Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][NH:5][CH2:6]2.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=2)[N:12]=1.C(N(C(C)C)CC)(C)C.N>O1CCOCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=3)[N:12]=1)[CH2:6]2
Reactant: CN1C2CCC1CNC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
A mixture of 8-methyl-3,8-diazabicyclo[3.2.1]octane (3.8 g, 30 mmol), 2-chloro-6-nitroquinoline (6.2 g, 30 mmol), diisopropylethylamine (10.5 ml, 60 mmol) and dioxane (100 ml) was stirred at reflux for 15 h. Aqueous ammonia (50 ml, 1 M) was added followed by extraction with dichloromethane (3×50 ml). Chromatography on silica gel with methanol:dichloromethane:aqueous ammonia (1:9:1%) as solvent gave the title compound as a solid. Yield 3.1 g (35%). Mp 152.1-154.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:14][C:15]1[N:16]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1ccc(OCCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCOc1ccc(C#N)cc1
Temperature: 0 °C
Yield: 75.9 %

Procedure:
There were dissolved, in 20 ml of dry N,N-dimethylformamide, 1.797 g of 4-(3-chloropropoxy)benzonitrile, 985 mg of 2-methylimidazole and 1 765 g of a 90% potassium t-butoxide, then the resulting solution was stirred at room temperature for 4.5 hours, poured into ice water, the resulting precipitates were filtered off and washed with water. The precipitates were recrystallized from a mixed solution of ethanol and water to give 1.682 g (yield 69.7%) of 4-[3-(2-methylimidazol-1-yl) propoxy]benzonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)COC21CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(C3)OCc3ccccc34)nn2)n1

