Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Br:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([Br:34])[CH:36]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc(Br)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-bromobenzene-1-sulfonyl chloride (46 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 40 mg (52%); 1H NMR (DMSO-d6, 300 MHz): δ 9.444 (s, 1H), 8.352 (s, 1H), 8.208-8.234 (d, 1H, J=7.8 Hz), 8.050-8.074 (d, 1H, J=7.2 Hz), 7.985-8.015 (d, 1H, J=9 Hz), 7.821-7.849 (d, 2H, J=8.4 Hz), 7.776-7.7.782 (d, 1H, 1.8 Hz), 7.643-7.714 (m, 3H), 6.753-6.759 (d, 1H, J=2.1 Hz), 1.777 (s, 6H); MS: m/z 625 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1cc(O)c2c(c1)NC1(CCCCC1)CC2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OCC(=O)O)cc2c1C(=O)CC1(CCCCC1)N2
Temperature: 40 °C
Reaction time: 9 h

Procedure:
A mixture of ethyl 2-{(5-hydroxy-4-oxospiro [1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Example 51 (1)) (0.15 g, 0.45 mmol), methyl iodide (0.071 g, 0.50 mmol), anhydrous potassium carbonate (0.094 g, 0.68 mmol), and dry DMF (4 ml) is stirred at 40° C. for 9 hours. After the addition of methyl iodide (0.14 g, 1.0 mmol), the stirring is continued for additional 4 hours. The solvent is removed by distillation and the residue is dissolved in ethyl acetate. The solution is washed with saturated brine, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:10). The earlier fractions containing oily materials are discarded. From the succeeding fractions, the desired product is obtained as a crystalline solid (0.067 g, 43%, m.p=158°-159° C.).
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH:6]=[C:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.C[Si](Cl)(C)C(C(C)C)(C)C>ClCCl>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C:7](=[CH:6][CH:5]=[C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][CH2:2][CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1=CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@]12CCCCC1=CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 3 °C
Reaction time: 8 h

Procedure:
After a mixture of 149.9 g (523 mmol) (3β)-3-hydroxyandrosta-5,7-dien-17-one and 56.9 g (836 mmol) imidazole in 500 mL of dichloromethane was cooled to 3° C., 144 mL (732 mmol) dimethylthexylsilyl chloride was added dropwise over 90 min, keeping the temperature below 6° C. After stirring at room temperature overnight, the mixture was washed with 500 mL of water, and the aqueous layer was back-extracted with 200 mL of dichloromethane. The combined organic layers were washed with 500 mL of saturated aqueous NaHCO3, dried over sodium sulfate, and concentrated. The resulting solid was suspended in 700 mL of methanol containing 14 mL of triethylamine, and the suspension was refluxed for 20 minutes. After cooling in a refrigerator overnight, the precipitate was filtered, washed with 600 mL of methanol/H2O (9:1), and dried by suction for 2 hr. further drying at 40° C. under high vacuum afforded 185.1 g (82.5% yield) of (3β)-3-[[1,1,2-trimethylpropyl)dimethylsilyl]oxy]androsta-5,7-dien-17-one as a beige solid: mp 119°-125° C.; Anal. Calcd for C27H44O2Si: C, 75.64; H, 10.34; Si, 6.55. Found C, 75.82; H, 10.29; Si, 6.72.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[C:13]([CH2:35][O:36][CH3:37])=[C:14]([CH:33]=[CH2:34])[N:15]=[CH:16][C:17]=1[N:18]2S(C1C=CC(C)=CC=1)(=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([O:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[C:13]([CH2:35][O:36][CH3:37])=[C:14]([CH:33]=[CH2:34])[N:15]=[CH:16][C:17]=1[NH:18]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CO
Product: C=Cc1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
A solution of 0.23 g of sodium in 10 ml of methanol is added drop by drop with stirring to a suspension of 0.5 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-vinyl-beta-carboline in 20 ml of methanol. After 72 hours of stirring at room temperature, it is evaporated to dryness and the residue is chromatographed over silica gel with dichloromethane/ethanol=10/1 as eluant. 0.135 g of 5-benzyloxy-4-methoxymethyl-3-vinyl-beta-carboline with a melting point of 183°-185° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CC(=O)O)c1

Procedure:
3-Aminophenylacetic acid was prepared from a solution of 3-nitrophenylacetic acid (5.08 g, 28 mmol) in absolute ethanol (100 ml) which was hydrogenated at 40° C. and 40 psi in the presence of 5% Pd/C catalyst for 3 hours. The catalyst was removed by filtration, and upon removal of the solvent in vacuo, a highly viscous yellow oil remained which resisted crystallization.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[N:8][C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([CH2:9][CH2:10][CH2:11][CH:12]=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(Cl)c(Cl)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Reaction time: 2 h
Yield: 59.3 %

