Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(OCC)n1ccnc1
Temperature: 130 °C
Yield: 72.4 %

Procedure:
Imidazole (6.81 g, 0.10 mol, 1.0 eq), triethyl orthoformate (66.5 mL, 0.40 mol, 4.0 eq) and para-toluenesulfonic acid (0.5 g) were combined and heated at 130° C. Ethanol was slowly distilled off. After the distillation of the ethanol ceased, the reaction was distilled using a floor pump (0.1 mm). Excess triethyl orthoformate distilled at 50° C. and then the product was distilled at 78°-84° C. to give the title compound (12.316 g, 72%). B. 2-Butyl-1H-imidazole
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([N:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=1)[CH3:7])C.[BH4-].[Li+].C1COCC1.Cl>CO>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:9]3[N:8]([CH:6]([CH3:7])[CH2:5][CH2:4][OH:3])[CH:12]=[N:11][N:10]=3)=[N:14][CH:15]=[C:16]([Cl:34])[CH:17]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:32])([F:31])[F:33]
Reactant: CCOC(=O)CC(C)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCO)n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{3-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-butyric acid ethyl ester (27 mg, 0.05 mmol), lithium borohydride (2.0M, 0.14 ml, 0.28 mmol), 1.5 ml of THF and 0.02 ml of methanol was stirred at room temperature for 2 hours. The mixture was mixed with diluted HCl (1.0M), extracted with ethyl acetate, and the extracts were combined and washed with brine and dried. After concentration the residue was purified by prep TLC to afford title compound as a white solid. 1H NMR: (DMSO-d6, ppm): 9.03 (s, 1H), 8.30 (m, 1H), 8.11 (m, 1H), 8.02 (m, 1H), 7.91 (m, 1H), 7.83 (m, 1H), 3.28 (m, 1H), 3.19 (m, 2H), 1.91 (m, 2H), 1.42 (d, 3H). MS (ES) [M+H]+ expected 510.0. found 510.0.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1>CO.[Pd]>[O:1]=[C:2]1[CH:8]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1ccccc1C=CC1CCCCNC1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCC1CCCCNC1=O

Procedure:
The title material of Example 85 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [C:1]1([C@:7]2([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C@H:8]2[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:30][N:20]([CH2:19][C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:8]1[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl [((1S,2R)-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (39.2 g, 92 mmol), accessed via the method of 11A, and methyl iodide (39.2 g, 276 mmol, 3 eq) in 300 mL THF cooled to 0° C. was added 1M sodium bis(trimethylsilyl)amide in THF (138 mL, 138 mmol, 1.5 eq). The reaction mixture was stirred 2 h at 0° C. followed by 16 h at ambient temperature. The reaction mixture was partitioned between EtOAc and water, the phases separated, the aqueous phase extracted twice with EtOAc, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to an amber oil. The crude material was purified by flash chromatography (SiO2, eluted successively with DCM/hexanes (1:1), DCM, and EtOAc/hexanes (1:4)) to give the title compound (22.25 g, 58 mmol, 63%) as a pale yellow oil. ES-LCMS m/z 404.30(M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[S:37])[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=S)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C

