Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[C:16]([F:23])[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[C:16]([F:23])[CH:15]=1
Reactant: Fc1cc(Br)ccc1N=C=S
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Fc1cc(Br)ccc1Nc1nc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) was diluted in dichloromethane (5 mL) and treated with 4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The dark solution was stirred at 45° C. for 15 minutes, then 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once. The reaction was heated in a 45° C. oil bath overnight, then cooled and concentrated at reduced pressure. The dark residue was diluted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by flash chromatography on silica gel eluted on a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was collected as a light pink solid (0.60 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H), 7.55–7.41 (m, 3H), 7.35–7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:21][N:22]([CH3:35])[C:23](=[O:34])[C@@H:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C@@H:24]([CH3:25])[C:23]([N:22]([CH3:35])[CH3:21])=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: C[C@H](NCc1ccccn1)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N(Cc2ccccn2)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 789 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 253-2 (2.56 mmol, crude form) as starting materials, respectively 821 mg (Isomer A, colorless amorphous) and 406 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH3:8][C:2]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:11])([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: CC(C)(CCC(=O)O)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CCCO)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminovaleric acid (14.0 g) and triethylamine (5.25 g) in tetrahydrofuran (280 ml), ethyl chloroformate (5.64 g) was added with ice-cooling and then stirred for 30 minutes. The resulting triethylamine hydrochloride was removed by filtration. To filtrate was added sodium borohydride (5 g) in water (90 mg) with ice-cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated to a volume of 120 ml in vacuo and extracted with dichloromethane. The dichloromethane layer was washed with diluted hydrochloric acid and then water, dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue which was then purified by silica gel chromatography to give 4-methyl-4-(p-nitrobenzyloxycarbonyl)aminopentanol.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Cl:12][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9]
Reactant: O=C1NCCN1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1CCCl

Procedure:
A solution of 5.00 g (38.42 mmol) of 1-(2-hydroxyethyl)imidazolidin-2-one 44-1 and 3.82 mL (52.39 mmol) of thionyl chloride in 75 mL of chloroform was stirred at reflux for 4 hours. The reaction was concentrated in vacuo to an orange oil, which was redissolved in chloroform and washed twice with water. The organic layer was dried and reconcentrated to give the crude desired product as an orange solid. The solid was used as obtained from the reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:32][CH3:33])[CH2:4][CH2:3]1.[CH:34]1([CH:37]=O)[CH2:36][CH2:35]1.[BH4-].[Na+]>CCO>[CH:34]1([CH2:37][NH:1][C:2]2([CH2:5][O:6][C:7]3[CH:16]=[C:15]4[C:10]([C:11]([O:17][C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]6)=[CH:12][CH:13]=[N:14]4)=[CH:9][C:8]=3[O:32][CH3:33])[CH2:3][CH2:4]2)[CH2:36][CH2:35]1
Reactant: O=CC1CC1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N)CC5)c(OC)cc34)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NCC6CC6)CC5)c(OC)cc34)ccc12

Procedure:
The compound of Example 3 (100 mg) was refluxed with cyclopropanecarbaldehyde (2 eq) in EtOH (8 ml) for 4 hours. To the reaction was added NaBH4 (2.2 eq), the reaction was refluxed for 20 minutes and evaporated. The residue was purified with silica gel column to give the titled product (40 mg). Mass: (M+1), 498
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one (Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (8:1 to 4:1) gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.3 mL). The colorless precipitate was collected by filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 243° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].[C:43]([C:46]1[CH:53]=[C:52]([Cl:54])[C:49]([C:50]#[N:51])=[C:48]([I:55])[C:47]=1O)(=[O:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([C:46]1[C:47]([O:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[C:48]([I:55])[C:49]([C:50]#[N:51])=[C:52]([Cl:54])[CH:53]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)c1cc(Cl)c(C#N)c(I)c1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C#N)c(I)c1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
Diethyl azodicarboxylate (2.3 mL, 14 mmol) was added slowly to a solution of triphenylphosphine (3.79 g, 14.5 mmol) and tert-butyl (2-hydroxyethyl)carbamate (2.3 g, 14 mmol) in tetrahydrofuran (93 mL) and cooled in an ice bath. After stirring for 15 minutes, the 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile (3.1 g, 9.6 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 N HCl, and brine, then dried over magnesium sulfate and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate as a tan solid (3.2 g, 71%). LCMS calculated for C16H18ClIN2O4Na (M+Na)+: m/z=487.1; found: 486.9.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC>[C:7]1([CH:6]([OH:13])[CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Solvent: CCCCCC
Product: CCC(O)c1ccccc1
Reaction time: 17 h
Yield: 25 %

Procedure:
To 2.2 mL solution of diethylzinc in hexane, 0.2 mL of benzaldehyde and 2 mg of a mixture of compounds 6 and 7 was added. After 17 h, the reaction was quenched by the addition of a few drops of saturated ammonium chloride. Solvent extraction (CH2Cl2/H2O), followed by drying and evaporation of the organic solvent, and flash chromatography, resulted in the isolation of the addition product (1-phenyl-1-propanol) in 25% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH:14]([CH3:16])[CH3:15])=O>C(O)(=O)C.C(O)C>[CH3:11][C:12]1[C:14]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2

