Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and pyridine-3-sulfonyl chloride hydrochloride salt, of Preparation 2, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.03 (d, 1H), 8.77 (m, 3H), 8.29 (d, 2H), 8.03 (m, 1H), 7.40 (m, 1H), 7.15 (m, 4H), 7.04 (d, 1H), 6.90 (d, 1H), 6.84 (s, 1H), 4.41 (s, 2H), 4.34 (s, 2H), 3.62 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 487 (M−1).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=1[CH3:34])=O>>[CH3:28][C:26]1[NH:27][C:23](/[CH:21]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)=[C:24]([CH3:34])[C:25]=1[CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CCC(=O)O

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=O.Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:25][OH:26]
Reactant: NO
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=O)c3cc(F)ccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the acetaldehyde derivative from Step 2 (3.3 g, 10.18 mmol), hydroxylamine hydrochloride (1.42 g, 20.4 mmol), ethanol (25 mL) and triethylamine (2.06 g, 20.4 mmol) was stirred at room temperature for 30 minutes. The solvent was evaporated away and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was purified by column chromatography on silica gel using a 1:2 mixture of ethyl acetate:hexane as eluent. The title compound was obtained as a yellow solid, mp: 146°-150° C.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2Cl)=[N:14][C:13]([Cl:18])=[CH:12][CH:11]=3)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]([CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)[CH3:21]>>[Cl:18][C:13]1[N:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])=[C:16]2[NH:29][CH:26]1[CH2:27][CH2:28][CH:23]([CH2:22][N:20]([CH3:21])[CH3:19])[CH2:24][CH2:25]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CCC1
Product: CN(C)CC1CCC(Nc2c(C(=O)C3CCC3)cnc3ccc(Cl)nc23)CC1

Procedure:
(6-Chloro-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)(cyclobutyl)methanone was prepared with conditions described in Example 131 using cyclobutyl(4,6-dichloro-1,5-naphthyridin-3-yl)methanone and trans-4-((dimethylamino)methyl)cyclohexanamine.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of sesamol (2.00 g, 14.48 mmol) in DMF (15 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.65 g of an 80% dispersion in mineral oil, 21.67 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.55 g, 1 7.37 mmol), and the resulting brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to a residue that was dried briefly under high vacuum producing a brown oil.
Reaction SMILES: Cl.[Br:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][NH2:13])[C:6]=2[S:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>C(O)C>[Br:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][N:13]=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[C:6]=2[S:5][CH:4]=1
Reactant: NNc1ncnc2c(Br)csc12
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: Brc1csc2c(NN=Cc3cccnc3)ncnc12
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A suspension of (7-bromothieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (168, 29 mg, 0.12 mmol) and 3-pyridinecarboxaldehyde(18 mg, 0.17 mmol) in ethanol (2 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration to yield 3-pyridinecarboxaldehyde(7-bromothieno[3,2-d]pyrimidin-4-yl)hydrazone (32 mg, 81% yield) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][CH2:13]O)[N:8]=1)[CH3:6].S(Cl)([Cl:26])=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:26][CH2:13][CH2:12][C:9]1[N:8]=[C:7]([CH:5]([CH3:6])[C:4]2[CH:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:2]([F:1])[CH:3]=2)[O:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCO)no1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Yield: 87.9 %

Procedure:
To a solution of 2.62 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-hydroxyethyl)-1,2,4-oxadiazole in 60 ml of dry benzene was successively added 2.0 g of thionyl chloride and 0.67 g of pyridine with ice-cooling. After stirring and heating with reflux for 1 hour, the reaction mixture was washed with water. The organic phase was further washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to give 2.44 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, m.p. 72°-72.5° C.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCCC)n1

Procedure:
A mixture of 5.7 g. 3-butylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-butylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100°C./0.5 mm.) for 30 minutes to remove all traces of volatile material. Refractive index of product nD26 1.5132. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:7]2
Reactant: Clc1cccc2c1CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Cl)cccc2C1

Procedure:
Prepared in analogy to example 1.1 from 5-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [73075-43-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:10])/[C:6](=[CH:8]/[CH3:9])/[CH3:7].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:15]=1[CH:8]([CH3:9])[CH:6]([CH3:7])[C:5]2=[O:10]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: COc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c2c1C(=O)C(C)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
AlCl3 (64 g, 0.48 mol) and CH2Cl2 (250 ml) (dried with magnesium sulfate) were placed under an argon atmosphere in a 500 ml three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and 1,4-dimethoxybenzene (48.4 g, 0.35 mol, dissolved in CH2Cl2 (75 ml)) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −2° C. to −5° C. the mixture was allowed to come to ambient temperature and was stirred overnight. The dark red mixture was then refluxed for 2 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the resulting yellow mixture was transferred to a separation funnel, the lower CH2Cl2 layer was isolated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure to give a dark brown liquid. This residue was distilled using a 15 cm Vigreux column to obtain an orange-yellow light viscous liquid (110-115° C., 0.8 mbar). The liquid was purified via column chromatography [(SiO2, 25×9 cm) eluent: cyclohexane:ethylacetate (1:1)] to afford 2,3-dimethyl-4,7-dimethoxy-1-indanone (36) (9.53 g, 12%), Rf 0.35 (cyclohexane:ethylacetate (5:1)) as an orange liquid. The liquid was found to be a mixture of the two isomers of 4,7-dimethoxy-2,3-dimethyl-1-indanone (36a to 36b approximately 4:1).
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[SH:26])[CH3:14].O>CO>[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[S:26][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:14]
Reactant: CCn1c(S)nc2ccccc2c1=O
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 4 h
Yield: 48.3 %

