Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([NH:31][CH2:32][CH2:33]Br)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][CH2:33][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]=[C:11]2[C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:10][CH2:9]2)=[CH:16][CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-ol (120 mg, 0.4 mmol) was added in several portions to a suspension of sodium hydrid (NaH, 1.3 mmol, activated by removal of oil) in dimethylformamide (DMF, 5 ml). 2-(Boc-amino)ethyl bromide was added after one hour and the resulting mixture stirred for 3 days at room temperature. DMF was evaporated, the residue diluted with ethylacetate and extracted with water. Removal of the solvents from the dried (Na2SO4) extract afforded an oil which was further purified by chromatography. Yield: 100 mg (0.23 mmol, 56%)
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])=[O:19])[C:10]([O:12]C)=[O:11])=[O:4].O.[Li+].[OH-].Cl>C1COCC1>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]([NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Cl:29])=[O:19])[C:10]([OH:12])=[O:11])([OH:4])=[O:2]
Reactant: COC(=O)COc1cc(C(=O)OC)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cc(C(=O)O)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
The crude product from step a) is converted in analogy to examples 1b) to 1d) into methyl 3-methoxycarbonylrnethoxy-4-[3-(2-chloro-4-fluorobenzoyl)ureido]-benzoate, of which 50 mg (0.11 mmol) are dissolved in 5 ml of THF, and 1 ml of water is added. To this are added 27 mg (1.1 mmol) of LiOH, and the reaction is stirred at room temperature until the precursor has reacted completely. The reaction is monitored by LC-MS. After completion of the reaction, the mixture is acidified with dilute hydrochloric acid and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4, filtered and concentrated in a rotary evaporator, and the residue obtained in this way is purified in a preparative HPLC system (column: Waters Xterra™ MS C18, 5 μm, 30×100 mm, mobile phases: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 28 mg (0.068 mmol) of the desired product are obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]#[N:28])[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 78.4 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (Example 11, Step 3, 130 mg, 0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (139 mg, 1.0 mmol) to afford the title compound (151 mg), a white solid, in 78% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[N:4]1)[CH3:2].[H][H]>CO>[NH2:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[CH:6]=1
Reactant: [H][H]
Reactant: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1[N+](=O)[O-]
Solvent: CO
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1N
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Pt/Vd (3%/0.6% wt/wt on carbon, 50 mg, 0.008 mmol, 0.005 equiv) was added to a stirring solution of 3-[1-ethyl-5-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-3-yl]benzonitrile (0.54 g, 1.53 mmol, 1 equiv) in methanol (15.3 mL). A 3-way stop cock with a hydrogen balloon was installed and the reaction vessel was subjected to alternating vacuum and H2 gas (4×). The resulting mixture was stirred at 22° C. for 2 hours. The mixture was then subjected to alternating vacuum and nitrogen gas (4×) before the mixture was filtered through a nylon syringe filter and concentrated in vacuo to afford 3-[5-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-3-yl]benzonitrile. The crude reaction product was carried forward without further purification. Calcd (M+1)+: 323.1. Found: 323.0.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.CS(O[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=O)=O.O>CN(C=O)C>[O:17]1[CH2:18][CH2:19][CH:14]([N:6]2[CH:5]=[C:4]([I:3])[CH:8]=[N:7]2)[CH2:15][CH2:16]1
Reactant: Ic1cn[nH]c1
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnn(C2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
As shown in step 2-ii of Scheme 2, sodium hydride (6.101 mL of 60% NaH/mineral oil, 137.3 mmol) was added slowly to a solution of 4-iodopyrazole (24.21 g, 124.8 mmol) in 200 mL of anhydrous DMF at 0° C. The solution was stirred for 1 hour at 0° C. and tetrahydro-2H-pyran-4-yl methanesulfonate (Compound 1010, 22.5 g, 124.8 mmol) in 100 mL of anhydrous DMF was added dropwise. The reaction mixture was heated at 100° C. for 18 hours, at which time an additional 8.0 g of (Compound 1010) in 25 mL of anhydrous DMF was added dropwise. The reaction mixture was heated at 100° C. for an additional 24 hours. The mixture was cooled to room temperature and 100 mL of water was added. The mixture was extracted with EtOAc (3×100 mL) and the combined organics were washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a semi-solid. Recrystallization from DCM yielded 1-(tetrahydro-2H-pyran-4-yl)-4-iodo-1H-pyrazole (Compound 1011, 11.96 g). A second crop of crystals was obtained upon trituration of the mother liquor with hexanes (5.26 g, 49.6% total yield): ESMS (M+H)=279.0.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>ClCCl>[C:18]([O:21][CH2:22][C:23]([N:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:1]([CH3:3])[CH3:2])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(C)NC1CCCCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(C(C)C)C1CCCCC1
Yield: 99.5 %

