Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][O:15][CH3:16])=[O:13].Cl[C:18]1[C:23]([CH:24]=O)=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[C:12](=[O:13])[N:14]([O:15][CH3:16])[C:18]2[N:19]=[C:20]([S:26][CH3:27])[N:21]=[CH:22][C:23]=2[CH:24]=1
Reactant: CONC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: CSc1ncc(C=O)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2ccc([N+](=O)[O-])cc2Cl)cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2-(2-Chloro-4-nitrophenyl)-N-methoxyacetamide (49.3 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (41.2 mmol) were dissolved in DMF (600 mL). The solution was cooled to 0° C., and K2CO3 (91 mmol) was added in one poroom temperatureion. The mixture was stirred at 0° C. for 2 h and then at room temperature for 48 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to 60 mL. Water (600 mL) was added. The precipitate was filtered, washed twice with EtOH and dried. The by-product (Z) -6-(2-chloro-4-nitrophenyl)-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one O-methyl oxime was separated by reflux of the mixture for 4 h in EtOH and hot filtration of the suspension through a sintered glass funnel. Evaporation of the filtrate and drying gave 6-(2-chloro-4-nitrophenyl)-8-methoxy-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a solid (63%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:25]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:28]3[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:31]([CH3:38])=[CH:30][CH:29]=3)=[C:18]5[CH:17]=[CH:16][C:15]4=[C:14]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]([CH3:49])=[CH:41][CH:40]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Br:50]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:50][C:21]1[C:22]2[C:27]3=[C:26]4[C:25](=[CH:24][CH:23]=2)[C:12]([C:5]2[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][C:14]([C:39]2[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]([CH3:49])=[CH:41][CH:40]=2)=[C:15]4[CH:16]=[CH:17][C:18]3=[C:19]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH3:38])=[CH:30][CH:29]=2)[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixed solution of 1.9 g of the above-mentioned 1,3,6-tri(4-methylnaphthalene-1-yl)pyrene, 0.64 g of N-bromosuccinimide and 15 ml of dimethylformamide was stirred under nitrogen gas stream at a temperature of 60° C. for 6 hours. After cooling the mixed solution to room temperature, 50 ml of water was injected thereinto to extract therefrom with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and thereafter vacuum dried under a temperature of 70° C. to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylnaphthalene-1-yl)pyrene as pale-yellow powder.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([C:3]([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:21])[F:22])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:30])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: C1COCCN1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1)N1CCOCC1
Yield: 28 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using morpholine instead of cyclopropanemethylamine, to the title compound (28 mg, 28%) which was obtained as a yellow oil. MS: m/e=470.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 17 g (0.0466 mole) of Boc-N-methyl-L-alanyl-L-alanine benzyl ester in 150 ml of dry dichloromethane, cooled at -10° C., was added 100 ml trifluoroacetic acid, which was previously cooled at -10° C. The reaction mixture was stirred for 16 hours at -5° C., then poured carefully with good stirring into a mixture of 177 g of sodium bicarbonate, ice, and 150 ml of dichloromethane. The organic layer was separated and the aqueous layer was further extracted with another 60 ml of dichloromethane. The combined organic layers were washed with 3×50 ml of saturated sodium bicarbonate solution, dried over mangesium sulfate, and evaporated to give 11.6 g (91% of theory) of crude product which was used in step 3 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O.[CH:26]([NH2:28])=[O:27]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[NH:28][CH:26]=[O:27]
Reactant: NC=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Solvent: O=CO
Solvent: O
Product: O=CNC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 160 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A mixture of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.081 mol) in formic acid (120 ml) and formamide (300 ml) was stirred for 16 hours at 160° C. The reaction mixture was cooled, poured out into water (600 ml) and the resulting precipitate was filtered off and dried. This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, and dried, yielding 8.78 g (22.5%) of (±)-N-[[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl](4-chlorophenyl)methyl]formamide (interm. 64).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:14]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(O)c1
Product: O=C(Nc1cccc(O)c1)C1CCCC1
Yield: 56.5 %

Procedure:
By using 3-aminophenol (1.0 g) and cyclopentanecarbonyl chloride (607 mg) as starting materials, the title compound (531 mg) was obtained in the same manner as that of Reference Example 18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzenethiol (9.86 g, 77 mmol), 1-chloro-4-nitrobenzene (12.72 g, 81 mmol) and potassium carbonate (21.25 g, 154 mmol) in acetonitrile (300 mL) is stirred at room temperature under inert atmosphere for 48 h. The mixture is diluted with water (750 mL) and the aqueous phase is extracted with dichloromethane (2×500 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated in the presence of some impurities as a yellow solid (19.4 g, 78 mmol) (HPLC-MS Method 2: retention time: 2.132 min, m/z no mass signal).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)C(C)(C)C)=[C:6]([C:15]2(O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:22][CH3:23])=[CH:4][CH:3]=1.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([C:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]=2)[C:5]([O:22][CH3:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1C1(O)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Cl)c(N)c1C1=CCOCC1
Yield: 73.6 %

