Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1-Aminopropan-2-ol (60.0 g, 799 mmol) was charged to a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, and heated to 120° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at 120-125° C. On completion of the addition, stirring was continued at 115-120° C. for 2.5 h. NaOH (50%, 12.78 g, 160 mmol) was added followed by water (25 mL) and the mixture was stirred at 70 to 75° C. for 15 min. The organic phase was separated and washed with water (4×25 mL) at 70 to 75° C. The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C. Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 104 mL and the golden solution was stirred overnight at 50° C. (bath) under nitrogen. Karl Fischer titration showed 0.052% water.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.FC(F)(F)C(O)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2cc(OC[C@H]3CCNC3)ccc2c1

Procedure:
The procedure is the same as for Example 2 (Stage 2.2) starting from 1.75 g (5.34 mmol) of tert-butyl (S)-3-(naphth-2-yloxymethyl)pyrrolidine-1-carboxylate and 5.00 ml (67.31 mmol) of trifluoroacetic acid. The product is obtained in the form of an oil after purification on a column of silica gel, elution being carried out with a dichloromethane/methanol/aqueous ammonia (90/9/1) mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:32][S:33]([O:22][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Reaction time: 10 h

Procedure:
To the solution of 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol (0.2 g, 0.68 mmol) in THF (4 mL) was added i-Pr2NEt (0.4 mL, 2.3 mmol) at 0° C. followed by methanesulfonyl chloride (0.1 mL, 1.3 mmol). The reaction mixture was stirred for 10 h. Diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl methanesulfonate. LRMS m/z (M+H) Calcd: 373.4. found: 373.0.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:11][CH2:12][CH3:13]
Reactant: CC[O-]
Reactant: Fc1ccc(CBr)c(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCc1ccc(F)cc1Br

Procedure:
By the method of Example 1, Step A, 10.9 g (0.041 mole) of 2-bromo-4-fluorobenzyl bromide and 18.2 ml of a 21% by weight solution of sodium ethoxide in ethanol were reacted in 50 ml of tetrahydrofuran, yielding 7.18 g of ethyl 2-bromo-4-fluorobenzyl ether.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28])=[O:23]>>[CH2:1]([N:8]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]([O:21][CH3:20])=[O:23])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)Cc1ccccc1
Yield: 64.9 %

Procedure:
42.8 g of N-benzyl-tryptamine (i.e., 3-(2-benzylaminoethyl)-indole) and 35.0 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 42.0 g of N-benzyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-benzyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 75.0%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Product: O=C(Cc1ccc(O)c(O)c1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 17 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxyphenylacetic acid in 17% yield. The product was chromatographed on silica. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=359, 1H NMR (MeOH-d4): 3.56 s (2H), 6.10 s (1H), 6.59 dd, 8, 2 Hz (1H), 6.66 d, 8 Hz (1H), 6.78 d, 2 Hz (1H), 7.03 t, 8 Hz (1H), 7.11 t, 8 Hz (1H), 7.25 t, 8 Hz (1H), 7.31–7.35 m (2H), 7.51 d, 7 Hz (1H), 7.55 dd, 8.1 Hz (1H), 7.99 d, 8 Hz (1H).
Reaction SMILES: [OH:1][C@H:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([O:33][CH:34]([CH3:36])[CH3:35])[CH:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.O1CCOCC1.[ClH:49]>O1CCOCC1>[ClH:49].[OH:1][C@H:2]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:3][NH:4][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:27])=[C:22]([O:33][CH:34]([CH3:36])[CH3:35])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)NS(C)(=O)=O
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-[3′-(isopropoxy)-4′-[[(methylsulfonyl)amino]-carbonyl]-4-biphenylyl]ethyl]carbamate (65 mg) in 1,4-dioxane (2 ml) was added hydrochloric acid 1,4-dioxane solution (4N, 4 ml) at room temperature and the mixture was stirred at the same temperature for 2.5 hours. The mixture was evaporated under reduced pressure to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-isopropoxy-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (38 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Cl)[CH2:12]Cl>C(O)C.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1ncccc1N
Yield: 130.5 %

