Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:22])([F:21])[CH2:12]OS(C(F)(F)F)(=O)=O.[C:23]1([S:29]([N:32]2[C:36]3[CH:37]=[N:38][C:39]([C:48]#[N:49])=[C:40]([CH2:41][CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[C:35]=3[C:34]3[CH:50]=[CH:51][CH:52]=[N:53][C:33]2=3)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([S:29]([N:32]2[C:36]3[CH:37]=[N:38][C:39]([C:48]#[N:49])=[C:40]([CH2:41][CH:42]4[CH2:47][CH2:46][N:45]([CH2:12][C:11]([F:10])([F:21])[F:22])[CH2:44][CH2:43]4)[C:35]=3[C:34]3[CH:50]=[CH:51][CH:52]=[N:53][C:33]2=3)(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1CC1CCNCC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1CC1CCN(CC(F)(F)F)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
N,N-Diisopropylethylamine (100 mg, 0.77 mmol) and trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (100 mg, 0.43 mmol) in THF (1 mL) were added to a solution of 9-benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile in THF (4 mL) and resultant mixture stirred at ambient temperature for 30 min. The mixture was then filtered through a 2 g Sill SPE cartridge, eluting with THF. The THF washings were concentrated in vacuo and the resultant residue was purified by flash chromatography (silica, 2 g column, Si H SPE, 0-20% ethyl acetate in DCM) to afford title compound as a white solid (0.16 g, 85%). 1H NMR (CDCl3, 400 MHz): 9.81 (d, J=2.9 Hz, 1H), 8.81-8.75 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=7.9 Hz, 2H), 7.66-7.59 (m, 1H), 7.55-7.45 (m, 3H), 3.35-3.27 (m, 2H), 3.02-2.88 (m, 5H), 2.32-2.21 (m, 2H), 1.86-1.60 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][CH:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]2=[O:32])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure A above using 3,5-difluorophenylacetic acid (Oakwood) and 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-X), the title compound was prepared as a solid having a melting point of 236-239° C. The reaction was monitored by tlc on silica gel (Rf=0.7 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].Cl[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CC(C)=CCCl
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1c(I)cc(C(C)O)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)-4-iodo-pyridine (2.99 g, 10 mmole) was dissolved in 15 ml dry dimethylformamide in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C., was treated with sodium hydride (400 mg, 10 mmole), and the mixture was stirred 1 h at room temperature. The mixture was treated with 1-chloro-3-methyl-2-butene (1.2 ml, 11 mmole) and sodium iodide (150 mg, 1 mmole) and the reaction mixture was stirred 18 h at room temperature. The reaction mixture was diluted with 100 ml ethyl acetate, was washed with 4×50 ml 50% saturated 1:1 sodium chloride/sodium bicarbonate, and was dried over anhydrous potassium carbonate. The dried organics were concentrated in vacuo to a yellow oil which was crystallized from 25 ml hexane to give 3.2 g (87%) of 2-chloro-3-(3-methyl-2-butenyloxy)-6-(1-hydroxyethyl)-4-iodo-pyridine as an off-white solid, Melting Point: 80-81° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].Cl>O.CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-2-nitrotoluene (7.0 grams, 45 mmol), 4-methoxyphenol (6.2 grams, 50 mmol) and dimethylformamide (45 mL) was added potassium tert-butoxide (5.1 grams, 45 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water, acidified with 1 M aqueous hydrochloric acid, and the aqueous phase was extracted 3 times with ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-20% ethyl acetate-hexane afforded 3.5 grams of 4-(4-methoxy-phenoxy)-2-methylnitrobenzene as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.Cl.Cl.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>CC(O)C>[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[N:7]([CH2:8][C:9]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=3[C:11]#[N:12])[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=2)[CH2:25]1
Reactant: N[C@@H]1CCCNC1
Reactant: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Agent: Cl
Solvent: CC(C)O
Product: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 60 °C

