Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][S:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNS(=O)(=O)Cc1ccccc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 24 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with benzylsulfonyl chloride under the conditions described in example 2 to yield 24% of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(O)C>[CH2:23]([O:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(O)cc1Cl
Yield: 16 %

Procedure:
In ethanol was dissolved 5.0 g of 4-hydroxy-3-chlorophenol, and an aqueous solution of 1.38 g of sodium hydroxide and 8.6 g of n-dodecyl bromide were added to the solution under reflux in a nitrogen atmosphere. The mixture was refluxed for 6 hours and cooled, and the thus-obtained solution was put into a 1N aqueous solution of hydrochloric acid and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dehydrated on anhydrous magnesium sulfate and concentrated. The concentrate was purified by using a silica gel column to obtain 1.73 g of 4-dodecyloxy-3-chlorophenol.
Reaction SMILES: C(O)CCC.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCO
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 111.7 %

Procedure:
To a solution of n-butanol (316 ml), water (24 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 9 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 10-12 hours. The crystals were collected by filtration, washed with n-BuOH and dried in vacuo at 40-50° C. to yield 40.1 g (94%) of Terazosin.HCl dihydrate. The product of this example was characterized by XRD and DSC melting point as shown in FIGS. 1 and 2 and in Table I as Trial H. This procedure was repeated in n-butanol using the water volumes indicated in Table I and yielding the results indicated for Trials G, I and J.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(Cl)Cl>[C:18]([NH:22][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CC(C)(C)N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)NCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (400 mg, 1.18 mmol) in tetrahydrofuran (6 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of tert-butylamine (1.24 ml, 11.8 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 19 hours at ambient temperature. The reaction mixture was diluted with methylene chloride, and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9]([N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1[CH:17]=[C:16]([CH:18]=C)[N:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:13]=1[O:24][CH3:25])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:4]([O:8][C:9]([N:11]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1[CH:17]=[C:16]([CH:18]=[O:1])[N:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:13]=1[O:24][CH3:25])=[O:10])([CH3:5])([CH3:7])[CH3:6]
Reactant: C=Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c(C(=O)OC)n1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1nc(C=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
Ozone was bubbled through a solution of methyl 4-[bis(tert-butoxycarbonyl)amino]6-ethenyl-3-methoxypyridine-2-carboxylate (0.382 g, 0.935 mmol) in CH2Cl2 (9.35 ml) at −78° C. until the solution turned blue. Oxygen was bubbled through the reaction mixture until the solution turned yellow and triphenylphosphine (0.294 g, 1.122 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then adsorbed onto celite and the residue was purified by flash column chromatography (ISCO, SiO2 24 g, hexanes/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate (279 mg, 0.680 mmol, 72.7% yield) as a light yellow oil. ESIMS m/z 411 ([M−H]+); 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (s, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 1.43 (s, 18H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>[Zn+2].[Br-].[Br-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccc(N)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5° C. and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C., and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:48]=[CH:47][C:40]([C:41]([NH:43][CH:44]2[CH2:46][CH2:45]2)=[O:42])=[CH:39][N:38]=1.C(OC(C)C)(=O)C>>[CH:44]1([NH:43][C:41](=[O:42])[C:40]2[CH:47]=[CH:48][C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[N:38][CH:39]=2)[CH2:46][CH2:45]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1ccc(Br)nc1
Solvent: CC(=O)OC(C)C
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-N-cyclopropylnicotinamide following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.74 min, m/z=456.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.82 (m, 2H), 1.13 (s, 3H), 1.22 (s, 3H), 1.49 (d, 3H), 2.17 (m, 3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 5.66 (m, 1H), 6.40 (s, 1H), 6.99 (d, 1H), 7.20-7.31 (m, 5H), 7.60 (d, 1H), 7.68 (d, 2H), 8.07 (d, 1H), 8.89 (s, 1H). The compound was dissolved in refluxing isopropyl acetate and allowed to cool slowly to it to afford a solid with mp 191-194° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy -2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (2.1 g) in ethanol (10 ml) was added a solution of sodium hydroxide (0.26 g) dissolved into water (10 ml). After heating on a hot water bath for 5 minutes, the mixture was cooled by adding ice-water and was made acidic by addition of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The resultant residue was separated and purified by silica-gel column chromatography (eluting with ethanol:methylene chloride=3:100) to give the title compound (1.3 g, 65.2%) as colorless crystals, mp 79–81° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(Cl)nc1

