Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+].[C:19](OC(=O)CCCC)(=O)[CH2:20]CCC>>[CH3:19][C:20]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[N:1]=1
Reactant: CCCCC(=O)OC(=O)CCCC
Reactant: Nc1cccnc1Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cccnc2n1-c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A mixture of (1.0 g, 4.97 mmol, 1.0 eq) 4-[(3-amino-2-pyridinyl)amino]phenol in 25 ml of valeric anhydride was heated to reflux for 8 hours. The reaction mixture was cooled, poured into 150 ml of 0.5N HCl, stirred 10 minutes, and extracted twice with ether. The ether extracts were combined, washed three times with saturated NaHCO3, once with H2O, once with brine, dried over MgSO4, and concentrated to give an oil. The oil was taken up in 100 ml CH3 OH and treated with 60 ml of 2N NaOH and allowed to stir at room temperature for 1 hour. The mixture was concentrated, poured into 200 ml of H2O and washed twice with ether. The aqueous layer was neutralized, and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed once with H2O, dried over MgSO4, and concentrated to give 0.7 g of a solid. Silica gel chromatography eluting with 10% CH3OH/CH2Cl2 gave 510 mg, 38%, of a solid. M.P.: 268°-2690° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCC(=O)O)ccc1O
Reactant: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CCC(=O)Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of 55 g of 3-(3-tert-butyl-4-hydroxyphenyl)-propionic acid, 35 g of phenol, 7 g of dimethylformamide, 19.1 g of phosphorus oxychloride and 250 ml of toluene was stirred at 70° C. for 6 hours. The mixture was cooled to room temperature, and 800 ml of toluene was added thereto. The mixture was washed with water and an aqueous solution of sodium hydroxide, followed by washing with water. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give 66.5 g of phenyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate as a white crystal, m.p. 106°-109° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8](Cl)=[O:9])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[S:23]C(=O)N(CC(Cl)=O)[C:20]=2[CH:29]=1>>[O:1]=[C:2]1[N:6]([CH2:7][C:8](=[O:9])[S:23][C:19]2[CH:20]=[CH:29][CH:16]=[CH:17][CH:18]=2)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1
Reactant: O=C(Cl)Cn1c(=O)sc2ccccc21
Reactant: O=C(Cl)Cn1c(=O)sc2ccc(Cl)cc21
Product: O=C(Cn1c(=O)sc2ccccc21)Sc1ccccc1

Procedure:
The procedure of Example 3 was followed utilizing 2-oxo-3-benzothiazolineacetyl chloride in lieu of 5-chloro-2-oxo-3-benzothiazolineacetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]=[CH:12][C:8]=2[C:9]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([NH2:36])(=[O:34])=[O:35])[CH:28]=2)=[O:11])=[CH:20][CH:21]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(F)cc2)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)c(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.3 %

Procedure:
A solution of 2-(4-fluorophenoxy)-4-tert-butylbenzoic acid (0.11 g, 0.39 mmol) and thionyl chloride (0.28 mL, 3.9 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure, and to the resulting oil was added a solution of 3-amino-benzenesulfonamide (73 mg, 0.42 mmol) in pyridine (4 mL). The solution was stirred at room temperature 15 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0%-50% EtOAc-hexanes) to obtain a white solid which was recrystallized from EtOAc and hexanes. 2-(4-Fluorophenoxy)-4-tert-butyl-N-(3-(aminosulfonyl)phenyl)benzamide (85 mg, 50% yield) was obtained as a white solid. LC/MS: m/z 443.3 (M+H)+ at 3.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35].C(N(CC)CC)C>O1CCCC1>[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:35]
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, 4-aminobutyric acid ethyl ester hydrochloride (3.19 g, 0.019 mole) and triethylamine (1.92 g, 0.019 mole) were added simultaneously and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was partitioned between methylene chloride and water. The combined methylene chloride layers were extracted with dilute sodium hydroxide, then with water. The methylene chloride layer was separated, dried, and evaporated to dryness (5.3 g) (76% crude yield). A 2-g sample was recrystallized from absolute ethanol, and dried under high vacuum overnight to give 1.47 g, mp. 169°-71° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1[C:11]([C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CCn1ccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: COC(=O)CCn1ccc(-c2ncccc2CO)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To methyl 3-(3-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate in MeOH (10 mL) was added HCl (2 N, 1.2 mL, 10 eq.). The mixture was stirred at rt for 4 h, concentrated, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (51 mg, 67%) as an oil. LRMS (M+H+) m/z 262.