Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:7]=[C:8]=[N:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])[CH2:3][CH2:4][CH3:5].C([N:20]=[C:21]=[N:22]C1C=NC=CC=1)(C)(C)C>>[C:21]([N:22]=[C:8]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[NH:7][C:2]([CH3:1])([CH3:6])[CH2:3][CH2:4][CH3:5])#[N:20]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCCC(C)(C)N=C=Nc1cccnc1
Product: CCCC(C)(C)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-(1,1-dimethylbutyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1,1-dimethylbutyl)-N'-3-pyridylguanidine was obtained with a melting point of 188.0°-188.5° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:12]1[CH:16]=[CH:15][N:14]2[CH:17]=[N:18][CH:19]=[C:13]12>C(=S)=S.ClCCl>[C:5]([C:19]1[N:18]=[CH:17][N:14]2[CH:15]=[CH:16][S:12][C:13]=12)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1cn2cncc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: S=C=S
Product: CC(C)(C)C(=O)c1ncn2ccsc12

Procedure:
Aluminum chloride (6.0 g) was added to a solution of 6.1 ml of pivaloyl chloride in 50 ml of carbon disulfide. The mixture was stirred. A solution of 1.2 g of imidazo[5,1-b]thiazole in 20 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature for 48 hr. Dichloromethane (200 ml) was added to the reaction mixture. The mixture was washed with water and a saturated aqueous sodium hydrogencarbonate solution in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.92 g of 7-pivaloylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 27.6 g (107 mmol) of trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol and 9.99 ml (128 mmol) of methanesulfonyl chloride in 350 ml of dichloromethane was added under stirring at 0–10° C. 29.6 ml (213 mmol) of triethylamine within 20 minutes. The reaction-mixture was stirred for 1 hour at room temperature. It was then partitioned between dichloromethane, 1N HCl and water. The dichloromethane-phase was dried over magnesium sulfate and concentrated to yield 38.2 g crude trans-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexylmethyl ester as colorless viscous oil, MS: 354 (M+NH4+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C[S:19][C:20]1C2C(=CC(C(N3CCOCC3)=O)=CC=2)N[CH:21]=1>>[CH2:20]([S:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:21]
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Product: CCSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized from (1H-indol-6-yl)(morpholino)methanone (1.5 g, 6.52 mmol, 1.0 eq) in an analogous manner as described for 1b). Yield: 1.3 g. Mass spectroscopy: m/z: [M+H]+=291.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32].CO>CN(C=O)C>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2nnc(-c3cnccn3)n2CCN1Cc1cccc(Cl)c1Cl
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a slurry of Intermediate 1 (60 mg, 0.18 mmol) and cesium carbonate (237 mg, 0.73 mmol) in DMF (1.4 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (65 mg, 0.27 mmol). After 5 h, the reaction was quenched with sat aq NH4Cl, poured into brine, and extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give a brown sludge. Trituration with MeOH provided the desired product as a beige powder (60 mg, 88%). MS (ESI): mass calcd. for C16H12Cl2N6O, 374.0; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.77 (s, 2H), 7.57 (dd, J=7.9, 1.2 Hz, 1H), 7.49-7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 4.86-4.75 (m, 4H), 3.90-3.81 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: CCCON=C(C(=O)CBr)C(=O)OCC
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCCON=C(C(=O)OCC)c1csc(N)n1
Reaction time: 1 h
Yield: 58.3 %

Procedure:
85 g of ethyl 4-bromo-2-propoxyimino-acetoacetate are added dropwise to 23 g (0.3 mole) of thiourea in 155 ccs of water and 75 ccs of ethanol at 25°, while stirring. After one hour, the hydrobromide which has precipitated in the meantime is decomposed by adding concentrated ammonia up to pH 6. After filtering off the product, washing with water and diisopropyl ether and drying, 45 g of ethyl 2-(2-aminothiazol-4-yl)-2-propoxyimino-acetate are obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 9, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate 0.90 g, 0.0065 mole), and dimethylsulfate (0.76 g, 0.006 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.13 g, yield: 89.6%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cccc2c1C(=O)C(O)=CC2=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1C(=O)C(O)=C([N+](=O)[O-])C2=O
Yield: 43 %

Procedure:
A solution of 3-hydroxy-5-methyl-1,4-naphthoquinone (1.9g) in chloroform (200ml) was nitrated with fuming nitric acid according to example 1(a). A yield of 1.01g (43%) of material of m.p. 148°-149° C (d) was obtained. (Found; C, 56.69; H, 3.16; N, 5,73; C11H7NO5 requires; C, 56.66; H, 3.03; N, 6.01%).
Reaction SMILES: [CH3:1][CH2:2][N:3]=[C:4]=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.Br[C:14]1C=C(N)C(N)=CC=1.C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[N:5]1[C:6]2[CH:7]=[CH:8][CH:14]=[CH:1][C:2]=2[NH:3][CH:4]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(Br)cc1N
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc2[nH]cnc2c1
Temperature: 65 °C
Reaction time: 19 h

