Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]=[CH:20]2)([O-])=O>CO.[Pd]>[NH2:14][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)[CH2:20]2
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(N)cc3C2)CC1
Reaction time: 48 h

Procedure:
To a solution of 5-nitro-indene bocpiperazine (0.740 g, 2.13 mmol) in methanol (20 mL) was added Pd/C (0.280 g, 2.63 mmol). The reaction mixture was stirred under H2 for 48 h. When the hydrogenation was complete, the reaction mixture was passed through a pad of Celite® and washed several times with methanol. The collected organics were then concentrated in vacuo and gave the title product. LC/MS: [(M+1)]+=318;
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10]Cl)=[N:5][N:4]=[N:3]1.[OH:12][C:13]1[C:14]([SH:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:19][C:14]2[C:13]([OH:12])=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:5][N:4]=[N:3]1
Reactant: Oc1cccnc1S
Reactant: Cn1nnnc1SCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ncccc1O
Yield: 42.9 %

Procedure:
1-Methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) and 3-hydroxy-2-mercaptopyridine (1.3 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (1.4 g) and potassium iodide (0.1 g), and the mixture is refluxed for 5 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with chloroform-methanol and recrystallizing from ethyl acetate-n-hexane to give 1-methyl-5-[3-(3-hydroxy-2-pyridyl)thiopropyl]thio-1,2,3,4-tetrazole (1.2 g) as pale yellow granules, m.p. 87.5°-88.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[CH:7]=1)[CH3:2].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:23]=[O:24])=[C:8]([CH3:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc(Br)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of (4-bromo-3-methyl-phenyl)-carbamic acid ethyl ester (210 mg) in THF (4 mL) was added n-BuLi (0.71 mL, 2.5 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 40 min, then DMF (0.31 mL) was added. The mixture was stirred at −78° C. for 40 min and then warmed up to room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution (11 mL) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=5:95 to 40:60) to give (4-formyl-3-methyl-phenyl)-carbamic acid ethyl ester: MS (ESI): m/z 206 (M+1); 1H NMR (CDCl3, 400 MHz) δ 10.14 (s, 1H), 7.75 (d, 1H), 7.39 (dd, 1H), 7.32 (s, 1H), 6.92 (s, 1H), 4.25 (q, 2H), 2.65 (s, 3H), 1.32 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1.O.Cl.[Cl-].[Na+].O>[Cl:15][CH2:16][CH2:17][CH2:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)C(OC)c1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(OC)c1ccc(NS(=O)(=O)CCCCl)cc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-2-methoxyacetate (0.6 g, 3.07 mmol) in anhydrous pyridine (6 mL) under argon was added 3-chloropropane-1-sulfonyl chloride (0.5 mL, 4.11 mmol) dropwise. The exothermic reaction was cooled briefly over a cold H2O bath. After stirring for 1 hr, the reaction was diluted with H2O, 1 M HCl and brine and extracted with EtOAc. The combined organics were washed with 1 M HCl, H2O and brine then dried over Na2SO4 and concentrated in vacuo to give methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate as an orange oil (1.03 g, quant. yield). The product was used without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:30][CH3:31])=O)C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:30][CH3:31]
Reactant: COC(=O)c1cc(OC)cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC)cc(N2CC[C@H](N)[C@H](OC)C2)c1

Procedure:
The same operation as in Example (40e) was performed using methyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methoxybenzoate obtained in Example (257b) (106 mg, 0.25 mmol), a 10% palladium-carbon catalyst (42 mg), methanol (2 mL) and ethyl acetate (2 mL), to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:19]C)[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:21][S:22][CH2:23][CH2:24][OH:25].[Na].Cl.N>>[NH2:1][C:2]1[N:10]=[C:9]([O:25][CH2:24][CH2:23][S:22][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1nc2c(N)nc(Cl)nc2n1Cc1ccccc1
Reactant: CSCCO
Agent: Cl
Agent: N
Agent: [Na]
Product: CSCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 27 %