Procedure:
The object product (82 mg, 41%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (120 mg), 3H-spiro[2-benzofuran-1,3′-pyrrolidine] (100 mg) and potassium carbonate (138 mg).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1)C1C=CC=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]2[C:18](=[O:19])[N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH:15]=[N:14][C:13]=2[CH:24]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)N=C[C@H]1CCCCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1O)N=C[C@H]1CCCCN1C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To (R,Z)-3-(benzyloxy)-2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one (241) (215 mg, 0.614 mmol) in 25 ml of CH2Cl2 at 0° C. was added 25 ml of CH2SO3H. The mixture was stirred at 0° C. for 10 min and then at RT for 2 h, diluted with CH2Cl2, neutralized with cold 1.0 M NaHCO3, extracted with CH2Cl2, dried over Na2SO4, filtered, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2 (1:15) to afford 122 mg (70%) of the title product. 1H NMR (CDCl3), 7.75 (d, 1H, J=5.7 Hz), 7.28 (s, 1H), 6.70 (s, 1H), 4.08 (m, 1H), 3.83 (d, 3H), 3.61 (m, 1H), 3.08 (m, 1H), 1.91 (m, 1H), 1.81 (m, 1H), 1.71-1.55 (m, 4H); 13C NMR 167.81, 163.46, 148.53, 145.71, 140.84, 121.23, 111.89, 111.39, 56.45, 49.83, 39.96, 24.71, 23.22, 18.60; MS m/z+283.7 (M+Na).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH:24]=[O:25])=[C:16]([F:21])[CH:15]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (93 mL, 0.66 mol) in dry tetrahydrofuran (300 mL) at −50° C. was added n-BuLi (212 mL of 2.M in hexanes, 0.53 moL) dropwise. The solution was stirred at room temperature for 30 mins. This solution was then added dropwise to a cooled (−75° C.) solution of 1-bromo-3,5-difluorobenzene (84 g, 0.44 mol) in dry tetrahydrofuran (900 mL). The mixture was stirred at −78° C. for one hour. Dry dimethylformamide (63.6 mL, 0.82 mol) was added and the mixture was stirred for two hours. The cooling bath was removed and the mixture was slowly warmed to room temperature. The mixture was diluted with diethyl ether and poured into cooled 1 M aqueous hydrochloric acid (1 L). The aqueous phase was extracted with diethyl ether. The combined phases were dried, filtered, and the solvent was removed in vacuo to give the crude product. The crude was re-crystallized with ethyl acetate and petroleum ether to afford the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:11]1)(C(C)(C)C)(C)C.[SiH](CC)(CC)CC.[CH3:35][C:36]1[O:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[N:38][C:37]=1[CH:48]=O>C(#N)C>[CH3:35][C:36]1[O:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[N:38][C:37]=1[CH2:48][O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:26])([CH3:27])[C:19]([OH:21])=[O:20])[CH2:11]1
Reactant: Cc1ccc(-c2nc(C=O)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2nc(COC[C@@H]3CCC[C@H](COC(C)(C)C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexyl-methoxy]-2-methylpropionate are added to a mixture of 20 mg of BiBr3 and 30 mg of HSiEt3 in 0.5 ml of acetonitrile. 38 mg of 5-methyl-2-p-tolyloxazole-4-carbaldehyde in 0.2 ml of acetonitrile are added dropwise, and the mixture is stirred at room temperature overnight. The resulting black solid is filtered and the filtrate is concentrated and taken up in 1 ml of trifluoroacetic acid. The solution is stirred at room temperature overnight. The solvent is distilled off under reduced pressure and the residue is purified by HPLC. This gives 3.4 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid as a colorless oil. C24H33NO5 (415.24); MS (ES−): 414.25 (M−H+).
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([CH:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[Li+].[Li+].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([C:9]1[N:8]2[C:12](=[CH:11][CH:10]=1)[CH:5]([C:3]([N:2]([CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])[CH2:6][CH2:7]2)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C(=O)C1CCn2cccc21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN(C(=O)C1CCn2c(C(=O)c3ccccc3)ccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (52 g, 216 mmol), lithium carbonate (24 g, 325 mmol, 1.5 equivalents), and toluene (155 mL) were heated to a reflux temperature of 100° C. to 105° C. Benzoyl chloride (37.5 g, 267 mmol, 1.25 equivalents) was added, and the entire reaction mixture was allowed to reflux for an additional 6 hours to 8 hours. Once the reaction was complete, the mixture was cooled to 70° C. to 80° C., lithium carbonate was filtered off and the filter cake washed with 100 mL warm toluene, and the combined filtrate and washings were seeded with a few crystals of 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide. Hexane (100 mL) was added to the warm toluene solution to effect crystallization, and the mixture was stirred for 30 minutes; then another 80 mL of hexane was added. The mixture was stirred for 1 hour to 2 hours at room temperature, cooled to 0° C. to 5° C., filtered, washed with hexane (150 mL) and dried under vacuum at 60° C. to 70° C. to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (61.7 g, 82.8% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:28])[O:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[CH:5]1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Cl:38])[N:32]=1>CN(C)C=O>[Cl:38][CH2:37][C:33]1[N:32]=[C:31]([CH2:30][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([C:17]3[C:16](=[O:27])[O:15][C:14](=[O:28])[C:13]=3[C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]([CH3:3])[CH:5]=3)=[CH:19]2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: ClCc1cccc(CCl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CCl)n4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reaction time: 65 h

