Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=2[O:22][CH2:23][O:24][CH3:25])=[N:7][NH:6][C:5]1=[S:26])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([N:4]1[C:5]([S:26][CH3:27])=[N:6][N:7]=[C:8]1[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=1[O:22][CH2:23][O:24][CH3:25])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1C(C)C
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1C(C)C
Temperature: 80 °C
Yield: 94.9 %

Procedure:
4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F63-03, 1.96 g, 5.14 mmol) and potassium carbonate (710.4 mg, 5.14 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) was added and then methyl iodide (0.32 mL, 5.14 mmol) was added. After heating at 80° C. for 1 hour while stirring, the mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding water, the reaction system was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain yellow syrup. After purification by silica gel column chromatography (chloroform, methanol), 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxy methoxyphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F63-04, pale yellow syrup, 1.93 g, 95%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[S:9](Cl)(=[O:11])=[O:10].[N:13]1C=CC=CC=1>C(Cl)Cl>[CH:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: Nc1ccc(S(N)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a 0° C. solution of the aniline from step E (940 mg, 4.0 mmol) in 30 mL of DCM and 5 mL of pyridine was added methanesulfonyl chloride (0.40 mL, 4.0 mmol). The resulting mixture was stirred at this temperature for 2 h before being diluted with 100 mL of DCM. The solution was washed with 1N HCl (3×25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried and concentrated to afford sulfonamide P which was used in the next step without further purification. LCMS (M+H)=314.1
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.N12CCCN=C1CCCCC2.C1(P([N:52]=[N+:53]=[N-:54])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:52]([CH2:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:4]=2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)=[N+:53]=[N-:54]
Reactant: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1sc(-c2cc(CN=[N+]=[N-])cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution (7 mL) of the compound (1.3 g, 3.4 mmol) obtained in Example 95c in tetrahydrofuran were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol) and diphenylphosphoryl azide (1.1 g, 4.1 mmol), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=85/15) to give the title compound (1.1 g, 80%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[C:6]=2[CH:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B(O)O)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=5)[C:6]=4[CH:20]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(C(F)(F)F)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (67 mg, 54%), MS (ISP) m/z=423.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-trifluoromethyl-phenyl)-1H-benzo[d]imidazole (intermediate I) (100 mg, 293 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (72.5 mg, 352 μmol).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1.[C:25]1([O:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[C:34]([CH3:47])[CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:47][C:34]1[CH:33]=[C:32]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:37]=[CH:36][C:35]=1[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ccc1-c1cn([C@H]2CC[C@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Temperature: 80 °C

Procedure:
A mixture of trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.347 g, 0.000788 mol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl phenyl ether (0.27 g, 0.000867 mol), tetrakis(triphenyl-phosphine)palladium(0) (0.054 g, 0.000047 mmol), and sodium carbonate (0.209 g, 0.00197 mol) in N,N-dimethylformamide (15 mL) and water (10 mL) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. The mixture was allowed to cool to ambient temperature and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine/dichloromethane (5:95) followed by methanol/triethylamine/ dichloromethane (3:5:92) as mobile phase to yield trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol). Trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.376 g, 0.000757 mol) was dissolved in refluxing ethanol (10 mL) and a preheated solution of maleic acid (0.264 g, 0.00227 mol) in ethanol (5 mL) was added. The mixture was refluxed for 15 minutes, cooled to ambient temperature and the precipitate collected by filtration, washed with cool ethanol and dried to give trans-5-(2-methyl-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate (0.153 g, 0.000181 mol): 1H NMR (DMSO-d6, 400 MHz) 8.22 (s, 1H), 7.42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s, 1H), 6.89 (d, 1H), 6.16 (s, 6H), 4.58 (m, 1H), 3.3 (br, 9H), 2.68 (s, 3H), 2.22 (s, 3H), 2.01 (br, 6H), 1.57 (br, 2H) RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 23 min with 0.1 M ammonium acetate, 1 mL/min) Rt 7.30 min. MS: MH+497.
Reaction SMILES: [OH-].[K+].CO.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N+:24]([O-])=[O:25])[CH:18]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13](=[C:22]1[CH:21]=[C:20]([CH3:23])[C:19](=[N:24][OH:25])[CH:18]=[C:17]1[Cl:16])[C:14]#[N:15]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC1=CC(=C(C#N)c2ccc(Cl)cc2Cl)C(Cl)=CC1=NO
Reaction time: 2 h

