Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[K].CC(C)([O-])C.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CS(C)=O.O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCBr
Reactant: CCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
0.35 g of the crude 2-(3-fluoro-4-hydroxyphenyl)-5-(4-n-hexylphenyl)pyrazine was dissolved in 3 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran. To the resulting solution, was added 0.12 g of potassium-tertbutoxide. The obtained mixture was stirred at room temperature for 30 minutes and then 0.22 g of n-nonyl bromide was added thereto. The mixture was stirred at room temperature for additional five hours. Then the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and with a 30% aqueous solution of sodium hydroxide and then repeatedly washed with water until the washing liquor showed a pH value of approximately 7. Then the ethyl acetate phase was dehydrated over sodium sulfate and the solvent was distilled off. Thus 0.48 g of a crude reaction product was obtained. The crude reaction product was purified by silica gel column chromatography and recrystallized from acetone. Thus 0.41 g of the title compound was obtained. Phase transition temperature: 93.0° C. (C→Sc);
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH2:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]1[NH2:57]>>[CH2:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]1[NH:57][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NC1Cc2ccccc2C1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NC1Cc2ccccc2C1
Yield: 84 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 2,3-dihydro-1H-inden-2-amine, the title compound was obtained as an off-white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.15 (m, 6H), 7.07-6.98 (m, 2H), 6.06 (s, 1H), 5.90 (d, J=7.2 Hz, 1H), 4.92-4.80 (m, 1H), 4.42 (s, 2H), 3.84-3.74 (m, 2H), 3.47-3.32 (m, 4H), 2.90 (d, J=4.7 Hz, 1H), 2.85 (d, J=4.7 Hz, 1H), 2.47 (s, 3H); MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:5][CH:4]1[C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[CH:7]=1.[FH:16].F.F.C(N(CC)CC)C>>[F:16][CH:4]([C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[CH:7]=1)[CH:3]([OH:5])[CH2:2][OH:1]
Reactant: F
Reactant: O=C1OCc2cc(C3OC3CO)ccc21
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C(F)C(O)CO)ccc21
Temperature: 25 °C

Procedure:
A solution of 5-[3-(Hydroxymethyl)oxiran-2-yl]-2-benzofuran-1(3H)-one (1.2 g, 5.8 mmol) in TEA.3HF (triethylamine trihydrofluoride) (10 mL) was warmed to 110° C. for 8 hours, and then cooled to RT. The reaction mixture was extracted with EtOAc (200 mL), washed with NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was separated and purified with prep-TLC to give product the title product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:20]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:15]([OH:20])[OH:16])[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](C(O)O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-tetrahydropyran-2-one (150 mg, 0.58 mmol) and Dess-Martin periodinane (380 mg, 0.86 mmol) in CH2Cl2 (15 mL) is stirred at ambient temperature for 3 hours. The mixture is diluted with tBuMeO (20 mL), washed with saturated Na2S2O3 solution, saturated NaHCO3 solution, dried (MgSO4) and concentrated to give 139 mg (87%) of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dihydroxy methyl)tetrahydro-2H-pyran-2-one as white powder which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[CH3:24][C:21]([CH3:25])([CH2:22][CH3:23])[CH:20]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[O:26][CH3:30]
Reactant: CI
Reactant: CCC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 66.62A (0.39 g, 1.1 mmol) in DMF (5 mL), was added NaH (0.034 g, 1.4 mmol). The mixture was stirred at room temperature for 10 minutes and then iodomethane (0.20 mL, 3.2 mmol) was added. The mixture was stirred at room temperature for 60 minutes and then it was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:9 EtOAc/hexane) and gave 66.62B, colorless oil, in 64% yield (260 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7]2.C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:18][C:17](=[O:19])[CH2:16][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1
Reactant: COc1cc2c(cc1OC)CN(CC(=O)O)CC2
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred suspension of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride (822 mg, 2.86 mmol) in anhydrous DCM (30 ml), DMAP (523 mg, 4.28 mmol) and EDC (712 mg, 3.71 mmol) were added. The mixture was stirred at room temperature for 1 hour and then (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.200 g, 2.86 mmol) was added. The mixture was stirred at room temperature for 48 hours, then diluted with DCM and washed with 1N HCl, dried over Na2SO4 and evaporated. The desired product was first purified by flash chromatography on silica gel (DCM:MeOH 10:0.2) followed by preparative HPLC (Method 2). The title compound was obtained (1.354 g, 73% yield). MS/ESI+ 653.18 [MH]+; [αD]=−43.91, c=0.69 in MeOH); 1H NMR (300 MHz, DMSO-d6) δ ppm 8.60 (s, 2H) 7.20 (d, 1H) 7.13 (d, 1H) 7.01 (dd, 1H) 7.07 (t, 1H) 6.64 (s, 1H) 6.58 (s, 1H) 6.10 (dd, 1H) 3.81-3.99 (m, 2H) 3.70 (s, 3H) 3.71 (s, 3H) 3.35-3.56 (m, 4H) 3.19-3.28 (m, 2H) 2.57-2.81 (m, 4H) 1.11-1.34 (m, 1H) 0.49-0.67 (m, 2H) 0.16-0.44 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:14]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution of 2-fluoro-6-nitrophenol (10.0 g, 63.6 mmol) in DMF (25.0 mL) was charged with methyl iodide (5.94 mL, 95.5 mmol) and potassium carbonate (13.2 g, 95.5 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (25 mL), washed with Brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a brown oil, 11.0 g (101% yield). 1H NMR (CDCl3, 400 MHz): δ=4.08 (d, J=2.02 Hz, 3 H), 7.14 (td, J=8.34, 4.80 Hz, 1 H), 7.35 (ddd, J=10.74, 8.34, 1.64 Hz, 1 H), 7.58 (dt, J=8.27, 1.55 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 62.2 %

