Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CC(C)(C)C(=N)NO
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.68 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([Cl:10])[C:7]([N+:11]([O-:13])=[O:12])=[C:6](Cl)[CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([NH:29][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=[C:8]([Cl:10])[C:7]=1[N+:11]([O-:13])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(C2CC2)nc1Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
6-Cyclopropyl-2,4-dichloro-3-nitro-pyridine (160 mg, 0.8 mmol) was dissolved in THF (2 mL) and triethylamine (104□l, 0.8 mmol) and benzylamine (81□l, 0.8 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours by which time a yellow precipitate had formed. The volatiles were removed in vacuo and the residue was stored in a stoppered flask at room temperature for 10 days. The residue was purified by column chromatography on silica gel eluting with 99:1 DCM:MeOH then 98:2 DCM:MeOH to give the title compound (185 mg) as a yellow crystalline solid.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([O-])=O>O.C1COCC1.[Zn]>[C:13]1([NH:12][C:9]2[CH:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonium chloride (48 mg, 9 mmol) in water (1 mL) was added to a stirred solution of (4-nitro-phenyl)-phenyl-amine (200 mg, 0.9 mmol) in THF (4 mL). Zinc powder (48 mg, 7.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 2 hours then filtered over celite. The filtrate was extracted with ethyl acetate and the ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated to 160 mg (96%) of N-phenyl-benzene-1,4-diamine. LCMS: 185.1 (M+1)+, 93.9%, 1H NMR: (DMSO-d6): 67.2 (t, 2H), 7.0 (d, 2H), 6.8 (m, 2H), 6.7 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([Cl:20])[C:7]=1[OH:8]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO3 solution and water, dried over Na2SO4, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). 1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)=O.[NH2:21][C:22]([NH2:24])=[O:23]>Cl.O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:24][C:22](=[O:23])[N:21]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)[CH:10]=1
Reactant: Cc1cc(C(=O)/C=C/c2cccc(Cl)c2Cl)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3cccc(Cl)c3Cl)[nH]c(=O)n2)ccc1O
Temperature: 120 °C
Yield: 25.2 %

Procedure:
A mixture of (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one (123 mg, 0.4 mmol) and urea (28 mg, 2.0 mmol,) (SIGMA-ALDRICH) in 4N HCl/dioxane (5 mL) was heated to 120° C. in a sealed vessel overnight. The reaction was complete as determined by LCMS, and the solution was cooled to room temperature. The crude reaction mixture was purified by reverse-phase HPLC (acetonitrile/10 mM aqueous ammonium acetate) to yield the desired product (35 mg, 25%) 1H NMR (400 MHz, d6-DMSO): 7.93 (s, 1H), 7.80-7.82 (dd, 1H), 7.49-7.58 (m, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 2.18 (s, 3H). MS (EI) for C17H12Cl2N2O2: 348.5 (MH+).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CS(Cl)(=O)=O.[NH2:15][C:16]1[N:21]=[C:20](N)[N:19]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:17]=1.[N:35]1C=CC=CC=1>>[NH2:15][CH:16]1[N:21]=[C:20]([C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[N:19]=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([O:33][CH3:34])=[CH:25][CH:24]=2)[N:17]1[NH2:35]
Reactant: c1ccncc1
Reactant: COc1ccc(-c2nc(N)nc(N)n2)c2ccccc12
Reactant: O=C(O)c1cccnc1
Agent: CS(=O)(=O)Cl
Product: COc1ccc(C2=NC(C(=O)c3cccnc3)=NC(N)N2N)c2ccccc12
Reaction time: 3 h

Procedure:
Nicotinic acid (2.98 grams) was dissolved in 40 ml of pyridine, 1.39 grams of methanesulfonyl chloride was added thereto, and the mixture was heated to reflux for thirty minutes. Then 2.7 grams of 2,4-diamino-6-(1-methoxy-4-naphthyl)-s-triazine was added thereto, the mixture was heated to reflux for four hours, and the refluxing was continued for three hours more after addition of 0.35 gram of methane sulfonyl chloride. After the reaction was completed, pyridine was evaporated therefrom, water was added to the residue, the crystals separated out were collected by filtration, well washed with water, added to 130 ml of methyl alcohol, the mixture was heated to reflux for twenty minutes, and the crystals were collected by filtration when the solution was still hot. The crystals were then suspended in 50 ml of methyl alcohol, the suspension was heated to reflux for three hours, and dioxane was added to the suspension to afford 2-amino-4-nicotinoyl-amino-6-(1-methoxy-4-naphthyl)-s-triazine, beige needles, melting point 208° to 209° C. The yield was 1.84 grams.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C1(C)C=CC=CC=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.ClS(NC(N)=O)(=O)=O>O>[CH3:1][C:2]1[C:7]([NH:8][C:27]([NH2:26])=[O:28])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Reactant: O=C=NS(=O)(=O)Cl
Agent: NC(=O)NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1NC(N)=O