Procedure:
3-Amino-2-picolinic acid (4.14 g) was suspended in ethanol (100 ml) at room temperature with stirring. DMAP (3.7 g) was added and the reaction was stirred for 1 hour at room temperature. A further equivalent of DMAP (3.7 g) was added and the suspension disappeared, and then EDC (5.80 g) was added and the reaction was stirred at room temperature for 17 hours. The ethanol was evaporated to give a dark oil, water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulphate. Evaporation of the solvent gave ethyl 3-amino-2-picolinate as a solid (6.5 g), mixed in a 2:1 ratio with DMAP.
Reaction SMILES: [C-:1]#[N:2].[K+].C(O)(=O)C.[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[NH:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:1]#[N:2])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(Nc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#CC(O)c1cccc(Nc2ccccc2)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 g of KCN and 1.8 ml of acetic acid were added to 2.5 g of the aldehyde thus obtained dissolved 40 ml of ethanol and then left overnight under stirring. Then, the reaction mixture was poured into 100 ml of 2N-HCl and the extraction was effected with benzene. After washing with NaCl aqueous solution, the benzene layer was condensed to yield 2.7 g of 3-anilino-α-cyanobenzylalcohol.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: CN
Product: CNC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (39 mg, 70%) which was obtained as a white solid. MS: m/e=326.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CCCNC(=O)c1nnc2c(-c3ccccn3)cccc2c1N
Yield: 39 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-(tributylstannyl)pyridine (220 mg, 0.600 mmol) were reacted to afford the title compound (60 mg, 39% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.79 (m, 1H), 8.52 (br, 1H), 8.26-8.21 (m, 1H), 8.14-8.09 (m, 1H), 8.05-7.98 (m, 1H), 7.88-7.75 (m, 2H), 7.34 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=308 (M+H). HPLC 1.53 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C:19]1[O:23][C:22]([CH2:24][NH2:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C:19]1[O:23][C:22]([CH2:24][NH:25][C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3[C:3]=2[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=3)=[CH:21][CH:20]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: Cc1ccc(CN)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCc2ccc(C)o2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 61.2 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (47.6 mg, 0.19 mmol) and 5-methyl-2-furanmethanamine (Acros Chemical Company) (100 μL, 0.98 mmol) was added a solution of K2CO3 (0.11 g, 0.76 mmol) in H2O (1.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) to give 37 mg (62%) of the title compound as a beige solid. Mp: 125-127.5° C. MS m/z: 319 (M+1), 294, 225, 195, 147. 1H NMR (CD3OD, 400 MHz): δ 2.28 (s, 3), 2.53 (s, 3), 4.72 (s, 2), 5.97 (d, 1, J=3.0), 6.24 (d, 1, J=3.0), 6.66 (s, 1), 7.34 (m, 1), 7.43 (t, 2, J=7.7), 7.71 (dd, 2, J=7.1, 1.4). HRMS: Calcd for M+H, C19H18ON4: 319.1555. Found: 319.1566.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:5]=2[S:6][C:7]=1[C:8](Cl)=[O:9]>O1CCOCC1>[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]3[O:15][CH2:16][O:17][C:12]3=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([OH:1])=[O:9]
Reactant: O=C(Cl)c1sc2cc3c(cc2c1Cl)OCO3
Reactant: O
Solvent: C1COCCO1
Product: O=C(O)c1sc2cc3c(cc2c1Cl)OCO3

