Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)[CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(CCN2CCNCC2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
4-(methylsulfonylamino) benzoic acid (2.16 g, 10.05 mmol) was added to a stirring solution of 1-hydroxybenzotriazole hydrate (1.36 g, 10.05 mmol) and dicyclohexylcarbodiimide (2.08 g, 10.05 mmol) in DMF (30 mL) at 25° C. under nitrogen. After 45 minutes, 1-[2-(6-methyl-2-pyridyl)ethyl]piperazine (2.27 g, 11.05 mmol) was added as a suspension in DMF (15 mL). The resulting mixture was stirred at room temperature overnight. The work-up was performed as disclosed in Example 5 to give 2.94 g (73%) of the title compound which was treated with ethanolic HCl to afford 2.15 g of product as a dihydrochloride: mp 165°-167° C.; 1H NMR (DMSO-d6): δ10.14 (s, 1H), 8.19 (m, 1H), 7.63 (m, 2H), 7.45 (d, J=8.72 Hz, 2H), 7.25 (d, J=8.71 Hz, 2H), 3.85-3.20 (m, 12H), 3.06 (s, 3H), 2.67 (s, 3H); IR (KBr): 3420, 3000, 2560, 1640 cm-1 ; MS (m/z) 403 (MH+, 25%) 217 (30), 91 (100).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10](=[O:12])[CH3:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>COC(OC)N(C)C>[CH3:3][N:4]([CH3:9])/[CH:5]=[CH:11]/[C:10]([C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1)=[O:12]
Reactant: CC(=O)c1cnc2ccccn12
Agent: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cnc2ccccn12

Procedure:
Unpurified imidazo[1,2-a]pyridin-3-ylethanone [1-1] was dissolved in 400 mL of N,N-dimethylformamide dimethylacetal, and overheated overnight under reflux. The dimethylformamide dimethylacetal was distilled off under reduced pressure, and then diethyl ether was added to the residue. Thus obtained solid was separated by filtration and dried under reduced pressure, to obtain 5.06 g of (E)-3-(dimethylamino)-1-imidazo[1,2-a]pyridin-3-yl-2-propen-1-one [1-2] as a light brown solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)=[N:25][NH:26][CH:27]=4)[CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:35]N(C(OC)OC)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:24]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)=[N:25][N:26]([CH3:35])[CH:27]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(C)cc4)n3)cc2)CC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCN1CCN(Cc2ccc(Nc3nccc(-c4cn(C)nc4-c4ccc(C)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 61 h

Procedure:
[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 101) (165 mg; 0.364 mMol) is suspendend in toluene (3 mL) and treated with DMF-DMA (168 mg; 1.32 mMol, 187 μL) at rt. The mixture is stirred at reflux for a total of 102 h whereby additional DMF-DMA is added after 48 h (187 μL), after 61 h (187 μL) and after 82 h (374 μL). Upon completion of the reaction and cooling to rt the solvent is removed under reduced pressure. The crude product mixture is purified by reversed phase chromatography (Lichroprep® RP18 15-25 μM; eluting with 18% CH3CN (0.1% TFA)/82% H2O (0.1% TFA)). The pure fractions 27-34 are combined and evaporated. The residue is dissolved in H2O (2 mL) and neutralized with 1N NaOH. The crystalline product (free base) is filtered off, washed with H2O and dried at 60° C. to obtain the title compound as beige crystalline powder.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14](=[O:24])[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:17][CH:18]=1>C(Cl)Cl.O>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14](=[O:24])[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:17][CH:18]=1
Reactant: CCOC(=O)c1cc(=O)c(-c2ccccc2OC)co1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(=O)c(-c2ccccc2O)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (3.0 ml) was added dropwise to a stirred solution of ethyl 5-(2-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (3.2 g) in methylene chloride (100 ml) at 5°-10° C. The mixture was stirred for 2 hours at room temperature, then cooled to 5° C. and carefully diluted with water (50 ml). The solid title product was recrystallised from ethanol (mp 187°-189° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:15][CH2:14][C:11]([CH2:16][CH2:17][CH3:18])([CH2:12][O:13]2)[CH:10]([C:19]([F:22])([F:21])[F:20])[O:9]3)=[CH:4][CH:3]=1.[C:23]([C:27]12CO[C:30](C3C=CC(C#CCOC)=CC=3)(OC1)[O:29][CH2:28]2)(C)(C)C>>[CH3:30][O:29][CH2:28][C:27]#[C:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:13][CH2:12][C:11]([CH2:16][CH2:17][CH3:18])([CH2:14][O:15]2)[CH:10]([C:19]([F:21])([F:22])[F:20])[O:9]3)=[CH:4][CH:3]=1
Reactant: COCC#Cc1ccc(C23OCC(C(C)(C)C)(CO2)CO3)cc1
Reactant: CCCC12COC(c3ccc(I)cc3)(OC1)OC2C(F)(F)F
Product: CCCC12COC(c3ccc(C#CCOC)cc3)(OC1)OC2C(F)(F)F

