Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)C(C)C)(C)C.Cl>ClCCl.N1C=CC=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][N:23]1[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]2[C:27]1=[O:28]
Reactant: OCC(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1OCC(F)(F)F
Reaction time: 22 h

Procedure:
A dichloromethane (21 mL) solution of 3.9 mL of 2,2,2-trifluoroethanol and 4.3 mL of pyridine was added dropwise to a dichloromethane (83 mL) solution of 9.0 mL of trifluoromethanesulfonic anhydride under cooling with ice over a period of 25 minutes. Thereto was dropwise added a dichloromethane (60 mL) solution of 8.50 g of N-hydroxyphthalimide and 18.5 mL of N,N-diisopropylethylamine at the same temperature over a period of 45 minutes, which was then stirred for 22 hours. To the reaction mixture was added 100 mL of 1 mol/L hydrochloric acid. The organic layer was separated, washed sequentially with 1 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) and washed with hexane to provide 4.43 g of N-(2,2,2-trifluoroethoxy)phthalimide as white solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Na].Cl[C:27]1C=CC(N2C(=O)C3CCCCC=3N(C)C2=O)=CC=1C(O)=O.C(Br)(C)C>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH3:23])[C:14]2=[O:24])=[CH:9][C:3]=1[C:4]([O:6][CH:7]([CH3:27])[CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl
Reactant: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Agent: [Na]
Solvent: CC(C)Br
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate via the sodium salt of the corresponding carboxylic acid and isopropyl bromide there is obtained isopropyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 26.2 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)octanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (581 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.66 ml) and 1-methyl-2-chloropyridinium iodide (918 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)octanamide (350 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>[Ni].C(O)(C)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[NH2:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Into an autoclave, 1.05 g of Raney Nickel catalyst (10 wt %) and 100 ml of isopropanol were introduced, and 10.0 g of 2,5-bis(trifluoromethyl)nitrobenzene was added thereto in small amounts. Hydrogen gas was blown until 5 kg/cm2 with stirring, and the temperature was increased to 70° C. Reaction was carried out at from 70 to 90° C. for 8 hours. After the temperature was recovered to room temperature, hydrogen gas was evacuated, and the Raney Nickel was subjected to filtration and washed with isopropanol. The solvent was concentrated to obtain 2,5-bis(trifluoromethyl)aniline (6.42 g, yield 73%, purity by GC 99.4%). As a result of analysis by GC-Mass, 1H-NMR and 19F-NMR, the product was confirmed to be 2,5-bis(trifluoromethyl)aniline.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[F:18])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[C:11]([F:18])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cc(F)cc1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2,4,6-trifluorobenzyloxy)pyridine (2.29 g, 0.009 mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 3.03 g (79.5%), m.p.181°-183 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:27]([CH:24]5[CH2:26][CH2:25]5)(=[O:29])=[O:28])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)C4CC4)cc3CO1)CO2
Yield: 42.4 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and cyclopropanesulfonyl chloride (75 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white solid (85 mg, 43%), MS (ISP) m/e=416.1 [(M+H)+].
Reaction SMILES: [CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1.[Br:25]N1C(=O)CCC1=O.CN([CH:36]=[O:37])C>>[CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH:15]([O:37][CH3:36])[CH:16]([Br:25])[C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C=O
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Product: COC1C2=CN([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)N=C3C=NNC(=O)C(=C23)C1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of nucleoside 6.6 (10 mg, 0.030 mmol) in DMF (0.5 mL) was added N-bromosuccinimide (11.25 mg, 2.10 eq.) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 1 hr then quenched with MeOH (0.5 mL). The mixture was evaporated to dryness and the residue was purified on a silica gel column with 5% MeOH in CH2C1 to give compound 14.1 as a mixture of diastereoisomers (8 mg, 65%). The isolated compound was characterized by 1H NMR, COSY, NOESY and LCMS. 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H, NH), 8.54 (s, 1H, H-4), 8.00 (s, 1H, H-1), 6.24, 6.21 (2s, 1H, H-1′), 5.22-5.08 (m, 4H, 3×OH, H-8), 4.77-4.73 (m, 1H, H-9), 3.95-3.7 (m, 4H, H-3′, H-4′ 2×H-5′), 3.24, 3.21 (2s, 3H, OCH3), 0.68, 0.66 (2s, 3H, CH3). ES MS: 501.7 (+CH3COO−).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O.CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:5]([OH:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[CH:19][CH:18]=1
Reactant: O=C(O)CCC(F)(F)F
Reactant: Brc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCC(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4,4,4-trifluorobutanoic acid (1.0 g), oxalyl dichloride (0.820 mL) and bromobenzene (3.71 mL) was added DMF (0.008 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aluminum chloride (1.408 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a mixture of the residue, ethanol (15 mL) and THF (5 mL) was added sodium borohydride (0.266 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water at 0° C., the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.49 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].S(Cl)([Cl:12])=O.[CH3:14]O>>[ClH:12].[CH3:14][O:8][C:7](=[O:9])[C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC(C)C[C@@H](N)C(=O)O
Product: COC(=O)[C@H](N)CC(C)C
Product: Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
D-leucine (43.63 g, 333 mmol) is dissolved in methanol (400 mL) and cooled to 0° C. To this is added dropwise thionyl chloride (25.5 mL, 350 mmol). The reaction is allowed to stir 16 hours at room temperature at which time the volatiles are removed to give an off-white solid. The product is recrystallized from ethyl acetate/methanol to give D-leucine methyl ester hydrochloride as a fluffy white solid.
