Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A suspension of 1.85 g (4.74 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of N,N-dimethylformamide was treated with 1.73 g (23.7 mmol) of diethylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. There were obtained 1.54 g (76%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo-[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a pale yellow oil. A sample was recrystallized from ether and gave white crystals; m.p. 151°-153° and [α]D20 =+35.5° (MeOH, c=1%).
Reaction SMILES: P1(OCC)[O:6][CH2:5][C:4]([CH2:9][CH3:10])([CH2:7][Br:8])[CH2:3][O:2]1.BrCC1C=CC(CBr)=CC=1>>[CH2:9]([C:4]([CH2:7][Br:8])([CH2:5][OH:6])[CH2:3][OH:2])[CH3:10]
Reactant: CCOP1OCC(CC)(CBr)CO1
Agent: BrCc1ccc(CBr)cc1
Product: CCC(CO)(CO)CBr
Temperature: 100 °C

Procedure:
2-Ethyl-2-bromomethyltrimethylene ethyl phosphite (IV), 97 grams, 0.372 mole and α,α'-dibromo-p-xylene, 48.9 grams, 0.186 mole, were mixed in a 500 ml. flask equipped with an air condenser and a nitrogen inlet tube. The mixture was slowly heated to 100° C., at which time the reaction was completed, leaving a white solid. The solid was washed with two 100 ml. portions of benzene-acetone (50/50) and then ground in a morter to a fine powder. The powder was boiled in benzene-acetone (50/50) for several minutes, cooled to 10° C., filtered and dried in a vacuum oven at 50° C. for 12 hours. There was obtained 109 grams of product, m.p. 242° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.Br[C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: COC(=O)[C@H](C)Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](C)N1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.6 %

Procedure:
To a solution of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (20.1 mg, 0.0475 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (1 mL) was added triethylamine (23 μL, 0.17 mmol) and methyl (2S)-2-bromopropanoate (9.5 mg, 0.057 mmol). The reaction solution was stirred at room temperature for 4 h. The solvent was removed to give the desired product (6.2 mg, 28%). LCMS calculated for C23H30ClN6O3 (M+H)+: m/z=473.2; Found:473.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cccc(O)c1)c1ccccc1
Yield: 58.7 %

Procedure:
By using 3-aminophenol (1.0 g) and benzoyl chloride (644 mg) as starting materials, the title compound (573 mg) was obtained in the same manner as that of Reference Example 18.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:48])[C:34]([CH2:46]O)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:31]>>[CH2:38]([O:37][C:35](=[O:36])[C:34]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH2:46][O:26][C:25](=[O:27])[CH2:24][N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:23][CH2:22]1)[C:33]([O:32][CH2:30][CH3:31])=[O:48])[CH3:39]
Reactant: O=C(O)CN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Product: CCOC(=O)C(COC(=O)CN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)(C(=O)OCC)c1ccccc1

Procedure:
The [4-(4′-trifluoromethylbiphenyl-2-carbonyl-amino)piperidin-1-yl]acetic acid obtained in Example 8d) and the 2-hydroxymethyl-2-phenylmalonic acid diethyl ester obtained in Example 1-2a) were subjected to reactions similar to those in Example 1g) to give the title compound (90 mg) (see Table 58).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](O)=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[OH:12][CH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:5]=1[CH2:6][OH:7]
Reactant: Cc1ccc(C(=O)O)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(CO)c1
Yield: 63.9 %

Procedure:
4-Methylphthalic acid (1.40 g, 7.8 mmol) was dissolved in tetrahydrofuran (80 ml) under an argon atmosphere, and lithium aluminum hydride (742 mg, 19.5 mmol) was added, which was followed by reflux under heating for 4 hours. Water was added to the reaction mixture on an ice bath, and the mixture was extracted with ethyl acetate. The organic extract was washed successively with saturated aqueous potassium sodium tartrate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel column chromatography [developing solution: a mixed solution of ethyl acetate and hexane (volume ratio 2:3)] to give 759 mg of 3,4-dihydroxymethyltoluene (yield 64%).
Reaction SMILES: S(Cl)(C)(=O)=O.[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9]O.C(N(C(C)C)CC)(C)C.[Cl-:26].[Li+]>ClCCl.O>[I:6][C:7]1[C:14]([I:15])=[CH:13][C:12]([I:16])=[CH:11][C:8]=1[CH2:9][Cl:26]
Reactant: [Cl-]
Reactant: OCc1cc(I)cc(I)c1I
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: ClCc1cc(I)cc(I)c1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Mesyl chloride (4.24 ml, 56 mmol) was added dropwise into a suspension of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry dichloromethane (140 ml) containing diisopropylethylamine (11 ml, 64 mmol) and lithium chloride (4.24 g, 100 mmol) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 5 h at room temperature, then cold H2O (100 mL) was added. The resulting aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with NaHCO3 aq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cold absolute ethanol (25 mL). 9.05 g of 2,3,5-triiodobenzyl chloride in the form of a white clean solid was obtained in 90% yield.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[OH-].[Na+].C([O:10][C:11](=O)[C:12](=[CH:16]OCC)[N+:13]([O-:15])=[O:14])C>O>[OH:10][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:16][N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CSC(=N)N
Reactant: CCOC=C(C(=O)OCC)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc([N+](=O)[O-])c(O)n1