Procedure:
A solution of intermediate 13 (0.365 g, 1.06 mmol) and potassium hydroxide (0.24 g, 4.27 mmol) in glycol (0.5 mL) was stirred at 100° C. overnight. The reaction mixture was poured into water and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (eluent: cyclohexane/EtOAc:90/10) to give title compound (0.187 g, 73%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([C:10]1([OH:13])[CH2:11][CH2:12][C:5]2([O:4][CH2:3][C:2]([CH3:14])([CH3:1])[CH2:7][O:6]2)[CH2:8][CH2:9]1)[CH:16]=[CH2:15]
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: C=CCBr
Product: C=CCC1(O)CCC2(CC1)OCC(C)(C)CO2

Procedure:
The title compound is prepared from 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=223 [M+H—H2O]+.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28]Br>>[Br:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: BrCCCBr
Product: O=C(c1ccc(OCCCBr)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Reaction of 2-(4-hydroxybenzoyl)-3-phenylbenzofuran with 1,3-dibromopropane according to the procedure of Example 4 gives 2-[4-(3-bromopropoxy)benzoyl]-3-phenylbenzofuran.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.CCN(C(C)C)C(C)C.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[O:9]=[C:4]1[C:3]([CH2:2][NH:1][C:23]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:24])=[N:8][N:7]=[CH:6][NH:5]1
Reactant: O=C(Cl)C1CCC1
Reactant: NCc1nnc[nH]c1=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96 mmol) and DIEA (0.829 mL, 4.76 mmol) in anhydrous N,N-DMF (20 mL) and anhydrous pyridine (2 mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL, 3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo and was purified by chromatography on silica gel [eluting with 5% MeOH in DCM (200 mL)×10% MeOH in DCM (800 mL)], affording the title compound; 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d, 2H); 7.97 (br. t, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100) [MH+], HPLC: tR=1.56 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([CH3:42])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:35]([CH3:42])[CH:34]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1ccnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (INTERMEDIATE QQQQ, 55.8 mg, 0.117 mmol), (4-chloro-2-methylphenyl)boronic acid (Indofine Chemical, Hillsborough, N.J., 21.93 mg, 0.129 mmol), Pd(AmPhos)2Cl2 (4.14 mg, 5.85 mmol), potassium phosphate (74.5 mg, 0.351 mmol), 1,4-dioxane (439 μl), and water (146 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. LCMS showed two peaks with mass of protected desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 1 h, triflic acid (0.05 mL) was added drop wise. Following an additional 1 h of stirring, the mixture was diluted with 2-PrOH, then concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 0-60% EtOAc/Heptane, then with 100% EtOAc). The resulting material was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-6% MeOH/DCM) to give 4-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (24.08 mg, 0.058 mmol, 49.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.10 (d, J=4.4 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.88 (dd, J=2.0, 8.8 Hz, 1H), 7.61-7.53 (m, 3H), 7.43 (dd, J=1.9, 8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 1.97 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7](B1OC(C)(C)C(C)(C)O1)=[CH:6]2.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40](I)=[CH:41][N:42]=2)[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.[Pd]>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([C:40]([C:7]3[N:8]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)=[CH:41][N:42]=2)[N:39]=1
Reactant: COc1cc2cc(B3OC(C)(C)C(C)(C)O3)n(S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: Clc1ccc2ncc(I)n2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2cc(-c3cnc4ccc(Cl)nn34)n(S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a solution of 5,6-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (120 mg, 0.262 mmol, 1.0 equiv) in acetonitrile (3.41 mL) was added 6-chloro-3-iodoimidazo[1,2-b]pyridazine (95 mg, 0.341 mmol, 1.3 equiv), palladium catalyst (25 mg, 0.0341 mmol, 0.1 equiv) and sodium carbonate (3.41 mL, 1.0 M, 10.0 equiv). The solution was stirred at 150° C. in the microwave for 10 minutes. Purification using column chromatography gave 80 mg of the yellow solid, 63%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C:5](=[O:7])[CH:4]=[C:3]1N1CCCC1.C[OH:15]>Cl>[OH:15][C:3]1[C:2]([CH3:13])([CH3:1])[O:6][C:5](=[O:7])[CH:4]=1
Reactant: CO
Reactant: CC1(C)OC(=O)C=C1N1CCCC1
Agent: Cl
Product: CC1(C)OC(=O)C=C1O
Temperature: 88 °C

