Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[C:8]([CH3:11])=[N:9][CH:10]=1.O.NN>C(OCC)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][NH2:13])[C:8]([CH3:11])=[N:9][CH:10]=1
Reactant: Cc1ncc(Cl)cc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1ncc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 119 %

Procedure:
To an ethanol (10 mL) solution of 2-((5-chloro-2-methyl-pyridine-3-yl)methyl)isoindole-1,3-dione (0.20 g), hydrazine monohydrate (0.50 mL) was added, and heat-refluxing of the reaction solution was carried out for 2 hours. The reaction solution was allowed to be cooled to room temperature, diethyl ether (50 mL) was added to the reaction solution, and the reaction solution was agitated for 30 minutes at room temperature. C-(5-chloro-2-methylpyridin-3-yl)methylamine (0.13 g) was obtained by filtering off insoluble matters in the reaction solution and condensing the obtained filtrate under reduced pressure.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[C].[Pd].CO>[CH2:9]([N:1]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To methanol (1 kg) were added trans-4-aminocyclohexanol (200 g), benzaldehyde (553 g) and 10% palladium carbon (20 g), and the mixture was stirred under a hydrogen atmosphere at 60° C. for 24 hr. After cooling to room temperature, the catalyst was filtered off and washed with methanol (400 g). The filtrate and washings were added dropwise to water (2 kg) at 50° C. After cooling to room temperature, the precipitate was collected by filtration, washed with water:methanol=2:1 (volume ratio, 400 g) and dried under reduced pressure to give the title compound (472 g, yield 92%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].O.[C:26]([O:30][C:31]([NH:33][C@@H:34]([C:39](O)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:37][CH:36]([CH3:38])[CH2:35][C@@H:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[C:39](=[O:40])[NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(−)-3-Amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) was dissolved in N,N-dimethylformaldehyde (5 mL), and to the solution were sequentially added N-tert-butoxycarbonyl-D-leucine monohydrate (382 mg), 1-hydroxybenzotriazole (207 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (294 mg) under cooling on ice, followed by stirring at room temperature for one hour. The resultant mixture was extracted with ethyl acetate and water, and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (chloroform:methanol=50:1), whereby the title compound (832 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:24][C@@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[NH:26]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:26]3[C@H:25]([CH3:24])[CH2:29][CH2:28][S:27]3(=[O:31])=[O:30])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 41.4 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (294 mg) described in Preparation Example 108 and (R)-3-methylisothiazolidine 1,1-dioxide (94 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (123 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][N:12]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.ON1C=CC=CC1=O.[CH2:40]([NH:44][NH2:45])[CH:41]([CH3:43])[CH3:42].S([O-])([O-])(=O)=O.C(O)(=O)C>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[CH2:40]([NH:44][NH:45][C:27]([C@@H:11]1[CH2:10][C@@H:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[CH2:13][N:12]1[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:16])=[O:15])=[O:29])[CH:41]([CH3:43])[CH3:42]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Reactant: CC(C)CNN
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: O=c1ccccn1O
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NNCC(C)C)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(step 1) To a solution of 4.4 g (9.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid in 200 ml CH2Cl2 were added 1.2 g (10.8 mmol,1.1 eq) N-hydroxy-2-pyridone, followed by 2.2 g (10.7 mmol, 1.1 eq) N, N-dicyclohexylcarbodiimide in 25 ml CH2Cl2 at 0° C. over a period of 30 min. The suspension was stirred for additional 4 h at that temperature before 4.2 ml (33.0 mmol, 3.4 eq) NEM and 1.9 g (mmol, 1.05 eq) isobutylhydrazine.sulfate were added. The reaction mixture was stirred at RT over night. The suspension was treated with 0.55 ml (9.6 mmol, 1.0 eq) glacial acetic acid in 10 ml water and stirred for 1.5 h, diluted with aq. NaHCO3 (5%) and extracted with CH2Cl2. The combined organic phases were washed with 1M KHSO4 solution, water and brine, dried over Na2SO4 and evaporated. Tituration with hexane yields 5.02 g (quant) (2S,4R)-4-(4-Methoxy -benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N′-isobutyl-hydrazide, which was directly subjected to the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:21])[C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:12]([CH3:21])=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)C(C)Br
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C

Procedure:
A suspension of 4-fluorobenzamide (12.9 g) and ethyl 4-bromo-3-oxopentanoate (Chem Abs No. 36187-69-6; 5.24 g) in anhydrous toluene (120 ml) was heated at 140° C. for 19 h, using a Dean-Stark trap. The solution was allowed to cool, filtered, and the residual solid washed with toluene (30 ml). The combined filtrate and washings were concentrated in vacuo to give a brown oil, which was purified by Biotage flash chromatography on silica gel (90 g column), eluting with ethyl acetate:cyclohexane (5:95, 7.5:92.5, 10:90), to give thetitle compound as a yellow solid (2.98 g).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:36])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[C:23]=1[CH2:32][CH2:33][CH2:34][CH3:35])=[O:21])=[CH:11]2.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:36])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[C:23]=1[CH2:32][CH2:33][CH2:34][CH3:35])=[O:21])=[CH:11]2
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OC)ccc3c2)c2ccccc2n1C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)c2ccccc2n1C
Reaction time: 4 h
Yield: 107.3 %