Procedure:
Sodium hydride (60% dispersion in oil, 42 mg, 1.8 mmol), 3-(1-methyl-indol-3-yl)-4-(indol-3yl)-furan-2,5-dione (236 mg, 0.7 mmol) and dimethylformamide (8 mL) were stirred at room temperature for 1 h. The reaction mixture was cooled with ice and 2,6-bis-chloromethyl-pyridine (520 mg, 3.0 mmol) was added in one portion. Stirring was continued at room temperature for 65 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried with MgSO4, filtered and evaporated. Chromatography (ethyl acetate/heptane:50/50) gave the title compound, which was not pure. Further purification by Kugelrohr distillation (oil pump, 150° C.) afforded 156 mg of the sub-title product.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[O:12][C:28]([O:30][CH3:31])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CCc1ccc(O)c(C2CCCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 3-(3-cyclopentyl-4-hydroxy-phenyl)propanoate (857 mg, 3.27 mmol) and triethylamine (911 μL, 6.53 mmol) in dichloromethane (5 mL) under a N2 atmosphere at 0° C. was added methyl chloroformate (463 mg, 377 μL, 4.90 mmol) dropwise. After 1 h, the reaction mixture was partitioned between dichloromethane/water, separated and the aqueous layer was extracted once more with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 88% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.20 (d, J=1.7 Hz, 1H), 7.09-7.03 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.83 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.58 (m, 2H), 1.54-1.47 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH3:9])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13]>C(COC)OC>[CH3:1][C:2]([CH2:7][CH2:8][CH3:9])([CH2:5][O:6][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:3][O:4][S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(C)(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC(C)(COS(N)(=O)=O)COS(N)(=O)=O
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 10 g. (0.076 mol.) of 2-methyl-2-propyl-1,3-propanediol in 200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodium hydride followed by an additional 400 ml. of dimethoxyethane. After stirring overnight the suspension is cooled to 4° C and a solution of 31.2 g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethane is added dropwise. The resulting suspension is stirred overnight at room temperature. The mixture is then filtered, the filtrate is concentrated and the residue washed with heptane. The residue is then chromatographed through SilicAR, CC-7 and eluted with 25% acetone-chloroform. The solid obtained after removel of the solvent is crystallized from a mixture of ethyl acetate-hexane-methylene chloride to afford 2-methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol, m.p. 92°-94° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:28])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)([CH3:35])[CH3:34])[CH3:30].O>CN(C=O)C>[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:18]([CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:28])[CH:12]=2)[S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:38][CH:37]=1)([CH3:34])[CH3:35])[CH3:30]
Reactant: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)OC(C)(C)C)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
NaH (60% by weight in oil, 23 mg, 0.55 mmol) was washed with DMF (5 mL) and fresh DMF (5 mL) was added. The reaction was cooled to 0° C. and a solution of {3-[(pyridine-3-sulfonylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (184 mg, 0.486 mmol) in DMF (1 mL) was added. The reaction was stirred for 1 h and 2-(4-bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester (145 mg, 0.51 mmol) in DMF (1 mL) was added. The reaction was warmed to room temperature and was heated at 100° C. for 2 h. Water was added and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with water (5×), dried (MgSO4), filtered and concentrated. Flash chromatography (2:1 hexanes:EtOAc) provided 2-(4-{[(3-tert-butoxycarbonylmethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (138 mg). 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.76 (m, 1H), 7.97 (m, 1H), 7.40 (m, 1H), 7.19 (d, 2H), 7.13 (m, 1H), 7.02 (d, 2H), 6.76 (m, 1H), 6.67 (m, 2H), 4.41 (s, 2H), 4.33 (s, 4H), 4.10 (q, 2H), 1.52 (s, 6H), 1.49 (s, 9H), 1.17 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), thiomorpholine (3.0 g, 30 mmol), and K2CO3 (2.0 g, 14 mmol) in DMF (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The crude product that precipitated was collected by filtration, dried in vacuo, and purified by flash chromatography (silica gel, 4×15 cm, eluted with 20% ether in CHCl3) and recrystallized three times from methanol (MeOH) (0.49 g, 15%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:15]2[C:24]3[CH:23]=[CH:22][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:33])[C:16]=2[N:34]=1)(C)(C)C>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:35][CH2:36][O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:15]2[C:24]3[CH:23]=[CH:22][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:33])[C:16]=2[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Yield: 78.6 %

Procedure:
A solution of hydrochloric acid (5 mL of 1.5 M in ethanol) was added to a mixture of tert-butyl{4-[4-amino-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate (823 mg, 1.41 mmol) and ethanol. The reaction was heated at reflux for 30 minutes and became homogeneous. The solvent was removed under reduced pressure. The residue was recrystallized from methanol, isolated by filtration, washed with diethyl ether, and dried under reduced pressure to provide 534 mg of 2-(4-aminobutyl)-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as yellow crystals.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([N:11]([CH2:17][C:18]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>N.[Ni].CO>[N:1]1[C:10]2[CH:9]([N:11]([CH2:17][C:18]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(CN(CCCC#N)C2CCCc3cccnc32)nc2ccccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Reaction time: 16 h
Yield: 66.7 %