Procedure:
104.5 gm of S-methyl-isothiourea (0.75 mol) and 53.3 gm (1.333 mol) of sodium hydroxide solution are stirred together for 10 minutes in 350 ml of water. 114.5 gm (0.605 mol) of ethyl-ethoxymethylene-nitroacetate are then slowly added thereto, the temperature being kept at 20° C. by cooling. The precipitate is extracted and washed with a little ice-cold water. It is dissolved in approximately 9 liters of hot water and acidified with concentrated hydrochloric acid with cooling. The precipitated product is extracted and washed with ether.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][N:7]=1)=[O:5])C.[Cl-].[Mg+2].[Cl-].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C(O)C>[CH:20]1([NH:23][C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][N:7]=2)=[O:5])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccnc(C(=O)OCC)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCO
Product: CCOC(=O)c1ccnc(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.5 g (24.64 mmol) of diethylpyridine 2,4-dicarboxylate (Example 50A) were dissolved in 55 ml of ethanol. 0.47 g (4.93 mmol) of magnesium chloride was added, and the mixture was then cooled to 0° C., 8.44 g (147.83 mmol) of cyclopropylamine were slowly added dropwise and the reaction mixture was stirred at 0° C. for 15 min and stirred further at RT for 2 days. The reaction mixture was evaporated. The residue was dissolved in water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
A mixture of ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (379 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 5 hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (299 mg, yield: 83%). This was recrystallized from ethanol-hexane. Melting point: 104–105° C.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][NH:8][C:9](=[O:41])[CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[O:20][C:21]3[N:22]=[C:23]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[C:26]=3[N:27]=2)=[CH:14][C:13]=1[CH3:40])(C)(C)C>FC(F)(F)C(O)=O>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C:23]2[N:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[C:26]3[N:27]=[C:19]([C:15]4[CH:16]=[C:17]([CH3:18])[C:12]([O:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:42])=[O:5])=[O:41])=[C:13]([CH3:40])[CH:14]=4)[O:20][C:21]=3[N:22]=2)=[CH:38][CH:37]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)NCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)NCC(=O)O)c(C)c3)nc12
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
50 mg of (2-{4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetylamino)-acetic acid tert-butyl ester were dissolved in 1 ml of trifluoroacetic acid and the mixture was stirred for 30 min. Then the solvent was removed in vacuo to yield 37 mg of the title compound.
Reaction SMILES: C([NH:8][C:9]1[N:13]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[N:12]=[C:11]([Br:19])[C:10]=1[N+:20]([O-])=O)C1C=CC=CC=1.[OH-].[Na+].Br>CCO.[Pd]>[BrH:19].[NH2:20][C:10]1[CH:11]=[N:12][N:13]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:9]=1[NH2:8]
Reactant: O=[N+]([O-])c1c(Br)nn(CC(O)CO)c1NCc1ccccc1
Agent: [Pd]
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: Nc1cnn(CC(O)CO)c1N
Reaction time: 3.5 h

Procedure:
A mixture of 3-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propane-1,2-diol (4-4) (7.0 g; 18.8 mmol) in EtOH (150 ml) containing 10% Pd/C as catalyst (Engelhard, 50% wet, 0.7 g dry weight) and NaOH (solid, 800 mg, 18.8 mmol) was hydrogenated in an autoclave (1 l) at 16 bar for 3.5 hours. The reaction mixture was filtered to remove the catalyst under an inert atmosphere, in an ethanolic solution containing HBr (47%, 7.1 ml, 57 mmol). The solvent was evaporated off under reduced pressure to give a solid. After washing with cold EtOH, the 3-(4,5-diaminopyrazol-1-yl)propane-1,2-diol hydrobromide was obtained as an off-white solid.
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[N+:18]([O-])=O)#[N:2].[ClH:21]>C(O)C.C(OCC)(=O)C.O1CCOCC1.[Ni]>[ClH:21].[ClH:21].[NH2:2][C:1]1[NH:18][C:5]2[CH:6]=[C:7]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COc1ccnc(-c2ccc(NC#N)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc3nc(N)[nH]c3c2)c1