Procedure:
To a stirred solution of 75 parts of potassium hydroxide in 240 parts of methanol, are added 27 parts of 2,4-dichlorobenzeneacetonitrile. Then there is added a solution of 25.5 parts of 1-chloro-4-methyl-3-nitrobenzene in 40 parts of methanol (exothermic reaction: temperature rises to 40° C). Stirring is continued for 2 hours while meantime the mixture is allowed to cool to 20° -25° C. 1000 parts of water are added. Upon the addition of a mixture of acetic acid and water (1:1 by volume), an oil is precipitated. The supernatant aqueous phase is decanted and the oil is taken up in methylbenzene. The solution is evaporated. The oily residue is triturated in a mixture of 2,2'-oxybispropane and petroleumether, yielding 2,4-dichloro-α-[2-chloro-4-(hydroxyimino)-5-methyl-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile.
Reaction SMILES: [ClH:1].[CH2:2]([NH:6][CH2:7][C:8]1([CH3:22])[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9]1)[CH:3](C)C.[C:23](O)(C(F)(F)F)=O.Cl>>[ClH:1].[CH3:22][C:8]1([CH2:7][NH:6][CH:2]([CH3:3])[CH3:23])[S:12](=[O:14])(=[O:13])[C:11]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CNCC1(C)Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: Cl
Product: CC(C)NCC1(C)Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Yield: 48 %

Procedure:
The title compound was prepared in the same way as 5-(N-isobutylaminomethyl)4,5-dihydro-5-methylthieno[2,3-b]thiophene-2-sulfonamide-6,6-dioxide hydrochloride. Thus 5-(N-isopropylcarbamoyl)-4,5-dihydro-5-methylthieno[2,3-b]thiophene-2-N-t-butylsulfonamide-6,6-dioxide (3.0 g, 7.3 mmol) was reduced with borane-dimethylsulfide complex (5.0 mL, 50 mmol), deprotected with TFA, and converted to the HCl salt to give the title compound as a white solid (1.32 g, 48% over two steps), mp=132°-135° C. Anal. Calc. for C11H18N2O4S3.HCl.1/2H2O: C, 34.41; H, 5.25; N, 7.29. Found: C, 34.42; H, 5.19; N, 7.11.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:23][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Li+:25]>O.CO.O1CCCC1>[N:18]1([CH2:17][CH2:16][CH2:15][O:14][C:12]2[CH:13]=[C:8]3[CH:7]=[C:6]([C:4]([O-:5])=[O:3])[NH:23][C:9]3=[N:10][CH:11]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1.[Li+:25]
Reactant: CCOC(=O)c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To the suspension of 0.19 g (0.6 mmol) 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 0.4 ml water, 0.4 ml methanol and 0.4 ml tetrahydrofuran was cooled to 0° C. and treated with 0.63 ml (0.63 mmol) of a 1M aqueous lithium hydroxide solution. After stirring for 5 hours at room temperature the volatile components were evaporated at a rotary evaporator and the residue dried under high vacuum over phosphorus pentoxide to give 0.18 g (100%) of the compound as a light yellow solid (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][CH2:8][C:9]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)=[O:10])=[O:6].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][CH:8]([C:9]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)=[O:10])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:6]
Reactant: O=C(CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccoc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccoc1
Yield: 91.9 %

