Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:5]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 38.3 %

Procedure:
Under nitrogen atmosphere, 44.4 g (0.192 mole) of 2-amino-2'-chlorobenzophenone was added in four portions at 15 min intervals to a stirred melt (130°-135° C.) of 33.5 g (0.211 mole) of 2-chloro-3-nitropyridine. Heating was continued for 30 min at 130°-125° C. and for 45 min at 145° C. The reaction mixture was cooled to 110° C. and 200 ml of hot toluene was added. To the cooled mixture (room temperature) 100 ml of 10% aqueous sodium hydroxide was added and stirring was continued for 15 min. The toluene layer was separated and washed three times with 75 ml portions of water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 300 ml of methylene chloride and the solution was stirred with 100 g of fluorisil for 30 min. The mixture was filtered, rinsing the fluorisil filter-cake several times with methylene chloride. The combined filtrates were treated in the same manner with an additional 100 g of fluorisil. The methylene chloride was separated by filtration and concentrated in vacuo. The residue was crystallized from ethyl acetate-cyclohexane to give 26.0 g of a bright yellow solid, m.p. 119° C. A second crop (7.0 g) was obtained from the filtrate and recrystallized from isopropyl ether, m.p. 118°-119° C. The total yield amounted to 49% of theory.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(Cl)C>>[C:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(Cl)c1ccccc1
Agent: CCCl
Product: CCOP(=O)(OCC)C(=O)c1ccccc1
Yield: 97.4 %

Procedure:
To 140.57 grams (1.0 mole) of benzoyl chloride at 90° C. there were added 166.2 grams (1.0 mole) of triethyl phosphite over a period of 1 hour. Ethyl chloride evolution ceased at the end of this period. The unreacted benzoyl chloride and triethyl phosphite were removed by distillation at reduced pressure, terminal conditions being 100° C. and 8 mm. leaving a residue of 236 grams (90% yield) of diethyl benzoylphosphonate which was reacted with diethyl sodium phosphite as in Example 1 to produce tetraethyl phenyl hydroxymethane diphosphonate. This was hydrolyzed and the hydrolysis product purified in the same manner as in Example 1 to produce phenyl hydroxymethane diphosphonic acid as a viscous syrup having an acid number of 822 mg. KOH/mg (Theory is 836 mg. KOH/gm); % P 22.8 (Theory 22.9%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH:33]1([C:39]2[C:43](=C)[CH:42]=[CH:41][CH:40]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O.C1COCC1>[CH:39]1([C:33]2([C:10]3[C:9]4[CH2:8][C:7]5[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=5)[C:14]=4[CH:13]=[CH:12][C:11]=3[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:40]=[CH:41][CH:42]=[CH:43]1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: C=C1C=CC=C1C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1C1(C2C=CC=C2)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
To a THF (30 ml) solution including 5.0 g (18.6 mmol) of 2,7-di-tert-butylfluorene, a hexane solution (13.5 ml, 21.6 mmol) of n-butyllithium was added dropwise at −78° C. under nitrogen, followed by stirring at room temperature for 6 hours. Next, a THF (20 ml) solution including 3.42 g (23.4 mmol) of cyclohexylfulvene was added dropwise at 0° C. under a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. The resultant reaction solution was decomposed with cold water, and then extracted with ether. The extract was dried over magnesium sulfate and then filtered, and the used solvent was removed from the filtrate under reduced pressure, thereby obtaining a solid. This solid was recrystallized from methanol to obtain 5.36 g of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([O:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (5.00 g) in dimethyl formamide (150 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (15.47 g). The reaction mixture was stirred at room temperature for 30 mins then allyl bromide (2.39 ml) was added, and stirring continued for a further 36 h at room temperature. The mixture was poured into water (200 ml) and the emerging precipitate was filtered and triturated with boiling methanol to give the desired compound as a beige solid in 50% yield. 1H NMR (360 MHz, DMSO-d6) 5 4.04 (2H, dd, J=6.45 Hz, J=1.84 Hz, OCH2CHCH2), 5.08 (2H, m, OCH2CHCH2), 5.88 (1H, m, OCH2CHCH2), 7.23 (1H, dd, J=12.45 Hz, J=3.00 Hz, 6-H), 7.36 (6H, m, Ph+8-H), 7.81 (1H, d, J=12.45 Hz, 5-H), 11.94 (1H, bs, NH).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2].[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl.[OH-].[Na+]>Cl.O.C1COCC1>[ClH:16].[S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NNc1ccc(S(N)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a stirred solution of 2-Sulfamyl-5-amino-pyridine (3 g) in concentrated hydrochloric acid solution (23 ml) was added NaNO2 (1.4 g, 20 mmol) in water (23 ml) while maintaining the temperature between −5° C. and 0° C. After the reaction mixture was stirred at 0° C. for 1.5 hours, SnCl2 (19 g) in concentrated hydrochloric acid solution (25 ml) was added, and the resulting reaction mixture was stirred at 0° C. for 1 hour, then room temperature overnight. The pH of the reaction solution was adjusted to 8 by addition of NaOH (24 g) in water (30 ml), followed by the addition of THF (200 ml). After stirred at room temperature for 30 minutes, the reaction mixture was filtered through Celite®. The aqueous layer was extracted with THF (3×200 ml) and ethyl acetate (2×200 ml). The combined organic layers were dried with sodium sulfate (Na2SO4), and concentrated in vacuo. The product was dissolved in 10% HCl in methanol (50 ml), and the solvent was removed in vacuo to give title compound (2.5 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[N-]1C=CN=C1.[NH2:42][O:43][CH2:44][CH2:45][OH:46]>C1COCC1>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:42][O:43][CH2:44][CH2:45][OH:46])=[O:7]
Reactant: NOCCO
Reactant: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: COCC#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The title compound was prepared from reaction of the product of Example 5, Step B, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]-amino]benzoic acid. This product (200 mg, 0.60 mmol) was dissolved in dry THF (5 mL) and CDI (193 mg, 1.19 mmol) added. After 0.5 hours at room temperature, TLC showed complete conversion to the desired imidazolide. A solution of 2-(aminooxy)ethanol (184 mg, 2.39 mmol) in dry THF (2 mL) was added and the reaction mixture stirred overnight at room temperature. The reaction solvent was then removed under reduced pressure and the resulting residue partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (50 mL). The EtOAc layer was then dried (Na2SO4), the solvent removed under reduced pressure, and the resulting oil purified by column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (165 mg, 71%); mp (EtOAc/Et2O) 121-123° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.85 (br s, 1 H), 7.46-7.38 (m, 1 H), 7.32 (dd, J=12.1, 1.7 Hz, 1 H), 7.29-7.21 (m, 1 H), 7.14 (dd, J=8.4, 1.6 Hz, 1 H), 6.79 (td, J=8.8, 4.7 Hz, 1 H), 4.74 (br s, 1 H), 4.30 (s, 2 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.9 Hz, 2 H), 3.32 (s, 3 H). Anal. Calcd for C19H17F3N2O4: C, 57.9; H, 4.4; N, 7.1. Found C, 57.9; H, 4.3; N, 7.0.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][CH2:35][NH:36][CH2:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCCCCCOc1ccc(CNCCc2ccc(Cl)c(Cl)c2)c2ccccc12