Procedure:
Combine 7-chloro-6-(4-tert-butylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (53 mg, 0.13 mmol) with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100° C. for 2 h. Cool the reaction mixture to room temperature, concentrate in vacuo and purify the residue by SCX chromatography to obtain 7-chloro-6-(4-tert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil. Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% aqueous HCl /acetonitrile (9:1 to 1:9) over 3 0 min, detector at 230 nm].
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4](=[N:6][OH:7])[CH3:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:7][N:6]=[C:4]([CH3:5])[CH3:3])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)=NO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1ccc([N+](=O)[O-])cc1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a 0° C. slurry of sodium hydroxide (82 g, 2 mol) in DMF (1.5 L) was added acetone oxime (125 g, 1.7 mol). After stirring 45 min, 1-fluoro-4-nitrobenzene (218 g, 1.55 mol) was added over 45 min. After stirring at room temperature for 2.5 h, the reaction was poured into cold brine (4.5 L). The mixture was stirred at 0° C. for 2 h. The solid was collected by filtration, washed with water (4×1.5 L) and dried to provide 300 g (99%) of 2-propanone O-(4-nitrophenyl)oxime.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:30]1[CH:31]=[CH:32][C:27]([C@@H:8]2[C@H:9]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:25][CH:26]=3)[C:10]3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4][C:5]=3[CH2:6][CH2:7]2)=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 400 mg (0.94 mmol) of cis-1-{2-[4-(6-methoxy-2-phenyl 1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy] ethyl} pyrrolidine in 25 mL of methylene chloride at 0° C. was added, dropwise with stirring, 4.7 ml (4.7 mmol) of a 1.0 M solution of boron tribromide in methylene chloride. After 3 hours at room temperature, the reaction was poured into 100 mL of rapidly stirring saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to afford 287 mg (74% yield) of lasofoxifene as the free base.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(F)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1-chloro-4-fluorobenzene and isolated as light-yellow gum (4.0 mg, 23%). MS (m/e): 425.3 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][S:35]([C:38]1[CH:53]=[CH:52][C:41]([O:42][C:43]2[N:48]=[CH:47][N:46]=[C:45]3[NH:49][N:50]=[CH:51][C:44]=23)=[CH:40][CH:39]=1)(=[O:37])=[O:36].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:49]2[C:45]3=[N:46][CH:47]=[N:48][C:43]([O:42][C:41]4[CH:40]=[CH:39][C:38]([S:35]([CH3:34])(=[O:36])=[O:37])=[CH:53][CH:52]=4)=[C:44]3[CH:51]=[N:50]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3[nH]ncc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
Boc-3-hydroxypiperidine (Alfa Aesar, Ward Hill, Mass., USA; 80 mg, 0.4 mmol) and triphenylphosphine (136 mg, 0.52 mmol) were added to a solution of 4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 31; 100 mg, 0.34 mmol) in tetrahydrofuran (1 mL). The mixture was cooled to 0° C., and then diisopropylazodicarboxylate (102 μL, 0.52 mmol) was added. The mixture was stirred overnight, then silica gel (˜500 mg) was added, the solvents were evaporated and the product was eluted from a silica gel column with 50% ethyl acetate/hexanes to give 3-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.5 mg, 6.5%) as a solid.
Reaction SMILES: [K].CC([OH:7])(CC)C.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:17]1[CH:18]=[C:19]([OH:35])[C:20]2[C@H:26]3[CH2:27][C:28]([CH2:31][OH:32])=[CH:29][CH2:30][C@@H:25]3[C:24]([CH3:34])([CH3:33])[O:23][C:21]=2[CH:22]=1)([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:22][C:21]([CH2:20][C:19]([OH:35])=[O:7])=[O:23].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:17]1[CH:18]=[C:19]([OH:35])[C:20]2[C@H:26]3[CH2:27][C:28]([CH2:31][OH:32])=[CH:29][CH2:30][C@@H:25]3[C:24]([CH3:34])([CH3:33])[O:23][C:21]=2[CH:22]=1)([CH3:15])[CH3:16]
Reactant: CCC(C)(C)O
Agent: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(CO)C[C@H]21
Agent: [K]
Solvent: c1ccccc1
Product: CC(=O)CC(=O)O
Reaction time: 2 h