Procedure:
7.6 g of N-(3,4-dichlorobenzoyl)-(3-furylcarbonyl)methylamine, 1.2 g of 61% sodium hydride and 4.7 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 9.0 g of ethyl 3-(3,4-dichlorobenzoylamino)-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 91.9%
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[H][H]>CC(O)C>[C:7]1([C@H:5]([OH:6])[CH2:4][CH2:3][N:2]([CH3:13])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CC(C)O
Product: CN(C)CC[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
Chiral hydrogenation of 3-(dimethylamino)propiophenone was carried out (see formula (13) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex synthesized in Example 2 and using 3-(dimethylamino)propiophenone(886 mg; 5.0 mmol) as the substrate and 2-propanol (5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 250° C., and the reaction time was set to 12 hours. As a result, (R)-1-phenyl-3-(dimethylamino)propane-1-ol was obtained at a conversion rate of 100%, isolation yield of 89% (796 mg; 4.45 mmol), and enantiomeric excess of 97%. HPLC (column: CHIRALCEL OD; size: 4.6 mm×250 mm; made by Daicel Chemical Industries Ltd.; solvent: 9:1 hexane/2-propanol; temperature: 30° C.; UV wavelength: 254 nm; flow rate: 0.5 ml/minute; tR of (R)-1-phenyl-3-(dimethylamino)propane-1-ol: 14.4 minutes (98.4%); tR of S alcohol: 20.4 minutes (1.6%)); [α]26D+31.8° (c: 1.67; CH3OH); absolute structure: R; literature value: [α]D+27.6° (c:1.61; CH3OH),(R).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:32]=[CH:31][C:19]([CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:32]=[CH:31][C:19]([CH2:20][CH2:21][NH:22][CH3:23])=[CH:18][CH:17]=2)=[C:4]([OH:33])[CH:3]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CNCCc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 87 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethyl(methyl)carbamate (60 mg, 0.12 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.72 mL, 0.72 mmol) to afford the desired product (22 mg, 50%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.72 (s, 1H), 8.72 (s, 1H), 7.76 (d, J=5.4 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.31 (s, 1H), 7.24 (d, J=8.1 Hz, 2H), 5.85 (d, J=5.4 Hz, 1H), 3.30-3.23 (m, 2H), 3.09-3.02 (m, 2H), 2.65 (s, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=9.03 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>C1COCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of 1-iodo-2-nitrobenzene (1.12 g, 4.5 mmol) in anhydrous THF (15 mL) cooled to minus 40° C. under nitrogen atmosphere, a solution of phenylmagnesium chloride (2 M in THF, 2.4 mL, 4.8 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for five minutes at minus 40° C., followed by addition of isobutyraldehyde (0.545 mL, 6.0 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (6 mL), poured into water (80 mL), and extracted with ethyl acetate three times (100 mL). Combined organic phase was washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(2-nitrophenyl)-2-methyl-propanol (0.876 g, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (dd, 1H, J=1.2 and 8.2 Hz, Ph-H), 7.73 (dd, 1H, J=1.4 and 7.9 Hz, Ph-H), 7.61 (m, 1H, Ph-H), 7.39 (m, 1H, Ph-H), 5.03 (dd, 1H, J=4.5 and 5.8 Hz, Ph-CH), 2.42 (d, 1H, J=4.5 Hz, OH), 2.02 (m, 1H, CH), 0.95 (d, 3H, J=6.7 Hz, CH3), 0.89 (d, 3H, J=6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 148.48 (C), 138.91 (C), 132.95 (CH), 128.85 (CH), 127.95 (CH), 124.21 (CH), 73.79 (CH), 34.30 (CH), 19.66 (CH3), 17.01 (CH3).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.[BrH:18]>CC#N.CCCCCC.C(O)(=O)C>[Br:18][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:9])[CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Br
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 132 μL (1.00 mmol) of phenylacetyl chloride in 1.0 mL of anhyd MeCN was added 1.05 mL (2.10 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane. After stirring 1 h at room temperature, the mixture was cooled (0° C.) and 300 μL (1.50 mmol) of 30 wt % HBr in acetic acid was added dropwise (gas evolution). After stirring 15 min, the mixture was concentrated in vacuo and rapidly chromatographed on a 2 g silica SPE column (Waters Sep-Pak) with 50% CH2Cl2-hexane to afford the title compound as a pale yellow oil (201 mg, 94%). 1H-NMR (300 MHz, CDCl3) δ7.2-7.4 (m, 5H), 3.95 (s, 2H), 3.92 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23]C(CCl)=[CH:19][CH:18]=1>C(O)C>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COC(=O)C2CCC(O)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 4-hydroxycyclohexanoate (8.61 g, 50 mmole) in 50 ml ethanol was added a solution of potassium hydroxide 85% (3.63 g, 55 mmole) and the mixture was stirred for 6 hours at 70° C. The mixture was evaporated under reduced pressure, coevaporated two times with N,N-dimethylformamide and reduced to about 100 ml. 4-Methoxybenzyl chloride (9.4 g, 60 mmole) was added and the mixture was stirred for 18 hours at 60° C. The mixture was evaporated under reduced pressure and 250 ml ethyl acetate was added. The organic phase was washed five times with water, dried with sodium sulfate and evaporated under reduced pressure. Yield: 13.2 g=100% (crude)
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Br:9].[F-].[K+].[CH2:12](Br)Br>CN(C=O)C>[CH2:12]1[O:8][C:7]2[C:2](=[C:3]([Br:9])[CH:4]=[CH:5][CH:6]=2)[O:1]1
Reactant: BrCBr
Reactant: Oc1cccc(Br)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc2c1OCO2
Temperature: 135 °C
Yield: 30.1 %