Procedure:
A mixture of 0.18 mole of 4-methoxy-phenylhydrazine, 0.27 mole of methyl-isopropyl ketone, five drops of acetic acid and 300 ml of ethanol was refluxed for 3 hours and then the solvent was evaporated. The dark residue (28 g of hydrazone) was dissolved in 125 ml of ethanol. After adding 54 ml of a 15 % by weight solution of concentrated sulphuric acid in ethanol the mixture was refluxed for 2.5 hours. The white precipitate (ammonium sulphate was filtered and the filtrate was diluted with 750 ml of water, neutralized with a few ml of aqueous 5N NaOH and extracted with ether. The dried extract was distilled in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=2[Cl:20])[C:7]=1[NH:8][CH2:9][CH2:10]O)#[N:2].S(Cl)([Cl:23])=O>>[Cl:23][CH2:10][CH2:9][NH:8][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=2[Cl:20])[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1NCCO
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1NCCCl

Procedure:
A solution of 4-cyano-5-(2-hydroxyethyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (3.0 g; prepared as described in Example 27) in thionyl chloride (25 ml) was heated under reflux for 5 hours. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane (100 ml). The dichloromethane solution was washed with water (2×200 ml), dried over anhydrous magnesium sulphate and evaporated to give an orange gum, whicn was chromatographed using dichloromethane as eluent. Evaporation of the eluate containing the major component gave 5-(2-chloroethyl)amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole, m.p. 125°-128° C., in the form of a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:17])[CH:3]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[Cl:1][C:2]1[C:6]2[N:7]([C:20](=[O:21])[CH2:19][Cl:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:17])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2
Solvent: CC#N
Product: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2C(=O)CCl
Yield: 63 %

Procedure:
First, 3-chloro-1-methyl-1,4,9,10-tetrahydropyrrolo[3,2-b]-[1,5]benzodiazepin-10-one (1.7 g, 6.86 mmol), is refluxed for 1 hour in a mixture with acetonitrile (50 ml) and chloroacetyl chloride (4.0 ml, 52.9 mmol). The mixture is concentrated in vacuo, the residue is taken up in water (20 ml) and filtered and the solid residue is chromatographed using dichloromethane/cyclohexane/ethyl acetate (1:2:1 v/v) as eluant. A wine-red solid is isolated from the eluate, yielding colorless crystals (1.4 g) of mp. 284°-285° C. (D) after purification with tert.butyl methyl ether.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26]Cl)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]>CO.C(OCC)(=O)C>[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
To a liquid prepared by dissolving with stirring 7.5 g (0.052 mol, 1.0 eq.) of 2-mercaptobenzimidazole and 61.5 g (0.319 mol, 5.8 eq.) of a 28% sodium methoxide solution in 120 mL of methanol, a liquid prepared by dissolving the whole amount of 4-pentyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 6.9 g of amorphous solidified product. The product was recrystallized from an ethyl acetate/1-hexane mixed liquid, to obtain 4.3 g of colorless crystals (HPLC: 98.5 Area %, yield 10.6%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([CH2:18][NH2:19])[OH:17]>>[OH:17][CH2:16][CH2:18][NH:19][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cnc2c(Cl)nc3ccccc3n12
Reactant: NCCO
Product: Cc1cnc2c(NCCO)nc3ccccc3n12

