Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[Cl:17][C:18]1[N:19]=[C:20]([C:27]2[CH:48]=[CH:47][C:30]([O:31][CH2:32][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[C:29]([C:49]([F:52])([F:51])[F:50])[CH:28]=2)[C:21]2[CH:26]=[CH:25][NH:24][C:22]=2[N:23]=1.[O:53]1[CH2:58][CH2:57][CH:56](O)[CH2:55][CH2:54]1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[N:19]=[C:20]([C:27]2[CH:48]=[CH:47][C:30]([O:31][CH2:32][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:36][CH2:35]3)=[C:29]([C:49]([F:50])([F:51])[F:52])[CH:28]=2)[C:21]2[CH:26]=[CH:25][N:24]([CH:56]3[CH2:57][CH2:58][O:53][CH2:54][CH2:55]3)[C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Reactant: OC1CCOCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4c3ccn4C3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanomethylenetributylphosphorane (1.1 mL) was added to a mixture of tert-butyl 4-{2-[4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (1.0 g), tetrahydro-2H-pyran-4-ol (0.36 mL), and toluene (30 mL) at room temperature in a nitrogen atmosphere, and the reaction mixture was stirred overnight while heating to reflux. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=67:33 to 33:67), whereby tert-butyl 4-(2-{4-[2-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (1.04 g) was obtained as a yellow amorphous material.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CC(N(C)C)=O>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 71.5 %

Procedure:
In 20 ml of dimethylacetamide were dissolved 1.3 g of 5-fluorouracil. To this solution were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 180° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.22 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.43 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 86.4% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[CH3:14])[CH2:8]1.CCN(C(C)C)C(C)C.[N:29]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[C:30]=[O:31].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO.ClCCl>[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:4]=[C:3]([NH:2][C:30]([NH:29][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:31])[CH:18]=[C:17]([F:19])[CH:16]=2)[CH2:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC[C@@H](Oc2cc(N)cc(F)c2)C1
Reactant: O=C=Nc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H](Oc2cc(F)cc(NC(=O)Nc3cccnc3)c2)C1
Temperature: 10 °C

Procedure:
A 22 L 3-neck RBF equipped with a cooling bath, mechanical stirrer, thermocouple, and nitrogen bubbler was purged with nitrogen for at least ten minutes. The flask was charged with 1.441 kg (4.990 mol) 1-[(R)-3-(3-amino-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone HCl salt and 14.4 L (10 vol) dichloromethane. The solution was stirred, and 0.710 kg (5.489 mol) DIPEA was charged. The solution was cooled to 10±5° C. in an ice/brine bath. The reaction was charged with 0.659 kg (5.489 mol) 3-isocyanato-pyridine and the solution warmed to room temperature and stirred for three hours. The reaction was monitored by TLC (1:9 methanol:ethyl acetate/PMA stain) and HPLC. The reaction stirred at room temperature for five more hours, and another 0.009 kg (0.075 mol) 3-isocyanato-pyridine was added. The solution stirred for 15 more hours, and the reaction was deemed complete. The solution was poured into a 50 L extractor containing 14.4 L (10 vol) saturated sodium bicarbonate, and the flask was rinsed with an additional 1.44 L (1 vol) dichloromethane. The layers were separated, and the organic layer was washed with 14.4 L (2×10 vol) water. The organic layer was dried with 1.69 kg sodium sulfate for at least 20 minutes before proceeding to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11](O)[CH:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(c1ccc(F)cc1)C(O)n1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-1-ol (1 g, 2.68 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h, cooled to RT and then cooled to 5° C. in ice-water bath. 15% aqueous solution of KOH was added dropwise to the reaction mixture (pH 9-10), followed by extraction with EtOAc (3×10 mL). The combined organic extracts were washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum and purified by column chromatography using 100-200 silica gel, using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers (150 mg), which was separated by HPLC. Yield: 15 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.68 (t, 2H), 7.54 (s, 1H), 7.21 (s, 2H), 7.16 (t, 2H), 6.97 (s, 1H), 4.8 (bs, 1H), 4.39 (bs, 1H), 3.85 (bs, 1H), 3.60 (bs, 1H), 3.13 (bs, 5H), 1.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20](OCC)=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH2:31])[CH3:26]>>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH:31][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[N:10]1)[CH3:26]
Reactant: CCOC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccccc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccccc1