Procedure:
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH:18]=1>>[N:17]1([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:5]=[N:4][CH:3]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Product: Fc1ccc(CNc2cncc(-n3cnc4ccccc43)n2)cc1
Yield: 52.7 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (240 mg, 1.01 mmol) and benzimidazole (130 mg, 1.1 mmol) furnished the product (170 mg, 53%).
Reaction SMILES: O/[N:2]=[CH:3]/[C:4]1[S:8][CH:7]=[C:6]([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH:5]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O>[C:11]([CH2:10][CH:9]([C:6]1[CH:5]=[C:4]([C:3]#[N:2])[S:8][CH:7]=1)[N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)#[N:12]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(/C=N/O)c4)c3)ncnc21
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C#N)c4)c3)ncnc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(5-[(E)-(hydroxyimino)methyl]-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in pyridine (1 mL, 0.01 mol), methanesulfonyl chloride (100 μL, 0.001 mol) was added. The mixture was stirred at 60° C. for 2 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 0.1 N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 4-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+1).
Reaction SMILES: [Li+].[Cl-].[Br:3][C:4]1[CH:5]=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Br:19]C(Br)(F)C(F)(F)F>C1COCC1>[Br:3][C:4]1[C:5]([Br:19])=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(Br)Br
Reactant: CC(C)(C)OC(=O)c1c(F)ncc(Br)c1F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)nc(Br)c(Br)c1F
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Into a solution of TMPMgCl LiCl (1.0 M×6.8 mL, 6.8 mmol) in THF (5.0 mL) at −45° C. was added dropwise a solution of tert-butyl 5-bromo-2,4-difluoronicotinate (1.32 g, 4.5 mmol) in THF (5.0 mL). The mixture was stirred for 15 min then dibromotetrafluoroethane (1.0 mL, 6.8 mmol) was added. After 15 min at −45° C., the temperature was allowed to rise to room temperature. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica chromatography (0-10% ethyl acetate in hexanes) to give tert-butyl 5,6-dibromo-2,4-difluoronicotinate (1.29 g, 77%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])=[CH:9][C:8]=1[C:27]1[CH:28]=[N:29][CH:30]=[N:31][CH:32]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)=[O:12])=[CH:9][C:8]=1[C:27]1[CH:32]=[N:31][CH:30]=[N:29][CH:28]=1
Reactant: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(O)c(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
BBr3 1 M in DCM (3.85 mL, 3.85 mmol) was added dropwise to a stirred solution of 4-methoxy-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (100 mg, 0.257 mmol) in DCM (1.027 mL) at −70° C. and then stirred at RT for 2.5 days and under reflux for 2 days. The RM was treated with MeOH and the solvent was evaporated off under reduced pressure to give the crude product was purified by preparative HPLC (Condition 8, 50% for 0.2 min then 50% to 100% in 15 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.29 min, m/z=376.0 [M+H]+, m/z=374.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.13 (d, J=8.6 Hz, 1H) 7.36 (d, J=8.6 Hz, 2H) 7.87 (d, J=9.0 Hz, 2H) 7.93 (dd, J=8.6, 2.2 Hz, 1H) 8.09 (d, J=2.0 Hz, 1H) 9.09 (s, 2H) 9.17 (s, 1H) 10.24 (s, 1H) 10.82 (br. s, br. s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.O>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: C#CCC1=CC(O)CC1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example B in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with water, washed with diethyl ether, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult C-11), ##STR9##
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(S(C)(=O)=O)c2)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylsulfonylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (16%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH3:19])[CH:9]([C:14](=O)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:25]>C(O)(=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:15][C:14]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:18]([CH3:19])[N:25]=1
Reactant: [NH4+]
Reactant: COC(=O)C(C(C)=O)C(CC(C)=O)c1ccc(F)cc1
Agent: Cl[Fe](Cl)Cl
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(F)cc2)cc(C)nc1C

Procedure:
A suspension of 28.0 g (100 mmol) of methyl 3-(4-fluorophenyl)-2-(1-oxoethyl)-5-oxohexanoate (=Xa from Example 1), 120 g of ammonium acetate and 120 g of iron(III) chloride hexahydrate in 1000 ml of glacial acetic acid was refluxed, with stirring, until the precursor could no longer be detected by thin-layer chromatography (4 h). The mixture was cooled and then filtered, and the solid residue was washed with ethanol and toluene. The filtrate was evaporated and then the residue was suspended in water, the pH was adjusted to 8-9 by addition of solid sodium bicarbonate, and the mixture was extracted several times with ether. The combined extracts were washed with saturated NaCl, dried over MgSO4 and evaporated. Purification of the crude product by column chromatography (silica gel, cyclohexane/ethyl acetate 2:1) provided 23.6 g (91%) of XVa in the form of white crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][C@H:4]([NH:21]C(=O)OC(C)(C)C)[CH:5]([C:7]1[N:8]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[N:10][CH:11]=1)[OH:6]>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C@H:4]([CH:5]([C:7]1[N:8]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[N:10][CH:11]=1)[OH:6])[CH2:3][CH:2]([CH3:29])[CH3:1]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)c1cncn1COCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(O)c1cncn1COCc1ccccc1