Procedure:
To a solution of 5.0 g of N-isopropylcyclohexylamine and 4.3 g of triethylamine in 100 ml of dry dichloromethane was added dropwise 5.8 g of acetoxyacetyl chloride with stirring under ice-cooling, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was successively washed with an aqueous sodium bicarbonate solution and water, dried under reduced pressure to obtain 8.5 g of 2-acetoxy-N-cyclohexyl-N-isopropylacetamide in an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[C:5]([CH3:25])=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:25][C:5]1[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)=[N:7][C:2]([NH:32][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 150 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
To a solution of tert-butyl 4-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.35 g, 0.95 mmol) and 1-methyl-1H-pyrazol-4-amine (0.14 g, 1.43 mmol) in n-BuOH (5 mL) was added DIPEA (0.25 g, 1.9 mmol). The reaction mixture was stirred at 150° C. for 16 h then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as black oil (0.45 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.O.[NH2:21][NH2:22]>CCCCO>[F:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4]([CH:6]3[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]3)=[N:21][NH:22]2)=[CH:15][CH:16]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 36 %

Procedure:
A solution of 1-[4-(2,4-difluoro-benzoyl)-piperidin-1-yl]-ethanone (1.7 g, 6.4 mmol), 6 mL of hydrazine hydrate and 13 mL of n-BuOH was refluxed for 48 hours. The reaction mixture was concentrated in vacuo, the residue was diluted with water (30 mL) and then extracted with ethyl acetate (50 mL). The solvent was removed in vacuo to yield the crude product as an oil. It was washed with heptane and the solvent was filtered to yield the title product (0.60 g, 2.3 mmol, 36% yield) as a white solid. MS (ESI) m/z 261.6 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.44 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@H:8]2[CH2:10][C@@H:5]1[CH2:6][N:7]2[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[Br:18][C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[C:22](Br)=[N:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[C:22]([NH:15][C:14]2[CH:13]=[CH:12][C:11]([N:7]3[CH2:6][C@H:5]4[CH2:10][C@@H:8]3[CH2:9][N:4]4[CH:1]([CH3:3])[CH3:2])=[CH:17][CH:16]=2)=[N:21][CH:20]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(N)cc1
Solvent: CCN(CC)CC
Product: CC(C)N1C[C@H]2C[C@@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1