Procedure:
Potassium (1 g) was added to 2-methyl-2-butanol (16 ml) under a nitrogen atmosphere. The mixture was warmed, at 80°, until all the metal had reacted. The excess alcohol was removed by vacuum distillation and the dry residue was dissolved in dry benzene (45 ml). Two ml of this solution were added to HU-211 (300 mg, 0.78 mmoles) dissolved in dry benzene (30 ml). The solution was stirred, under a nitrogen atmosphere, for 2 hrs., then it was washed with a dilute HCl solution (1N), followed by a sodium bicarbonate solution (1N) and then with water. The organic layer was dried over MgSO4, and evaporated. The oil obtained was chromatographed on silica gel (15 gr.) Elution with ether:petroleum ether (1:10) gave the diacetate of HU-211 (99 mg) followed by traces of the monoacetate (on the allylic alcohol moiety), eluted with ether:petroleum ether (2:10), followed by the monoacetate (4c), 150 mg, identified by the I.R. peak at 1760 cm-1 ; 1H NMR δ2.28 (3H, s, OCOCH3), 2.98 (1H, dd, C-2 equat. H), 4.02 (2H, q, C-7 H), 5.72 (1H, d, C-6 H), 6.52, 6.66 (atom. H).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1>>[C:8]([OH:13])(=[O:14])[CH2:9][CH2:10][C:11]([OH:7])=[O:12].[CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: O=C1CCC(=O)O1
Agent: C/C=C/C=C/CO
Product: O=C(O)CCC(=O)O

Procedure:
Trans,trans-hexa-2,4-dien-1-ol and succinic anhydride are reacted in the presence of N,N-dimethylaminopyridine to provide trans,trans-hexa-2,4-dien-1-ol monosuccinate. An aqueous solution of an excess of the monosuccinate is activated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and coupled with human serum albumin, to provide a poly(diene) derivative 11.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1Br
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Bromobenzoic acid (10 g, 49.75 mmol) was added in portions with stirring to an ice cold nitrating mixture of 98% H2SO4 (25 mL) and 69% HNO3 (12 mL) maintaining the temperature of the mixture below 5° C. The reaction mixture was stirred for 1 h. below 5° C. It was poured into ice water (200 mL). The white crystalline product obtained was filtered, washed with water and dried.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.[OH:19][C:20]1[C:25](I)=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1>[Cu](I)I.C(OCC)(=O)C.O.CN(C)C(=O)C>[OH:19][C:20]1[C:25]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: c1cn[nH]c1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(-n2cccn2)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 22.6 %

Procedure:
Pyrazole (0.60 g), cesium carbonate (3.6 g), N,N-dimethylglycine (0.76 g), and copper iodide (I) (0.76 g) were added to an N,N-dimethylacetamide (20 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (2.00 g) in a nitrogen atmosphere, followed by stirring at 90° C. for 2.5 hours. The reaction solution was adjusted to room temperature, water and ethyl acetate were added, and an insoluble precipitate was removed. The pH was adjusted to pH 2 with the addition of 6M hydrochloric acid. Then, organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. Ethyl acetate was added to the obtained residue, a solid precipitate was collected by filtration, and a green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.35 g) was thus obtained. Thereafter, the filtrate was collected, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 0:1), and a light green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.02 g) was thus obtained.
Reaction SMILES: [F-].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=1[F:37].[H-].[Na+].[CH:40]1([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([N:53]3[CH2:56][CH:55]([OH:57])[CH2:54]3)=[O:52])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41]1>CS(C)=O.CCOC(C)=O>[CH:40]1([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([N:53]3[CH2:54][CH:55]([O:57][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=4[F:37])[CH2:56]3)=[O:52])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: Cc1nccc(Cl)c1F
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [F-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
KF (73 mg, 1.25 mmol) was dried under vacuum for 2 hours and then stirred with Kryptofix-222 (282 mg, 0.75 mmol) and 4-chloro-3-fluoro-2-methylpyridine (40 mg, 0.28 mmol) in DMSO (3 ml) at 120° C. for 16 hours in a sealed tube. After cooling to room temperature, NaH (100 mg of a 60% dispersion in mineral oil, 2.5 mmol) and 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (63 mg, 0.25 mmol) were added and stirred for a further 8 hours. The reaction was diluted with EtOAc (30 ml) and washed with saturated NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to give the title compound (32 mg, 35%) as yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:29]=[N+:30]=[N-:31])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:29]([C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:30]=[N-:31]
Reactant: COc1ncc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(tert-butyldimethylsilyloxy)-1-(2-methoxypyrimidin-5-yl)ethanol (4.4 g, 15 mmol) and diphenylphosphonic azide (16.7 mL, 77.3 mmol) was dissolved in toluene (53 mL). The mixture was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (11.8 mL, 77.3 mmol) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at 60° C. overnight. The mixture was washed with water (50 mL) and 5% HCl (50 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (0-25% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[CH:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[N:4]=1)=[O:20])(=[O:17])=[O:16]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1cn(C)cn1
Solvent: Cc1ccccc1
Product: Cc1cn(C)c(C(=O)NS(=O)(=O)c2ccccc2Cl)n1
Yield: 37.1 %

