Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:26])([C:22](OC)=[O:23])[CH3:21])=[CH:15][CH:14]=1)(OC)=[O:8].[NH4+].[Cl-].Cl>C(OCC)(=O)C.O1CCCC1>[OH:8][CH2:7][C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:26])([CH3:21])[CH2:22][OH:23])=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)(C)Cc1ccc(CC(C)(C)C(=O)OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)Cc1ccc(CC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To 500 ml of dry tetrahydrofuran was added 11.4 g of lithium aluminum hydride and 60 g of 1,4-bis(2-carbomethoxy-2-methylpropyl)benzene. The mixture was stirred overnight at room temperature. To the thick reaction mixture was added 300 ml of ethyl acetate, 30 ml of saturated aqueous NH4Cl, and 5 ml of concentrated HCl The mixture was stirred and filtered. Solvent was evaporated from the filtrate and the residue was recrystallized from benzene to obtain 20 g of 1,4-bis(3-hydroxy-2,2-dimethylpropyl)benzene. The solid from the above filtration was slurried with 50 ml of H2O, 20 ml of concentrated HCl, and 150 ml of benzene and heated at reflux for 1 hour. The benzene layer was then separated, dried over MgSO4 at 80° C, filtered hot and then cooled to precipitate an additional 10 g of 1,4-bis(3-hydroxy-2,2 -dimethylpropyl)benzene, m.p. 104°-105° C.
Reaction SMILES: N1(N[C:7]2[NH:8][C:9]3[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([O:17]C)[C:10]=3[N:11]=2)CCN=C1.C(C1C2NC=NC=2C(C)=CC=1[NH:31][N:32]1[CH2:36][CH2:35][N:34]=[CH:33]1)C.COC.Cl.[NH+]1C=CC=CC=1>>[OH:17][C:12]1[C:10]2[N:11]=[CH:7][NH:8][C:9]=2[C:15]([CH3:16])=[C:14]([NH:31][N:32]2[CH2:36][CH2:35][N:34]=[CH:33]2)[CH:13]=1
Reactant: CCc1c(NN2C=NCC2)cc(C)c2nc[nH]c12
Reactant: COc1ccc(C)c2[nH]c(NN3C=NCC3)nc12
Agent: COC
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Cc1c(NN2C=NCC2)cc(O)c2nc[nH]c12

Procedure:
(2-imidazolinylamino)-7-methoxy-4-methylbenzimidazole is made in the same manner as 4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole except that 2-methoxy-5-methylacetanilide is used instead of 3-ethyl-6-methylacetanilide (see Example 2). Cleavage of the methyl ether is achieved with pyridinium hydrochloride to afford 7-hydroxy-5-(2-imidazolinylamino)-4-methylbenzimidazole.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH:8][C:9](C2C=CC(N)=CC=2)=O)=[CH:3][CH:2]=1.BrC#[N:20]>CO>[NH2:20][C:9]1[NH:8][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[N:7]=1
Reactant: N#CBr
Reactant: Nc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: CO
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
Alternatively, 6.0 mmol of dianiline was treated with 6.3 mmol BrCN in 15 mL CH3OH at reflux for 3 h. The reaction mixture was cooled to ambient temperature and precipitate was filtered off to give the corresponding 2-aminobenzimidazole.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1

Procedure:
[2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(4-chloro-phenyl)-ethylamine. MS (ISP): 318.1/320.3 (100/39) (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.47 (d, 2H), 7.23-7.28 (m, 4H), 7.12 (d, 2H), 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:9][C:8]1[C:3]([CH2:2][OH:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1ncccc1OCc1ccccc1
Yield: 66 %

Procedure:
2-hydroxymethyl-3-hydroxypyridine (100.3 g, 620.7 mmol) was dissolved in acetone (1 L). Potassium carbonate (180 g, 1.3 mol) was added followed by benzyl bromide (127 g, 745 mmol). The mixture was heated at reflux for 48 hours. The resultant mixture was cooled to room temperature and filtered through celite. The filter cake was washed with acetone (1 L). The combined filtrate was concentrated in vacuo to provide an orange oil. This oil was purified by silica gel column chromatography using 10-40% ethyl acetate/hexanes as eluant. The resultant tan solid was recrystallized from hexanes to provide the product (88.2 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (t, 1H), 7.4 (m, 5H), 7.15 (d, 2H), 5.1 (s, 2H), 4.8 (d, 2H), 4.3 (t, 1H).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([NH:17][C:18](=O)[O:19]C(C)(C)C)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7].F[C:27](F)(F)C(O)=O>ClCCl>[C:18]([NH:17][C@H:5]([CH2:4][O:3][CH:2]([F:25])[F:1])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:7])(=[O:19])[CH3:27]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Yield: 65.7 %