Procedure:
A mixture of 1.0 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.18 g of 2-methylpiperazine and 10 ml of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 28% aqueous ammonia. The solution was neutralized with a 10% aqueous solution of acetic acid and cooled with ice. The crystals were collected by filtration, dissolved in a 10% aqueous solution of acetic acid, treated with activated charcoal, adjusted to pH 8-9 with 29% aqueous ammonia, and cooled with ice. The crystals were collected by filtration and washed successively with water and ethanol to give 0.80 g of 5-amino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([C:28]([F:31])([F:30])[F:29])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([C:28]([F:31])([F:30])[F:29])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)nc2C(F)(F)F)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C(F)(F)F)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A mixture of methyl 4-chloro-2-[(3-hydroxypropyl)amino]-3-({[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]carbamothioyl}amino)benzoate (1.85 g, 3.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.79 g, 4.12 mmol) and triethylamine (0.57 mL, 4.16 mmol) in tetrahydrofuran (20 mL) was stirred at 50° C. for 3 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (1.50 g, 3.27 mmol, 87%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:58])([NH:54][CH:55]([CH3:57])[CH3:56])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:9]=[CH:10][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:58])([NH:54][CH:55]([CH3:56])[CH3:57])=[O:53])=[CH:49][CH:50]=6)=[CH:12][CH:13]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CC(C)NS(C)(=O)=Nc1ccc(Br)cc1
Product: CC(C)NS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-(propan-2-yl)-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.12 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].CO.C(=O)([O-])[O-].[NH4+:43].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 78 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 78% of theory, C26H27N7O3 (485.6) Rf value: 0.31 (silica gel; dichloromethane/methanol=5:1) ##EQU43##
Reaction SMILES: N1CCCCC1.[C:7]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=O)#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1C=CC=CC=1>O>[C:7]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=[CH:29][C:30]([OH:32])=[O:31])#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCCCCCC#Cc1cnccc1C=O
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC#Cc1cnccc1C=CC(=O)O
Temperature: 80 °C
Yield: 57.3 %