Procedure:
To the solution obtained from step 2 is added 5,8-dibromo[1,2,4]triazolo[1,5-a]-pyrazine (1.6 g; 5.8 mmol) and triethylamine (3.4 mL). The resulting mixture was heated at reflux for 70 h, after which the reactor contents were cooled down and filtered to remove solids. The filter cake was washed with 2-MeTHF (2×5 mL) and the filtrate used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:14]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(-c2ncccc2CO)c1
Product: COc1cccc(-c2ncccc2CCl)c1
Reaction time: 2 h
Yield: 55 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [2-(3-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to furnish 600 mg (55%) of 3-(chloromethyl)-2-(3-methoxyphenyl)pyridine as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:6]=2[C:5]([F:20])=[C:4]([F:21])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([S:35]([N:9]2[C:10]3[C:2]([F:1])=[CH:3][C:4]([F:21])=[C:5]([F:20])[C:6]=3[N:7]([C:12]3[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=3[F:19])[C:8]2=[O:11])(=[O:37])=[O:36])[CH2:34][CH2:33]1
Reactant: O=c1[nH]c2c(F)cc(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c(F)cc(F)c2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4,6,7-trifluoro-1-(2-fluoro-4-iodo-phenyl)-1,3,-dihydrobenzimidazol-2-one (0.2 gm, 0.41 mmol) in dry THF (4 ml) under nitrogen was cooled to −78° C. and a solution of 1.0 M LiHMDS (0.41 ml, 0.41 mmol) was added slowly, (2 ml) followed by addition of cyclopropanesulfonyl chloride (0.050 ml, 0.49 mmol). This reaction mixture was kept stirring at room temperature for 16 hours, concentrated to dryness and was taken into EtOAc. The EtOAc was washed with water, dried over sodium sulfate and concentrated to dryness. The residue obtained 1-cyclopropanesulfonyl-4,5,7-trifluoro-3-(2-fluoro-4-iodo-phenyl)-1,3-dihydro-benzimidazol-2-one 5 was taken into dioxane (2 ml) and to this 1.0 N NaOH (0.5 ml) was added and kept stirring at room 50° C. for 16 hours. TLC indicated incomplete reaction, the product was purified by HPLC to provide off-white solid (4.4 mg) M+H+: 484.7, M−H+: 486.7. 1H NMR (CDCl3, 300 MHZ): 0.9-1.1-(m, 2H); 1.1-1.2 (m, 2H); 2.45-2.55 (m, 1H); 6.05 (s, 1H); 6.44-6.54 (m, 1H); 7.1 (s, 1H); 7.4-7.7 (d, 1H); 7.38-7.44 (dd, 1H); m/z=485 [M−1]−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of compound 5g (0.26 g, 0.49 mmol) in DCM (8 mL) was added TFA (2 mL). The solution was stirred at rt for 3 h, and concentrated to obtain a residue that was washed with Et2O (3×20 mL) and isolated as a yellow solid, compound 40. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.52-8.63 (m, 1H), 8.11-8.24 (m, 4H), 8.01-8.11 (m, 2H), 7.79-7.98 (m, 5H), 7.61-7.75 (m, 1H), 6.49 (d, J=5.6 Hz, 1H), 4.11 (br. s., 4H), 3.83-3.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O3: 478.2 (M+H). Found 478.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>S(Cl)(Cl)=O>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: COc1cccnc1C(=O)O
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: COc1cccnc1C(=O)Nc1nnn[nH]1
Yield: 8.6 %

