75(m, 3H), 6.65–6.61 (m, 2H), 4.17 (t, 2H, J=6.65 Hz), 3.17 (d, 1H, J=13.69 Hz), 3.06 (d, 1H, J=13.69 Hz), 2.96 (t, 2H, J=6.65 Hz) 2.33 (s, 3H), 2.21 (s, 3H), 1.35 (s, 3H); HRMS (ES+) m/z exact mass calcd for C35H34NO5 548.2437, found 548.2415.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=3)[CH2:13][O:12][C:11]2=[O:25])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:26](OCC)(OCC)OCC>>[CH3:9][C:6]1[C:7]2[NH:8][CH:26]=[N:1][C:2]=2[CH:3]=[C:4]([N:10]2[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[CH2:13][O:12][C:11]2=[O:25])[CH:5]=1
Reactant: CCOC(OCC)OCC
Reactant: CCCOc1ccc([C@H]2COC(=O)N2c2cc(C)c(N)c(N)c2)cc1
Product: CCCOc1ccc([C@H]2COC(=O)N2c2cc(C)c3[nH]cnc3c2)cc1

Procedure:
The (S)-3-(3,4-diamino-5-methylphenyl)-4-(4-propoxyphenyl)oxazolidin-2-one was dissolved in triethyl orthoformate and was refluxed for 30 minutes. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform-methanol gradient (0→10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32](OC)=[O:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[BH4-].[Na+].[NH4+].[Cl-].CCOC(C)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][CH2:32][OH:33])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(CCO)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of methyl 2-(N-(4-(2-chlorophenyl)pyridin-3-yl)-3,5-bis(trifluoromethyl)benzamido)acetate (0.15 g, 0.29 mmol, example 88) in methanol (2.00 mL) was cooled down to 0° C. To the light yellow suspension was added NaBH4 (22.0 mg, 0.58 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). The product containing fractions were combined and partially evaporated upon which crystallisation started. The supernatant light brown solution was pipetted off and the remaining solid dried under high vacuum. Colorless crystals (0.024 g; 16%). MS (ESI): m/z=489.08 [M+H]+.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20][CH3:21].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:22][CH2:17][C:18]#[C:19][CH2:20][CH3:21])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCC#CCO
Reactant: CS(=O)(=O)c1nsc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCOc1nsc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
In 2.5 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-chlorophenyl)-1,2,4-thiadiazole and 117 mg of 2-pentyne-1-ol were dissolved, to the resulting solution was added 56 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 290 mg of 5-(3-chlorophenyl)-3-(2-pentynyloxy)-1,2,4-thiadiazole (the compound (78) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)CCC>C1COCC1.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>[NH2:1][C:2]1[C:12]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Nc1c(-c2ccco2)cc(Br)c2c1C(=O)NC2=O
Yield: 52.5 %

Procedure:
In a similar manner to Step 1 of Example 10, 3-amino-4-iodo-6-bromophthalimide (100 mg, 0.273 mmol) was dissolved in THF (5 mL), and the solution was treated with 2-(tributylstannyl)furan (0.129 mL, 0.410 mmol) and bis(triphenylphosphine)dichloropalladium (15 mg, 0.022 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=50/1, 40/1) to obtain 3-amino-4-(furan-2-yl)-6-bromophthalimide (44 mg, yield 52%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:9])[CH3:8].ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:15]#[N:14])[CH:4]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1cccn1C
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C#N)cn1C
Temperature: 25 °C
Yield: 33.9 %

Procedure:
1-(1-Methyl-1H-pyrrol-2-yl)-ethanone (4.00 g, 32.48 mmol) in dry methylene chloride (30 mL) was cooled to −78° C. under nitrogen. Chlorosulfonyl isocyanate (2.8 mL, 32.5 mmol) was added dropwise, and the mixture allowed to warm to room temperature over 1 h. The reaction was cooled down to −78° C. and dimethylformamide (8 mL) was added. The reaction was allowed to warm up to room temperature (2 h) and was then poured into a 1 N sodium carbonate solution, which was extracted with methylene chloride. The organic layers were washed with water, dried (anhydrous MgSO4) and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate:hexanes 1:5 to 1:3) to afford 5-acetyl-1-methyl-1H-pyrrole-3-carbonitrile (1.63 g, 34%), which was used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:31])=[C:16]([CH3:22])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CSc1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)ccc1S(C)=O
Temperature: 0 °C
Yield: 63.1 %