Procedure:
By reaction of 4-chloro-1-methylimidazo[1,2-a]quinoxaline (example 2) with ethanolamine according to a procedure that is similar to that followed in example 3 there is obtained 4-(2-hydroxyethylamino)-1-methyl imidazo[1,2-a]quinoxaline. m.p. (DSC)=173.4° C. (onset); IR (KBr): 3415, 3217, 1558 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7.÷7.2 (3H,m), 7.2 (1H,m), 6.6 (1H,m), 5.3 (1H,sb), 3.85 (3H,m), 2.8 (3H,s); UV (EtOH): λmax =225, 242, 271, 301, 314, 327 nm. Elementary analysis for C13H14N4 (m.w. 242.28): calcd. C 64.45, H 5.82, N 23.12%; found C 64.29, H 5.91, N 23.13%.
Reaction SMILES: C(O[C:4](=[O:34])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:17]3[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[C:16]=3[N:15]=2)[CH2:9][CH2:8]1)C.CO.[NH3:37]>>[OH:26][C:25]1[C:20]([CH2:19][N:18]2[C:17]3[CH:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[C:16]=3[N:15]=[C:14]2[NH:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][C:4]([NH2:37])=[O:34])[CH2:12][CH2:11]2)=[N:21][C:22]([CH3:27])=[CH:23][CH:24]=1
Reactant: N
Reactant: CCOC(=O)CCN1CCC(Nc2nc3c(C)cc(C)cc3n2Cc2nc(C)ccc2O)CC1
Solvent: CO
Product: Cc1cc(C)c2nc(NC3CCN(CCC(N)=O)CC3)n(Cc3nc(C)ccc3O)c2c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of 3-{4-[1-(3-Hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionic acid ethyl ester (0.0065 mol) in methanol/NH3 7N (15 ml) was stirred in a sealed vessel at 70° C. for 12 hours. The solvent was evaporated until dryness. The residue (0.3 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.09 g, 32%) was crystallized from diisopropylether. The precipitate was filtered off and dried, yielding 0.086 g of 3-{4-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionamide (compound 5, 30%, melting point: 212° C.).
Reaction SMILES: [CH:1]12[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C[Al](C)C.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>ClCCl>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:25][CH:23]([OH:22])[CH2:24][N:3]2[CH2:4][CH:5]3[CH:8]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1C2CCC1CNC2
Agent: C[Al](C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1C2CCC1CN(CC(O)COc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 3-azabicyclo[3.2.1]oct-8-yl(methyl)carbamate (Preparation D; 1.68 g, 7.0 mmol) in dichloromethane (35 mL) at 25° C. under nitrogen was added trimethylaluminum (3.75 mL of 2.0 M in hexanes, 7.0 mmol). After stirring at 25° C. for 30 min, 4-(2-oxiranyl-methoxy)benzonitrile (Preparation E(i); 1.22 g, 7.0 mmol) was added in one portion, and the mixture was stirred overnight. The mixture was quenched with 3 N NaOH (11.5 mL) and stirred for 1 h. Water (30 mL) was added, and the aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford an oil. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 2.35 g (81%) of the subtitle compound as a white solid.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([C@@:12]1([CH3:39])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N+:14]2[C@@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:33][O:34][C:13]1=2)[CH:10]=[CH2:11].C([O-])(O)=[O:41].[Na+]>ClCCCl>[CH2:9]([C@@:12]1([CH3:39])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:14]([C@@H:32]([C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:33][OH:41])[C:13]1=[O:34])[CH:10]=[CH2:11]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C(C)(C)C
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C(C)(C)C)C1=O

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate (290 mg, 0.478 mmol; Example 363, Step B) in 1,2-dichloroethane (4.78 mL) was added 5 mL of sat. aq. NaHCO3 solution. The reaction mixture was heated to 50° C. for 3d. The reaction mixture was poured into a separatory funnel and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and the filtrate was concentrated. Purification by column chromatography using 25-35% ethyl acetate in hexanes on a 4 g silica gel column afforded the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([C:15]([C:12]2[N:13]=[CH:14][C:9]([N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[O:7])=[CH:10][CH:11]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: CN1CCNC1=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 53.6 %

Procedure:
Using 1-methyl-2-imidazolidinone (37 mg) and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (140 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (78 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCC1CCNCC1
Solvent: CO
Product: COC(=O)CCC1CCN(C(C)=O)CC1

Procedure:
Methyl 3-[piperid-4-yl]propionate (11 g) and acetic anhydride (35 ml) were heated together on a steam bath for 1 hour. The mixture was cooled and methanol (50 ml) was added to destroy excess anhydride. The solution was evaporated to dryness in vacuo and the residue was partitioned between chloroform (200 ml) and 2 N hydrochloric acid (100 ml) dried (Na2CO3) and evaporated to give methyl 3-[1-acetyl-piperid-4-yl]propionate (13 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: c1ccc(C2CO2)cc1
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OCC(O)c2ccccc2)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde with styrene oxide gave 3-(2-hydroxy-2-phenylethoxy)benzaldehyde as a clear oil. Yield (0.9 g, 48%): 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.23-7.41 (m, 8H), 7.16 (d, J=8.0 Hz, 1H), 5.35 (dd, J=8.2, 3.4 Hz, 1H), 3.93-4.0 (m, 1H), 3.82-3.89 m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@:11]2([CH2:26][OH:27])[C@H:9]1[CH2:10]2)=[O:7])(C)(C)C.[C:28]([C:31]1[N:32]=[C:33]([CH2:40]C(O)=O)[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=12)(=[O:30])[CH3:29]>C(Cl)Cl.CO>[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:13]1[CH2:12][C@:11]2([CH2:26][OH:27])[C@@H:9]([CH2:10]2)[N:8]1[C:6](=[O:7])[CH2:40][C:33]1[N:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]2=[C:31]([C:28](=[O:30])[CH3:29])[N:32]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)NCc2cccc(Cl)c2F)C[C@@]2(CO)C[C@@H]12
Reactant: CC(=O)c1nc(CC(=O)O)n2ccccc12
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1nc(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)n2ccccc12

Procedure:
was prepared using the protocols described for the preparation of Example 758 from (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]-hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B28) and (1-acetyl-imidazo[1,5-a]pyridin-3-yl)-acetic acid (prepared as described in Scheme A19). Rf, TLC (CH2Cl2/MeOH 9:1)=0.40; MS (UPLC/MS): 499.4/501.4 [M+H]+, 521.4/523.4 [M+Na]+, 543.5/545.5 [M+HCOO]−; tR (HPLC conditions f): 1.66 min.