Procedure:
40 ml of water are added to a solution of 70 mmol of the compound of Step A in 250 ml of dioxane. After 20 hours' reflux and then return to ambient temperature, a precipitate forms. After filtration and rinsing with water until neutral, the precipitate is dried over P2O5 under reduced pressure, allowing the expecting product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CN.Cl.C[CH2:35][N:36](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH:36][CH3:35])(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNS(=O)(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (200 mg, 0.47 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated under reflux for 3 h, then concentrated under vacuum. The residue was diluted with 10 ml of CH2Cl2 and added dropwise into a solution of MeNH2.HCl (318 mg, 4.75 mmol, 10.00 equiv) and DIEA (917 mg, 7.11 mmol, 15.00 equiv) in CH2Cl2 (20 mL) at 0° C. The resulting solution was stirred for overnight at room temperature, concentrated under vacuum, and purified by Prep-HPLC, yielding 100 mg (49%) of 2,3-bis(4-methoxyphenyl)-N-methylquinoxaline-6-sulfonamide as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
53 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(4-methoxyphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[OH:27][C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[CH:23][C:18]([C:16](=[O:17])[CH2:15][O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])=[CH:19][C:20]=1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(C(=O)CO[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc(C(C)C)c1O
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 15.63 g (100 mmol) of (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanol and 16.5 g (250 mmol) of potassium hydroxide in 100 ml of N-methylpyrrolidone a solution of 12.73 g (50 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 400 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 6.37 g of compound 110, m.p. 83-84° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+].[CH2:21]1COCC1>O.Cl>[CH3:21][CH:9]1[CH2:10][CH2:11][CH2:12][C:8]1([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:17])[CH3:1])[C:13]([OH:15])=[O:14]
Reactant: C1CCOC1
Reactant: COC(=O)C1(C(=O)NCCC(C)C)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCNC(=O)C1(C(=O)O)CCCC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentanecarboxylate (820 mg, 3.4 mmol) in 25 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (260 mg, 6.12 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 700 mg (90%) of methyl 1-[N-(3-methylbutyl)carbamoyl]-cyclopentanecarboxylic acid as a white solid. MS [M+H]+ 228.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:14]2[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:13]12)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[N:14]3[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:13]23)=[O:11])[CH2:4][CH2:3]1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCN(CC(=O)N2CC=C(c3cccc(C(F)(F)F)c3)n3ncc(C#N)c32)CC1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 1.3 g of N-methylpiperazine, 4.4 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 1.5 g of sodium carbonate in 75 ml of toluene was refluxed for 4 hours, then allowed to stand at room temperature overnight. The mixture was treated with 30 ml of 1N sodium hydroxide and the phases were separated. The aqueous phase was extracted twice with chloroform. The organic phases were combined, washed with water, dried, filtered and concentrated. The residue was heated to solution in 50 ml of ethyl acetate, filtered and cooled. The crystalline solid was collected, washed with ethyl acetate and hexane and dried, giving 1.8 g of the desired product, mp 178°-180° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:11]([Cl:10])(=[O:13])=[O:12])=[C:4]2[N:3]=[CH:2]1
Reactant: c1ccc2scnc2c1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2scnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Benzo[d]thiazole (1 g, 7.45 mol) was added dropwise to chlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 218 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.41 (s, 1H), 8.41 (dd, J=8.1, 1.0 Hz, 1H), 8.29 (dd, J=7.7, 1.1 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H). LC-MS: m/z 234.7 (M+H)+
Reaction SMILES: C([O:7][C:8]1[CH:21]=[C:20]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[C:11]2[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][S:14][C:10]=2[CH:9]=1)(=O)C(C)(C)C.CO.C([O-])([O-])=O.[K+].[K+]>O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:12]1[C:11]2[C:20]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[CH:21][C:8]([OH:7])=[CH:9][C:10]=2[S:14][CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C(=O)N(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1csc2cc(O)cc(C(=O)N(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a mixture of 4-(dimethylcarbamoyl)-3-(2-methoxy-2-oxoethyl)-1-benzothiophen-6-yl pivalate (128 mg) and MeOH (3 mL) was added K2CO3 (46.9 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (75 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:18])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:18][O:28]1)=[O:19])[CH3:2]
Reactant: C=C(CCOCCCC1CCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCOCCCC2CCCCC2)CO1

Procedure:
6.8 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate) are obtained by the procedure described in Example (1a) from 12.4 g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester and 18.7 g of m-chloroperbenzoic acid in 250 ml of methylene chloride. Thin layer chromatography on silica gel with petroleum ether/ethyl acetate/glacial acetic acid 80:20:3: Rf =0.65.