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S(=O)(=O)(O)O.N.[CH:11]1([CH2:17][C@H:18]2[C@H:22]([C@@H:23]([CH:25]3[CH2:27][CH2:26]3)O)[O:21][C:20]([CH3:29])([CH3:28])[N:19]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.O>[CH:11]1([CH2:17][C@H:18]2[C@H:22]([C@H:23]([CH:25]3[CH2:26][CH2:27]3)[N:1]=[N+:2]=[N-:3])[O:21][C:20]([CH3:29])([CH3:28])[N:19]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@H](O)C2CC2)OC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](N=[N+]=[N-])C2CC2)OC1(C)C
Yield: 53.5 %

Procedure:
A mixture of 1.63 g (25 mmol) of sodium azide, 1.5 ml of water and 10 ml of benzene is treated dropwise with 0.67 ml (12.5 mmol) of concentrated sulphuric acid while cooling with ice (<10°) and stirring. Thereafter, the mixture is cooled to 0°, the benzene phase is decanted off and dried over magnesium sulphate. The thus-obtained nitrogen hydride solution is added to a mixture of 368 mg (1 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate and 289 mg (1.1 mmol) of triphenylphosphine in 5 ml of benzene. Subsequently, 0.15 ml (1.1 mmol) of diethyl azodicarboxylate is added and the reaction mixture is stirred at room temperature overnight under argon. Thereafter, the reaction mixture is evaporated and, for purification, the residue is chromatographed on 50 g of silica gel using a 3:1 mixture of toluene and ethyl acetate as the eluent. There are obtained 210 mg of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylazidomethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 393 (M+H)+, as an oil which gradually crystallizes as well as 130 mg of educt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[CH2:29][O:30][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2CO)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)OCc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
3-[4-(3-Fluoro-benzenesulfonyl)-2-hydroxymethyl-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (74 mg, 0.170 mmol) was dissolved in 25 ml of THF and the mixture was cooled to −78° C. LDA (0.102 ml, 0.204 mmol) was added and allowed to stir for 30 minutes. Dimethylcarbamoyl chloride (0.023 ml, 0.255 mmol) was added and the mixture was allowed to warm to room temperature over 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH 95/5) to give 83 mgs (96%) of 3-[2-Dimethylcarbamoyloxymethyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C.C(OCC)(=O)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:5]=1)(=[O:26])=[O:25]
Reactant: O=C1NCCN1c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCc1cccc(N2CCNC2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Alternatively, 1-[3-(2-hydroxyethyl)phenyl]-2-imidazolidinone was suspended in acetonitrile (5 vol) at room temperature and under nitrogen. Triethylamine (1 vol) was added dropwise over 15 minutes. The mixture was cooled to 0° C. and methanesulfonyl chloride (0.73 vol) was added over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (10 vol). The mixture was washed with a saturated solution of ammonium chloride (2×3 vol), followed by water-brine 1:1 (2×3 vol). The organic phase was concentrated to 5 vol, ethyl acetate (5 vol) was added and the solution was evaporated to dryness, yielding the title compound as a cream-coloured solid (yield: 90% th).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28].ClC1N=NC=C(C2C=CC(C)=CC=2)C=1NN>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2cnnc(NN)c2Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cc1ccc(-c2cnnc(Cl)c2NN)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnn3c(=O)[nH]nc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirring solution of triphosgene (19.0 g, 64.0 mmol) in THF (200 mL) was cooled to 0° C. under argon and the mixture of 1-(4-chloro-5-p-tolylpyridazin-3-yl)hydrazine and 1-(3-chloro-5-p-tolylpyridazin-4-yl)hydrazine (3.0 g gross), prepared as described in Example 362C, was added over 3 min. The reaction mixture was allowed to warm to RT gradually and then stirred for 16 h. Solvent was removed under vacuum to reduce the reaction mixture to half its original volume, and the resulting suspension