Procedure:
A solution of 8.73 g (0.027 mol) of ethyl 4-(4-fluorophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 6 in 30 mL of 3-(diethyl-amino)propanamine was heated at reflux for 3 hr. The excess amine was stripped under vacuum and the residue triturated in 1:1 hexane/methyl t-butyl ether. The solid was recrystallized from triethylamine to yield 8.4 g of product, mp 82°-83° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:12][CH2:11][NH:10][S:9]1(=[O:14])=[O:13].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[CH3:7][N:8]1[S:9](=[O:14])(=[O:13])[N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CN1CCNS1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (14.49 g, 104.8 mmol) in anhydrous dimethylformamide (80 ml) was added dropwise over 4 minutes a solution of 2-methyl-1,2,5-thiadiazolidine-1,1-dioxide (14 g, 102.8 mmol) in anhydrous dimethylformamide (40 ml), under nitrogen. After 5 minutes, solid 4-nitrobenzyl bromide (22.43 g, 103.8 mmol) was added in one portion and stirring was continued at room temperature for 5 hours. Water (200 ml) was added and products were extracted into ethyl acetate (3×150 ml). The combined organic phases were washed with brine (1×50 ml), dried (Na2SO4) and concentrated. The crude residue was crystallized from ethyl acetate-hexane (70:30) to give 18.31 g (67%) of the title compound as pale yellow crystals. Purification of the mother liquors by flash chromatography (silica gel, hexane-ethyl acetate, 30:70) afforded a further 5.1 g (18.2%) of required product; mp 105°-107° C.; δH (250 MHz, CDCl3) 8.22 (2H, d, J=8.7 Hz, Ar--H), 7.57 (2H, d, J=8.7 Hz, Ar--H), 4.32 (2H, s, Ar--CH2 --), 3.36--3.21 (4H, m, N--CH2CH2 --N), 2.80 (3H, s, --NMe); m/z (CI) 270 (M+ -1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH3:10]O>>[C:1]([O:5][CH3:6])(=[O:4])[C:2]([CH3:10])=[CH2:3].[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[C:1]([O:5][CH3:6])(=[O:4])[C:2]([CH3:10])=[CH2:3]
Reactant: CO
Agent: C=CC(=O)OCCCC
Product: C=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
and 100 mL of toluene, and the reactor was nitrogen-purged. The reaction liquid was heated at 70° C. for 6 hours while being stirred, and a methyl methacrylate polymer (Mw=67,800, Mn=55,900, Mw/Mn=1.21) was thereby produced. Next, 210 g (1.64 mol) of n-butyl acrylate was dripped from the dropping funnel for over 2 hours, and heating was further performed at 70° C. for 4 hours. The reaction solution was then cooled to room temperature, and poured into 1.2 L of methanol. A methyl methacrylate-n-butyl acrylate-methyl methacrylate triblock copolymer (Mn=155,000, Mw/Mn=1.28) was thereby produced. The ratio of the individual constituents was as follows: methyl methacrylate:n-butyl acrylate=31:69 (weight ratio).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22](OC(=O)C)(=[O:24])[CH3:23].CO>N1C=CC=CC=1>[C:22]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:24])[CH3:23]
Reactant: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(C)=O
Reaction time: 8 h

Procedure:
To a solution of t-butyl (3RS)-3-hydroxytetradecanoate (20.0 g) in dry pyridine (100 ml) was added acetic anhydride (7.8 ml) at ambient temperature. The mixture was stirred at the same temperature overnight. Acetic anhydride (3 ml) was added to the mixture. The mixture was stirred for additional 2 hours at the same temperature. To the mixture was added methanol (50 ml) under ice-cooling. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The organic solution was washed with 1N hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (400 g) (chloroform:methanol 100:1 V/V) to give t-butyl (3RS)-3-acetoxytetradecanoate (14.04 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:27]1=[O:48].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[F:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]2[CH2:22][CH2:23][N:10]([C:6]3[N:5]=[CH:4][CH:3]=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=4)[C:7]=3[CH:8]=[O:9])[C:11](=[O:24])[C:12]=12
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccccn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccccn2)c1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A 100-mL flask equipped with a reflux condensor was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (297 mg, 0.57 mmol), 1-methyl-3-(pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 178b (186 mg, 0.57 mmol), sodium acetate (90 mg, 1.1 mmol), K3PO4 (234 mg, 1.1 mmol), PdCl2(dppf) (50 mg, 0.057 mmol), acetonitrile (25 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under nitrogen atmosphere for 3 hours. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 183a (178 mg, 61%) as a brown solid. MS-ESI: [M+H]+ 513.3.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(CBr)c1