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(dodecyloxy)-1-naphthaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.72 min (HPLC purity: 82.0%).
Reaction SMILES: N.Cl[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Cl)[N:6]=[CH:5][N:4]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([N:28](CC)CC)C.[Cl-].[Na+]>O.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:28])[N:6]=[CH:5][N:4]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(N)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a methylene chloride solution (50 mL) saturated with ammonia, commercially available 4,6-dichloro-5-nitropyrimidine (1.00 g, 5.44 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, the resulting residue was dissolved in dimethylformamide (10 mL), and then N-tert-butoxycarbonylpiperazine (1.15 g, 6.17 mmol) and triethylamine (3.59 mL, 25.8 mmol) were added thereto, followed by stirring under heating at 80° C. for 4 hours. After the reaction solution was allowed to stand for cooling, it was poured into water, sodium chloride was added thereto, and the precipitated crystals were recovered by filtration, washed with water, and dried to give 4-(6-amino-5-nitro-4-pyrimidinyl)-1-piperazinecarboxylic acid tert-butyl ester (888 mg, 2.74 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:10][CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14].[C:16]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][N:6]1[CH:5]=[C:4]([O:8][CH3:9])[CH:3]=[C:2](/[CH:14]=[CH:13]/[CH2:12][CH:11]([OH:15])[CH3:10])[CH2:7]1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: C=CCC(C)O
Reactant: COc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC1=CN(C)CC(/C=C/CC(C)O)=C1
Temperature: 140 °C