Procedure:
4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butan-1-ol (1.008 g, 2.59 mmol) was dissolved in DCM (35 ml) and Dess-Martin reagent (1.208 g, 2.85 mmol) was added at r.t. under N2. The reaction was left for 2 hrs. The reaction was quenched by the addition of 1M Na2S2O3 solution (10 ml), sat. NaHCO3 solution (40 ml) and DCM (80 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×80 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 15% EtOAc:85% heptanes and 100% EtOAc as eluent to give the product as a pale yellow oil (0.595 g, 59%): MS (ESI+) for C17H24Cl2N2O2Si m/z 388.4 [M+H]+; LC purity 91% (ret. time, 1.74 min); 1H NMR (500 MHz, CDCl3) δ 9.82 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 5.44 (s, 2H), 3.43-3.67 (m, 2H), 2.97 (t, J=7.49 Hz, 2H), 2.69 (t, J=7.25 Hz, 2H), 2.23 (quin, J=7.13 Hz, 2H), 0.78-1.02 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)[CH3:2].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[C:28](Cl)[N:27]=1>>[CH2:1]([O:3][CH2:4][C@@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:28]3[C:29]([Cl:33])=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[N:27]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(Cl)c(Cl)cc3Cl)CC2)cc1
Yield: 84.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-ethoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (500 mg) described in Preparation Example 167 and 2,3,5,6-tetrachloropyridine (488 mg), the title compound (651 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C=CC=CC=1>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[N+:13]([O-:15])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 11 parts of 4-(4-chlorophenyl)-4-piperidinol, 55.8 parts of benzene and 8.8 parts of methanol is stirred and refluxed for 1.50 hours. After stirring is continued overnight at room temperature, the reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with water and 8 parts of methanol are added. The whole is stirred for 10 minutes with silica gel. The latter is filtered off and the filtrate is evaporated. The residue is triturated with 2,2'-oxybis propane. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 9.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide; mp. 144.3° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[C:19]([C:18]1[N:14]([CH3:13])[C:15]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCc1cc(Br)ccc1NC#N
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(C#N)n2C)ccc1NC#N
Yield: 24 %

Procedure:
4-bromo-2-ethylphenylcyanamide (0.125 g, 0.5 mmol), tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added. Tri-tert-butylphosphine (10 wt % in hexane) (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stirred until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate and filtered through a plug of silica gel, the solvent was evaporated and the residue was flash chromatographed using 4/1 Hexane/THF to give (0.030 g, 24%) the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(Cc1cccs1)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(Cc1cccs1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 81.8 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-(thiophen-2-yl-methyl)-3-(L-arabinopyranosyl)urea and 5.0 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-(thiophen-2-yl-methyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:25]=4)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:37]O.N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:25]=4)[C:17]4[S:22](=[O:37])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: Clc1ccc(N2CCN(c3nc4c(c(Nc5cccc(CN6CCOCC6)c5)n3)SCC4)CC2)cc1
Agent: N
Solvent: CC(=O)O
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Nc3cccc(CN4CCOCC4)c3)c21
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
313.80 mg {2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl}-(3-morpholin-4-ylmethyl-phenyl)-amine are placed in 2.70 ml glacial acetic acid and cooled to 10° C. 57 μl hydrogen peroxide (35%) are added dropwise, then the mixture is stirred for 0.25 hours. Then the reaction mixture is stirred in 30 ml ice water and made basic with cold ammonia solution. The precipitate formed is suction filtered, washed with water and dried. The crude product is extracted with petroleum ether and diethyl ether, suction filtered and dried. The product is purified by chromatography (10 g Chromabond SiOH-cartridge). 140.0 mg of the product are obtained as a powder (m.p 244°-248° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH3:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][C:16]1[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:18]=[CH:19][CH:20]=1)[CH3:2].Cl.[O:29]([NH2:31])[CH3:30].C([O-])(=O)C.[Na+]>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[N:31][O:29][CH3:30])[CH3:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][C:16]1[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: CON
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=O)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=NOC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole (23 mg), methoxylamine hydrochloride (15 mg, 3 eq.), and sodium acetate (15 mg, 3 eq.) in methanol (1 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and aqueous sodium bicarbonate added to pH 9, then extracted with ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-[1-(methoxyimino)ethyl]-1H-benzimidazole. 1H NMR (CDCl3): δ 7.94 (d, 1H); 7.73 (dd, 1H); 7.73 (dd, 1H); 7.63 (d, 1H); 7.52 (m, 1H); 7.38-7.40 (m, 3H); 7.27 (m, 1H); 6.19 (d, 1H); 4.32 (s, 2H); 3.87-4.10 (m, 5H); 2.30 (s, 3H); 1.22 (t, 3H).
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[C:11](Cl)=[O:12].[NH2:14][CH:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:17][CH:16]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[C:19](=[O:20])[C@H:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[C@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-naphthoyl chloride (178 mg, 0.934 mmol) in CH2Cl2 (3 ml) was added a solution of aminopyrrolidinone of Example W (250 mg, 0.849 mmol) and triethylamine (146 mg, 1.44 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred at room temperature for 18 h. The solvent was then removed in vacuo and the resulting foam was purified by radial chromatography on a silica gel plate (4 mm) eluting with 2/98 EtOH/CH2Cl2 to give the title compound (380 mg, 100%) as a colorless foam. MS M+1 calcd for C26H25N2O4F 449, found 449. DSC=142.2°-151.5° C.@55.9 J/g.
Reaction SMILES: [C:1]([C@H:5]1[C:40](=[O:41])[N:39]2[CH2:42][C@@H:36]([CH2:37][C@H:38]2[C:43]([NH:45][C@:46]2([C:51](O)=[O:52])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[O:35][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:54][CH2:55][CH2:56][C@H:9]2[O:8][C:7](=[O:57])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:58][N:59]([CH3:64])[S:60](=[O:63])(=[O:62])[NH2:61].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOCC.C(OCC)(=O)C>[C:1]([C@H:5]1[C:40](=[O:41])[N:39]2[CH2:42][C@@H:36]([CH2:37][C@H:38]2[C:43]([NH:45][C@:46]2([C:51](=[O:52])[NH:61][S:60](=[O:63])(=[O:62])[N:59]([CH3:64])[CH3:58])[CH2:48][C@H:47]2[CH:49]=[CH2:50])=[O:44])[O:35][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:54][CH2:55][CH2:56][C@H:9]2[O:8][C:7](=[O:57])[NH:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCN1CCOCC1)O2)C(=O)O
Reactant: CN(C)S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCN1CCOCC1)O2)C(=O)NS(=O)(=O)N(C)C
Reaction time: 0.08 h
Yield: 64.7 %