Procedure:
1-[4-(3-Methoxyprop-1-ynyl)phenyl]-4-n-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 1-(4-iodophenyl)-4-propyl-3-trifluoromethyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl propargyl ether using the methodology described in Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[N:20]=[CH:21][N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=4)[CH:16]=[C:15]([F:43])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)[CH:16]=[C:15]([F:43])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)c3)n2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4c[nH]cn4)c3)n2)nc1
Temperature: 25 °C
Yield: 13.1 %

Procedure:
To a solution of 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1-trityl-1H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg, 0.04 mmol) in tetrahydrofuran (0.5 ml) added hydrochloric acid (0.14 ml, 2N aqueous). The resulting reaction mixture was heated at reflux for 45 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed successively with sodium hydroxide (30 ml, 1N aqueous), water (30 ml) and brine (30 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The isolated residue was purified on silica gel using 5% methanol in dichloromethane to yield the title compound (1.7 mg) as a beige solid. 1H-NMR (CDCl3), δ (ppm): 9.64 (bs, 1H), 8.69 (d, 1H), 8.44 (s, 1H), 8.29 (dd, 1H), 7.81 (m, 3H), 7.61 (dt, 1H), 7.54 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][O:14][CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][O:14][CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: Fc1ccccc1[C@]12COC[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2ccccc2F)COC[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
Zinc (powder, 21 g) was added to a solution containing (±)-(3aS*,6aS*)-6a-(2-fluorophenyl)tetrahydrofuro[3,4-c]isoxazole (5.6 g) in acetic acid (140 mL) at RT. The reaction solution was stirred at RT for 16 h. The insoluble matter was separated by filtration through celite and the filtrate was concentrated under reduced pressure. EtOAc and a sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride. The aqueous layer was further extracted with EtOAc three times. The organic layers were combined and dried over anhydrous MgSO4. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (5.46 g). ESI-MS; m/z 212 [M+H]+. 1H NMR (CDCl3) δ ppm 2.81-2.88 (m, 1H), 3.83 (dd, J=6.8, 12.0 Hz, 1H), 3.92 (dd, J=3.2, 8.8 Hz, 1H), 3.94-4.00 (m, 2H), 4.07 (dd, J=8.4, 9.2 Hz, 1H), 4.14 (dd, J=1.2, 8.8 Hz, 1H), 7.09 (ddd, J=1.2, 8.0, 12.4 Hz, 1H), 7.16 (ddd, J=1.2, 7.6, 8.0 Hz, 1H), 7.26-7.32 (m, 1H), 7.53 (dt, J=2.0, 8.0 Hz, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12](Cl)([Cl:14])=[O:13].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:12]([Cl:14])(=[O:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OC(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 4-acetominophenol (75.0 g), phosgene solution (450 mL, 20% in toluene), and ethyl acetate (1875 mL) was cooled to 0° C. N,N-Diethylaniline (94.7 mL) was added dropwise and the reaction was stirred at 0° C. for two hours. The reaction was then allowed to warm to room temperature. An aliquot for NMR analysis was taken four hours post addition. The reaction remained incomplete and was stirred at room temperature overnight. An-aliquot for NMR analysis after overnight stirring indicated no change had occurred in the reaction since the previous aliquot. The reaction was heated to 40° C. until phosgene gas evolution ceased (approximately 30 minutes). The reaction was cooled to room temperature and was then filtered. The filter cake was washed with ethyl acetate. NMR analysis of the filtered solid indicated it was N, N-diethylaniline related material. The filtrate was washed was washed with 0.1N HCl (375 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a pale yellow solid. The solid was triturated using ether (375 mL) for twenty minutes at room temperature. The solid was filtered and washed with ether. NMR analysis indicated product with residual ether remaining. The solid was dried overnight in a vacuum oven at ambient temperature to afford 77.55 g (73.3% yield). NMR and MS analysis indicated product. 1H NMR (300 MHz, CDCl3+DMSO-d6): δ 9.18 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s, 3H); MS m/z: 214 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12]C)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[C:19](O)(=[O:21])[CH3:20]>>[C:19]([O:11][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[CH:6][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To 36 g of 3-t-butyl-4-hydroxyanisole dissolved in 100 ml of anhydrous acetic acid was added a catalytic amount of concentrated sulfuric acid and the mixture was stirred at room temperature for 6 days. After the reaction solution was concentrated under reduced pressure, the concentrate was dissolved in 200 ml of acetonitrile and combined with 60 g of sodium iodide. To the resulting solution was added dropwise 51 ml of trimethylsilyl chloride at room temperature and then the mixture was heated under reflux for 3 hours. The reaction mixture was allowed to attain room temperature, and then concentrated under reduced pressure, combined with water and extracted with ethyl acetate. The extracted layers were washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated to give 47.0 g of 4-acetoxy-3-t-butylphenol as a colorless oil (quantitative).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:39])[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[C:33]([Cl:38])[CH:34]=5)[CH:29]=4)(=[O:27])=[O:26])[CH2:21][CH2:20]3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[ClH:38].[Cl:38][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:15]3[N:14]([CH3:39])[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=4[CH:16]=3)=[O:18])[CH2:20][CH2:21]1)(=[O:27])=[O:26])[CH:37]=[CH:36]2
Reactant: Cn1c(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCO
Product: Cn1c(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc2c1CCNC2
Reaction time: 1 h

