Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30](O)=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>O>[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1ncc(C(=O)O)c(C)n1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To 50 ml of N,N-dimethylformamide were dissolved 6.6 g (33 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 7.6 g (36 mmol) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 3.6 g (43 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 3.3 g (yield: 32%) of 4,4-difluoro-3-methyl-3-butenyl 2-butoxy-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=[O:7].C[Si](C)(C)[O-].[K+:15]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O-:8])=[O:7].[K+:15]
Reactant: COC(=O)c1ccco1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C([O-])c1ccco1
Yield: 90.6 %

Procedure:
The procedure of Example 1 was followed using methyl 2-furoate (2.52 g, 20 mmol), potassium trimethylsilanolate (2.56 g, 20 mmol), dry tetrahydrofuran (50 mL), and a 5 h reaction time. Potassium 2-furoate (2.72 g, 90% yield) was isolated as a light brown solid: 1H NMR (D2O, DSS) δ 6.55 (m, Ar--H, 1H), 7.0 (m, Ar--H, 1H) and 7.6 ppm (m, Ar--H, 1H). Anal. Calcd. for C5H3KO3 : C, 39.99; H, 2.01; K, 26.04. Found: C, 37.22, 37.41, 40.26; H, 2.33, 2.19, 2.34; K, 26.22.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[C:9]([NH:13][NH2:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].C[O:16][C:17](=O)[N:18]=[C:19](SC)[C:20]([C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[F:46])=[N:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[N:13]1[C:17](=[O:16])[NH:18][C:19]([CH:20]([C:34]2[CH:43]=[C:42]([O:44][CH3:45])[C:37]3[O:38][CH2:39][CH2:40][O:41][C:36]=3[C:35]=2[F:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)=[CH:24][CH:23]=2)=[N:14]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of 62 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 106 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 41d) and 88 μl of triethylamine in 5 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere with stirring. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of methanol, and then 133 mg of sodium cyanotrihydroborate, 49 μl of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (68 mg) as a light green solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: C[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](C)C3)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and (2,5-Dichloro-pyrimidin-4-yl)-[2-((S)-3-methyl-pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.035 g, 29%). MP: 65-85° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.37 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.25-7.20 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.64 (t, J=5.4 Hz, 2H), 3.43 (dd, J=9.5 Hz and 7.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.30-3.22 (m, 1H), 2.90-2.86 (m, 2H), 2.80 (dd, J=9.5 Hz and 7.5 Hz, 1H), 2.24-2.11 (m, 1H), 1.96-1.87 (m, 1H), 1.43-1.33 (m, 1H), 0.86 (d, J=6.6 Hz, 3H). MS: 587.16 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH2:12]([CH:11]([N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][C:6]=2[N:16]=[C:17]1[CH2:18][C:19]1[O:23][N:22]=[CH:21][CH:20]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccno1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)n1c(Cc2ccno2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 88.4 %

Procedure:
To 1.06 g 4-(1-Ethyl-propylamino)-3-(2-isoxazol-5-yl-acetylamino)-benzoic acid methyl ester were added 7.5 ml of 4M hydrochloric acid in dioxane. The reaction mixture was heated to 130° C. for 20 min in a microwave reactor. After cooling to rt 2 ml of water were added and the reaction was again heated to 130° C. for 20 min. The reaction was concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 0.85 g (90%) of 1-(1-Ethyl-propyl)-2-isoxazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9]C(=O)C(C)(C)C)[CH:3]=1.Cl.[OH-].[Na+]>>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)c(Cl)cn1
Temperature: 100 °C