Procedure:
To 2,3-dihydroxy-bromobenzene (3.0 g, 0.16 mole), KF (4.63 g, 0.080 mole), DMF (15 mL was added CH2Br2 (4.13 g, 0.024 moles). This suspension was heated to 135° C. for 3 hours, cooled and filtered. The filtrate was poured into 200 mL of ether and washed with water, 1 N KOH and brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum, to yield 2,3-Methylenedioxy-bromobenzene (1.45 g, 45 % yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][O:7][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: CC(C)(CO)CCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCBr)COC1CCCCO1
Yield: 90.4 %

Procedure:
According to the procedure for the preparation of 207d, 206a (78.0 g, 0.40 mol) was reacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49 mol) and p-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in CH2Cl2 (0.5 L) to yield 207a (101.0 g, 90%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=2.9), 3.83 (m, 1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98 (d, 1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H, J=8.5), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.01, 76.17, 61.85, 37.89, 34.66, 34.04, 30.62, 27.92, 25.60, 24.64, 24.56, 19.41. HRMS (LSIMS, nba): Calcd for C12H24BrO2 (MH+): 279.0960, found: 279.0955.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](=[O:14])(=[O:13])[NH:19][CH:16]1[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: NC1CC1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Reaction time: 3 h
Yield: 35 %

Procedure:
A round bottom flask was charged with methyl 4-chloro-3-(chlorosulfonyl)benzoate (12.0 g, 44.32 mmol) and 1,4-dioxane (100 mL) at 0° C. Cyclopropyl amine (9.31 mL, 137.8 mmol) was added dropwise and the mixture was stirred at that temperature for 3 h. The solvent was removed and the residue was treated with EtOAc. The organic phase was washed with brine, dried, and concentrated to get the title compound (4.5 g, 32% yield).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[Br:48])[C:37]1=[O:49].O>CN(C=O)C.C(OCC)(=O)C>[Br:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH:38]1[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[C:37]1=[O:49]
Reactant: NN1CCCC(c2ccccc2Br)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccccc3Br)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
BOPCl (1.48 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1.0 g), 1-amino-3-(2-bromophenyl)piperidin-2-one (1.26 g) and TEA (1.1 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature for three hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.130 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10](=[N:13][C:14]#[N:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10]([NH:19][CH3:18])=[N:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCN(Cc1ccc(Cl)nc1)C(=NC#N)SC
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C(=NC#N)NC
Yield: 81.4 %

Procedure:
To a mixture of 0.42 g of 1-(6-chloro-3-pyridylmethyl)-3-cyano-1-ethyl -2-methylisothiourea and 5 ml acetonitrile was added each 0.5 g of 40% methylamine aqueous solution at an hour interval in total six time (3.0 g), while refluxing and stirring. The reaction mixture was stirred for 6 hours in total. Then, the mixture was concentrated to afford 0.32 g of 1-(6-chloro-3-pyridylmethyl)-2-cyano-1-ethyl-3-methylguanidine (Compound No. 3).