Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]CC=C)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C(OCC)(=O)C.Cl[C:25]1[CH:30]=CC=C[C:26]=1Cl>CCCCCC>[OH:14][C:13]1[C:12]([CH2:30][CH:25]=[CH2:26])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(C(=O)OC)cc1CC=C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Yield: 97 %

Procedure:
The product of Step A (3.2 g, 13.8 mmol) was refluxed in 1,2-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:6]([C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Product: COc1cc(Cl)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3
Yield: 58 %

Procedure:
In a manner analogous to that described in Example 2, from 4-chloro-2-methoxybenzoyl chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2one (see Example 13 a)), after column chromatography, there was obtained a yield of 58% of theory of the title compound; m.p. 300 -303° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[Br:19][C:20]1[O:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[Br:19][C:20]1[O:21][CH:22]=[C:23]([C:25]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:26])[N:24]=1
Reactant: O=C(O)c1coc(Br)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(Br)n1
Yield: 12.4 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (741 mg, 2.82 mmol) and 2-bromooxazole-4-carboxylic acid (850 mg, 3.41 mmol). The product was purified by Flash-chromatography. Yield 12.4%. 1H-NMR (400 MHz; CDCl3): δ 1.20 (d, 3H), 4.18-4.47 (m, 2H), 4.51-4.65 (m, 1H), 6.64 (d, 1H), 7.48 (d, 1H), 7.72 (dd, 1H), 7.92-7.99 (m, 3H), 8.21 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH3:21])[CH:23]=2)[NH:27][C:26]1=[O:31])([OH:16])=[O:15]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 95 °C
Yield: 70.3 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (560 mg), 5-methyl-2-oxindole (300 mg), and piperidine (4 drops) in ethanol (4 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for an additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 496 mg of 4-(2-carboxyethyl)-3-methyl-5-(5-methyl -2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:24][CH:23]=1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
reacting the 4-(quinolin-2-ylmethoxy)phenylhydrazine product of step (4) with p-chlorobenzyl chloride, tetrabutylammonium bromide and diisopropyl ethyl amine to yield 1-(p-chlorobenzyl)-1-[4(quinolin-2-yl-methoxy)phenyl]hydrazine.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:40][CH3:41])(=O)=O.O>CC(C)=O>[CH2:40]([O:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29])[CH3:41]
Reactant: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 117.4 %

Procedure:
A mixed solution of N-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 135 (300 mg, 0.76 mmol), potassium carbonate (105 mg, 0.76 mmol) and diethyl sulfate (117 mg, 0.76 mmol) in acetone (15 mL) was refluxed with heating for 14 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of the title compound. Melting point: 174-175° C. (hexane).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(F)(F)F)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].Cl.Cl.[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][NH:26][CH2:27]2.C(N(C(C)C)C(C)C)C>CC#N>[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:16]([F:17])([F:18])[F:19])[CH2:27]2
Reactant: CN1C2CCCC1CNC2
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1C2CCCC1CN(Cc1ccc(N)cc1C(F)(F)F)C2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of 296 mg (0.85 mMol) N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (WO 2005/051366; Step 14.2) in 5 ml of CH3CN is added at 5° C. within 30 min to a solution of 213 mg (1.00 mMol) 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane dihydrochloride (synthesized according to Barnes, Roderick A. et al.: J. Am. Chem. Soc. 1953, 75, 975) and 0.7 ml (4 mMol) ethyldiisopropylamine in 10 ml CH3CN. After 1.5 h at 5-10° C., the solvent is evaporated off under reduced pressure. The residue is dissolved in EtOAc and washed with NaHCO3. The aq. phase is re-extracted with EtOAc and the combined organics are washed with water, brine and dried over Na2SO4. The solvent is evaporated off under reduced pressure and the residue is dissolved in a mixture of 10 ml MeOH and 2 ml of a 2 M NaOH solution and stirred at 50° C. for 3 h. The MeOH is evaporated off under reduced pressure, the mixture is diluted with water and extracted 3 times with EtOAc. The combined organics are washed with water and brine and dried (Na2SO4). The solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:13](=[O:20])[NH:14]2)([CH3:4])([CH3:3])[CH3:2].Cl[CH:32]([F:34])[F:33]>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:29])=[C:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=1)[C:13]([O:20][CH:32]([F:34])[F:33])=[N:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)Cl
Reactant: Cc1c(Cc2ccc(Br)cc2)c(=O)[nH]c2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [3-(4-bromobenzyl)-8-chloro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid tert-butyl ester and chlorodifluoromethane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:22](=[NH:23])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-trifluoromethylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1.[OH-].[Na+].Cl>CO>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1
Reactant: CCOC(=O)CCc1c[nH]c2cnc(-n3cnnc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1c[nH]c2cnc(-n3cnnc3)cc12
Temperature: 40 °C
Yield: 223.5 %