Procedure:
Using an analogous procedure to that described in Example 1, 6-chloropyrid-3-ylcarbonyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[C:23][Si](C)(C)C)=[CH:13][CH:14]=2)[C:9]([C:28]2[N:33]=[C:32]([O:34][C@H:35]3[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][CH2:39][C:36]43[CH2:38][CH2:37]4)[CH:31]=[N:30][CH:29]=2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[C:9]2[C:28]1[N:33]=[C:32]([O:34][C@H:35]2[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][CH2:39][C:36]32[CH2:38][CH2:37]3)[CH:31]=[N:30][CH:29]=1)#[CH:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccccc5C#C[Si](C)(C)C)cc34)n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccccc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(2-((trimethylsilyl)ethynyl)phenyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (110 mg, 0.162 mmol) and potassium carbonate (112 mg, 0.811 mmol) in MeOH (1623 μL) was stirred at RT for 2 h. The mixture was diluted with EtOAc (150 ml), added to a separatory funnel, and washed with water (2×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated to give (4R)-tert-butyl 4-(6-(5-(2-ethynylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (80 mg, 0.132 mmol, 81% yield) as a yellowish oil. MS (ESI, pos. ion) m/z: 606.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>C(OCC)(=O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13]
Reactant: Oc1ccccc1Cl
Reactant: Clc1ccnc2c(Cl)cccc12
Solvent: CCOC(C)=O
Product: Clc1ccccc1Oc1ccnc2c(Cl)cccc12
Temperature: 160 °C

Procedure:
A mixture of 2.0 g of 4,8-dichloroquinoline and 2.6 g of 2-chlorophenol was heated to 160° C. and stirred. Progress of the reaction was monitored by TLC. When no 4,8-dichloroquinoline remained, the reaction mixture was diluted with ethyl acetate, and washed with base to remove most of the excess phenol. To remove phenol remaining after washing, the product was purified using HPLC. Fractions containing product were combined, and solvent was removed using reduced pressure. The oily product crystallized. Yield: 1.36 g (46%). M.P. 56°-58° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10]CC)=O.O.[NH2:14][NH2:15]>CC(O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH:14][NH2:15])=[O:10]
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a one-liter four-necked flask were added 102.5 g (595 mmol) of ethyl (R,R)-2-hydroxycyclohexanecarboxylate and 400 mL of 2-propanol and stirring was started. Hydrazine monohydrate (44.7 g; 893 mmol) was dropped thereinto at 13° C. taking 30 minutes. After the dropping, the mixture was stirred at 80° C. for 9.5 hours. Followed by, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 30.10 g of the title compound. The yield was 32%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (350 mg, 0.782 mmol) (obtained as described in Reference Example 52(6)) in methylene chloride (18 ml) were added methanesulfonyl chloride (182 μl, 2.35 mmol) and triethylamine (329 μl, 2.35 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (410 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:25]([O-])=O.[Na+]>O>[CH2:4]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=[N:25]2)[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc(CN2CCC(n3nnc4ccccc43)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In this reference example, 2.0 g of 1-benzyl-4-(2-aminoanilino)-piperidine trihydrochloride obtained in the same manner as that of Reference Example 1 is dissolved in 30 ml of water and the solution is cooled to 0° C. To the cooled solution, 5 ml of a solution of 360 mg of sodium nitrite in 5 ml of water is added dropwise under the current of nitrogen gas over a period of 30 minutes. After completion of the dropwise addition, the reaction mixture is stirred at 0°-5° C. for one hour and then adjusted to pH 10.7. The reaction mixture is extracted with 30 ml of chloroform three times. The chloroform layer is washed with water and dried. The chloroform layer is concentrated to dryness under reduced pressure. The residue is subjected to silica gel chromatography [Wako Gel C-200, 150 ml, with a chloroform-methanol (10:1) as the eluent]. The eluate is concentrated to obtain 0.71 g of the desired product.
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[CH3:17][C:2]1([OH:1])[CH2:3][C@@H:4]([CH:14]([CH3:16])[CH3:15])[NH:5][CH2:6]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]
Reactant: CC(C)[C@@H]1CC(C)(O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H]1CC(C)(O)CN1
Reaction time: 16 h