Reaction SMILES: S(Cl)(Cl)=[O:2].[C:5]1(=[N:16]O)[CH:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:7]2[CH2:6]1>O1CCOCC1>[C:5]1(=[O:2])[CH:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:7]2[CH2:6][NH:16]1
Reactant: ON=C1CC2c3ccccc3CC12
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C1NCC2c3ccccc3CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (1.9 mL, 26.4 mmol) was added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime (1.5 g, 8.8 mmol) in 1,4-dioxane (44 mL), and stirred overnight at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (3×50 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1

Procedure:
Prepared analogously to Example 4.1.a. from 3-chloro-4-nitrophenol and (2-chloroethyl)diethylamine hydrochloride. Yield: 1.25 g (79.5% of theory); C12H17ClN2O3 (M=272.73); calc.: molecular ion peak (M+H)+: 273/275; found: molecular ion peak (M+H)+: 273/275; Rf value: 0.44 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]CC)=O)[CH:4]=[O:5])=[CH2:2].[CH2:13]([NH2:16])[CH2:14][NH2:15].[CH3:17][O-:18].[Na+]>CO>[CH:1]([N:3]([CH2:6][CH2:7][C:8]([NH:15][CH2:14][CH2:13][NH:16][C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5])=[O:10])[CH:17]=[O:18])=[CH2:2]
Reactant: C[O-]
Reactant: NCCN
Reactant: C=CN(C=O)CCC(=O)OCC
Agent: [Na+]
Solvent: CO
Product: C=CN(C=O)CCC(=O)NCCNC(=O)CCN(C=C)C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The apparatus of Example 2 was charged with 17.1 grams (0.1 mole) of ethyl 3-(N-vinylformamido)propionate, 3.0 grams (0.05 mole) of ethylenediamine and 0.12 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 3 hours, after which the ethanol coproduct was removed by distillation at reduced pressure. The mixture was then allowed to cool to room temperature yielding the crude product as a yellow solid. NMR analysis of the reaction mixture indicated nearly complete conversion of the ethylenediamine. The solid was recrystallized from toluene/acetone to give pale yellow crystals of 1,2-di-[3-(N-vinylformamido)propionamido]ethane. 1H NMR (CDCl3) δ, major rotamer: 2.46 (t, 4H, J=6.2 Hz), 3.30 (bs, 4H), 3.86 (t, 4H, J=7.3 Hz), 4.48 (d, 2H, J=8.7 Hz), 4.70 (d, 2H, J=15.8 Hz), 6.54 (d,d, 2H, J=9.1 Hz, J=15.6 Hz), 6.90 (bs, 2H), 8.25 (d, 2Hz, J=5.6 Hz); minor rotamer: most peaks overlapped with peaks of the major rotamer, except, 6.68 (bs, 2H), 7.13 (d,d, 2H, J=9.3 Hz, J=16.3 Hz), 8.14 (d, 2H, J=5.3 H). Major/minor rotamer ratio: 76:24.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:6]=1
Reactant: COC(=O)Cc1cccc(CCCCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Cc1cccc(CCCCOS(=O)(=O)c2ccc(C)cc2)c1
Yield: 63.4 %

Procedure:
A solution of {3-[4-hydroxybutyl]phenyl)acetic acid methyl ester (300 mg, 1.35 mmol) and p-toluenesulfonyl chloride (513 mg, 2.7 mmol) in pyridine (5 ml) was stirred at RT for 18 hr. The reaction was diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and cold 1N HCl, dried, and the solvent evaporated to give the title compound as an oil (322 mg, 63%). MS (ESI) 377.3 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH3:9][O:10][C:11](Cl)=[O:12]>C(OCC)C>[CH3:9][O:10][C:11]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:12]
Reactant: COC(=O)Cl
Reactant: C[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)N[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of D-alanine (5 g, 56.1 mmol) in 1 N NaOH (152 mL, 152 mmol) at 0° C. is added a solution of MeOC(O)Cl (6.5 mL, 84.2 mmol) in diethyl ether (30 mL). The mixture is stirred in ice bath for 3 hours and then adjusted to pH 9 with 1 N NaOH. After stirring at room temperature for 1 hour, the mixture is washed with ether (3×50 mL), acidified to pH ˜2 with 5 N HCl, extracted with EtOAc (5×50 mL). The organic extract is washed with water, brine, and then dried (MgSO4). The solvent is removed to yield compound cxxxiv, N-methoxycarbonyl-D-alanine, as colorless oil (6.48 g, 79%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].I[CH3:27]>C1COCC1.CCOC(C)=O.O>[CH3:1][C@@H:2]1[C@H:7]([N:8]2[CH2:12][CH2:11][N:10]([CH3:27])[C:9]2=[O:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H]1[C@H](N2CCNC2=O)CCCN1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