Procedure:
EDCI.HCl (2.348 g, 12.25 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (2.078 g, 11.11 mmol), N-Boc-L-proline (2.311 g, 10.74 mmol) and 1-hydroxybenzotriazole (1.742 g, 12.89 mmol) in CH2Cl2 (40 mL), and stirred at ambient conditions for 19 h. The mixture was then diluted with CH2Cl2, washed with water (2×), dried (brine; MgSO4), filtered, and concentrated in vacuo to provide a brown foam. Acetic acid (40 mL) was added to the foam, and the mixture was heated at 65° C. for 90 min. The volatile component was removed in vacuo, and the residue was dissolved in EtOAc and washed carefully with saturated NaHCO3 solution (2×), and the organic phase was dried (brine; MgSO4), filtered, and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; EtOAc) to provide benzimidazole M1a as a tan foam (2.5 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 12.49-12.33 (four br s, 1H), 7.71 (d, J=2, 0.54H), 7.60 (app br s, 0.46H), 7.50 (d, J=8.6, 0.45H), 7.40 (d, J=8.4, 0.55H), 7.26 (m, 1H), 4.96-4.87 (m, 1H), 3.64-3.51 (m, 1H), 3.44-3.38 (m, 1H), 2.38-2.21 (m, 1H), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H). LC/MS: Anal. Calcd. for [M+H]+ C16H2181BrN3O2; 368.03. found: 368.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]2[C:16](=O)[O:15]C(C)(C)[O:13]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]([OH:13])[C:16]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CON(C(=O)C=C(O)C(=O)NS(C)(=O)=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of N-[bis-(4-fluoro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.43 mmol) and methanesulfonamide (0.062 g, 0.52 mmol) in anhydrous N,N-dimethylformamide (3 ml) was treated at 25° C. with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 ml). After 1 h, the reaction mixture was then quenched by the addition of ethyl acetate and 1 N hydrochloric acid. The organic phase was washed successively with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution ethyl acetate-methanol 0-20%) gave 0.129 g (67% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.78, 2.81,2.87 and 2.88 (3H, 4 s, SO2CH3), 3.15, 3.16, 3.18 and 3.20 (3H, 4 s, OCH3), 6.22, 6.25 and 6.27 (1H, 3 s, CH), 6.75-6.89 (1H, m, CH), 7.17-7.54 (8H, m, aromatics). HRMS (ESI/neg) calculated for C19H17F2N2O6S, [M−H]−: 439.077540; found: 439.077728.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH3:13][C:14]1[C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:21][CH2:20][C:19]1[C:14]([CH3:13])=[N:15][CH:16]=[CH:17][CH:18]=1)=[S:12]
Reactant: Fc1ccc(N=C=S)c(Cl)c1Cl
Reactant: Cc1ncccc1CN
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: Cc1ncccc1CNC(=S)Nc1ccc(F)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichloro-4-fluorophenylisothiocyanate and C-(2-methylpyridin-3-yl)methylamine using General Procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.47 (s, 3H), 4.69 (m, 2H), 7.21 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 7.46 (t, 1H, J=8.9 Hz), 7.54-7.67 (bs, 1H), 7.58 (dd, 1H, J=1.4 Hz, J=7.7 Hz), 8.26-8.42 (bs, 1H), 8.33 (dd, 1H, J=1.7 Hz, J=4.8 Hz), 9.49 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile −0.1M ammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt 3.69 min. (90.8%); MS: M+H− 342.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[F-:26].[Cs+]>CS(C)=O>[F:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(F)c23)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A solution of Intermediate 71 (104 mg) in dimethyl sulfoxide (2 ml) was added with cesium fluoride (284 mg, Wako Pure Chemical Industries) and stirred at 150° C. for 8 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. The residue was added with water (20 ml), extracted with ethyl acetate (20 ml) and washed twice with saturated brine (10 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (21.1 mg).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22](C)([CH3:26])C(O)=O)=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C([O:45][C:46](=[O:56])CCSC1SC(N)=NC=1)C>>[CH3:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:13]([CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][CH2:22][CH2:26][C:46]([OH:56])=[O:45])=[CH:19][N:20]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: Sc1ccccc1
Product: C[C@H]1CC[C@H](N(CCCSc2ccccc2)C(=O)Nc2ncc(SCCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].Br[CH2:17][CH2:18][CH:19]([Br:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([CH2:17][CH2:18][CH:19]([Br:21])[CH3:20])[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: CC(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1N(CCC(C)Br)S(C)(=O)=O
Reaction time: 1 h
Yield: 65.6 %