Procedure:
2.0 g of 1,4-dimethylimidazole and 4.3 g of 2-chlorophenylsulfonyl isocyanate in 200 ml of toluene are refluxed for 6 h. The precipitate which forms on cooling is filtered off with suction and washed with acetone. The residue is suspended in acetonitrile/methanol and refluxed for 0.5 h. After cooling, the solid is filtered off with suction and dried under reduced pressure. 2.3 g of N-(2-chlorophenylsulfonyl)-1,4-dimethylimidazole-2-carboxamide with a melting point of 230°-231° C. are obtained. (Active ingredient Example No. 113).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][N:7](C)[C:8](=O)OCC1C=CC=CC=1)=[O:4]>O1CCCC1.[C].[Pd]>[CH3:1][N:2]([CH3:19])[C:3](=[O:4])[CH2:5][CH2:6][NH:7][CH3:8]
Reactant: CN(C)C(=O)CCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNCCC(=O)N(C)C
Reaction time: 16 h

Procedure:
Benzyl [2-(dimethylcarbamoyl)ethyl]methylcarbamate (I-140) (0.62 g, 2.35 mmol) was dissolved in tetrahydrofuran (15 ml), and 10% palladium-carbon (containing about 50% water, 0.15 g) was added, followed by stirring for 16 hours under hydrogen gas atmosphere. The catalyst was removed by filtration, and the solvent was evaporated away under reduced pressure to obtain a yellow oil (0.31, quant.).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[N:30]1([CH2:29][CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[C:8]4[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=4[S:10][C:11]=3[CH:12]([CH3:14])[CH3:13])=[CH:19][CH:20]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ClCCN1CCCCC1
Reactant: CC(C)c1sc2ccccc2c1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1sc2ccccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-[(4-hydroxy)phenoxy]-2-(isopropyl)benzo[b]thiophene (1.71 g, 6.0 mmol) in 100 mL of anhydrous DMF is added finely ground anhydrous K2CO3 (8.30 g, 60 mmol) and 2-chloroethylpiperidine (1.54 g, 9.0 mmol). The resulting solution is stirred under N2 at room temperature for 16 h. The reaction is then partitioned between EtOAc and H2O. The layers are separated and the organic is washed several times with H2O. The organic is dried (Na2SO4) and concentrated in vacuo to an oil that is chromatographed (SiO2, 0-5% CH3OH/CHCl3) to provide [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(isopropyl]benzo[b]thiophene as a brown oil. This material is treated with Et2OoHCl to provide 1.27 g (54%) of [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(isopropyl]benzo[b]thiophene hydrochloride as a white solid.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C@H:12]1[CH2:18]O)=O)C1C=CC=CC=1.[CH2:20]([O:27]C(N1C[C@@H](SC)C[C@H]1CO)=O)[C:21]1C=CC=CC=1>>[CH3:17][C:14]1([CH3:16])[CH2:15][N:11]2[C@H:12]([CH2:18][C:20](=[O:27])[CH2:21][CH2:9]2)[CH2:13]1
Reactant: CC1(C)C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CS[C@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Product: CC1(C)C[C@H]2CC(=O)CCN2C1
Yield: 36 %

Procedure:
In a similar manner to the procedures described in Preparative Examples 12(v)′, 12(vi)′ and 12(vii)′ above, reactions were conducted in turn, using (S)-1-benzyloxycarbonyl-4,4-dimethyl-2-hydroxymethylpyrrolidine [obtained as described in Preparative Example 17(i)′ above] instead of (2S,4S)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methylthiopyrrolidine, to give the title compound as a brown oil (yield: 36%).