Procedure:
Boron tribromide (18.78 mL of a 1 M solutioin in methylene chloride; 18.78 mmol) in 20 mL of methylene chloride was added under nitrogen dropwise over fifteen minutes to a solution of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (3.09 g, 6.26 mmol), prepared in the previous step, in 125 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 4 h. Water was added to the reaction at ice bath temperature. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.22 g, 100%) as a brown solid foam, MS m/z: 479 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: COC(=O)/C=C/CC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Palladium-carbon (containing 50% water, 0.376 g) was added to a solution of tert-butyl (2R,5R)-2-(3,4-difluorophenyl)-5-{(E)-4-methoxycarbonyl-3-butenyl}pyrrolidine-1-carboxylate (1.3 g) in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for six hours. Palladium-carbon in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=2)=[C:15]2[C:10]([C:11]([C:25]([F:28])([F:27])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=1O>ClCCl>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:52]3[CH:53]=[C:48]([F:47])[CH:49]=[CH:50][C:51]=3[F:54])[CH:18]=2)=[C:15]2[C:10]([C:11]([C:25]([F:27])([F:28])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)c1
Reactant: Oc1cc(F)ccc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(OCc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)c1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
Thirty-eight milligrams (38 mg; 0.1 mmol) of [3-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenyl]-methanol (see preparation of Example 7) were dissolved in 1 ml of dichloromethane followed by the addition of 28 μl of Et3N (0.2 mmol). The mixture was cooled to −30° C. and 12 μl of MsCl were added. Stirring continued at 0° C. for 1.5 hours. To the resulting solution, 85 mg of Cs2CO3 (0.25 mmol) were added followed by the addition of 65 mg (0.5 mmol) of 2,5-difluorophenol. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1M aq HCl and product was extracted with dichloromethane. Flash column chromatography (SiO2, dichloromethane/heptane, 1:1, as an eluant) afforded 2-benzyl-3-{3-[(2,5-difluorophenoxy)methyl]phenyl}-7-(trifluoromethyl)-2H-indazole in 41% yleld.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([CH2:36][CH2:37]Br)=[CH:34][CH:33]=1)([O-:31])=[O:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[C:22]([CH2:21][N:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:20][CH2:19][N:18]([CH2:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=2)[CH2:17][CH2:16]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 24 h
Yield: 68.3 %

Procedure:
A solution of compound (20) (1.56 g, 3.89 mmol), 4-nitrophenethyl bromide (1.79 g, 7.78 mmol), anhydrous K2CO3 (1.61 g, 11.67 mmol) and KI (1.94 g, 11.67 mmol) dissolved in dry toluene (150 ml) was stirred for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (25) as a yellow oil (1.46 g, 68% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=O)[CH3:21]>>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:20]1[CH3:21]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: COC(=O)CCCCCNC(C)=O
Product: COC(=O)CCCCCn1c(C)nc2ccccc21
Yield: 15.4 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 6-acetylamino-hexanoic acid methyl ester (112 mg, 0.6 mmol) yielded the title compound as yellow oil (20 mg, 15%). 1H NMR (DMSO) δ 1.32-1.83 (m, 6H), 2.29 (t, J=7.1Hz, 2H), 2.80 (s, 3H), 3.55 (s, 3H), 4.38 (t, J=7.3, 2H), 7.48-7.56 (m, 2H), 7.76 (d, J=8.1Hz, 1H), 7.91 (d, J=8.1Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:17]1([NH:16][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1=O
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccccc1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of 2-[N-(t-butyloxycarbonyl)]amino-cyclohexanone (0.785 g, 3.69 mmol, aniline (0.68 mL, 7.46 mmol) and glacial acetic acid (0.22 mL) in THF (10 mL) was added NaBH(OAc)3 (1.173 g, 5.53 mmol) and the mixture was stirred at 60□ C. overnight. The reaction was cooled to room temperature, diluted with CH2Cl2 (60 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous phase was washed with CH2Cl2 (2×25 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated under reduced pressure. Purification and separartion of the resultant brown oil by flash chromatography on silica gel (Hexanes/EtOAc, 9:1) afforded the low polarity cis-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer (0.095 g, 9%) and the high polarity trans-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer (0.412 g, 39%), both as pale yellow solids.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2].[H][H]>CN(C)C=O.[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=CC=O)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCC=O)cs1
Reaction time: 4.5 h
Yield: 91 %

Procedure:
To a solution of 2-acetylamino-4-(2-formylvinyl)thiazole (2.24 g) in N,N-dimethylformamide was added 10% palladium on carbon (11.2 g) and hydrogen gas was bubbled thereinto for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1 V/V) to give 2-acetylamino-4-(2-formylethyl)thiazole (2.06 g).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=477.1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14](O)[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O>CS(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[CH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cccc(Oc2ccccc2)c1
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: C=Cc1cccc(Oc2ccccc2)c1
Yield: 74.1 %