Procedure:
The manner in which certain aryl substituted olefinic amine compounds possessing a branched side chain are provided can vary. Using one synthetic approach, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47: 5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The required halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Recl. Trav. Chim. Pays-Bas 74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluensulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C@H:8]([F:13])[CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.O[C@@H](CCCC)CC(OC)=O.[CH2:25]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](O)=[C:40](F)[CH:39]=2)=[N:36][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:25]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([O:5][CH2:6][CH2:7][C@H:8]([F:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:40][CH:39]=2)=[N:36][CH:37]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCC[C@@H](F)CCOS(C)(=O)=O
Reactant: CCCCCCOc1cnc(-c2ccc(O)c(F)c2)nc1
Agent: CCCC[C@H](O)CC(=O)OC
Product: CCCCCCOc1cnc(-c2ccc(OCC[C@H](F)CCCC)cc2)nc1
Yield: 48.5 %

Procedure:
The titled compound was synthesized from (R)-3-fluoroheptyl methanesulfonate, derived from methyl (S)-3-hydroxyheptanoate (98.0% ee, [α]D20 =-8.71°), and 5-n-hexyloxy-2-(4-hydroxy-3-fluorophenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=O)=[C:6]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N+:17]([O-:19])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:16])=[N:8]2
Reactant: CCOC(=O)CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)nc2cc(Cl)ccc2[n+]1[O-]
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(5-chloro-2-nitrophenylamino)-3-oxopropanoate (1.5 g, 5.2 mmol) in anhydrous DMF (8 mL) was added dropwise to a solution of potassium tert-butoxide (1.2 g, 10.5 mmol) in anhydrous DMF (5 mL) at 0° C. under nitrogen, after which the mixture was stirred for 2 h. The cold mixture was diluted with water (50 mL), acidified to pH 2 with 2 N HCl and extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with water (45 mL), dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (3:7), to provide 6-chloro-2-(ethoxycarbonyl)-3-hydroxyquinoxaline-1-oxide as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, 1H), 7.46 (d, 1H), 7.34 (dd, 1H), 4.55 (q, 2H), 1.45 (t, 3H) ppm; ESI MS m/z 267 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14](Br)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:13][C:12]=3[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1

Procedure:
The title compound was prepared from 1,3-di-cyclohexylmethyl-8-bromo xanthine (0.7 g, 0.0017 mol) and piperidine (0.28 g, 0,003 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. 266° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:11])[CH3:10].[BH4-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1CCCCC1.O>[CH2:9]([N:11]([CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:14](=[O:16])[CH3:15])[CH3:10]
Reactant: CCN
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCO
Solvent: O
Product: CCN(Cc1ccncc1)C(C)=O
Reaction time: 0.33 h
Yield: 82 %

Procedure:
A mixture of pyridine-4-carboxaldehyde (XI; 10.71 g, 0.1 mole) and ethyl amine (12.88 g of a 70% water solution, 0.2 mole) were stirred for 20 min. Cyclohexane (75 ml) was added and the mixture was refluxed for 16 hrs under a Dean-Stark trap. The mixture was then concentrated in vacuo. Ethanol (100 ml) and sodium borohydride (five 0.4 g tablets, 50 mmole) were then added to the residue and mixture was stirred for 3 hrs in an ice bath. The mixture was concentrated in vacuo and the residue was dissolved in acetonitrile (100 ml) and filtered. Acetic anhydride (10.38 ml, 0.11 mole) was added and the reaction was stirred for 2 days. Sodium carbonate (15.9 g, 0.15 mole) was added and the solution was refluxed for 20 min. The mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel using 5% methanol/ethyl acetate as the eluent to give the product (14.57 g, 82%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:25][N:24]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cn1
Yield: 23.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)picolinamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.140 g; 0.605 mmol), 5-(3-fluorobenzyl)picolinic acid (0.139 g; 0.605 mmol), HATU (0.254 g; 0.668 mmol) and N,N-diisopropylethylamine (0.262 mL; 1.52 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.057 g (23%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)c1
Yield: 206 %

Procedure:
To a solution of 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.51 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.96 ml) and water (0.96 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were recrystallized from ethanol to give 7-(2-chloro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 162) (1.5 g) as colorless crystals.
Reaction SMILES: O1CCCC1.C([O:8][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=O)C.[CH3:32][NH2:33]>CO>[CH3:32][NH:33][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=[O:8]
Reactant: CCOC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To 5 ml of tetrahydrofuran were added 130 mg of 4-[2-ethoxycarbonyl-4-phenyl-3-butynylamino]quinazoline and 3 ml of a 40% solution of methylamine in methanol, and the mixture was stirred at 60° C. for an hour, then at room temperature for 24 hours. The reaction mixture was concentrated and purified by means of flash chromatography (Isolera™ manufactured by Biotage AB) to give 113 mg of 4-[2-methylaminocarbonyl-4-phenyl-3-butynylamino]quinazoline.