Procedure:
6-amino-9-benzyl-2-chloro-8-methoxypurine (190 mg, 0.56 mmol) was added to 2-methylthioethanol (3 ml) containing sodium (110 mg, 4.78 mmol). The mixture was heated for 2 hours. Thereto were added 2N hydrochloric acid and 28% aqueous ammonia in order. The mixture was extracted with 3% methanol/chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (59 mg, yield 27%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:27]=[CH:26][O:25][CH:24]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccoc2)n1
Product: c1cn(CCCc2ccc(OCc3coc(-c4ccoc4)n3)cc2)cn1
Yield: 93 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-furyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-furyl)oxazole. The yield was 93%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 85-87° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:41])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added ClCO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1M aqueous HCl, saturated aqueous Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38; found: [M+H]+=372.3.
Reaction SMILES: N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[C:44]([CH:45](O)[CH3:46])=[C:43]([F:48])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2.[C:49]1(=[O:59])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51](=[O:58])[NH:50]1>C1COCC1>[F:34][C:35]1[C:44]([CH:45]([N:50]2[C:51](=[O:58])[C:52]3[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:49]2=[O:59])[CH3:46])=[C:43]([F:48])[CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1c(F)cc2ncccc2c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1c(F)cc2ncccc2c1F)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (3.8 g, 18.9 mmol) and triphenylphosphine (5.4 g, 20.5 mmol) in THF (50 mL) was stirred for 30 min, and a solution of 1-(5,7-difluoroquinolin-6-yl)ethanol (3.3 g, 15.8 mmol) and isoindoline-1,3-dione (2.7 g, 17.4 mmol) in THF (50 mL) was added dropwise. The reaction mixture was heated at 50° C. overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound as a white solid (2.6 g, 49%). LCMS (method A): [MH]+=339, tR=5.81 min.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1.[CH2:10]([OH:14])CCC>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Fe+2].C1(C)C=CC(S([O-])(=O)=O)=CC=1>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([CH:10]=[O:14])[S:5][CH:6]=2)[O:2]1
Reactant: c1scc2c1OCCO2
Reactant: CCCCO
Agent: [Fe+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O=Cc1scc2c1OCCO2
Temperature: 80 °C
Reaction time: 144 h

Procedure:
A di-ol triblock copolymer, of the structure HO-BAB-OH, was synthesized from 3,4-ethylenedioxythiophene and a precursor that contained a hydroxyl group at one end and an EDOT group at the other end. This precursor was prepared by reacting a mono-amino mono-hydroxyl terminated poly(ethylene glycol) oligomer with 3,4-ethylenedioxythiophene-2-carboxaldehyde under the conditions described in Example #18, Part A. 3,4-Ethylenedioxythiophene-2-carboxaldehyde was prepared according to the Mohanakrishnan method in high yield (Mohanakrishnan et al., Tetrahedron, 55, 11745-11754 (1999)). The tri-block copolymers were made as follows: 2 mmol of PEGmonoEDOT with average molecular weight of 1500 Dalton and 170 mmol EDOT were mixed in butanol and heated at 80° C. To this solution, a solution of Baytron® C from Bayer (50% iron p-toluenesulfonate in butanol) was added drop-wise over 30 minutes. The reaction was stirred at room temperature for 6 days then the product was filtered and extracted with copious amount of water. Butyl acetate (150 mL) was added under stirring and the butanol was removed by fractional distillation. The resulting butyl acetate suspension was mixed with a trimer of hexamethylene diisocyanate at a ratio NCO/OH of 1.2 (Bayhydrur XP 7007 from Bayer). This mixture was used to cast coatings on primed iron panels. The resulting polyurethane coatings had a conductivity of 1×10−4 S/cm.
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[CH3:18][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH2:20][NH2:21]>C(Cl)Cl>[CH3:22][C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:18])[CH2:20][NH:21][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CN)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4.0 ml (30 mmol) of NEt3 and 4.22 g (30 mmol) of benzoylchloride were added in succession at 0° C. to a solution of 1.86 g (10.0 mmol) of 2-methyl-2-phenylpropylamine hydrochloride in DCM (30 ml) and the mixture was stirred for 1 h at RT. It was then diluted with DCM and washed with a 10% aqueous hydrochloric acid, a saturated aqueous Na2CO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 2.48 g (9.8 mmol, 98%) of N-(2-methyl-2-phenylpropyl)benzamide were obtained as the residue, which was reacted further with no additional purification.
Reaction SMILES: [Na:1].COC1OCC(C[O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[CH3:31][C:32]1([CH2:40][CH2:41]O)[O:39][CH2:38][C:35]2([CH2:37][CH2:36]2)[CH2:34][O:33]1>>[Na:1].[CH3:30][C:13]1[C:14]([CH2:18][S:19]([C:21]2[NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[N:22]=2)=[O:20])=[N:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:41][CH2:40][C:32]1([CH3:31])[O:33][CH2:34][C:35]2([CH2:37][CH2:36]2)[CH2:38][O:39]1
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: CC1(CCO)OCC2(CC2)CO1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC3(CC3)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 5.5 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 2-(6-methyl-5,7-dioxaspiro[2.5]oct-6-yl)ethanol obtained in the step (35a) to obtain the title compound (163 mg, total yield: 5.5%) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH3:32]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][N:19]([C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH3:32])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COCC(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)N(C)C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Sodium hydride (60% in oil, 16 mg) was added to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[(methoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 20 min. Methyl iodide (57 mg) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (170 mg).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:13])=[NH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.CC[O-].[Na+].[CH3:21][S:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29]N)=O)=[CH:25][CH:24]=1.Cl.CCOCC>C(O)C>[ClH:1].[CH3:21][S:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]2[NH:29][N:13]=[C:11]([C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:9]=3)[N:12]=2)=[CH:25][CH:24]=1
Reactant: N=C(N)c1cccc(CN2CCCC2)c1
Reactant: CSc1ccc(C(=O)NN)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CSc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a stirred ethanolic suspension of 3-pyrrolidin-1-ylmethyl-benzamidine hydrochloride salt (1:2) (414 mg, 1.5 mmol, 1.5 eq.) in 15 ml ethanol was added over 3 minutes 1.2N NaOEt in ethanol (3.4 ml, 4 eq.) and stirring was continued for 30 min. at r.t. 4-Methylsulfanyl-benzoic acid hydrazide (182 mg, 1 mmol) in ethanol at 20° C. was then added and the mixture heated to reflux for 50 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4, affording a foam after solvent evaporation. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (1.0 ml, 2 mmol) was added. After 30 min. the solvent was evaporated and the residue was dried overnight under high vacuum at 30° C. affording the title compound (200 mg, 52% yield) as a yellow foam. MS: m/e=351.5 (M+H+).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)cc1

