Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]1)=[O:16])[CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:32]([C@@H:31]1[CH2:35][CH2:36][CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33])=[O:16])[CH3:13])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H](NC(=O)[C@@H]1CCCC[NH2+]1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.27 g (37.54 mmol) of the hydrochloride from example 21A and 10.50 g (48.81 mmol) of N-Boc-L-proline are dissolved in methylene chloride (30 ml) and cooled to 0° C. Subsequently, the solution is treated with 18.56 g (48.81 mmol) of HATU and 5.82 g (45.05 mmol) of ethyldiisopropylamine and stirred at 0° C. for 30 min. After further addition of 11.64 g (90.10 mmol) of ethyldiisopropylamine, the mixture is stirred at room temperature for 72 h and then evaporated. The residue is taken up using ethyl acetate and the solution is washed with aq. citric acid and aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by means of silica gel chromatography using cyclohexane/ethyl acetate 5/1. 18.25 g (99% of th.) of product are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:21])[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCCN
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and propylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (5 mg) and a syn-form compound (5 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1
Reactant: CN1CCN(S(=O)(=O)Nc2ccc(CO)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(S(=O)(=O)Nc2ccc(C=O)cc2)CC1
Reaction time: 0.42 h
Yield: 33.6 %

Procedure:
To a solution of oxalyl chloride (1.06 mL, 12.1 mmol) in CH2Cl2 (20 mL) was added DMSO (1.8 mL, 25.4 mmol.) at −60° C. and the mixture was stirred for 25 min. A solution of 4-(4-methyl piperazinyl)sulfonamido benzyl alcohol (3.0 g, 10.5 mmol) in CH2Cl2 (25 mL) and DMSO (5 mL) was added and the mixture was stirred for 1.5 h at −60° C. Triethylamine (7.4 mL) was added and the mixture was partitioned between brine and EtOAc. The organic extract was concentrated, then purified by flash chromatography to yield the title compound (1.0 g, 33%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([S-:13])[CH3:12].[Na+].Cl>CN(C)C=O>[CH2:11]([S:13][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(C)cc1C#N
Yield: 87.1 %

Procedure:
(Step 1) A mixture of 2-fluoro-5-methylbenzonitrile (7.5 g) and sodium ethanethiolate (4.9 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 3 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-(ethylsulfanyl)-5-methylbenzonitrile (8.57 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3].[Li]CCCC.C[O:20][C:21](=O)[O:22]C>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:21]([OH:22])=[O:20])=[CH:7][C:6]=1[CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(Br)cc1C
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCOc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-allyloxy-5-bromo-1,3-dimethyl-benzene (23.6 g, 98.0 mmol) in THF (150 mL) is added at −75° C. a solution of n-BuLi (90 mL, 1.5 M in diethyl ether). The temperature remains at −75° C. The mixture is stirred for 30 min and then transferred via double-tip canula into a cooled (0° C.) solution of dimethylcarbonate (21.4 g, 238 mmol) in THF (90 mL). The mixture is stirred for 2 h at 0° C., then warmed to rt during 15 h. The solvent of the mixture is evaporated and re-evaporated from EtOH (200 mL) to remove most of the butylacetate side product. The mixture is taken up in 2 N aq. LiOH (150 mL) and EtOH (200 mL) and stirred at rt for 2 h, then at 60° C. for 1 h. The EtOH is evaporated and the remaining mixture is diluted with 0.5 N aq. NaOH and extracted with diethyl ether (200 mL). The org. extract is washed with 1M aq. NaOH (5×50 mL) and the combined aq. washings are re-extracted with ether (100 mL). The aq. phase is acidified with 25% aq. HCl and extracted with DCM (5×50 mL). The combined org. extracts are dried over Na2SO4, filtered, evaporated and dried in vacuo at 60° C. for 15 h to give 4-allyloxy-3,5-dimethyl-benzoic acid (8.0) as yellow-brown solid. LC-MS: tR=0.90 min.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH2:22]([N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])[C:23]([CH3:24])=[O:25]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(=O)CCl
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC(C)=O)c(=O)[nH]c1=O
Yield: 44 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (145 mg, yield: 44%).