was cooled to an ice bath. Ice water (300 mL) was added, followed by stirring for 1 h. The product was collected by filtration and washed with 0.1 M aqueous HCl (50 mL×2), then H2O (50 mL×2). After drying under vacuum at 50° C. for 2 d, the title compound, 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2.2 g) was obtained as a yellow solid. MS [M+H]+ 261; HPLC retention time=2.75 min; 1HNMR (400 MHz, THF-d8) δ 11.69 (s, 1H), 8.10 (s, 1H), 7.49-7.51 (m, 2H), 7.34-7.35 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl.F[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[N:18][CH:17]=[CH:16]2>CC(N(C)C)=O>[CH:19]1[C:20]2[C:15](=[CH:14][C:13]([O:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Fc1ccc2cnccc2c1
Reactant: NC1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N[C@H]1CC[C@H](Oc2ccc3cnccc3c2)CC1
Reaction time: 0.5 h

Procedure:
6.1 g (53 mmol) of 4-amino-cyclohexanol were dissolved in 50 ml of dimethyl acetamide and 4.24 g (106 mmol) of sodium hydride (60%) were added at room temperature. After the reaction mixture was stirred for 30 minutes under argon, a solution of 6.49 g (35.3 mmol) of 6-fluoro-isoquinoline hydrochloride was added and the mixture was stirred at room temperature overnight. For workup, the solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic layer was separated, dried with magnesium sulfate and evaporated to yield 8.64 g of the crude product, which was used without further purification. Rt=0.77 min (Method B). Detected mass: 243.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1)[CH3:17]
Reactant: CCN
Reactant: Cc1ccc(C(=O)c2cccs2)c(Cl)n1
Product: CCNc1nc(C)ccc1C(=O)c1cccs1

Procedure:
In a sealed tube were heated and stirred 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine and a 70% ethylamine aqueous solution. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-ethylamino-6-methyl-3-(thiophene-2-carbonyl)pyridine. NMR1: 7.97 (1H, d, J=8.1 Hz), 7.62 (1H, dd, J=5.0, 1.1 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1.S(Br)([Br:16])=O>O1CCOCC1.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:16])=[CH:8][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(OCCCCl)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: ClCCCOc1ccc(CBr)cc1
Reaction time: 0.17 h

Procedure:
A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol No. 162 (10.6 g, 52.8 mmol) in dioxane (0.125 1) was cooled to 0° C. and treated with a dropwise addition of thionyl bromide (12.0 g, 58.0 mmol). After 10 minutes the reaction was complete. The dioxane was diluted with ethyl ether and washed with water, brine, and then dried over MgSO4. The material was concentrated down to yield 15 g of an oil: 1H NMR (DMSO) 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.6 Hz), 4.68 (s, 2H), 4.08 (t, 2H, J=5.9 Hz), 3.77 (t, 2H, J=6.4 Hz); MS (FAB) 266 (M+H+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH:29]2[CH2:33][CH:32]([O:34][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:31]([CH2:52][OH:53])[C:30]2=[CH2:54])=[C:22]([Cl:55])[N:21]=1>O1CCCC1>[NH2:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH:29]2[CH2:33][CH:32]([OH:34])[CH:31]([CH2:52][OH:53])[C:30]2=[CH2:54])=[C:22]([Cl:55])[N:21]=1
Reactant: C=C1C(CO)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1C(CO)C(O)CC1n1cnc2c(Cl)nc(N)nc21
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
Then, 0.27 ml (0.274 mmol) of 1M TBAF solution in tetrahydrofuran was added dropwise to a solution which had been prepared by dissolving 73 mg (0.137 mmol) of [3-(2-amino-6-chloro-purine-9-yl)-5-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclopentyl]-methanol in 0.7 ml of tetrahydrofuran at room temperature, and the resulting mixture was stirred for 1.5 hrs. After completion of the reaction, the reaction mixture was condensed and the residue thus obtained was isolated by HPLC to obtain 34 mg of the title compound (yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46](Br)[CH:45]=1>>[CH3:41][O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)[CH:45]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)c1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (15.0 mg, 0.0278 mmol) and 3-bromobenzoic acid methyl ester (7.1 mg, 0.033 mmol) instead of 4-bromobenzoic acid methyl ester, in the same manner as Example 1-D-08, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid methyl ester was obtained, and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-52) as a yellow powder (10.4 mg, 86%).