Procedure:
15.5 g (0.517 moles) of a 80% sodium hydride dispersion, containing 20% of mineral oil, are added in small portions, within 0.5 hours, to a suspension of 100 g (0.5 moles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 800 ml of dry xylene at room temperature, and the mixture is heated then to 130° C. within one hour. 102.5 ml (184.5 g, 0.85 moles) of 1,3-dibromo-butane are added dropwise, within 3 hours, to the mixture at 130°-135° C., and the mixture is stirred at the same temperature for additional 4 hours. Thereafter the mixture is cooled, washed twice with 200 ml of water, twice with 250 ml of 1 n aqueous sodium hydroxide solution, once with 200 ml of water, twice with 200 ml of 1 n aqueous hydrochloric acid solution and finally twice with 200 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 109.65 g (66%) of crude 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-3-bromo-butane are obtained as a dark yellow oil; this substance can be utilized in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20]O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and Dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-dimethyl-amine as light brown semisolid, MS: 385 (MH+, 1Br).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([OH:45])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:5][NH:6][C:7]([C@:9]1([OH:45])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 137.2 %

Procedure:
To a solution of tert-butyl (3R,4R)-3-[(tert-butoxyamino)carbonyl]-3-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1-carboxylate (740 mg, 1.15 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred at room temperature for 1.5 h. The solvent was concentrated in vacuo and methanol was used to chase residual trifluoroacetic acid. The residue was precipitated from ether as a white solid to yield 856 mg (97%) of (3R,4R)-N-tert-butoxy-3-hydroxy-4-(4-((2-methylquinolin-4-yl) methoxy)phenylsulfonamido)piperidine-3-carboxamide as the trifluoroacetic acid salt. MS: (M+H)+=543.1.
Reaction SMILES: [C:1]([C@:5]1(N)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]1[C@H:11](O)[CH3:12])([CH3:4])(C)C.C1CC(=[O:24])C2C(=CC=CC=2)C1>C1COCC1>[CH2:12]1[CH:4]([OH:24])[CH2:1][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:11]1
Reactant: C[C@@H](O)C1C=CC=C[C@@]1(N)C(C)(C)C
Reactant: O=C1CCCc2ccccc21
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 915.3 %

Procedure:
Borane methylsulfide complex (neat, ~10M, 0.44 mL, 4.4 mmol) was added to a solution of (1R, 2S)-2-tert-butyl-2-aminophenylethanol [Angew. Chem. Int. Ed. Engl. 26 1141 (1987)] (120 mg, 0.62 mmol) in THF (22 mL) at ambient temperature and stirred for 16 hrs; α-Tetralone (906 mg, 6.2 mmol) as a solution in THF (3 mL) was added to the preceding solution over a 1 hr, stirred for 15 min after addition was completed, cooled to 0° C., and quenched with methanol (20 mL). After stirring the quenched reaction for 18 hrs, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (30 mL), washed with pH 4 phosphate buffer (30 mL), water (30 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol 841 mg (91% yield) 82% ee.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Add 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (16.8 g.) to a solution of sodium borohydride (6 g.) in methanol (500 cc.), swirl the mixture which boils spontaneously. When all the material has been added and the reaction has subsided, add acetic acid (15 cc.). Reduce the mixture in volume by evaporation of most of the solvent, add water and extract the product with ether. Evaporate the washed and dried extracts to obtain crude crystalline product (16.8 g.), m.p. 102°-5° on recrystallization from acetonitrile.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared from the product of Example 4 and 4-fluoro-2-trifluoromethyl-benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][NH:14][CH3:15]>C(OCC)(=O)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[N:3]=[C:2]([N:14]([CH3:15])[CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CNC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (2.65 g, 12.5 mmol) in ethyl acetate (200 ml), a 50% aqueous dimethylamine solution (1.10 ml) was dripped in at −15 degrees Celsius, this was further agitated for 1 hour, then agitated for 1 hour at 0 degrees Celsius, then at room temperature for 16 hours. The reaction liquid was poured into ice water and extraction was carried out 2 times with ethyl acetate. After washing together with the ethyl acetate layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=1:1), and 827.4 mg of 6-chlor-4-dimethylamino 2-methyl-5-nitropyrimidine (yield 31%) was obtained. The MS measurement result, and the NMR data for the obtained 6-chlor-4-dimethylamino-2-methyl-5-nitropyrimidine are shown below.