Reaction SMILES: N1CCC[CH:2]1[C:6](C)=[CH:7][C:8]([O:10][CH3:11])=[O:9].Br[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].Cl.[OH2:27]>CN(C)C=O>[C:19]1(=[O:20])[N:15]([CH2:14][CH:7]([C:6](=[O:27])[CH3:2])[C:8]([O:10][CH3:11])=[O:9])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COC(=O)C=C(C)C1CCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Methyl 3-tetrahydropyrrolyl-2-butenoate (29.0 g, 171.3 mmol) and N-(bromomethyl)phthalimide (43 g, 179.91 mmol) were dissolved in 250 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 16 hours under a nitrogen atmosphere. After checking completion of the reaction with TLC, 1N HCl and water were added into the reaction mixture. The produced solid was filtered under a reduced pressure while washing with hexane and then recrystallized in 100% ethanol, thereby to obtain the desired product (32.26 g, 68%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.BrBr.[NH2:9][C:10]([NH2:12])=[S:11].C(O)C>O1CCOCC1>[NH2:12][C:10]1[S:11][C:3]([CH:2]([CH3:6])[CH3:1])=[CH:4][N:9]=1
Reactant: NC(N)=S
Reactant: CC(C)CC=O
Agent: BrBr
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)c1cnc(N)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
2 ml (18.6 mmol) of 3-methylbutyraldehyde were dissolved in 15 ml of dioxane. 40.4 ml (18.6 mmol) of a solution 2% v/v of bromine in dioxane was dropped therein at 0° C. The mixture was maintained at room temperature under stirring for 2 hours, then 2.83 g (37.2 mmol) of thiourea and 5 ml of ethanol were added. After 6 hours at room temperature the solution was evaporated to dryness, the residue was dissolved in methylene chloride and the product extracted with 1M hydrochloric acid; the aqueous layer was made basic by using 30% ammonium hydrate and extracted again with methylene chloride. The organic phase was dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on a silica gel column, eluting with cyclohexane-ethylacetate to give 1.1 g (42% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][C:3]=1OC.[Li+].[OH-:22].[CH3:23][OH:24]>O>[C:5]([O:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:17][CH:18]=1)=[O:24])([CH3:17])([CH3:6])[CH3:4]
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)CNC(=O)NCc1ccc(N)c(OC)c1
Agent: [Li+]
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NCC(=O)O)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
50 (7.5 g, 21.3 mmol) was dissolved in 50 nil of MeOH and 50 ml of water, LiOH (4 équivalent, 2.0 g) was added and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture is concentrated and 200 ml of water are added, then extracted twice with AcOEt. The water is acidified to pH 3 with concentrated HCl 36%, then extracted twice with AcOEt. The combine organic phase are dried over Na2SO4, filtered and concentrated to afford 56 (6.81 g, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow solid, MS (ESI+): m/z=485.3 ([M+H]+).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C>C1COCC1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]([OH:31])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:19])([CH3:20])[CH3:21]
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: CCCCC(C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 295 %

Procedure:
2-phenyl-1,3-dithiane (Aldrich) (3.79 g; 19.3 mmol) was mixed with dry distilled THF (20 mL) under a nitrogen atmosphere. The solution was cooled to −60° C. and n-butyl lithium (1.6M in pentane, 1.56 mmol, 9.74 mL) was added slowly by syringe. The reaction mixture was warmed to −20° C. and held at that temperature for 30 minutes, and then held at −10° C. for 15 minutes. The yellow solution was cooled to −78° C. and (1-Formyl-pentyl)-carbamic acid tert-butyl ester (1.6 g, 1.4 mmol, in 5 ml THF) was added rapidly (over 20 seconds) and 60 seconds later a mixture of 2 mL acetic acid and 5 mL THF was added rapidly. After warming to 23° C. the solution was concentrated at reduced pressure. Excess 2-phenyl-1,3-dithiane was removed by its crystallization away from the desired product using a minimum of ethyl acetate in hexane. The mother liquors were concentrated and chromatographed using a hexane-ethyl acetate gradient to afford 1.7 g of {1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester. (56% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)[N:7]=1.C(=O)(O)[O-].[Na+]>Cl.C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH2:9]2)[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(C2CCCC(O[Si](C)(C)C(C)(C)C)C2)nc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)nc1Br