Procedure:
To a solution of the acid from Step 2 (46.6 mg) and N,N-dimethylsulfuric diamide (29.3 mg) in DMF (1 mL) was added DIPEA (52 DMAP (28.8 mg) and DBU (40 μL). The reaction mixture was stirred 5 minutes before adding HATU (26.9 mg). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with Et2O and ethyl acetate and quenched with water and acetic acid (pH=4). The mixture was extracted with diethyl ether (3×). The combined organic phases were washed with water (3×), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 10% methanol in dichloromethane) afforded the desired product (34.2 mg). LRMS (ES+) m/z 896.50 (M+H)+. By following the procedures outlined in Example 106 and using the appropriate reagent (depicted below the structure as Rg.), the following compounds were prepared.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[N:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68]([OH:70])=O)[C:56]([CH3:71])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:68](=[O:70])[CH2:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([CH3:71])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:48]=[CH:47][C:46]([CH:43]3[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[CH2:45][CH2:44]3)=[N:51][CH:50]=2)[N:58]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HOBt (71 mg, 0.52 mmol), EDCl.HCl (0.11 g, 0.59 mmol) and DIPEA (0.16 mL, 0.90 mmol) were added to a stirred solution of 2-(2-(2-(2-((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-methylpyrimidin-4-ylethyl)phenyl)acetic acid (A19) (96 mg, 0.18 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (174 mg, 1.81 mmol) was added in one portion and the resulting mixture was stirred for 18 hours at room temperature. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The volatiles were removed in vacuo and the residue adsorbed onto silica gel and purified by chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-25% MeOH in DCM) to give the title compound A20 as a clear oil (72 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=2.4 Hz, 1H), 8.14-8.06 (m, 1H), 7.93 (dd, J=8.5, 2.7 Hz, 1H), 7.37 (s, 1H), 7.26-7.22 (m, 4H), 7.10 (d, J=8.5 Hz, 1H), 5.91 (s, 1H), 5.73 (s, 1H), 4.24 (s, 2H), 3.69 (s, 2H), 3.09 (dd, J=9.7, 6.0 Hz, 2H), 2.97-2.90 (m, 2H), 2.86-2.72 (m, 3H), 2.12 (s, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.68 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 5.018 min; m/z 531 [M+H]+.
Reaction SMILES: [CH:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].[CH3:17][C@H:18]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C(OCC)(=O)C>[CH:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][N:20]3[CH2:21][CH:22]([CH3:24])[CH2:23][CH:18]([CH3:17])[CH2:19]3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: CCC(C)C1CCC2(CC1)OCC(CCl)O2
Solvent: CCOC(C)=O
Product: CCC(C)C1CCC2(CC1)OCC(CN1CC(C)CC(C)C1)O2
Yield: 75.1 %

Procedure:
24.7 g (0.1 mol) of 8-s-butyl-2-chloromethyl-1,4dioxaspiro [4,5] decane and 45.2 g (0.4 mol) of cis-3,5-dimethylpiperidine are stirred at 140° C. for 16 hours and cooled, 200 ml of ethyl acetate are added, the mixture is washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo and the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate). 24.3 g (75% of theory) of 8-s-butyl-2-(3,5-dimethylpiperidin-1-ylmethyl) -1,4-dioxaspiro[4,5] decane are obtained as an oil of refractive index nd20 1.4762.