Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:12])(C)[CH2:9][CH2:10][C:5]2=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[C:3]([C:13]([O:15][CH2:21][CH3:22])=[O:14])=[CH:4][C:5]2[CH2:10][CH2:9][CH2:8][CH2:12][C:6]=2[N:7]=1
Reactant: CCO
Reactant: CC1(C)CCc2cc(C(=O)O)c(O)nc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(nc1O)CCCC2

Procedure:
2-Hydroxy-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (11.0 g) was dissolved in ethanol (100 ml), sulfuric acid (3.4 ml) was added and the mixture was stirred with heating to reflux for 12 hr. The reaction mixture was concentrated under reduced pressure to a half volume, the residue was basified with 8 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (50:50-85:15) was concentrated under reduced pressure to give the object compound (3.45 g).
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[N:8]=[CH:7][CH:6]=[CH:5][NH:4]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]Br)[CH2:27][CH2:26]1>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][N:8]2[CH:7]=[CH:6][CH:5]=[N:4][S:3]2(=[O:10])=[O:9])[CH2:27][CH2:26]1
Reactant: O=S1(=O)N=CC=CN1
Reactant: COc1cc2ncnc(N3CCC(CCBr)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CCN4C=CC=NS4(=O)=O)CC3)c2cc1OC

Procedure:
Sodium hydride (0.19 g. of a 50% dispersion in oil) was added to a stirred solution of 2H-1,2,6-thiadiazine-1,1-dioxide (0.52 g) in dimethylformamide (4 cm3). After 0.5 hours 1-(6.7-dimethoxyquinazolin-4-yl)-4-(2-bromoethyl)piperidine (0.60 g) was added and the mixture was warmed at 70° for 10 hours. The solvent was removed in vacuo, water was added and the mixture was extracted with chloroform (4×20 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on silica (Merck 60. 9385) eluting with methanol:ethyl acetate, 1:19, to give an oil which was crystallised from ethyl acetate to afford 1-(6,7-dimethoxyquinazolin-4-yl)-4-[2-(1,1-dioxo-1,2,6-thiadiazin-2-yl)ethyl]piperidine as microcrystals, m.p. 176°-8°, (0.18 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=1
Reactant: NS(=O)(=O)c1ccc(C2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccnc(N2CCC(c3ccc(S(N)(=O)=O)cc3)CC2)c1
Reaction time: 3 h

Procedure:
A mixture of the product from part (i) (100 mg) and 5% palladium/carbon (25 mg) in ethanol (25 ml) and acetic acid (25 ml) was hydrogenated at 3.5 bars at room temperature for 3 hours. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol (19:1) gave some impurity and further elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:1) gave the pure product. The combined product-containing fractions were evaporated to give the title compound as a monohydrate, m.p. 290°-295° (with decomp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:26]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 7 h
Yield: 76 %

Procedure:
To a well stirred solution of 2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.327g, 1.21 mmol) and 3,4-dimethoxybenzoyl chloride (0.557 g, 2.77 mmol) in CH2Cl2 (20 ml) was added AlCl3 (0.616 g, 4.62 mmol) portion-wise over a 15 minute period. After 7 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 60:40 Et2O/hexanes) afforded the title compound (0.402 g, 0.92 mmol, 76%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5](OC)=O.[Na].ClC1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>O.O1CCOCC1>[Cl:20][C:18]1[N:19]=[C:5]([CH2:4][C:3]([OH:2])=[O:9])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=1
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)nc1CC(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of malonic acid dimethyl ester, sodium salt (8.067 g, 52.4 mmol), as prepared in the previous step, 2,6-dichloro-nicotinonitrile (4.53 g, 26.2 mmol), as prepared in Example 6b, and dioxane (40 mL) was stirred at 80° C. for 1 h. The resulting easily stirred reddish-brown opaque thin slurry was allowed to cool to rt, 6 M HCl (aq) (80 mL) was added, and the mixture was vigorously stirred at 65-70° C. for 5 h open to air. The resulting clear dark amber solution containing a small amount of dark material was allowed to cool to rt, diluted with water (80 mL), and extracted with DCM (3×100 mL). The organic layers were combined, dried (2×Na2SO4), and concentrated under reduced pressure at 60° C. to provide the crude title compound as a dark brown oil (6.2 g, quantitative yield). A NMR spectrum of the reaction following malonate addition indicated a ˜1:2 mixture of desired/undesired regioisomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C@@H:35]([OH:37])[CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C@@H:35]([OH:37])[CH2:34][CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3C[C@@H](O)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC[C@H](O)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 77 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,5S*)-5-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (148 mg, 0.217 mmol) prepared in Example 163h, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (80.5 mg, 77%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2ccc(-c3ccc(Cl)cc3)cc2s1
Yield: 18 %