Procedure:
In 250 ml. of dimethyl sulfoxide were dissolved 7.0 g of α-(3-phenoxyphenyl)ethyl alcohol and 0.5 g of m-dinitrobenzene as a polymerization inhibitor. The solution was subjected to reaction at 160° C. for 10 hours. After cooling, the reaction mixture was incorporated with 250 ml. of dichloromethane, and washed with 600 ml. of water. The resultant dichloromethane layer was separated after removal of the dimethyl sulfoxide, and dried with magnesium sulfate. Then the dichloromethane in the layer was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography. From hexane eluate was obtained 4.75 g of 3-phenoxystyrene.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[N:13]=[C:14]([CH2:17][OH:18])[S:15][CH:16]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19]I>C(Cl)Cl>[CH3:19][O:18][CH2:17][C:14]1[S:15][CH:16]=[C:12]([CH2:11][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[N:13]=1
Reactant: O=[N+]([O-])c1cnn(Cc2csc(CO)n2)n1
Reactant: CI
Agent: N#N
Solvent: ClCCl
Product: COCc1nc(Cn2ncc([N+](=O)[O-])n2)cs1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazol-2-yl)methanol (419 mg, 1.74 mmol) in CH2Cl2 (15.0 mL) was added to a suspension of Ag2O (604 mg, 2.61 mmol) and MeI (0.33 mL, 5.21 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.36. LC-MS-conditions 07: tR=0.68 min, [M+H]+=256.27.
Reaction SMILES: O[CH2:2][S:3]([O-:5])=[O:4].[Na+].Cl[C:8]1[C:9](Cl)=[C:10]([CH3:15])[C:11](C)=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CS(C)=O.CO.C(OCC)(=O)C.[I-].[Na+]>[CH2:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=2[CH2:2][S:3](=[O:4])[O:5]1
Reactant: Cc1ccc(Cl)c(Cl)c1C
Reactant: O=S([O-])CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: O=S1Cc2ccccc2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127 %

Procedure:
Sodium hydroxymethanesulfinate (Rongalite™) (180 g; 1.17 mol) was suspended in DMSO (400 mL) and left to stir for 10 min. before dichloro-o-xylene (102.5 g; 0.59 mol), potassium carbonate (121.4 g; 0.88 mol) and sodium iodide (1.1 g; 7 mmol) were added consecutively. More DMSO (112 mL) was used to rinse residual materials into the reaction mixture before the whole was allowed to stir at room temperature. The initial endothermic reaction became mildly exothermic after around 1 h causing the internal temperature to rise to ca. 32-33° C. The reaction as followed by TLC (ethyl acetate/hexane, 50:50) and found to be complete after 3 h. The reaction mixture was diluted with methanol/ethyl acetate (20:80; 400 mL) and the solids were filtered off, and washed with more methanol/ethyl acetate (20:80; 100 mL, 2×50 mL). The filtrate was transferred to a separating funnel and brine (1 L) was added. This caused more sodium chloride from the product mixture to precipitate out. The addition of water (200 mL) redissolved the sodium chloride. The mixture was shaken and the organic layer was separated and then the aqueous layer was extracted further with methanol/ethyl acetate (20:80; 200 mL), 150 mL, 250 mL). The combined extracts were dried (Na2SO4) and rotary evaporated (bath 37-38° C.). More solvent was removed under high vacuum to give the sultine 10 as a pale orange liquid (126 g) that was found by 1H NMR spectroscopy to be relatively free of by-product but containing residual DMSO and ethyl acetate (FIG. 1).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([CH2:14][CH2:15][CH2:16][N+:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([CH3:28])[CH:24]=2)=[CH:19][CH:18]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCCC(C1C=CC=CC=1)=O.CC1C=C(C2C=CN=CC=2)ON=1.[BH4-].[Na+]>CO>[CH3:28][C:25]1[CH:24]=[C:23]([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[OH:13])[CH2:18][CH:19]=2)[O:27][N:26]=1
Reactant: Cc1cc(-c2cc[n+](CCCC(=O)c3ccccc3)cc2)on1
Agent: Cc1cc(-c2ccncc2)on1
Agent: O=C(CCCCl)c1ccccc1
Agent: [BH4-]
Solvent: CO
Product: Cc1cc(C2=CCN(CCCC(O)c3ccccc3)CC2)on1
Reaction time: 8 h

Procedure:
To a 4.1 g. portion of 1-(3-benzoylpropyl)-4-(3-methyl-5-isoxazolyl)pyridinium perchlorate [prepared by the reaction of γ-chlorobutyrophenone and 4-(3-methyl-5-isoxazolyl)pyridine as described in the previous examples] in 200 ml. of methanol is added, portionwise with stirring, 4.1 g. of sodium borohydride. The mixture is allowed to stand at room temperature overnight, evaporated to about 1/2 volume and poured into ice water. The white solid is collected and recrystallized from acetonitrile, m.p. 108°-109°C.