Procedure:
Tert-Butyl {(1R)-1-[(difluoromethoxy)methyl]-2-[(4-fluorobenzyl)amino]-2-oxoethyl}carbamate (400 mg, 1.1 mmol) was stirred with trifluoroacetic acid (1.5 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, mixed with acetic anhydride-pyridine (1:1, 6 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-3-(difluoromethoxy)-N-(4-fluorobenzyl)propanamide (220 mg, 65.7%) as a white solid. Mp: 162.7° C. 1H NMR (300 MHz, CDCl3): (ppm) 7.24 (dd, 2H), 7.03 (t, 2H), 6.78 (w, 1H), 6.35 (d, 1H), 6.24 (wt, 1H), 4.71 (m, 1H), 4.44 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O1CCOCC1.[NH4+].[OH-]>C(OCC)C>[C:8]1([Sn:18]([CH3:20])([CH3:19])[CH3:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:7]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[Sn](C)(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
tert-Butyllithium (12.5 ml, 21.25 mmol, 1.7M in pentane) is added dropwise to a stirred solution of 2-bromonaphthalene (2 g, 9.66 mmol) in anhydrous diethyl ether (40 ml) under argon at -78° C. The solution is stirred for 15 min and then treated with a 2.71M solution of trimethyltin chloride in dioxane (4.63 ml, 12.55 mmol). The heterogeneous mixture is warmed to room temperature, diluted with diethyl ether (150 ml) and treated with 10% NH4OH solution (90 ml) for 5 minutes. The two phases are separated and the organic phase is washed with water followed by brine, dried over MgSO4 and concentrated to dryness. The oil is purified by flash silica chromatography (hexane) to give napthyltrimethyl stannane (2.69 g, 95.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2cccc(F)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(F)c1
Yield: 84.1 %

Procedure:
To a solution of (4RS,5SR)-5-(3-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (7.0 g, 20.6 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (12.9 ml, 103 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (5.43 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH2:22])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH2:16])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18].[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>CC(N(C)C)=O>[Br:23][CH:24]([CH3:28])[C:25]([NH:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][NH:22][C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:5](=[O:19])[C:6]1[C:14]([I:15])=[C:13]([NH:16][C:25](=[O:26])[CH:24]([Br:23])[CH3:28])[C:12]([I:17])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:18])=[O:26]
Reactant: NCCN(CCN)C(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(Br)C(=O)Br
Solvent: CC(=O)N(C)C
Product: CC(Br)C(=O)NCCN(CCNC(=O)C(C)Br)C(=O)c1c(I)c(NC(=O)C(C)Br)c(I)c(C(=O)O)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (77.8 mmol) of N,N-bis-(2-aminoethyl)-5-amino-2,4,6-triiodoisophthalic acid amide is dissolved in 500 ml of dimethylacetamide, and 75.5 g (350 mmol) of 2-bromopropionic acid bromide (Aldrich) is added in drops over 15 minutes at 0° C. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate, and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([NH2:24])(=[O:23])[CH:20]([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: CC(C)C(N)=O
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C(C)C)c1
Temperature: 90 °C
Yield: 92.4 %

Procedure:
A mixture of Example A3 (0.50 g, 1.882 mmol), isobutyramide (0.656 g, 7.53 mmol), Cs2CO3 (0.920 g, 2.82 mmol), and X-phos (0.045 g, 0.094 mmol) in dioxane (10 mL) was sparged with Ar, treated with Pd2(dba)3 (0.086 g, 0.094 mmol), sparged again with Ar and heated at 90° C. for 20 h. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration. The filtrate was washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (550 mg, 92%). MS (ESI) m/z: 317.1 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1O)=[O:6])([CH3:3])[CH3:2].C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]([NH:4][C:5]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:35])=[C:13]([NH:16][C:17]([C:19]3[N:20]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[N:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=3)=[O:18])[CH:14]=2)[CH2:9][CH:8]1[F:43])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)C1c2cc(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc2CC1F
Reaction time: 2 h

Procedure:
A solution of 5-chloro-2-hydroxy-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide (100 mg, 0.18 mmol) in dichloromethane is cooled to 0° C., treated with diethylaminosulfurtrifluoride (29 mg, 1.8 mmol), stirred for 2 hours, and treated with water. Organic layer is separated, dried over sodium sulfate, filtered, and evaporated. Purification by chromatography using ethyl acetate/hexane as eluent gives 5-chloro-2-fluoro-6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-indane carboxylic acid isopropylamide as solid; LC/MS: 542/544 (M+1)+; m.p.: 98-99° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[C:28]([F:32])[CH:29]=[C:30]([F:31])[C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[F:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]2[O:24][N:23]=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:21][CH2:20]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Temperature: 25 °C