Procedure:
1.45 g of 3-methoxy-2-pyridinecarboxylic acid, 30 ml of thionyl chloride and 0.95 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.18 g of N-(5-tetrazolyl)-3-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23]I)([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:28].O>CCOCC>[C:10]([C:7]([C:4]([C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23][OH:28])([F:21])[F:20])([F:17])[F:16])([F:3])[F:2])([F:6])[F:5])([F:9])[F:8])([F:13])([F:12])[F:11]
Reactant: CNC=O
Reactant: FC(F)(CCI)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: OCCC(F)(F)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Ethylene (56 g) was introduced to an autoclave charged with C4F9(CH2CF2)2I (714 g) and d-(+)-limonene (3.2 g), and the reactor heated at 240° C. for 12 hours. The product was isolated by vacuum distillation to provide C4F9(CH2CF2)2CH2CH2I. A mixture of C4F9(CH2CF2)2CH2CH2I (10 g, 0.02 mol) and N-methylformamide (8.9 mL, 0.15 mol) was heated to 150° C. for 26 hours. The mixture was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (3 mL) and p-toluene sulfonic acid (0.09 g) were added and the mixture stirred at 70° C. for 0.25 hours. Ethyl formate and ethyl alcohol were removed by distillation to give a crude product. The crude product was dissolved in ether, washed with 10 wt % aqueous sodium sulfite, water and brine, in turn, and dried over magnesium sulfate. Distillation provided the alcohol product, CF3(CF2)3(CH2CF2)2CH2CH2OH, (6.5 g, 83% yield): bp 94-95° C. a 2 mm Hg (266 Pascals).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([O:25][CH3:26])=[N:23][C:22]3[C:17]2=[N:18][C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[N:20][C:21]=3[NH2:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC[C:42]1[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:27][C:21]1[N:20]=[C:19]([O:28][CH2:29][CH2:30][O:31][CH3:32])[N:18]=[C:17]2[C:22]=1[N:23]=[C:24]([O:25][CH3:26])[N:16]2[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:42]2[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=2)[CH2:13][CH2:12]1
Reactant: OCc1ccc(CCl)cc1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CO)cc4)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
To the compound (0.84 g, 1.86 mmol) obtained in Example 9, Step (i) was added trifluoroacetic acid (12 ml), and the mixture was stirred at room temperature for 20 minutes. Trifluoroacetic acid was evaporated by an evaporator, and DMF (15 ml), 4-(chloromethyl)benzyl alcohol (0.32 g, 2.04 mmol), and potassium carbonate (1.28 g, 9.30 mmol) were added thereto, and the mixture was stirred at room temperature for 18 hours. The carbonate was removed by filtration, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted three times with chloroform/ethanol=3/1. The resultant was dried over magnesium sulfate, concentrated, and purified by silica gel column (chloroform/methanol=20/1) to give the subtitle compound (0.52 g, 1.11 mmol) as a white solid. Yield: 60%.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C(#N)C>[NH2:9][C:7]([C@H:2]([NH:1][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:8]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: CC(C)C[C@@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of D-Leucinamide (6.0 mmol) in acetonitrile (35 mL) was added 1,3-propanesultone (666 mg, 5.5 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with MeCN (2×20 mL). The solid was suspended in EtOH (50 mL). The suspension was stirred at reflux for 1 hour. The mixture was cooled to room temperature. The solid material was filtered, washed with acetone (1×20 mL) and dried in a vacuum oven (50° C.), affording the title compound (1.03 g, 74%): 1H NMR (D2O, 500 MHz) δ ppm 3.81 (m, 1H), 3.07 (m, 2H), 2.85 (t, 2H, J=7.3 Hz), 2.03 (m, 2H), 1.68 (t, 1H, J=7.8 Hz), 1.58 (m, 2H), 0.83 (m, 6H). 13C (D2O, 125 MHz) δ ppm 171.45, 59.39, 48.01, 45.41, 39.02, 24.24, 22.21, 21.47, 21.13. [α]D=−13.7° (c=0.0019 in water), ES-MS 251 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)[CH2:10][CH3:11]
Reactant: CCCI
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1ccc(=O)cc1
Temperature: 25 °C

Procedure:
The starting material may be prepared as follows: A solution of 4-hydroxypyridine (950 mg.) and 1-iodopropane (2.34 ml.) in acetone (30 ml.) was stirred under reflux for 2 hours with powdered potassium carbonate (2.76 g.). The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated from the filtrate and the residue was purified by chromoatograph on Kieselgel 60 (100 g.) eluting with methylene chloride/MeOH 100:0 to 80:20 v/v to give 1-n-propyl-4-pyridone (1.05 g.), an oil having n.m.r. in CDCl3 :-0.9(t, 3H); 1.75(m, 2H9; 3.7(t, 2H); 6.23(d, 2H); 7.28(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-n-propylpyridinium toluene-p-sulphonate.
Reaction SMILES: [CH2:1]([C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:17][CH:18]=3)[CH:13](O)[CH2:12][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(S(F)(F)[F:38])CC>ClCCl>[F:38][CH:13]1[CH2:12][C:11]2[CH:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:17][CH:18]=2
Reactant: CCCCCCCCc1ccc2c(c1)CC(O)c1cc(CCCCCCCC)ccc1-2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(c1)CC(F)c1cc(CCCCCCCC)ccc1-2

Procedure:
From 2,7-dioctyl-9,10-dihydrophenanthren-9-ol by reaction with DAST in abs. dichloromethane.
Reaction SMILES: [Cl:1][C:2]([Cl:10])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][OH:9].[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([Cl:10])[Cl:1]
Reactant: OCCCOCC=C(Cl)Cl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 4.7 %

Procedure:
To a mixture of 1.30 g of 3-(3,3-dichloro-2-propenyloxy)propanol, 2.02 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.89 g of triphenylphosphine and 20 ml of tetrahydrofuran was slowly added dropwise 1.42 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(3,3-dichloro-2-propenyloxy)propyloxy)benzene (yield, 4.7%), nD18.5 1.5530.