Reaction SMILES: N1C=CN=N1.[H-].[Na+].[N:8]1[NH:9][C:10]([SH:13])=[N:11][CH:12]=1.Br[CH2:15][CH:16]([C:39]1[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=1)[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[N:20]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:19]=1>CN(C)C=O>[Cl:30][C:25]1[CH:24]=[C:23]([C:21]2[N:20]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:19]=[C:18]([CH2:17][CH:16]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[CH2:15][S:13][C:10]3[NH:9][N:8]=[CH:12][N:11]=3)[CH:22]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COc1ccc(-n2nc(CC(CBr)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: Sc1ncn[nH]1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]nn1
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(CC(CSc3ncn[nH]3)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
5-{3-[5-(3.4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-yl]-2-m-tolyl-propylsulfanyl}-1H-1,2,4]-triazole. To a suspension of sodium hydride (4.0 mg, 60% dispersion in oil) in N,N-dimethylformamide (1.0 mL) at 0° C. was added a solution of 2H-[1,2,4]triazole-3-thiol (10.0 mg, 0.1 mmol, 1.1 equiv) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at 0° C. for 30 min then a solution of 3-(3-bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (48 mg, 0.09 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) was added. The reaction mixture was brought to room temperature then was stirred for 2 h. The reaction was quenched with satd aq ammonium chloride (1.0 mL), and the resulting mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC to yield the title compound (39 mg, 80%). HPLC: Rt=3.26 (Method B). MS (ESI): mass calculated for C28H25Cl2N5OS, 549.12; m/z found, 550.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.32 (br s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07-7.0 (m, 5H), 6.95 (dd, J=8.4, 21. HZ, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 3.70 (s, 3H), 3.48 (dd, J=12.9, 6.3 Hz, 1H), 3.36 (dd, J=12.7, 8.2 Hz, 1H), 3.26 (m, 1H), 3.07 (dd, J=14.9, 6.4 Hz, 1H), 2.91 (dd, J=14.9, 8.2 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2c[nH]c3ccccc23)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2c[nH]c3ccccc23)cc1)C(=O)O
Yield: 82.2 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(indole-3-carbonylamino)ethoxy]phenyl]propionate (650 mg), which is the product of Example 59, was reacted with aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to give the title compound (500 mg) as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][C@:8]1([CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[C@@H:9]1[CH:10]=[C:11]([CH3:15])[CH2:12]2)(C)(C)C.O.[C:27]1([S:33]([OH:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[C:27]1([S:33]([OH:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH2:17][CH2:16][C@@:8]1([CH2:7][C:6]([OH:25])=[O:5])[CH2:14][C@H:13]2[C@@H:9]1[CH:10]=[C:11]([CH3:15])[CH2:12]2
Reactant: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Tert-butyl[(1S,5R,6R)-6-(tert-butoxycarbonylamino)methyl-3-methylbicyclo[3.2.0]hept-3-en-6-yl]acetate (6.4 g, 18.2 mmol) and benzenesulfonic acid monohydrate (3.53 g, 20 mmol) were added to benzene (40 mL), and the mixture was heated with stirring for 2 hours. The resulting solid was collected by filtration to obtain the compound of interest as a white solid (5.8 g, 90%).