Procedure:
Piperidine (0.1 ml) was added to a stirred, homogeneous mixture of 3-(1-tridecynyl)pyridine-4-carboxaldehyde (0.73 g, 2.56 mmole, from Example 1), malonic acid (523 mg, 5.12 mmole) and pyridine (5 ml) under nitrogen and the mixture was heated to 80° C. for 1 hour. After then refluxing for an additional 3 hours the mixture was cooled, added to water (40 ml) and acidified to pH 1. The resulting precipitate was washed with water, dried and recrystallised from methanol to give 0.48 g (57%) of the title compound, mp 177°-178° C., νmax (mull) 2450 (broad), 1870 (broad), 1690, 1625, 1595 cm-1 ; δ(DMSO) 0.84 (3H, distorted t, terminal CH3), 1.23 (14H, m, alkylene chain), 1.45 (2H, m, CH2 (CH2)2C≡C), 1.59 (2H, m, CH2CH2C≡C), 2.54 (2H, t, J 6.6 Hz, CH2C≡C), 6.88 (1H, d, J 16 Hz, C=CHCO), 7.82 (1H, d, J 5 Hz, C-5H), 7.83 (1H, d, J 16 Hz, Ar CH=C), 8.52 (1H, d, J 5 Hz, C-6H), 8.64 (1H, s, C-2H), 12.81 (1H, s, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: N#CCOc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of crude (3-aminophenoxy)acetonitrile (ca 12.1 g) in toluene (50 mL) was added pyridine (6.6 mL) and methanesulfonyl chloride (6.3 mL) at 5° C. and the resultant mixture was warmed to ambient temperature. After 2 h, the crude product mixture was partitioned between 1N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic solution was washed with water, then concentrated with concomitant replacement of solvent with isopropanol. After cooling the resultant mixture to 5° C., the white crystalline product was collected, rinsed with cold isopropanol, and dried to afford 12.14 g (65.1% yield based on cyanomethyl tosylate) of N-(3-cyanomethoxyphenyl)methanesulfonamide (99.8% pure by HPLC). This material could optionally be recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>C(Cl)Cl.[OH-].[Na+]>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:37])[N:21]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:30])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: O=C(Cl)CCCCCl
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCCl

Procedure:
Compound (5) (2.44 g, 5.96 mmol) was reacted with 5-chlorovaleryl chloride (1.13 g, 7.29 mmol) in CH2Cl2 (150 mL) and 1N NaOH (200 mL) by the procedure used for (3). Silica gel column chromatography, eluting with 3% EtOH/CHCl3, gave (6) in quantitative yield as an oil: NMR δ 1.50-1.87 (m, 12H), 2.23-2.53 (m, 6H), 3.47 (t, 2H, J=6), 3.60 (t, 4H, J=6), 4.77 (s, 4H) , 7.33 (s, 10H) . Anal. (C29H38ClN3O4) C, H, N.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.FC(F)(F)[C:14](O)=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>O>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[CH:14]=[O:15]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4.91 g of 4-(trifluoromethyl)phenol and 68 ml of trifluoroacetic acid was gradually added 4.67 g of hexamethylenetetramine at room temperature. This mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, then 35 ml of water and 19 ml of 50% sulfuric acid were added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted three times with diethyl ether. The organic layers were combined and sequentially washed with 5 M hydrochloric acid and water. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.7 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7][OH:8].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>O1CCOCC1>[CH3:36][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34](=[O:35])[O:8][CH2:7][C:6]2[N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=3[Cl:22])[C:4]([CH3:23])=[N:3][C:2]=2[Cl:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CO)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: C1COCCO1
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2COC(=O)NS(=O)(=O)c2ccc(C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (150 mg) was dissolved in 1,4-dioxane (1.5 ml) and p-toluenesulfonyl isocyanate (99 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. To the residue was added ethanol (5 ml) and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate (2 ml), and hexane (13 ml) was added on an oil bath at 70° C. The mixture was allowed to cool and the precipitated crystals were collected by filtration. The crystals were dried by heating under reduced pressure to give (4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazol-5-yl)methyl N-(4-methylbenzenesulfonyl)carbamate (176 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:5])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Yield: 37 %

Procedure:
Using the procedure described in Example 55, Part B, 2-amino-N-(4-methoxyphenyl)benzamide (1.06 g, 4.36 mmol) was reacted with 4-acetylbenzoic acid to yield 292 mg (37%) of the title compound as a light yellow solid.