Procedure:
A suspension of 5,5-dimethyl-4-pyrrolidin-1-ylfuran-2(5H)-one (535 mg) in a mixture of MeOH (2 mL) and 5M HCl (8 mL) was heated at 88° C. for 2 hours. The mixture was cooled to room temp., extracted with CHCl3 (10×15 mL), combined, dried over Na2SO4, and evaporated to dryness to give 4-hydroxy-5,5-dimethyl-5H-furan-2-one as light brown solid. Yield: 359 mg, 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=1>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[C:14]([OH:16])[CH:15]=2)[N:3]=1
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: Nc1ccnc(Cl)n1
Solvent: CCO
Product: Nc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 47 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 4-amino-2-chloropyrimidine (70 mg, 0.5 mmol) and 5-amino-2-chlorophenol (78 mg, 0.5 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained in 47% yield a (60 mg) and used for the next step without additional purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)(=O)=O.C1CCN2C(=NCCC2)CC1>CO>[CH3:1][S:2][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ccc(C2=C(Oc3ccccc3)C(=O)CC2)cc1
Temperature: 60 °C

Procedure:
To the diketone of Step 1 (120 mg) in methanol (80 mL) was added DBU (0.1 mL). The resulting mixture was heated at 60° C. for 18 h. The methanol was then evaporated and to the crude mixture was added saturated aqueous ammonium chloride, the mixture was then extracted with EtOAc, the organic layer was dried over MgSO4, filtered, and the solvent evaporated under vacuum. The residue was purified by silica gel chromatography (20% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=1)[CH2:10][N:11]([CH:46]1[CH2:48][CH2:47]1)[C:12]([C@@H:14]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15]1)=[O:13])#[N:2].C([Sn]([N:70]=[N+:71]=[N-:72])(CCCC)CCCC)CCC>O1CCOCC1.CCOC(C)=O>[CH:46]1([N:11]([CH2:10][C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]3[N:70]=[N:71][NH:72][N:2]=3)[CH:51]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:49]=2)[C:12]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:15]2)=[O:13])[CH2:48][CH2:47]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCc2nn[nH]n2)c1
Temperature: 150 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-{[[3-(3-cyanopropoxy)-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in dioxane (0.17 M) was added tri-n-butyltin azide (3 eq.). The reaction was heated to 150° C. in a sealed tube for 18 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with saturated aqueous NH4Cl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, first 50% EtOAc in Hex to 100% EtOAc, then 5% MeOH in DCM) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])=[O:4].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1)#[N:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH3:12])[CH3:11])=[CH:25][CH:26]=1)#[N:14]
Reactant: CCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)(C)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Reaction time: 1 h

Procedure:
The starting material can be prepared, for example, as follows: 2.89 g of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride are added to a solution of 2.50 g of N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amine and 2.09 ml of triethylamine in 100 ml of CH2Cl2, and the mixture is stirred for 1 hour. The reaction mixture is washed twice with 50 ml of water each time and the combined aqueous phases are extracted with 50 ml of CH2Cl2. The crude product obtained from the organic phase by the customary procedure is purified by chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (98:2) as eluant to yield pure 4-methoxycarbonyl-4-methyl-pentanoic acid N-(2'-cyanobiphenyl-4-ylmethyl)-N-propyl-amide that has an Rf value of 0.56 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(=O)O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(=O)Cl)c2ccccc21

Procedure:
A stirred mixture of 1-methyl-3-indazolylcarboxylic acid (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was refluxed for 2 hours and the solvent was evaporated to give a residue of 1-methyl-3-indazolylcarbonyl chloride.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[C:21](O)=[O:22])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:29])=O>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH2:24][CH2:25][CH3:26])[C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[C:21]([Cl:29])=[O:22])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: CCCN(C(=O)C1CCCCC1C(=O)O)c1ccc(-n2ccnc2)cc1
Product: CCCN(C(=O)C1CCCCC1C(=O)Cl)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 15, react 2-[[[4-(1H-imidazol-1-yl)phenyl](propyl)amino]carbonyl]cyclohexanecarboxylic acid with thionyl chloride to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([NH:14][C:12]1[C:11]([C:19]([F:21])([F:20])[F:22])=[CH:10][C:9]2[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M130) (0.43 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (270 mg, 61%).