Procedure:
To a solution of ethyl 3-(5-(1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionate (0.115 g, 0.4 mmol) in methanol (5 mL) was added NaOH (4M, 0.5 mL, 2 mmol) and the mixture heated at 40° C. for 16 hours. After cooling the solution was neutralised (5M HCl) and the solvents evaporated to give 3-(5-(1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.23 g) as a colourless solid. 1H NMR (360 MHz, d6 -DMSO) δ 2.48-2.55 (2H, m), 2.96 (2H, t, J=7.1Hz), 7.54 (1H, s), 8.03 (1H, s), 8.62 (1H, s), 9.24 (2H, s) and 11.81 (1H, br s). This was used without further purification in the next step.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[N:4]1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[N:4]=1)#[N:9]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: N#Cc1ccn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 58.8 %

Procedure:
1.00 g of 1-(chloromethyl)-3-cyano-1H-pyrazole and 1.15 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.96 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.11 g of [(3-cyano-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (9), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[O:16][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:18][N:19]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:28].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([N:14]=[C:15]3[NH:19][CH:18]=[C:17]([CH2:20][C:21]([NH2:28])=[O:23])[O:16]3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCc1cc(Nc2ncc(CC(=O)OC)o2)nc(-c2cccc(Cl)c2)n1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CCc1cc(N=c2[nH]cc(CC(N)=O)o2)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 65 h
Yield: 71.3 %

Procedure:
A 20-mL vial was charged with methyl 2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)oxazol-5-yl)acetate (0.073 g, 0.20 mmol) and ammonium chloride (0.031 g, 0.59 mmol). To this was added methanol (4 mL) followed by NH3 (5.6 mL, 7N in methanol, 39 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 65 h. The crude reaction solution concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using dichloromethane/methanol (10:0 to 8:2) as eluent to afford 2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)imino)-2,3-dihydrooxazol-5-yl)acetamide (0.051 g, 72%) as an off-white solid. MW=357.79. M.p.>260° C. 1H NMR (DMSO-d6, 300 MHz) δ 8.68 (s, 1H), 8.61 (s, 1H), 8.37-8.32 (m, 2H), 8.00 (s, 1H), 7.63-7.52 (m, 2H), 5.34 (d, J=8.1 Hz, 1H), 5.19 J=8.1, 8.1, 3.3 Hz, 1H), 2.99 (dd, J=18.0, 8.4 Hz, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.44 (dd, J=18.3, 3.6 Hz, 1H), 1.27 (t, J=7.5 Hz, 3H); APCI MS m/z 358 [M+H]+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[NH:15][C:16](=[O:19])[CH2:17][Br:18].C(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[NH:15][C:16](=[O:19])[CH2:17][Br:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CBr)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(OS(=O)(=O)c2ccccc2)c1

Procedure:
To a mixture of 4.4 g. of benzene sulfonyl chloride and 5.7 g. of 3'-hydroxy bromoacetanilide in 100 ml. of methylene chloride is added dropwise 2.6 g. of triethylamine. The product is recovered by washing with cold water, drying and removal of the solvent. There is obtained 9.0 g. of the title compound, nD30 = 1.5830.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH3:7])=[NH:5])#[N:2].Cl.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1.N>O>[CH3:7][NH:6][C:4]([NH:3][C:1]([NH:9][C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1)=[NH:2])=[NH:5]
Reactant: Cc1cc(N)no1
Reactant: CNC(=N)NC#N
Agent: Cl
Agent: N
Solvent: O
Product: CNC(=N)NC(=N)Nc1cc(C)on1
Yield: 27.6 %