Procedure:
Similar to the synthesis of 1-(6-(4-pyrrazolyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, 4-chlorophenylboric acid, sodium bicarbonate, and Pd(PPh3)4 in DMF/water mixed solvent (5/1) was reacted to give the desired compound 0.020 g (18%). LC/MS 330 (M−1); LC retention time 2.70 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:31][CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[N:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CN1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1nc2c(cc(NC3CCN(C)CC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 125 °C

Procedure:
A degassed mixture of 3-benzyl-5-chloro-2,8-dimethyl-3H-imidazo[4,5-e][1,2,4]triazolo[4,3-a]pyridine (37 mg, 0.12 mmol, from Step 1), 1-methylpiperidin-4-amine hydrochloride (54 mg, 0.36 mmol, Matrix), NaOtBu (57 mg, 0.59 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17 mg, 0.030 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (13 mg, 0.014 mmol, Aldrich) in toluene (1.8 mL) was heated at 125° C. for 80 minutes. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered and concentrated. The product was isolated via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (9.8 mg, 21%).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1.[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C.O>[Cl:24][C:25]1[C:30]([NH:23][CH:21]2[CH2:20][N:19]([C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]=3)[CH2:22]2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Reactant: Clc1nccnc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nccnc1NC1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 53.6 %

Procedure:
Triethylamine (560 mg, 5.6 mmol), 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (557 mg, 2.8 mmol) and 2,3-dichloro-pyrazine (414 mg, 2.8 mmol) were dissolved in DMF (20 mL). The resulting mixture was heated to 90° C. overnight. The mixture was then diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give 3-chloro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-amine (479 mg, 1.5 mmol, 55% yield) as white solid. ESI-MS (M+1): 312 calc. for C16H14ClN5 311.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C)cc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
The above general procedure was followed using 4-chlorotoluene (126 mg, 1.00 mmol) and dibutylamine (129 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 4 hours at 70° C., the reaction mixture was adsorbed onto silica gel and chromatographed with 2% ethyl acetate/hexanes to give 196 mg (90%) of N,N-dibutyl-p-toluidine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])([CH3:4])([CH3:3])[CH3:2].[Cl-].C([NH+](CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].Cl>O.CN1CCCC1=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[NH:34][N:33]=[N:32][N:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(OCCCCCC#N)cc(C(C)(C)C)c1O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(OCCCCCc2nnn[nH]2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 50.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.79 g (0.012 mole) of 6-(3,5-di-t-butyl-4-hydroxyphenoxy)hexanenitrile, 2.45 g (0.018 mole) of triethylammonium chloride, 2.31 g (0.036 mole) of sodium azide and 150 ml of N-methylpyrrolidinone was heated at about 150° C. for about 72 hours. The reaction mixture was cooled and poured into water. The aqueous mixture was acidified to pH 1 with 10% hydrochloric acid and then extracted six times with 100 ml portions of diethyl ether. The diethyl ether extracts were combined, dried over magnesium sulfate and evaporated to provide a yellow oil. This oil was purified by silica gel chromatography eluting with 2:1 hexane:acetone containing 3 drops of acetic acid per 2000 ml of solvent, followed by recrystallization from a mixture of ethyl acetate and hexane to provide 2.2 g of 5-[5-(3,5-di-t-butyl-4-hydroxyphenoxy)pentyl]tetrazole as an off-white crystalline solid, m.p. 140°-141° C. Analysis: Calculated for C20H32N4O2 : %C, 66.6; %H, 8.95; %N, 15.5; Found: %C, 66.5; %H, 8.9; %N, 15.6.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:58][C:59]([NH2:66])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH2:61]>CN(C=O)C>[NH2:66][C:59]([CH3:58])([CH2:62][CH:63]([CH3:65])[CH3:64])[CH2:60][NH:61][C:24]([C:23]1[N:5]2[CH:6]=[C:7]([CH3:22])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:16])([F:15])[F:17])[C:18]([F:19])([F:20])[F:21])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NCC(C)(N)CC(C)C)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 mg (0.08 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 259A, dissolved in 0.3 ml of DMF, 40 mg (0.104 mmol) of HATU, dissolved in 0.3 ml of DMF, and then 16 mg (0.16 mmol) of 4-methylmorpholine were added to 10 mg (0.08 mmol) of rac-2,4-dimethylpentane-1,2-diamine. The mixture was shaken at RT overnight. The target compound was concentrated by preparative HPLC (Method 12). This gave 10 mg (25% of theory).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1.CC1C=CN=C(C2C=CC=CC=2)C=1.[N+]([O-])(O)=O.S(=O)(=O)(O)O.N>>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1ccnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C