Procedure:
A mixture of 4,5-dichloro-2-trimethylacetamido-pyridine (0.500 g, 2.02 mmol) and aqueous HCl (6N; 9.5 ml) was heated was heated at 100° C. for 17 h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water (˜15 ml), and the pH of the mixture was adjusted to ˜7.0 with 10% aqueous NaOH. The white precipitate was collected by filtration, washed with water (2×5 ml), and dried in vacuo over P2O5. The title compound was obtained as a white solid (0.284 g, 86%); 1H-NMR (500 Mz, DMSO-d6) 6.44 (s, 2H, NH2, exchangeable with D2O), 6.64 (s, 1H), and 8.03 (s, 1H) (3-H, 6-H); LC-MS (ESI, m/z) 4.37 min—163, 165, 167 [(M+H)+, Cl2 isotopic pattern].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:27][C:28]([F:31])([F:30])[F:29])(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCC(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a magnetically stirred solution of 3-chloro-5-hydroxybenzaldehyde (2.0 g, 12.8 mmol; see Example 1(ii) above) and potassium carbonate (2.3 g, 16.6 mmol) in DMF (35 mL) under nitrogen was added 2,2,2-trifluoroethyl p-toluenesulfonate (4.2 g, 16.6 mmol) at room temperature. The mixture was heated to 110° C. for 7 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2 N HCl (100 mL) and extracted with EtOAc (2×75 mL). The combined organic extracts were washed with 0.5 N HCl (2×50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (6:1) to afford the sub-title compound (1.9 g, 61%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][CH3:11])[C:7]#[N:8].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CO>CN(C=O)C>[CH2:19]([O:18][C:16]([C:15]1[N:10]([CH3:11])[C:9]2[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=2[C:7]=1[NH2:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: CNc1c(F)cncc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c2cncc(F)c2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
5-Fluoro-4-methylamino-nicotinonitrile (2.35 g, 15 mmol) was dissolved in DMF (50 mL) and the solution cooled in an ice-bath. This solution was treated portionwise with sodium hydride (900 mg, 60% in oil, 22.5 mmol). The mixture was allowed to warm to room temperature and stirring continued for 15 minutes at room temperature. Ethyl bromoacetate (2.49 ml, 22.5 mmol) was added and the mixture stirred for 30 minutes at room temperature The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was isolated, dried (Na2SO4) and evaporated to give a solid. Trituration of the resultant solid with methanol gave the title compound (1.85 g, 52%) as a yellow solid. LCMS (method B): RT=2.09 min, M+H+ 238.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[Cl:11]([O-])(=O)=O.[K+]>Cl>[Cl:11][C:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:1]=[CH:2][C:3]=1[OH:10]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
p-nitrophenol (69.55 g, 0.5 mole) was dissolved in 10 N HCl (200 ml) in a 1000 ml flask with heating and then cooled down. To the mixture was added 600 ml potassium chlorate (61.25 g, 0.5 mole) solution, gradually with stirring. Stirring was continued for 1 hour after completion of addition and mixture was left overnight at room temperature. After filtration with vacuuming, the filtrate was washed with distilled water and recrystallized with dilute acetic acid solution to yield pale yellow acicular crystal, 2-chloro4-nitro-phenol (80.2 g, m.p. 110–111° C., yield rate 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>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>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:7][N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(F)nc2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (1.75 g, 9.94 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.069 g, 9.94 mmol), Pd(PPh3)4 (1.149 g, 0.994 mmol) and K2CO3 (2.75 g, 19.89 mmol) in 1,4-dioxane (20 ml) was bubbled with argon for 10 min. The suspension was then stirred at 90° C. for 8 h. The mixture was filtered and the filtrate was diluted with EA, washed with water and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. The residue was recrystallized from MeOH to give the title compound as white solid (1.2 g, 61.3% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1H), 8.22 (s, 1H), 8.15 (dd, 1H), 7.93 (s, 1H), 7.18 (dd, 1H). LCMS (method B): [M+H]+=178, tR=1.80 min.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CO>ClCCl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CN1C(=O)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CN1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a solution of 1,1-dimethylethyl 2-methyl-3-oxo-1-pyrazolidinecarboxylate (0.98 g, 4.89 mmol) in dry dichloromethane was added borane dimethyl sulfide complex (1.16 ml, 12.24 mmol). The mixture was stirred at rt overnight. LCMS indicated ˜40% starting material left. Another portion of borane dimethyl sulfide complex (0.5 ml, 5.28 mmol) was added, and stirring continued overnight. Methanol was added dropwise to the reaction mixture until bubbling ceased. Water (1 ml) was then added, and the mixture was refluxed for 1 h. After cooling to rt, the mixture was concentrated to dryness under vacuum. The residue was taken up in water (30 ml) and dichloromethane (45 ml), the organic layer was separated, and the aqueous layer was extracted with dichloromethane (45 ml). The combined organic solution was dried (Na2SO4), filtered and concentrated to provide 1,1-dimethylethyl 2-methyl-1-pyrazolidinecarboxylate (0.48 g, 52.7%). LCMS: (2M+H)+ 372.9.
Reaction SMILES: [CH2:1]([C:3]([CH3:8])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH3:9][O:10][CH2:11][CH:12]=O.C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:9][O:10][CH2:11][CH:12]1[O:7][CH2:6][C:3]([CH2:1][CH3:2])([CH3:8])[CH2:4][O:5]1
Reactant: CCC(C)(CO)CO
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)COC(COC)OC1
Yield: 89 %

Procedure:
A mixture of 590 g (5 moles) of 2-ethyl-2-methyl1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 500 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The remaining solution was deionized using a mixed-bed ion exchanger, the solvent was removed under reduced pressure and the residue was distilled. 774 g (89% yield) of 2-methoxymethyl-5-ethyl-5-methyl-1,3-dioxane of boiling point 58° C./1 mbar were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:38][CH2:39][NH:40][C:29]([C:28]2[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=2/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)=[O:31])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with 2-pyrrolidin-1-yl-ethylamine to give the titled compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]([CH2:15][NH:16][C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:26])[O:6]1)=O.[C:27](#N)C>>[CH3:25][O:24][C:22](=[O:23])[C@@H:17]([N:16]([CH2:15][C:14]1[CH:5]([CH:3]=[O:2])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([Cl:26])[CH:10]=[CH:9][CH:8]=2)[CH3:27])[CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: COC(=O)C1Oc2cccc(Cl)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Reactant: CC#N
Product: COC(=O)[C@H](CC(C)C)N(C)CC1=Cc2c(Cl)cccc2OC1C=O
Yield: 71.4 %