Procedure:
4-{(5,6,7,8-Tetrahydro-quinolin-8-yl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-ylmethyl]-amino}-butyronitrile (840 mg, 1.75 mmol) was dissolved in NH3 saturated MeOH (15 mL), treated with Raney nickel (excess), and placed under 45 psi H2 on a Parr shaker for 16 hours. The mixture was diluted with MeOH and filtered through Celite. The cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 50:2:1) afforded the desired amine (560 mg, 66%) as an orange syrup. 1H NMR (CDCl3) δ −0.10 (s, 9H), 0.81 (t, 2H, J=9.0 Hz), 1.43-1.50 (m, 4H), 1.59-1.76 (m, 1H), 1.86-2.09 (m, 2H), 2.08-2.23 (m, 1H), 2.56-2.71 (m, 4H), 2.76-2.85 (m, 2H), 2.41 (t, 2H, J=8.1 Hz), 4.07-4.12 (m, 3H), 5.71 (d, 1H, J=11.1 Hz), 7.37 (d, 1H, J=11.1 Hz), 7.05 (dd, 1H, J=7.5, 4.5 Hz), 7.21-7.29 (m, 2H), 7.34 (d, 1H, J=6.6 Hz), 7.40-7.45 (m, 1H), 7.71-7.76 (m, 1H), 8.58 (d, 1H, J=3.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC([C:31]([OH:33])=[O:32])(F)F.C(Cl)Cl>C(N(CC)CC)C>[NH:12]([C:31]([O:33][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:32])[C@H:13]([C:17]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:18])[C@@H:14]([CH3:16])[OH:15]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phe-Thr-Ser-OMe.TFA, 6.4 g., and BOC-Thr-HSE, 4.6 g., is suspended in 100 ml. of methylene chloride. The reaction mixture is adjusted to a pH of 7 by the addition of triethylamine. After stirring the reaction mixture for 11/2 hours at 25° C., the crude product is isolated by filtration. The crude product is partially dissolved in 50 ml. methanol and precipitated by the addition of 450 ml. of ether. The partially purified product is isolated by filtration and this precipation process is repeated four times to give substantially pure BOC-Thr-Phe-Thr-Ser-OMe, 6.04 g.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(-n2ccnc2)cc1
Solvent: ClCCl
Product: CC(Cl)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(1H-imidazol-1-yl)phenyl]ethanol (280 mg) in dichloromethane (6 ml) was added thionyl chloride (1 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give 1-(1-chloroethyl)-4-(1H-imidazol-1-yl)benzene. To a solution of 4-(tert-butoxycarbonyl)-2-piperazinone (300 mg) in DMF (20 ml) was added sodium hydride (57 mg) in oil, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added the above obtained 1-(1-chloroethyl)-4-(1H-imidazol-1-yl)benzene, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The organic layer was washed with water and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 4-(tert-butoxycarbonyl)-1-[1-[4-(1H-imidazol-1-yl)phenyl]ethyl]-2-piperazinone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11](Br)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[N:20]=[C:19]([CH3:21])[N:18]([C:22]2[C:26]([CH3:27])=[N:25][NH:24][C:23]=2[OH:28])[N:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:24]4[N:25]=[C:26]([CH3:27])[C:22]([N:18]5[C:19]([CH3:21])=[N:20][C:16]([CH3:15])=[N:17]5)=[C:23]4[O:28][C:11]=3[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(Br)C(=O)c1ccc2occc2c1
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc5occc5c4)c(C)oc23)n1

Procedure:
The title compound is prepared from 1-(benzofuran-5-yl)-2-bromopropan-1-one (step 3) and 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (Intermediate KF) analogously to Example 6.2. MS: m/z 348.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13]I>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CI
Product: COC(=O)c1cc(Br)cc(OC)c1

Procedure:
Methyl 3-bromo-5-hydroxybenzoate (O6.032; 2.52 g) was alkylated with methyl iodide and worked up analogously to the conditions of O5.043. 2.5 g of the title compound were obtained.