Compound 354 (490 mg, 1.55 mmol) was dissolved in 15 mL dry THF. It was treated with NaH (60% in mineral oil, 125 mg, 3.1 mmol) for 15 min at RT. To the mixture was then added iodomethane (200 μL, 3.1 mmol). The mixture was stirred at RT for 1.5 hour, diluted with 150 mL EtOAc and 50 water. The organic phase was separated, washed with water, dried, concentrated, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (355, 470 mg, 92%). It was dissolved in 100 mL iPrOH. To it was added 10% Pd/C (0.5 g), and the mixture was hydrogenated at 40 psi on a Parr shaker for overnight. The mixture was filtered through celite and concentrated in vacuo to give 1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)imidazolidin-2-one (356) as a white solid in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].I[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:15].[Br:1][C:2]1[C:3]2[C:7]([CH:8]=[C:9]([F:11])[CH:10]=1)=[N:6][N:5]([CH3:15])[CH:4]=2
Reactant: Fc1cc(Br)c2cn[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c(Br)cc(F)cc2n1
Product: Cn1ncc2c(Br)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %
Yield: 58 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indazole (2.3 g, 10.7 mmol) in anhydrous DMF (36 mL) was added sodium hydride (60% dispersion in mineral oil, 0.51 g, 12.8 mmol, 1.2 eq.). After stirring at RT for 5 min, iodomethane (2.2 mL) was added, and the resulting mixture was stirred at RT overnight. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (200 mL) and brine (50 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by SiO2 chromatography eluting with hexane:EtOAc (3:1) to afford 4-bromo-6-fluoro-1-methyl-1H-indazole as a tan solid (1.42 g, 58%) and 4-bromo-6-fluoro-2-methyl-2H-indazole (0.29 g, 12%) as a tan solid. MS (ESI): m/z=229.1 [M+1]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[O:14][CH3:15].S(NN)(C1C=CC(C)=CC=1)(=O)=[O:17].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][C:7](/[CH:8]=[CH:29]/[C:30]([O:31][CH2:32][CH3:28])=[O:17])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1cc(OC)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of triethyl phosphonoacetate (0.60 mL, 3.02 mmol) in THF (5 mL) was added portion-wise NaH (60% dispersion in mineral oil, 360 mg, 9.00 mmol) over 2-3 mins. After effervescence had ceased, 4-hydroxy-3,5-dimethoxybenzaldehyde (547 mg, 3.00 mmol) was added portion-wise, washing in with THF (3 mL). More THF (2×2 mL) was added to the thick slurry and the resulting mixture was then heated to reflux for 21 hours. The mixture was then allowed to cool slowly to ambient temperature and the reaction quenched by the careful addition of saturated aqueous NH4Cl (20 mL). The organic solvent was then removed under vacuum and the resulting aqueous mixture was then extracted with DCM (10 mL, 5 mL and then 2 mL) using hydrophobic frits. The filtrate was then treated with Polymer Supported-TsNHNH2 resin (loading 3.22 mmol/g, 1.62 g, 5.23 mmol (3 eq wrt unreacted aldehyde)) and the mixture stirred for 16 hours to remove any unreacted aldehyde. The resin was then removed by filtration washing with DCM (5 mL, 10 mL and then 5 mL) and the filtrate reduced under vacuum to give the title compound (221 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of compound 17A (1.4 g, 6.76 mmol) and K2CO3 (1.4 g, 10 mmol) in DMF (60 mL) was added iodomethane (0.46 mL, 7.44 mmol). After the addition, the mixture was stirred at 40° C. overnight, then cooled to rt, partitioned between ether and water. The separated ether layer was washed with water and brine, then dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 10% EtOAc/hexane to yield the title compound (1.38 g, 92% yield).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:27]([O:26][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Product: CC(C)(C)OC(=O)n1c(N2CCCC[C@H]2C(=O)OCc2ccccc2)nc2ccccc21

Procedure:
The title compound was prepared by a similar method to Preparation 2 from tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate [see Preparation 46] and benzyl (2S)-2-piperidinecarboxylate [see J.A.C.S. (1 996), 118(7), 1629-1644]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane:ethyl acetate, in 5% increments to afford tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
A mixture of (4-amino-phenyl)-acetic acid (25 g) in acetic acid (200 mL) was treated with acetic anhydride (31.3 mL). The mixture was heated on a steam bath for 4 hours, then cooled, then treated with water (20 mL) and then evaporated. The residue was dried under vacuum to give the title compound (30.4 g) as a beige coloured solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methylsulfanyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methylsulfanyl-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=430.