Procedure:
7.0 ml of 28% methanolic solution of sodium methoxide and 2.82 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.56 g of 3-ethyl-2mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 4 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 2.47 g of the title compound.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH2:48][CH2:49][CH3:50])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[Cl:51]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH2:48][CH2:49][CH3:50])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[Cl:51])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCS(=O)(=O)c1ccc(Cl)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)(=O)c1ccc(Cl)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-1-chloro-4-(propylsulfonyl)benzene (Intermediate 126), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][O:16][C:14]([C@@H:9]1[CH2:10][C@@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a solution of methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (4.68 g, 19.1 mmol) in DCM (47 mL) at RT was added DIPEA (3.66 mL, 21.0 mmol) and 4-dimethylaminopyridine (233 mg, 1.91 mmol) followed by p-toluenesulfonyl chloride (3.82 g, 20.1 mmol). The reaction mixture was stirred at RT overnight, washed with 1N HCl (2 mL), saturated sodium bicarbonate (2 mL), and brine (2 mL), dried over sodium sulfate, filtered and concentrated to give a yellowish oil, which was purified by silica gel chromatography (80 g silica, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate (1.74 g, 23% yield) as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](OC)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([C@@H:24]2[O:25][CH:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:29][CH:28]=3)[CH2:21][CH2:22][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1CCC[C@@H](COc2ccc(F)cc2)O1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)[C@H]1CCCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (2.0 g), till the solid dissolved. This mixture was extracted with ethyl acetate (30 ml), dried (Na2SO4) and concentrated to give benzenesulfinic acid (1.5 g). To an ice-cooled mixture of benzenesulfinic acid (1.48 g, 10.5 mmol) and calcium chloride (1.15 g, 10.5 mmol) in dry CH2Cl2 a solution of (2RS,6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.5 g, 2.1 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-6-benzenesulfonyl-2-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 8 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H) m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[OH:11][N:12]([CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH:1]=[O:3]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To formic acid (1.5 mL, 39 mmol) at 0° C. was added acetic anhydride (375 μL, 3.9 mmol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and a solution of 2-[4-(hydroxyamino)-5-({4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)pentyl]pyrimidine (403 mg, 0.79 mmol) in THF (8 mL) was then added. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as a pale yellow foam (231 mg, 0.43 mmol, 54%).
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CS(C)=O.O>[NH2:13][C:12]1[C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(NC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ethyl 6-chloro-5-nitronicotinate (1.00 g, 4.33 mmol) prepared according to A. H. Berrie et al. (J. Chem. Soc. 1951, 2590) was dissolved in DMSO (2 mL) and cyclohexylamine (0.54 g, 5.4 mmol) was added. The mixture was stirred for 1 h at room temperature, diluted with water and the yellow precipitated collected by filtration. The product was washed with water and dried (0.95 g, 74% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)indoline (intermediate-26) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[F:23][C:15]1[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])ccc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC=C(c2cc(N)ccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A dried flask was charged with 4-(2-fluoro-5-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (645 mg, 2.00 mmol) and THF (10 mL). Lithium aluminium hydride (1M in THF, 20 mL, 20.0 mmol) was added slowly through a syringe under N2 (the reaction was very exothermic). The resulting mixture was stirred for 16 h at rt. Water was cautiously added to quench the reaction. The resulting mixture was filtered, and the filtrate was concentrated to dryness to give the title compound as a brown oil. 1H NMR (DMSO-d6, 400 MHz): δ=2.14 (s, 3H), 2.38-2.44 (m, 2H), 2.89-2.90 (m, 2H), 3.22 (brs, 2H), 5.95 (brs, 1H), 7.24-7.29 (m, 1H), 7.67-7.73 (m, 2H), 8.16 (s, 1H). MS (ES+): m/z 206.26 (100) [MH+]. HPLC: tR=1.68 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[N:28]=[C:27]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[N:28]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 90 was prepared from 2-(4-chlorophenyl)propanoic acid and N{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.34–7.27 (m, 4H), 7.22 (br s, 1H), 6.89 (d, 1H, J=7.6 Hz), 3.53 (q, 1H, J=7.2 Hz), 3.36 (m, 1H), 3.29 (m, 1H), 3.05 (d, 1H, J=11.6 Hz), 2.95 (d, 1H, J=10.4 Hz), 2.58 (m, 1H), 2.45–2.40 (m, 3H), 2.02–1.63 (m, 8H), 1.50 (d, 3H, J=7.2 Hz), 1.22 (dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 471.2 (M+H)+.