Procedure:
trans-(4-{2-[4-(5,7-Difluoro-benzo[d]isoxazol-3-yl)-piperazin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (2.59 g, 5.6 mmol) was dissolved in CH2Cl2 (40 ml) and 4 N HCl in dioxane (27.9 ml, 112 mmol) was slowly added. The resulting mixture was stirred over night at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 1.98 g (88%) as a white solid. m/z=365.2 ([M+H]+).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31](OC)=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21]CC(C)C)[C:11]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:44])C1C=CC=CC=1>>[C:1]([O:9][C:10]1([CH2:27][C:28]2[CH:33]=[C:32]([O:44][CH3:37])[CH:31]=[CH:30][C:29]=2[OH:36])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Product: CCN1C(=O)C(Cc2cc(OC)ccc2O)(OC(=O)c2ccccc2)c2cc(C)ccc21

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-4-methoxyphenyl)carbonate. 1H-NMR δ 8.05 (d, 2H), 7.58 (t, 1H), 7.45 (t, 2H), 7.13 (m, 2H), 6.8 (d, 1H), 6.65 (m, 2H), 6.03 (d, 1H), 5.87 (bs, OH), 3.78 (m, 1H), 3.67 (d, 1H), 3.52 (m, 1H), 3.39 (s, 3H), 3.29 (d, 1H), 2.32 (s, 3H), 0.92 (t, 3H). Calculated mass for C26H25NO5 431.17. Observed 454.1 (M+Na).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25]>C1COCC1>[CH2:21]([O:20][C:18]([C:14]1[S:13][C:17]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cccs1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C(O)C(C)C)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
A solution of i-Pr2NH (1.26 mL, 9.20 mmol) in THF (35 mL) at −78° C. is treated with n-BuLi (5.6 mL, 1.6M, 9.0 mmol) over the course of 3 minutes. The solution is warmed to rt for 10 min., then recooled to 78° C. Ethyl 2-thiophene carboxylate (1.00 mL, 7.44 mmol) is added dropwise and the resulting solution is stirred for 15 min., then isobutyraldehyde (0.81 mL, 9.14 mmol) is added and the reaction is warmed to rt and stirred overnight. The resulting solution is quenched with saturated NH4Cl (25 mL) and extracted with EtOAc (2×50 mL). Combined extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 30% EtOAc giving 5-(1-hydroxy-2-methyl-propyl)-thiophene-2-carboxylic acid ethyl ester (1.25 g, 73%) as a yellow oil. MS (ES): 211.1 [M+H−H2O]+.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1>C(#N)C.O>[OH:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:15]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)ncc1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.7 %

Procedure:
To a solution of sodium iodide (0.513 g) in acetonitrile (4 mL) was added chlorotrimethylsilane (0.434 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, a solution of 5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.185 g) in acetonitrile (6 mL) was added at room temperature. The reaction mixture was heated under reflux for 3 hr, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give the title compound (0.317 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Reactant: CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)NCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step c (55 mg) was dissolved in methylene chloride (2 ml), added with triethylamine (56 μl and added with n-heptanoyl chloride (39 μl, produced by Tokyo Kasei Kogyo). The reaction mixture was stirred at room temperature for 30 minutes, diluted with methylene chloride, washed with saturated aqueous sodium hydrogencarbonate, dried over magnesium sulfate and concentrated. The resulting residue was applied on a silica gel column and eluted with hexane/ethyl acetate (3:2) to obtain the title compound (47.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([OH:25])=[N:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:16][C:17]=2[CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].Br[CH2:34][CH2:35][O:36][CH3:37]>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]([O:25][CH2:34][CH2:35][O:36][CH3:37])=[N:14][C:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:16][C:17]=2[CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nc(O)c1C(=O)NCc1cccc(F)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 200 mg (0.58 mmol) N-[(3-Fluorophenyl)-methyl]-2-hydroxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 19) in DMF (8 ml) 15 mg (0.64 mmol, 60% w/w in mineral oil) NaH were added, followed by stirring at RT for 30 min. Then 88 mg (0.64 mmol) 2-bromoethyl-methylether were added and the RM was heated to 50° C. for 16 h. Subsequently water (10 ml) and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:7) provided 90 mg (0.22 mmol, 39%) N-[(3-Fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 21). [M+H]+404.2.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13]=2[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Temperature: 0 °C

Procedure:
2-p-Methoxyphenyl-3-p-methylbenzoylbenzofuran (4.9 g., 0.014 mol.) was combined with 50 g. of freshly distilled pyridine hydrochloride and the mixture was heated at 180°-190° for 4.5 hours. The hot mixture was poured with stirring onto an ice-5% aqueous hydrochloric acid mixture and the precipitate formed was extracted into ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure to give 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(O)(=O)C.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.CO>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 moles) from Step (1) is dissolved in the first distillate from Step (a) along with 50 L of tetrahydrofuran, cooled to −75° C.±20° C., and optionally diluted with 25 L of methanol, and 10 kg of acetic acid. Sodium borohydride (8 kg) as a solution in methanol and aqueous sodium hydroxide is added slowly. After the addition, the reaction mixture is warmed to 0° C.±25° C. The reaction mixture is quenched by the addition of 10 kg of acetic acid and 20 L of methanol and concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the aqueous layer separated. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation affording crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.