Procedure:
In a reactor are added 4.9 g of 1-cyano-3-methyl-guanidine, 6.7 g of 3-amino-5-methyl-isoxazole hydrochloride and 1.3 ml of water. The reaction mixture is heated until dissolution is complete, after which the reaction is exothermal. After cooling, the reaction mixture is taken up into 30 ml water followed by 3 ml ammonia (d = 0.89). It is then extracted with 30 ml methylene chloride. After drying, treatment with carbon black and evaporation of the solvent, the residue is crystallized from absolute ethanol, to give 2.7 g of 1-methyl-5-(5-methyl-isoxazol-3-yl)-biguanide. M.p. (cap.) = 140° C. followed by resolidification, then 150°-151° C. with introduction at 140° C. and heating at a rate of 2° C./minute.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]=1.[OH-].[Na+].Cl.O>CO>[C:10]([O:9][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:3]([OH:39])=[O:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1ccc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
4-(14-tert-Butoxycarbonyl-tetradecyloxy)-isophthalic acid 3-tert-butyl ester 1-methyl ester (381 mg, 0.69 mmol) was dissolved in methanol (10 ml). The solution was cooled to 0° C. and 4 N NaOH (1 ml) was added. The solution was allowed to warm to rt and more methanol (15 ml) was added. The reaction was stirred at rt for 30 min under N2, and at reflux for 2 h. The solution was cooled to 0° C. and 1 N HCl (1 ml) was added slowly. Water (25 ml) was added, and the solution was extracted with AcOEt (2×50 ml). The organic phases were pooled and washed with 1:1 water/sat. NaCl, dried over MgSO4, and concentrated under vacuum to yield an oily solid (326 mg, 89%)
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][CH:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25].Cl>>[NH2:26][C:24](=[O:25])[CH:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]2[CH2:5][C:2]([F:1])([F:21])[CH2:3]2)=[CH:11][N:10]=1)=[O:13])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(N)C(N)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 2-Amino-3,3-dimethyl-butyramide; hydrochloride (CAN 113582-42-6) as starting materials and isolated (32 mg, 47%); MS (ESI, m/z): 425.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([Cl:23])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
Piperidine-1,4-dicarboxylic acid monobenzyl ester (40.2 g, 0.15 mol) in dichloromethane (300 mL) was treated with oxalyl chloride (100 g, 0.79 mol). The reaction mixture was stirred at ambient temperature for 4 hours and the mixture was concentrated to afford crude 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (43 g), which was used without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])C.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[F:17][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:4](=[O:5])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=[C:15]3[C:14]=2[N:13]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Temperature: 135 °C
Yield: 85 %

Procedure:
In a vial were added 4a, phenyl hydrazine and triethylamine. The vial was sealed and heated to 135° C. for 12 hours. The product was collected by filtration and was washed with methanol in 85% yield. 1H-NMR (DMSO-d6) δ (ppm): 7.18 (1H, dd, J=7.41, 7.14 Hz), 7.50 (3H, m), 8.26 (3H, m), 8.81 (1H, s). m/z 281.3 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([O:37]C)=[O:36])[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (58 mg, 0.11 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.18 mL, 0.18 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 1 N hydrochloric acid (0.18 mL, 0.18 mmol). The solution was extracted twice with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (52 mg, 92%). 1H-NMR (400 MHz, DMSO-d6) δ 13.36 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.95 (d, J=9 Hz, 2H), 4.93 (s, 2H), 2.49-2.43 (m, 1H), 1.20-1.10 (m, 4H). HRMS (ESI) C29H20Cl2N2O4 calculated: 531.0873 [M+H]+, found: 531.0873 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][NH2:8])[CH:3]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[N:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: Cc1cc(CN)no1
Reactant: COC(OC)N(C)C
Product: Cc1cc(CN=CN(C)C)no1
Temperature: 25 °C

Procedure:
A solution of the C-(5-methyl-isoxazol-3-yl)-methylamine (150 mg, 1.3 mmol) in N,N-dimethylformamide dimethylacetal (2 mL, 14.4 mmol) was heated under reflux for 3 h. After cooling to room temperature, the solvent was evaporated to leave the title compound as a yellow oil (220 mg, 98%. m/z 168.2 (MH)