Procedure:
4-Methyl-2-phenylpyridine nitrate prepared from 4-methyl-2-phenylpyridine (26.3 g) and 69% nitric acid (15 ml) is added under cooling to conc. sulfuric acid (95 ml), and the mixture is heated with agitation at 90°-100° C. for 30 minutes. After cooling, ice water (300 ml) is added to the reaction mixture, and the mixture is adjusted to pH 3.5 with conc. aqueous ammonia. The crystals precipitated from the hot solution are collected by filtration and recrystallized from ethanol to give 4-methyl-2-(4-nitrophenyl)pyridine (13.3 g). M.P. 145°-147° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[N:7][C:8]=2[CH3:12])[N:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C)C=O.O.C(O[Pd]OC(=O)C)(=O)C>[CH3:12][C:8]1[N:7]=[CH:6][C:5]([CH3:13])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][CH2:19][CH3:20])=[O:17])=[N:3]2
Reactant: C=CC(=O)OCC
Reactant: Cc1ncc(C)c2nc(Br)ccc12
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(C)ncc(C)c2n1
Temperature: 150 °C
Yield: 86.7 %

Procedure:
A mixture of 2-bromo-5,8-dimethyl-1,6-naphthyridine (0.63 g, 2.7 mmol), ethyl acrylate (0.53 g, 5.4 mmol), diacetoxypalladium (121 mg, 0.5 mmol), PPh3 (0.35 g, 1.4 mmol), and NEt3 (0.82 g, 8.1 mmol) in N,N-dimethylformamide (5 mL) was heated in a microwave reactor at 150° C. for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated sodium chloride solution (50 mL×3), dried with sodium sulfate and concentrated to give 0.6 g of the crude product as a yellow solid, which was used for the next step without further purification. MS (ESI): m/z 257.1 [M+H]+.
Reaction SMILES: [Na].[C:2]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[C:2]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCN1
Agent: [Na]
Product: O=C1CCCCCCCCCCCN1

Procedure:
0.3 mol % of sodium salt of caprolactam and 0.3 mol % of the co-catalyst of the Example 13 were dissolved in molten caprolactam. The mixture was heated to 160° - 163°C for 120 minutes. The polymerizate contained almost theoretical equilibrium amount of the polyamide. Similar result was obtained with laurolactam, using the same amount of 1,3,5,5-tetramethyl-2,4,6-piperidine-trione at equal conditions of polymerization.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]3[S:22][C:23]([Br:26])=[CH:24][CH:25]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:30][CH2:31]O>>[CH2:30]([O:28][C:27](=[O:29])[C@H:19]([CH2:20][C:21]1[S:22][C:23]([Br:26])=[CH:24][CH:25]=1)[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH3:31]
Reactant: CCO
Reactant: O=C(N[C@@H](Cc1ccc(Br)s1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-3-(5-bromo-2-thienyl)-L-alanine (813 mg) was dissolved in EtOH (15 mL) and HCl (gas) was bubbled through the solution for 5 min at 0° C. The mixture was warmed to 50° C. and stirred for 1 h. After cooling to room temperature the solvent was evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 1:1) provided N-(9-fluorenylmethoxycarbonyl)-3-(5-bromo-2-thienyl)-L-alanine ethyl ester (767 mg): ESMS: m/z 500 MH+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 92 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.66 g) and (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.55 g) as starting materials, 5-benzyloxy-N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.98 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained. melting point: 138° C.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:28][CH3:29])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCC)c1
Reaction time: 1 h

Procedure:
A solution of 7.20 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of ethyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield ethyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.