Procedure:
40 of 6-methyl-2,4-dinitroaniline are stirred for 4 hours at 80° C. in 500 parts of toluene with 34 parts of chlorosulfonyl isocyanate. The suspension of the chlorosulfonyl urea obtained is mixed at 25° C. with 40 parts of water and saponified at 60° C. to give 6-methyl-2,4-dinitrophenyl urea.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:30]=[N:31][CH:32]=1.NC1C=NC=C(C)C=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])[CH:30]=[N:31][CH:32]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: Cc1cncc(NC(=O)Oc2ccccc2)c1
Agent: Cc1cncc(N)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-methylpyridin-3-ylcarbamate (0.274 g, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-5-methylpyridine) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and the mixture was heated to 60° C. After 4 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined and were washed with brine and dried over sodium sulfate, filtered and concentrated to form a residue. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound as a white foam (300 mg, 64%). MS (APCI 10V) AP+ 458.16; 1H NMR (400 MHz, DMSO) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.38 (s, 1H) 7.03 (m, 2H) 7.13 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.58 Hz, 1H) 7.4 (dd, J=7.8 Hz, 2 Hz, 1H) 7.70 (s, 1H) 7.96 (d, J=2 Hz, 1H) 8.20 (dd, J=8.8 Hz, 2.5 Hz, 1H) 8.41 (d, J=2.2 Hz, 1H) 8.55 (s, 1H) 8.64 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:18](N(CC)CC)C.ClC(OCC)=O.[C:31]1([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2(C)[CH2:42][NH2:43])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1>O.CC(C)=O>[C:31]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH:42]([CH3:18])[NH:43][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: CC1(CN)CCCN1C1=CCCCC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NC(C)C2CCCN2C2=CCCCC2)c1OC
Temperature: 0 °C

Procedure:
13 g of 2,3-dimethoxy-5-sulphamoyl-benzoic acid (0.05 mole), 150 ml of acetone, 35 ml of water and 5 g of triethylamine (0.05 mole) are placed in a 500 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The mixture is cooled to between 0° and +5° C. and 5.5 g of ethyl chloroformate (0.05 mole) is poured in drop by drop. The reaction medium is agitated until the precipitate is completely dissolved, then re-cooled to 0° C. and 9.7 g of 1-(1-cyclohexenyl)-methyl-2-aminomethylpyrrolidine (0.05 mole) is poured in drop by drop.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[N:10]([CH3:16])[C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:17])[CH:4]=[C:3]1[CH2:18][C:19]([OH:21])=[O:20].[C:22]([NH:25][CH:26](O)[CH3:27])(=[O:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:22]([NH:25][CH2:26][CH2:27][O:20][C:19](=[O:21])[CH2:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]([C:9]2[N:10]([CH3:16])[C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)=[O:8])=[C:5]([CH3:17])[CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)NC(C)O
Reactant: CSc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2c(C)cc(CC(=O)OCCNC(C)=O)n2C)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 1.1 g of 1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-oyl)pyrrole-2-acetic acid, 0.52 g of N-acetyl aminoethanol, 1.05 g DCC and 0.21 g of N,N-dimethylaminopyridine in 75 ml dry CH2Cl2 was stirred at ambient temperature for 16 hours, concentrated and extracted twice with 10 ml portions of CH2Cl2. The crude product is crystallized from ethyl acetate to yield 0.96 g (70% yield) of acetamidoethyl-1,4-dimethyl-5-(1-methyl-5-methylthiopyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC=CC=1)([O-])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].Cl>O.C(#N)C>[C:19]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: NCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: C=C(C)C(=O)NCCCC(=O)O
Temperature: 0 °C
Yield: 93 %

Procedure:
In a mixture composed of 80 g (2.0 mol) of sodium hydroxide, 400 ml of water and 4 ml of nitrobenzene was dissolved with stirring 214 g (2.0 mol) of γ-aminobutyric acid and the mixture was cooled to 0° C. To the aqueous solution, there were simultaneously added dropwise 230 g (2.2 mol) of methacrylic chloride and an aqueous solution containing 96 g (2.4 mol) of sodium hydroxide dissolved in 200 ml of water. After the completion of the reaction, 800 ml of acetonitrile was added to the reaction solution and the mixture was then acidified by adding 160 ml of concentrated hydrochloric acid and extracted with acetonitrile. The acetonitrile solution was concentrated to obtain 318.4 g of N-methacryloyl-γ-aminobutyric acid as an oily product.
Reaction SMILES: [O:1]1[CH2:5]CCC1.Cl[C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3Cl)[C:12](=[O:23])[C:11]=2[CH:10]=[CH:9][CH:8]=1.C1OCCOCCOCCOCCOCC[O:26][CH2:25]1.C[O-].[Na+]>CO.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:25][O:26][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:1][CH3:5])[C:12](=[O:23])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cccc2c1C(=O)c1c(OC)cccc1C2=O
Yield: 50 %