Procedure:
A solution of the product from part (e) (0.11 g., 0.26 mmole) in dichloromethane (2 ml.) and trifluoroacetic acid (2 ml.) is stirred at 10° for 30 minutes and at room temperature for 10 minutes. The reaction mixture is evaporated in vacuo and then concentrated from acetonitrile (three times) to give α-[(S)-1-amino-3-methylbutyl]-3-[(phenylmethoxy)methyl]-3H-imidazole4-methanol which contains 2.5M of trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[CH2:15]1[O:17][C@H:16]1[CH2:18][Cl:19]>C(O)(C)C>[Cl:19][CH2:18][C@H:16]([OH:17])[CH2:15][NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: ClC[C@H]1CO1
Solvent: CC(C)O
Product: O[C@@H](CCl)CNc1ccc(N2CCOCC2)c(F)c1
Yield: 99.3 %

Procedure:
3-Fluoro-4-morpholinyl aniline (39 g) is mixed with R-epichlorohydrin (18.5 g), isopropyl alcohol (200 ml) is added and heated for 16 hours at reflux temperature. The solvent is distilled to give 57 gm of N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42]2[O:44][CH2:43]2)=[CH:36][CH:35]=1>CO>[OH:44][CH:42]([CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[CH2:43][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Reactant: COc1ccc(OCC2CO2)cc1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccc(OC)cc1
Yield: 30 %

Procedure:
In 200 ml of methanol were dissolved 2 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.84 g of glycidyl 4-methoxyphenyl ether, and the solution was refluxed under heating for 3 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from a mixture of methanol and ethyl ether to give 0.85 g of dimethyl 4-[2-[4-[2-hydroxy-3-(p-methoxyphenoxy)propylamino]butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccc1)O2
Yield: 74.7 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 362 mg CDI (2.23 mmol) and 235 mg benzylamine (2.20 mmol) produced 507 mg of N-benzyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a brown oil.
Reaction SMILES: C(NC[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[CH3:11][C:12]([C:15]1[CH:16]=[C:17]([S:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[S:32][CH2:33][C:34]([N:36]([CH3:45])[CH2:37][CH2:38]C2C=CC=CN=2)=[O:35])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])[CH3:13]>>[CH3:22][C:21]([C:19]1[CH:18]=[C:17]([S:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[S:32][CH2:33][C:34]([N:36]([CH2:37][CH3:38])[CH2:45][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:35])[CH:16]=[C:15]([C:12]([CH3:13])([CH3:11])[CH3:14])[CH:20]=1)([CH3:23])[CH3:24]
Reactant: CCNCc1ccncc1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CCN(Cc1ccncc1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Substituting 4-(ethylaminomethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-ethyl-N-(4-pyridinylmethyl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]Cl)[CH3:13].C[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCC(CC)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C(=O)OC)cc1

Procedure:
A mixture of 51.7 g (0.34 mol) of 4-hydroxybenzoic acid methylester, 500 ml of dimethyl formamide, 60 g (0.40 mol) of 2-ethylhexylchloride and 21.8 g (0.40 mol) of sodium methylate was heated for 7 hours to boiling temperature and, after cooling and removal of the sodium chloride by filtration, was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride and chromatographed (eluent: methylene chloride) on silica gel (Merck) to yield 43 g (48% of the theoretical) of 4-(2-ethylhexyloxy)benzoic acid methylester. A refractive index of
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[C:18]([CH3:25])=[C:17]([N+:26]([O-:28])=[O:27])[C:16]=2[CH3:29])[CH2:12][C:11](=[O:30])[C:10]=1[C:31](=O)[CH2:32][CH3:33]>C(O)C>[CH2:2]([O:4][N:5]=[C:31]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[C:16]([CH3:29])=[C:17]([N+:26]([O-:28])=[O:27])[C:18]([CH3:25])=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=2[CH3:21])[CH2:12][C:11]=1[OH:30])[CH2:32][CH3:33])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c([N+](=O)[O-])c(C)c([N+](=O)[O-])c2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c([N+](=O)[O-])c(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
Ethoxyaminehydrochloride (0.36 g, 3.7 mmole) and then sodium hydroxide (0.15 g, 3.7 mmole) were added to a solution of 3-hydroxy-5-(2,4,6-trimethyl-3,5-dinitrophenyl)-2-propionylcyclohex-2-en-1-one (1.0 g; 2.7 mmole) in absolute ethanol (80 ml). The mixture was stirred at room temperature for a period of 24 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with water and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the product recrystallized from ethanol to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3,5-dinitrophenyl)cyclohex-2-en-1-one (0.45 g; 39.8%) as a white solid, mp 170° C.