Procedure:
A suspension of N-cyano-4-(4-methoxypyridin-2-yl)-2-nitroaniline (200 mg) in ethanol (10 ml) was hydrogenated over Raney-nickel (500 mg) under a hydrogen atmosphere for 12 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 20 g, dichloromethane:methanol:aqueous ammonia=100:10:1). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 2-amino-5-(4-methoxypyridin-2-yl)benzimidazole dihydrochloride (142 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[CH:17][N:16]=1>>[NH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:25][C:20]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Nc1cccc2cnccc12
Product: c1cc(NC2CCCNC2)c2ccncc2c1

Procedure:
Reaction of tert-butyl 3-oxopiperidine-1-carboxylate and isoquinolin-5-amine using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)c1
Yield: 32.7 %

Procedure:
Following a procedure similar to that described in Example 36(a), 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 1.51 g of 1-t-butoxycarbonyl-2-(2-hydroxyethyl)piperidine, 1.72 g of triphenylphosphine and 1.14 g of diethyl azodicarboxylate were reacted in 20 ml of methylene chloride. The mixture was then worked up as described in Example 36(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.630 g (yield 32%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>C1COCC1>[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a 0° C. suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride (50 mg, 0.100 mmol) in THF (1 mL) was added 2-amino-2-methylpropan-1-ol (17.8 mg, 0.401 mmol). The mixture was stirred for 1 hour at RT. The solvent was removed, and the residue was purified by reverse-phase preparative HPLC, using 0.1% NH4OH in ACN/water. The product fractions were combined and concentrated to provide (E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (8.5 mg, 15.4% yield). MS, m/z (C30H38FN5O4): calcd, 551.3. found, 552.4 [M+H].
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[C:17]([O:16][C:14]([NH:13][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][C:8]=1[C:9]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24]1)=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Step 3): A mixture of 5-isopropyl-N-tert-butoxycarbonylanthranilic acid (1.0 g, 3.58 mmol), 4-aminomethyl-1-diphenylmethylpiperidine (1.0 g, 3.57 mmol), triethylamine (0.37 g, 3.66 mmol) and DPPA (1.0 g, 3.63 mmol) in DMF was stirred at 0° C. for 30 mins and at room temperature for 2 hours. The mixture was poured into H2O and extracted with AcOEt. The extract was washed with H2O, dried over MgSO4 and evaporated and then the residue was purified by column chromatography on silica gel to give 2-(tert-butoxycarbonyl)amino-5-isopropyl-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 1.86 g (96.4%): mp 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a solution of compound 27 (815 mg, 4.08 mmol) in DMF (15 mL) were added t-butyldimethylsilyl chloride (738 mg, 4.9 mmol) amd imidazole (556 mg, 8.16 mmol). The thus obtained solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with 15% to 50% to give the compound 28 as a white solid (1.087 g, 85%). LCMS-ESI (POS), M/Z, M+1: Found 314.1, Calculated 314.1.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH:16]([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:29][CH:16]([F:15])[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH3:18]
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)F
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)F)cc3)cc2)C1
Yield: 12.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (150 mg, 0.78 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(2,2-difluoro-1-methyl-ethyl)-benzenesulfonyl chloride (321 mg, 1.26 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a colourless gum.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.O>CO>[NH:13]1[CH2:14][CH:15]=[C:16]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CCNC1
Temperature: 65 °C

Procedure:
KOH (8.19 g, 146 mmole), indole (3.87 g, 33 mmole) and piperidine-4-one hydrochloride (10.22 g, 85.7 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 4.26 g (71%) as a yellow solid with an m.p. of 172°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:18][C:19]([O:21]CC)=[O:20])=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+:25].Cl>O1CCCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.[Na+:25]
Reactant: CCOC(=O)Cc1oc(-c2ccc(F)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])Cc1oc(-c2ccc(F)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-4-(2-thienyl)-oxazol-5-ylacetate (94 mg) in tetrahydrofuran (3 ml) and ethanol (3 ml) was added 1N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for one hour. To the reaction mixture was added 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was dissolved in methanol (5 ml), 0.5M sodium methoxide (556 μl, methanol solution) was added to the solution and the solvent was removed under reduced pressure to obtain sodium 2-(4-fluorophenyl)-4-(2-thienyl)oxazol-5-ylacetate (90 mg) as pale brownish powder.