Procedure:
A solution of 5-chloro-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H-chromene-2-carboxylic acid methyl ester (1.4 g, 3.53 mmol) and N,N′-diisopropylethyl amine (2.44 mL, 14.14 mmol) in acetonitrile (3 mL) was heated in a sealed tube at 140° C. for 48 hours. The reaction mixture, after aqueous work-up, was extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified using flash chromatography over neutral alumina (eluant-hexanes-ethyl acetate 1:3, Rf=0.3) to afford (S)-2-[(5-chloro-2-formyl-2H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid methyl ester (1.02 g, 71.4%) as a solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:26])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:12]=1>O1CCCC1>[Cl:26][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[N:12][N:13]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:18][C:17]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(Cl)cc21
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(NC(=O)Nc2ccccc2)c2cc(-c3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
39 μl of phenyl isocyanate are added to a solution of 102.2 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]indazole in 2.5 cm3 of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 24 hours and is then evaporated. Purification of the crude product by chromatography on silica (eluant: methylene chloride/acetone (98/2, v/v)) makes it possible to obtain 122.5 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-3-yl]-3-phenylurea (colorless solid).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[N:19][OH:20])[NH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[CH:25]([C:31](OC)=O)[CH2:24]2.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:31]([CH:25]3[CH:26]4[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]4)[CH2:24]3)[O:20][N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN2CCC1CC2
Reactant: NC(CCCC1CCN(Cc2ccccc2)CC1)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCC(CCCc3noc(C4CN5CCC4CC5)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 4-(1-benzylpiperidin-4-yl)butanamide oxime (1.0 g), sodium hydride (0.15 g) and molecular sieves 4A (2.0 g) in tetrahydrofuran (50 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added dropwise a solution of methyl 3-quinuclidine carboxylate (0.49 g) in tetrahydrofuran (10 ml) and refluxed for 6 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The extracts were successively washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform to give 3-[3-(1-benzylpiperidin-4-yl)propyl]-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.5 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[N:32][CH:31]=[C:30]([NH2:34])[N:29]=2)[CH2:24][CH2:23]1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:30]4[N:29]=[C:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)[CH:33]=[N:32][CH:31]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cncc(N)n2)CC1
Product: CN1CCN(c2cncc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)n2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (133 mg, 0.434 mmol) and 4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine (92.159 mg, 0.47689 mmol) in a manner analogous to Example 2d. Product isolated as an off-white foam (28.64 mg, 14.2%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.07 (s, 1H), 8.91 (d, J=6.6 Hz, 1H), 8.59 (s, 1H), 8.41 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.6 Hz, 1H), 7.83 (s, 1H), 7.23 (t, J=14.5, 7.4 Hz, 1H), 3.32 (s, 3H), 3.56 (s, 4H), 2.40 (s, 4H), 2.23 (s, 3H). MS=465 (MH)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])[CH:12]=[CH:11]2)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[CH:35]([O:38][C:39]1[C:40](=O)[C:41](=[O:47])[C:42]=1[O:43]C(C)C)([CH3:37])[CH3:36]>CO>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH:2]([NH:1][C:40]3[C:41](=[O:47])[C:42](=[O:43])[C:39]=3[O:38][CH:35]([CH3:37])[CH3:36])[C:3]([O:5][CH3:6])=[O:4])[CH:9]=2)[N:14]=1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: COC(=O)C(N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)Nc1c(OC(C)C)c(=O)c1=O
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of methyl 2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 33 (2 TFA salt, 1.51 g) in CH3OH (15 ml) cooled with an ice bath, are added 0.96 ml of DIPEA and 495.6 mg of 3,4-diisopropoxy-3-cyclobutene-1,2-dione. The solution is stirred overnight at Rt. The solution is evaporated and the resulting residue is purified over silica gel using CH2Cl2/CH3OH (99.2/0.8) as eluent to give methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[(2-isopropoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propanoate 116.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][C:2]1[C:1]([OH:9])=[C:6]([C:16]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:17])[CH:5]=[C:4]([CH3:7])[CH:3]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(O)c(C(=O)C2CCCCC2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 194 g of 2,4-xylenol and 233 g of cyclohexylcarbonyl chloride was stirred at 110° C. for 1 hour and then thereto was gradually added 318 g of anhydrous aluminum chloride, followed by stirring for further 1 hour at 110° C. The reaction mixture was added to 2 liters of ice water and the organic layer was extracted with 2 liters of chloroform. The extract was washed successively with water and then with a saturated aqueous sodium chloride solution and thereafter dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane) to obtain 256.2 g of cyclohexyl 3,5-dimethyl-2-hydroxyphenyl ketone. Brown oily substance.