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of (+/−)-N-(3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide (97 mg, 0.206 mmol) in 6N HCl (687 μL), THF (687 μL) MeOH (687 μL) was stirred for 2 h. LCMS indicated that the reaction was completed. Solid sodium bicarbonate was added to neutralize the HCl. Dissolved in EtOAc and water. Organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to provide 72 mg of crude (+/−)-N-(3-bromo-5-((1R,35)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide in 98% yield. LCMS (m/z): 358.6 (MH+), 0.70 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:28].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:28])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C#N)nc2)CCN(C)C1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinonitrile (300 mg, 0.833 mmol), crushed KOH (140 mg, 2.499 mmol) in 12 mL tert-butanol was heated at 80° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was allowed to cool at RT, diluted with brine (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by Preparative HPLC followed by chiral HPLC to obtain 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxamide. 1H NMR (CDCl3, freebase) δ (ppm): 8.49 (s, 1H), 8.04 (d, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.85 (s, 1H), 6.78 bs (NH), 5.48 s (OH),4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomers II-136a-b.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24]C)=[C:17]([CH:26]([CH3:28])[CH3:27])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:26]([CH3:27])[CH3:28])[C:18]([OH:24])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
At −78° C., to a stirred solution of (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (2.00 g, 4.94 mmol) in CH2Cl2 (16.6 mL) was added 1M boron tribromide/ CH2Cl2 (10.4 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for 1.5 h. The reaction was quenched into crushed ice (18 g), diluted with H2O (20 mL) and extracted with ether. The combined ethereal extracts were washed with brine, dried (MgSO4) and concentrated. The crude product was purified on silica gel eluting with 15% acetone/hexane to give 0.97 g (50%) of the title compound as a white solid, mp 138° C.; 1H NMR (DMSO-d6) δ1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.34 [septet (under H2O peak), 2H], 3.84 (s, 2H), 7.04 (d, 2H), 7.17-7.25 (m, 3H), 7.44 (s, 2H), 9.11 (s, 1H). IR (KBr) 3400, 2950, 1580, 1320, 1200 cm−1. mass spectrum (EI), m/z 390 (M+). Anal. Calcd. for C26H30O3.0.2H2O: C, 79.24; H, 7.77; N, 0.12. Found: C, 79.27; H, 7.85; N, 0.12.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1>O>[CH:1]1([OH:4])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:10]1.[C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)OC1CCCCC1
Product: OC1CCCCC1
Reaction time: 4 h

Procedure:
Japanese Patent Application Laid-open No. 313447/1989 discloses an addition reaction of acetic acid with cyclohexene in the presence of both ZSM-5, a high silica content-zeolite, as a catalyst and water. According to this method, the reaction temperature is 120° C. and the reaction time is 4 hours resulting in the formation of cyclohexanol in a 12.5% yield and cyclohexyl acetate at most in a 65% yield. The reaction temperature is high and the catalytic activity is low.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:21]2[CH2:22][CH2:23][NH:24][C@H:19]([CH3:18])[CH2:20]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1c(Cl)nnc(C(=O)c2cccnc2)c1C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)c2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 89.6 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-3-yl-methanone (1.2 g, 4.84 mmol) and (R)-2-methy 1-piperazine (485 mg, 4.84 mmol) are added to a microwave vial followed by NMP (17 mL) and triethylamine (2.01 mL, 14.49 mmol). The vial is sealed and irradiated in the microwave at 170° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2). The resulting oil is co-evaporated with CH2Cl2 and heptane to afford the title compound as a powder (1350 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(Cl)=[O:40].[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:39]([N:49]3[CH2:50][CH2:51][N:46]([C:43](=[O:45])[CH3:44])[CH2:47][CH2:48]3)=[O:40])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2)c(OC(C)C)c1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(C(C)=O)CC2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of cis-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (5.48 g, 12.03 mmol, example 2) in methylene chloride (100 mL) cooled to 0° C. were sequentially added triethylamine (11.8 mL, 84.21 mmol) and phosgene (30.53 mL, 60.15 mmol, 21% solution in toluene). The reaction mixture was stirred at 0° C. under argon for 0.5 h or until thin layer chromatography (silica gel, 100% ethyl acetate) showed no starting material left. The solvent and excess reagents were removed under reduced pressure, and the residue was dried under vacuum for 1 h. The residue was dissolved in methylene chloride (100 mL) then a solution of 1-acetylpiperazine (1.619 g, 12.63 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred for 1 h at room temperature (or until no starting material was seen by thin layer chromatography). Saturated sodium bicarbonate solution (10 mL) was added. The product was extracted with methylene chloride (2×50 mL). The organic layers were washed with brine (1×20 mL), dried (anhydrous sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then with 5% methanol in ethyl acetate gave rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone as an orange foam (˜7.2 g). It was recrystallized with methylene chloride and ethyl ether (6.721 g, white solids). Additional amount of rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone (201 mg, tan color) was recovered from the mother liquor after purification by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then 5% methanol in ethyl acetate. Total yield: 6.922 g (94%). HR-MS (ES, m/z) calculated for C32H35N4O4Cl2 [(M+H)+] 609.2030, observed 609.2045.