Procedure:
A 5-liter round-bottom flask equipped with an overhead stirrer, thermocouple, and reflux condenser with a nitrogen/vacuum outlet was charged with 1200 mL of tetrahydrofuran, 138.5 grams of 1,8-dichloroanthraquinone, and 35.6 grams of 18-crown-6. This solution was deoxygenated, stirred under nitrogen, and heated until a clear solution was obtained. A solution of 165.0 grams of sodium methoxide in 1000 mL of methanol (prepared from sodium metal) was then added over a period of 30 min. The reaction mixture was heated at reflux for 24 hours, at which time TLC (silica gel, 1:1 EtOAc/toluene) indicated that the reaction was complete. The reaction was cooled overnight in an ice bath and the crystallized product isolated by filtration (82% crude yield). This material was recrystallized from 1000 mL of toluene to afford 1,8-dimethoxyanthraquinone in an overall yield of 50%.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:53][O:54][C:55]1[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[C:58]([O:64][CH3:65])[C:56]=1[NH2:57].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:57][C:56]2[C:58]([O:64][CH3:65])=[CH:59][C:60]([O:62][CH3:63])=[CH:61][C:55]=2[O:54][CH3:53])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 138°-140° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][CH2:11][C:12](O)=[O:13].FC(F)(F)S(O)(=O)=O.C(Cl)(Cl)Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:12](=[O:13])[CH2:11][CH2:10][Cl:9]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCl)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a stirred mixture of resorcinol (200 g, 1.82 mol) and 3-chloropropionic acid (200 g, 1.84 mol) was added trifluoromethane sulfonic acid (1 kg) in one portion. The solution was heated slowly over about 45 minutes to about 80° C. then cooled to room temperature over about 15 minutes and poured into chloroform (4.0 L). The organic portion was slowly poured into water (4.0 L) and the layers separated. The aqueous layer was extracted with chloroform (2×2.0 L). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave as an orange semi-solid (244.1 g) which was used crude in the next step. 1H-NMR (300 MHz, CDCl3): 12.56 (1H, s), 7.63 (1H, d, J=7.6), 6.376.46 (2H, m), 3.92 (2H, t, J=6.3), 3.41 (2H, t, J=6.3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](N)=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:20]=O.[BH3-][C:23]#[N:24].[Na+].OS(O)(=O)=O>CO.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([N:24]([CH3:23])[CH3:20])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: [BH3-]C#N
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)c1cc(C(C)(C)C)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of 1-(4′-nitrophenyl)-3-t-butyl-5-aminopyrazole (I mmol) and formaldehyde (10 mmol, 37% w/w in H2O) in MeOH (7.5 mL) was stirred at rt for 30 minutes. Acetic acid (2.5 mL) and NaCNBH3 (2 mmol) were added, and after 1 hour additional NaCNBH3 (2 mmol) was added. After 1 hour, 1N H2SO4 was added, the solvent was removed and the residue was neutralized with NaHCO3. The solid product was collected by filtration, washed with water and dried to give 1-(4′-nitrophenyl)-3-t-butyl-5-dimethylaminopyrazole (0.265 g, 92%). Transfer hydrogenation of the nitro compound (0.89 mmol) as described in general in Method L gave 1-(4′-aminophenyl)-3-t-butyl-5-dimethylaminopyrazole (0.228 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])=[CH:4][CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl.N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:14][CH:15]=1
Reactant: COC(CNCc1ccc(Br)cc1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
60.5 g (4-Bromo-benzyl)-(2,2-dimethoxy-ethyl)-amine (1, crude product) were dissolved in 270 ml of dichloromethane/pyridine (8:1). At 0° C. a solution of 76.0 g (386.4 mmol) p-toluenesulfonylchloride in 100 ml of dichloromethane was added and the solution was stirred at room temperature. After 3 h, the reaction mixture was washed twice with 2 N HCl and saturated sodium hydrogen carbonate-solution. The organic layer was dried over magnesium sulfate and evaporated. Final silica gel chromatography (heptane/ethylacetate 4:1) gave 59.9 g of the title compound. Rt=1.82 min (Method C). Detected mass: 396.1/398.1 (M−OMe−).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8](Cl)=[CH:9][C:10]=1[CH3:11])=[O:4].C([O-])([O-])=O.[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Yield: 30.4 %

Procedure:
A solution of 5.2 g (23.7 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester, 3.94 g (28.5 mmol) K2CO3 and 2.06 ml (23.7 mmol) morpholine in DMF (48 ml) was heated to 60° C. for 16 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 1.95 g (7.2 mmol, 30%) 2-chloro-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14]COC)[C@H:10]([CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.59 mmol, 0.93 g) in a mixture of methanol (2 mL) and DCM (0.5 mL) was added 4 N HCl in dioxane (5 mL) at room temperature and continued stirring for 1 h. The progress of the reaction was monitored by LCMS analysis of an aliquot of the reaction mixture. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and added 2 N sodium hydroxide solution (2 mL) followed by di-t-butyl dicarbonate (1 g) and the resultant reaction mixture was stirred at room temperature for 2 h. The organic layer was separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography by eluting with 50% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:5]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(Br)c3ccccc3)CC2)c1

Procedure:
Example 10 was prepared from bromo(phenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 486.1 (M+H)+.