Procedure:
To tert-butyl (2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate (532.2 mg, 2.18 mmol) dissolved in DCM (5.5 mL) was added TFA (1.8 mL). The mixture was stirred for 16 hours. The mixture was concentrated to give (5S)-3-methyl-5-(propan-2-yl)pyrrolidin-3-ol as a TFA salt. 1H NMR (500 MHz, CDCl3) δ 3.76 (s, 1H), 3.49-3.34 (m, 2H), 2.29-2.17 (m, 1H), 2.06-1.95 (m, 2H), 1.51 (s, 3H), 1.07-0.97 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][CH:3]=1.N[N:19]1[CH:23]=[N:22][N:21]=[CH:20]1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([C:8]2[C:23]3[N:19]([CH:20]=[N:21][N:22]=3)[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Reactant: Nn1cnnc1
Solvent: CC(=O)O
Solvent: O
Product: CC(Oc1ccc(Cl)cc1)c1ccnn2cnnc12
Yield: 9.7 %

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (14.5 g) in glacial acetic acid (100 ml) was added dropwise to a solution of 4-amino-1,2,4-triazole (5.0 g) in glacial acetic acid (100 ml). The solution was boiled under reflux for 4 hours and then poured into water (400 ml). The mixture was extracted with toluene. The combined organic extracts were washed with 10% sodium bicarbonate solution, then with water, dried over anhydrous magnesium sulphate, filtered, and evaporated under reduced pressure. Flash column chromatography of the residue on silica gel, using ethyl acetate/petroleum ether 1:1 as the mobile phase, afforded 1.52 g of 8-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[4,3-b]pyridazine. A pure sample was obtained by recrystallisation from a mixture of ethyl acetate and hexane, m.p. 98-99° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:23])[CH:14]=[CH:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncc(C=CC(=O)CCCCCNC(=O)OC(C)(C)C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(C=CC(O)CCCCCNC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A solution of 24-3 (1.419 g, 4.255 mmol) in THF (10 mL) and methanol (5 mL) was treated with sodium borohydride (162.0 mg, 4.282 mmol) and stirred at room temperature (1 h). The reaction was quenched with acetone and the solvent removed in vacuo. Purification via silica chromatography (hexane/ethyl acetate) afforded the title compound 24-4 (1.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.C([Li])CCC.[I:28]I>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[I:28]
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(I)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 3,5-difluoro-4′-propylbiphenyl (T-4) (18.0 g) and THF (200 ml) were added, and cooling was carried out to −74° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (56.4 ml) was added dropwise in a temperature range of −74° C. to −70° C., and stirring was carried out for another 1 hour. Subsequently, a THF (150 ml) solution of iodine (24.6 g) was added dropwise in a temperature range of −75° C. to −70° C., and stirring was carried out for 6 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (400 ml), and mixing was carried out. Toluene (300 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with an aqueous solution of sodium thiosulfate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by means of column chromatography (silica gel; heptane), and further purified by recrystallization from Solmix A-11, and thus 3,5-difluoro-4-iodo-4′-propylbiphenyl (T-5) (21.4 g) was obtained. The yield based on compound (T-4) was 77%.