Procedure:
A mixture of (1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.027 g, 0.10 mmol) and p-methoxybenzylamine (0.28 g, 2.03 mmol) in ethanol (1 ml) was refluxed under N2 overnight. The solvent was removed and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate/Et3N=6:4:0.2) to give (2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol, (−)-29a, 0.03 g (73.2%, [α]D=(−)71.9, c=1, MeOH).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:19][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Fmoc-Cl (27.6 g, 107.2 mmol) in 1,4-dioxane (950 mL) was added dropwise to a solution of (S)-methyl 2-amino-3-(4-nitrophenyl)propanoate (3A; 20 g, 89.3 mmol) and K2CO3 (14.8 g , 107.2 mmol) in water (80 mL) and 1,4-dioxane (150 mL) on an ice bath. After being stirred for 2 hours at room temperature, the mixture was poured into 1.2 L of water to precipitate a white solid, which was filtered and washed with cold water. The solid was dried under vacuum for 3 hours to give 40 g of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate 3B, which was directly used in step 2.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18](=[O:20])[CH3:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br-:21].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C1COCC1>[Br:21][CH2:19][C:18]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:20]
Reactant: COc1ccc(-c2c(C(C)=O)cnn2C(C)(C)C)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)CBr)cnn2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 32.1 %

Procedure:
To a solution of the compound (260 mg, 0.95 mmol) obtained in step 4 in THF (5 mL) was added dropwise a solution of trimethylphenylammonium tribromide (359 mg, 0.95 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 14 hr, and the precipitate was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 2→45% ethyl acetate/hexane) to give 2-bromo-1-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)ethanone (107 mg, 0.305 mmol, 31.9%) as a white powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:13])(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:24][CH:25]=2)=[CH:16][C:15]=1[O:46][CH:47]([CH3:49])[CH3:48])=[O:13])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 3-[[[[4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isopropoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (221 mg) in methanol (2.21 ml) and tetrahydrofuran (1.11 ml) was added 1N sodium hydroxide (0.950 ml) and the mixture was stirred at room temperature for 1 hour. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and to the residue was added water (50 ml). The mixture was acidified with 1N hydrochloric acid (pH=5.4) and extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave tert-butyl [3-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isopropoxy-4-biphenylyl]propyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (212 mg) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: C1CCNC1
Product: O=C(c1ccc2[nH]ccc2c1)N1CCCC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and pyrrolidine (0.210 g, 70%).