Procedure:
Compound XIII is prepared by the following series of reactions: (1) ethyl m-toluate is brominated with N-bromosuccinimide in CCl4 to give ethyl 3-bromomethylbenzoate; (2) the bromo compound is treated with sodio bis-tert-butyl malonate and the product heated in toluene with a catalystic amount of a strong acid (preferably p-toluene-sulfonic acid) to effect elimination and decarboxylation and afford m-ethoxycarbonylhydrocinnamic acid; (3) the latter compound is made to react with thionyl chloride and the resulting acid chloride is reduced with potassium or sodium borohydride to yield ethyl 3-(3-hydroxypropyl)-benzoate; (4) the hydroxy ester is treated with phosphorus tribromide is ether to give reagent XIII.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:24])[NH2:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]>ClCCl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)=[NH:23])(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]
Reactant: N=C(N)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A suspension of EXAMPLE 12B (0.421 g, 0.897 mmol) and diisopropylethylamine (0.50 mL) in dichloromethane (5 mL) was treated with 4-chloro-3-nitrobenzenesulfonyl chloride (0.252 g, 0.99 mmol), stirred at room temperature for 24 hours and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient from 0%-10% methanol/dichloromethane to give the desired product (0.33 g, 60%). MS (ESI) m/e 614 (M−H)−.
Reaction SMILES: NO.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17]S(C)(=O)=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:22][C@@H:23]([CH2:28]O)[CH2:24][CH2:25][CH2:26][CH3:27]>>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:28][C@H:23]([NH2:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCC[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: NO
Product: CCCC[C@@H](N)COCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using amino alcohol alkylation method A, but adding 1.1 equivalents of 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester instead of 1 equivalent, (R)-norleucinol (400 mg, 3.4 mmol) afforded, after purification (SiO2: 7:3:1 hexane:EtOAc:isopropyl amine), 195 mg (18%) of the title compound.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O)[C:3]([NH2:5])=[NH:4].O.NN>C(O)C>[NH:2]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13])[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1cccc(OCCCN)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a partial suspension of N-[3-(3-guanidinophenoxy)propyl]phthalimide hydrochloride (1.0 g; 2.95 mmoles) in 10 ml of 95% aqueous ethanol was added 0.27 ml of hydrazine hydrate. The mixture was stirred at ambient temperature for 17 hours and evaporated under reduced pressure to give the title compound. The product was used without further purification in Step E.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[F:26][C:27]([F:39])([F:38])[S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:38][C:27]([F:26])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Product: O=C(Nc1cccc(S(=O)(=O)C(F)(F)F)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-trifluoromethanesulfonyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 565.3 [(M+H)+]; mp 207° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][O:19][CH2:20][CH3:21])[N:14]([CH2:15][CH2:16][CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.O>C(O)C>[CH2:20]([O:19][CH2:18][C:13]1[N:14]([CH2:15][CH2:16][CH3:17])[C:10]2[C:9]3[CH:8]=[C:7]([O:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:21]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate (prepared as described in Example 410, 2.9 g, 6.0 mmol) and 4 M ethanolic hydrogen chloride (15 mL) in ethanol (20 mL) was heated at reflux for 2 hours. The solution was allowed to cool to ambient temperature and was concentrated under reduced pressure to approximately 17 mL, causing a solid to form. Water was added to dissolve the solid and the remainder of the ethanol was evaporated under reduced pressure. The aqueous solution was adjusted to approximately pH 13 with 50% aqueous sodium hydroxide, then was extracted with chloroform. The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was recrystallization from acetonitrile to yield 1.25 g of 2-(ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles, mp 176-178° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C1(CC(O)=[O:41])C2C(=CC=CC=2)CC=1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17](=[O:41])[CH2:18][CH2:19][CH:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1=CCc2ccccc21
Reactant: c1ccc2c(c1)CC(CCCN1CCN(c3cccc4c3OCCO4)CC1)C2
Agent: Cl
Product: O=C(CCC1Cc2ccccc2C1)N1CCN(c2cccc3c2OCCO3)CC1
Yield: 50 %

Procedure:
4-(benzodioxan-5-yl)-1-[3-(indan-2-yl)-propyl]piperazine and its hydrochloride, m.p. (K): 210° C., by reduction of 4-(benzodioxan-5-yl)-1-[3-(indan-2-yl)propionyl]-piperazine (yield: 50%), which was itself prepared in a yield of 86% from 3-(indan-2-yl)-propionic acid, m.p. (K): 75°-78° C., and N-(benzodioxan-5-yl)piperazine.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:31][CH3:32])[C:26]=1[O:27][CH2:28][C:29]#[CH:30])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:21](=[O:22])[C:20]1[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH2:28][C:29]#[CH:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
To a mixture of 1 ml of ethyl acetate and 0.2 g of 2-methylcyclopentylamine hydrochloride was added 0.48 ml of triethylamine and then, a mixture of 0.25 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of ethyl acetate was added dropwise thereto under ice cooling. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.21 g of N-(2-methylcyclopentyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 68 of the present invention) represented by the formula: