Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].S(O)(O)(=O)=O.[NH2:15]O.[OH-].[Na+].C(OC(=O)C)(=O)C>O.C1(C)C=CC=CC=1>[C:1](#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: NO
Reactant: C=CCCCCCC=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C=CCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 150 %

Procedure:
Into a nitrogen-substituted 500 mL volume flask, toluene (200 g) and the crude 7-octenal (30.5 g) (90.0% in gas chromatography simple area %, net: 27.5 g, 0.22 mol; cis-6-octenal: 6.3% in gas chromatography simple area %, tras-6-octenal: 4.0% in gas chromatography simple area %) obtained by the technique of Synthesis Example 1 were charged. An aqueous solution of 35.5% by mass hydroxylamine sulfate (55.5 g; net: 19.7 g, 0.12 mol) was added thereto, and then the mixture was cooled to 0° C. An aqueous solution of 18% by mass sodium hydroxide (53.3 g; net: 9.6 g, 0.24 mol) was added thereto at a temperature in a range of 10 to 20° C. over 1.0 hour. After completion of the reaction, water (100 g) was added and the resulting two layers were separated. After acetic anhydride (24.5 g, 0.24 mol) was added to the organic layer, azeotropic dehydration was carried out by heating at an internal temperature of 120° C. for 3 hours. The organic layer was separated, and the obtained organic layer was distilled under a reduced pressure of 670 Pa, to obtain crude 7-octenonitrile (25.0 g) (90.2% in gas chromatography simple area %, 22.5 g, 0.18 mol; cis-6-octenonitrile: 3.9% in gas chromatography simple area %, tras-6-octenonitrile: 3.4% in gas chromatography simple area %) as a distillate.
Reaction SMILES: N1[C:10]2[C:5](=NC=CN=2)[C:4](=O)NC1=O.N1C=[CH:17][C:16](=O)NC1=O.C[Si](C)(C)[CH2:23][CH2:24][O:25][CH2:26][Cl:27]>>[CH2:24]([O:25][CH2:26][Cl:27])[C:23]1[CH:4]=[CH:5][CH:10]=[CH:17][CH:16]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c(=O)c2nccnc2[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using pteridin-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 53%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[N+]=[N-].F.[Al](F)(F)[F:16]>CCCCCC>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([F:16])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: F[Al](F)F
Reactant: [N-]=[N+]=Nc1ccccc1C(F)(F)F
Agent: F
Solvent: CCCCCC
Product: Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A mixture of 13.58g. (0.07 mole) of 2-trifluoromethylphenylazide, 100 ml. of hexane, and 20 ml. of anhydrous hydrogen fluoride was treated with 1.0g. of AlF3, and the reaction mixture was then aged for 10 hours at room temperature with agitation. The reaction mixture was then cooled, vented, and rinsed from the bomb with 60 ml. of dichloromethane, followed by 50 ml. of water. After blowing off the hydrogen fluoride, the aqueous rinse was added to the residue, which was cooled to 0° C. and made alkaline (pH about 11) with KOH pellets. The residue was then extracted twice with 100 ml. of dichloromethane per extraction; and the extracts were dried over MgSO4, and then concentrated under reduced pressure to yield 9.68g. (77%) of a brown oil. Structure of the final product as 2-trifluoromethyl-4-fluoroaniline was confirmed by IR and NMR. The final product had a b.p. of 87°-90° C. at 40 mm. Hg.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16]([CH2:17]O)=[CH:15][C:14]2[CH:19]=[CH:20][S:21][C:13]=2[S:12]1(=[O:23])=[O:22])[CH3:5])[CH3:2].[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].CS(OS(C)(=O)=O)(=O)=[O:33]>C1COCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16]([CH2:17][N:26]2[CH2:27][CH2:28][O:33][CH2:25][CH2:24]2)=[CH:15][C:14]2[CH:19]=[CH:20][S:21][C:13]=2[S:12]1(=[O:23])=[O:22])[CH3:5])[CH3:2]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCOC(C)OCCCCN1C(CO)=Cc2ccsc2S1(=O)=O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C)OCCCCN1C(CN2CCOCC2)=Cc2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
To a solution of the product from Step C (2.52 g, 6.98 mmol) and triethylamine (1.41 g, 13.9 mmol) in anhydrous THF (20 mL) at 0° C. was added methanesulfonic anhydride (1.58 g, 9.07 mmol). The ice bath was removed and the reaction mixture was allowed to proceed for 20 min; the reaction mixture was again cooled on ice and morpholine (5 mL) was added. This mixture was stirred for 3 h at ambient temperature, evaporated to dryness and extracted with ethyl acetate (2×100). The combined extracts were dried (MgSO4), evaporated to dryness and purified by column chromatography (silica, 50% ethyl acetate/hexane) to give an oil (2.52 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([Cl:40])=[O:39])=[CH:36][CH:35]=1>ClCCl>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([C:33]([F:32])([F:43])[F:44])=[CH:35][CH:36]=4)[CH2:20][CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NC1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1)c1ccc(C(F)(F)F)cc1
Yield: 31.6 %

Procedure:
Combine 1-(4-(4-fluorophenyl)phthalazin-1-yl)piperidin-4-amine (110 mg, 0.34 mmol), triethylamine (0.14 mL, 1.02 mmol) and dichloromethane (2 mL) at room temperature. Add 4-(trifluoromethyl)-benzoyl chloride (85 mg, 0.41 mmol) to the mixture and stir at room temperature overnight. Concentrate the reaction mixture and purify the resulting residue by flash chromatography (20:5:1. hexane:ethyl acetate: 2 M ammonia in methanol). Add 1 N HCl in diethyl ether to a solution of the isolated product in dichloromethane/methanol and remove the solvents under a stream of nitrogen gas to yield the title compound as a solid (57 mg, 32%). ES/MS m/z 495.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11]OC(OC)OC.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[CH:11]=[N:20][N:19]=[N:18]2)=[CH:5][CH:4]=1
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2cnnn2)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The mixture of 4-methoxybenzylamine (27 g), trimethylorthoformate (52.4 ml), sodium azide (19.2 g) and acetic acid (176 ml) was stirred at 80° C. for 14 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with a 1 N aqueous solution of hydrochloric acid, water, a saturated aqueous solution of sodium hydrocarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound (17.6 g) having the following physical data.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:4]([C:3]2[C:2]([SH:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1S
Reaction time: 20 h
Yield: 59 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (5.4 g, 14 mmol) was added to a suspension of 2-mercaptonicotinic acid (2.0 g, 13 mmol), 4-chloroaniline (1.7 g, 13 mmol) and N,N-diisopropylethylamine (4.5 mL, 26 mmol) in anhydrous N,N-dimethylformamide (20 mL) at room temperature, and the mixture was stirred for 20 hours. Water (20 mL) was added thereto, the precipitated solid was filtered off, and washed with ethyl acetate. The resulting solid was dried at 40° C. under reduced pressure to give 2.0 g of the title Reference Compound as a yellow solid (Yield: 59%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:10][C:3]=12.FC(F)(F)C(O)=O.C=O.C([BH3-])#N.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ccnc3[nH]2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2cc3c(Cl)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 17E (200 mg, 0.6 mmol) in dichloromethane (10 mL) was added 0.5 mL trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in dichloromethane (20 mL), washed with sodium bicarbonate solution and concentrated. The residue was dissolved in methanol (2 mL) and treated with formaldehyde (120 mg, 37% in water) and sodium cyanoborohydride (57 mg, 0.9 mmol). The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane and the organic phase was washed with water and concentrated to afford the title compound. LCMS: 250 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([NH2:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(N)C#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N)C=Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 3-(4-chloro-phenyl)-1-methyl-prop-2-ynylamine (1.5 g, 8.4 mmol), triethylamine (0.12 mL, 0.86 mmol, 0.1 eq.) and Lindlar catalyst (150 mg) in 40 mL of 1:1 methanol-dichloromethane was stirred for 1 hr, filtered through a CELITE pad and concentrated to provide 1.5 g of 3-(4-chloro-phenyl)-1-methyl-allylamine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][N:46]=[N+:47]=[N-:48])=[CH:18][CH:17]=1)[OH:15])([CH3:11])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc(C(O)=Nc3c(C(C)C)cccc3C(C)C)c3c(C(=O)O)cccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc(C#CCCCCN=[N+]=[N-])c2cccc(C(=O)O)c12

Procedure:
A solution of 0.50 g (0.82 mmol) N-(2,6-diisopropylphenyl)-4-(6-tosyloxy-1-hexinyl)-naphthaline-1,8-dicarboxylic acid imide and 0.36 g (5.5 mmol) sodium azide were stirred for 17 hours at room temperature under nitrogen atmosphere. 250 ml acetic acid and saturated sodium chloride solution were added to the reaction mixture. After mixing, the organic phase was removed and washed once with saturated sodium chloride solution and two times with water. The organic phase was dried with MgSO4 and the solvent was evaporated in a rotary evaporator at a temperature of the water-bath of 25° C. The obtained oil (0.40 g) was purified on silica gel ((60 Å, 60-200 μm) free flow agent: methylene chloride. 0.10 g (25% of the theoretical yield) of a orange-yellow solid material were obtained.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[N:28]=1>O1CCOCC1.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:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[N:28]=1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)n1
Temperature: 100 °C

Procedure:
A stirred mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (254.3 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium (79.16 mg, 68.50 μmol), 2-methyl-6-(tributylstannyl)pyridine (523.6 mg, 1.37 mmol) in dioxane (degassed) was heated at 100° C. for 28 h, complete by LC-MS solvent removed and chromatographed: 89:9:1(DCM/MeOH, NH4OH)gradient. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (1 H, s), 8.15 (1 H, dd, J=8.3, 1.3 Hz), 7.98 (1 H, dd, J=7.5, 1.3 Hz), 7.73-7.78 (2 H, m), 7.58-7.69 (4 H, m), 7.36 (1 H, d, J=7.6 Hz), 7.16 (1 H, d, J=7.6 Hz), 6.11-6.19 (1 H, m), 2.33 (3 H, s), 1.82 (3 H, d, J=7.0 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)n1
Product: Cc1cccc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
6 g of 5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)-2H-pyridazin-3-one and 2 g of phosphorus oxychloride were mixed. The mixture was stirred for 4 hours on an oil bath of 130° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4 mg of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[C:4]([Cl:12])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:18][NH:19][CH3:20]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([N:19]([CH3:20])[CH3:18])=[O:10])=[C:4]([Cl:12])[N:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1c(Cl)nc(Cl)nc1Cl

Procedure:
To a solution of the subtitle product of step ii) (2.0 g) in DCM (20 ml) and sodium bicarbonate (1.36 g) in water (20 ml) at 0° C. was added dimethylamine (1.00 ml, 40% aqueous) dropwise. The reaction mixture was stirred at room temperature for 2 h before DCM (40 ml) was added and the aqueous layer separated. The organic layer was washed with water (20 ml), brine (10 ml) and dried (MgSO4). The solid was filtered and the solvent evaporated to dryness under reduced pressure. The residue was purified by column chromatography (EtOAc/isohexane (1:1)) to yield the subtitle compound as an off white solid. Yield 1.9 g
Reaction SMILES: NC1CCN([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)CC1.[C:19]([NH:26][C:27]([NH2:29])=[O:28])([C:21]1[S:25][CH:24]=[CH:23][CH:22]=1)=[O:20].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][CH:31]1[CH2:32][CH:33]([NH:29][C:27]([NH:26][C:19]([C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[O:28])[CH2:34][CH2:35][NH:30]1
Reactant: c1ccncc1
Reactant: NC(=O)NC(=O)c1cccs1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: O=C(NC(=O)c1cccs1)NC1CCNC(Cc2ccc3ccccc3c2)C1

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.0 g, 0.0047 m) and 1-(then-2-oyl)urea (0.65 g, 0.0042 m) in pyridine (5 cm3) was refluxed for 9.5 hours. The solvent was evaporated, water added, and the precipitated title compound filtered and washed well with water. This was recrystallised from ethanol, converted to the hydrochloride salt in ethanol with ethanolic HCl, and recrystallised from ethanol, 0.5 g, at the hydrochloride, m.p. 217°-219° C.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].C([Li])CCC.[Cl-].[NH4+].[O:26]1[CH2:30][CH2:29][CH2:28]C1>>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:28][C@H:29]([CH2:30][OH:26])[O:3][C:1]2=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
123 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-butyllithium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbutylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCc1ccccc1
Yield: 84.5 %

Procedure:
A stirred mixture of 6-methoxy-4methyl-8-nitro-5-(7-phenylheptoxy) quinoline [Example 1b](2.0 g, 0.005 mol) de-greased 40 mesh Fe filings (5 g) H2O (20 ml), HOAc (4 ml) and n-Bu2O was heated at 80°-85° C. for 1 h, cooled and filtered. The solid was thoroughly extracted with Et2O (500 ml) and the extract was dried (Na2SO4) treated with charcoal and concentrated to an oil. Crystallization from pet ether gave 1.6 g (85%) of 8-amino-6-methoxy-4-methyl-5-(7-phenylheptoxy) quinoline as yellow green crystals, mp 61°-63° C. A second crystallization from pet ether (Darco) provided the analytical sample as glistening yellow crystals, mp 64°-65° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.[CH2:17]([NH2:20])[CH2:18][NH2:19].C(Cl)[Cl:22]>ClC(OCC)=O>[ClH:22].[NH2:19][CH2:18][CH2:17][NH:20][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: NCCN
Reactant: ClCCl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Cl
Product: NCCNC(=O)c1cnccn1
Reaction time: 1 h

Procedure:
A solution of 25.0 g of pyrazinecarboxylic acid in 300 ml of methylene chloride and 20.1 ml of ethyl chloroformate was treated dropwise at 0° within 1/2 hour with 31 ml of triethylamine. After 1/2 hour the solution obtained was added dropwise at 0° to 68 ml of ethylenediamine in 200 ml of methylene chloride and the mixture was left to stir further for 1 hour without external cooling. Thereafter, the precipitated material was filtered off and the filtrate was evaporated to dryness on a rotary evaporator under reduced pressure. The residue was recrystallized twice from isopropanol, whereby there was obtained N-(2-aminoethyl)pyrazine-2-carboxamide hydrochloride, m.p. 205°-207°.
Reaction SMILES: OC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.N1C=CC=CC=1OCCC1C=CC(OC(=O)N(C)C2C=CC=CC=2)=CC=1>>[O:21]=[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Agent: CN(C(=O)Oc1ccc(CCOc2ccccn2)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 50% of the isomeric methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester was isolated, see characterization below. 1H NMR (400 MHz; CDCl3): δ 3.05 (t, 2H), 3.41 (br s, 3H), 4.14 (s, 2H), 6.08 (t, 1H), 6.66 (d, 1H), 6.90 (dd, 1H), 7.02 (br s, 2H), 7.10 (d, 2H), 7.25-7.42 (m, 6H); HPLC-MS: m/z=349.2 (M+1); Rt=3.04 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:30]1[C:34]([CH:35]=O)=[N:33][N:32]=[N:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[NH:33][N:32]=[N:31][N:30]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1nnn[nH]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
In 1,2-dichloroethane (14 ml)/acetic acid (7 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.70 g). To the solution were added tetrazole-5-carbaldehyde (0.31 g) and sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=15:1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.67 g).