Procedure:
To 320 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylthio)phenyl}-3(2H)-furanone (Example 381) in 50 ml dichloromethane, was added 172 mg of 70% m-chloroperoxybenzoic acid. The mixture was stirred at 0° C. for an hour, which was followed by addition of 30 ml 5% aqueous sodium bicarbonate. The solution was stirred for another 10 minutes. Then the mixture was concentrated in vacuo, and was extracted with 50 ml water and dichloromethane (30 ml×3). Then the organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to give 211 mg of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{3-methyl-4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ1.57 (s, 6H), 2.36 (s, 3H), 2.73 (s, 3H), 6.77 (m, 1H), 6.86 (m, 2H), 7.50 (m, 1H), 7.66 (m, 1H), 7.99 (d, J=8.4 Hz, 1H). IR (cm−1): 1698,1624,1592,1384, 1310,1206,1072,915.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][C:29](=[N:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][NH:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.B.O1CCCC1>O1CCCC1>[CH2:16]([O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][C@@H:29]([NH:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][NH:27]1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: B
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: -20 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
Under nitrogen atmosphere, (±)-camphorsulfonic acid (0.697 g, 3.00 mmol) and tetrahydrofuran (2 ml) was added to (2S)-5-benzyloxyimino-piperidine-2-carboxylic acid benzyl ester (0.169 g, 0.50 mmol), and the mixture was cooled down to −20° C. Borane-tetrahydrofuran complex (1.06 M tetrahydrofuran solution, 2.4 ml, 2.54 mmol) was added to the mixture for 1.5 hours, and the obtained mixture was stirred for 6 hours. The reaction mixture was analyzed with high performance liquid chromatography to find that the reaction mixture contained 0.140 g of the title compound, and the reduction reaction proceeded with yield of 82%. The diastereo selectivity was (2S,5R)/(2S,5S)=87.8/12.2 (75.6% de).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:14].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:14])[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])c(Cl)cc1Cl

Procedure:
The reaction is carried out as in Example 10 a) by reacting chlorobenzene with 2-chloro-5-nitrobenzoyl chloride in the presence of aluminium chloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncc2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of 90 (0.68 g, 2.28 mmol) in DMF (10 mL) was added imidazole (0.54 g, 7.93 mmol) and tert-butyldimethylsilyl chloride (0.68 g, 4.56 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h, at which point it was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3; gradient=5-20%) to afford 0.49 g (52%) 91 as a white solid: 1H (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 6.87 (s, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.33 (d, J=5.6 Hz, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.79 (q, J=5.2 Hz, 1H), 4.16 (q, J=5.2 Hz, 1H), 3.77 (m, 2H), 3.64 (dd, J=12.0, 7.2 Hz, 1H), 0.84 (s, 9H), 0.00 (s, 6H); MS (+)-ES [M+H]+ m/z 415.4.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@H:12]([CH2:28][CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[CH:20]=3)=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH2:28][CH3:29])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)=O)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)O)n[nH]1
Yield: 84.6 %

Procedure:
(R)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)butan-2-yl)-1H-pyrazole-5-carboxamide (225 mg, 0.55 mmol) was treated with sodium borohydride using the method of Example 102. Thus, 192 mg (85%) of title compound was obtained. 1H-NMR (400 MHz; CDCl3/MeOD): δ 1.00 (t, 3H), 1.46-1.67 (m, 5H), 4.28-4.44 (m, 3H), 4.94 (q, 1H), 7.61 (m, 2H), 7.53 (d, 1H), 7.69 (d, 1H), 7.80 (d, 1H), 8.00 (d, 1H).