Procedure:
To 5-(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (280 mg), a saturated solution hydrochloride in ethanol (25 ml) was added at room temperature, followed by stirring for 1 hour. The reaction mixture was then concentrated. Water (10 ml) was added to the concentrate, followed by concentration under reduced pressure, whereby the title compound (210 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19](=[O:25])[CH:20]=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:17].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:16]([O:18][C:19](=[O:25])[C:20]([C:7]([C:4]1[CH:3]=[C:2]([Cl:1])[O:6][N:5]=1)=[O:9])=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:17]
Reactant: O=C(O)c1cc(Cl)on1
Reactant: CCOC(=O)C=CN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
A solution of 5-chloro-isoxazole-3-carboxylic acid (791 mg, 5.43 mmol) (preparation described in WO03093250 A2) in dichloromethane (27.2 mL, 0.2M) cooled to 0° C. was treated with oxalyl chloride (0.71 mL, 8.15 mmol, 98%) followed by a few drops of N,N-dimethylformamide. The reaction was allowed to gradually warm up to 25° C. The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was dissolved in dichloromethane and re-concentrated twice to remove residual oxalyl chloride. The residue was then dissolved in dichloromethane (16 mL, 0.34M) and treated dropwise with a solution of ethyl-3-(dimethylamino)acrylate (0.79 g, 5.51 mmol) in triethylamine (1.6 mL, 11.47 mmol). The resulting red/orange reaction solution was heated to 60° C. overnight. At this time, the reaction was cooled to 25° C. and then partitioned between water (50 mL) and dichloromethane (100 mL). The organics were then washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40M column, 50-60% ethyl acetate/hexanes) afforded 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (300.6 mg, 20%) as a red oil.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.Cl.[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCNC(=O)NC(C)C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
Isopropyl isocyanate (0.187 mL, 1.90 mmol) was added dropwise to a stirred solution of 1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one dihydrochloride (prepared as described in Example 398, 1.0 g, 1.90 mmol) and triethylamine (0.530 mL, 3.80 mmol) in dichloromethane (20 mL) at room temperature. After 1.5 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, gradient elution with 2-12% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.730 g of N-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)-N′-isopropylurea as an opaque solid, mp 98-101° C.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].N12CCCN=C1CCCCC2.Cl>C(O)C>[SH:24][C:23]1[N:22]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:8]=2)[N:25]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccnc(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(S)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Yield: 92.9 %

Procedure:
A solution of 3-oxo-3-(2-phenyl-pyrimidin-4-yl)-propionic acid ethyl ester (2.74 g, 10.1 mmol), N-methylthiourea (1.39 g, 15.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-en (1.57 g, 10.3 mmol) in ethanol (30 ml) was heated under reflux for 18 hours. After the solution was acidified by addition of hydrochloric acid, ethanol was removed under reduced pressure, and the resulting solid was filtered, washed with water and dried to afford 2-mercapto-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (2.78 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1)[CH3:2].C1N=C[N:15](C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:8](=[O:10])[C:7]4[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=4)[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1.[CH2:1]([O:3][C:4]1[N:5]=[N:15][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cn1
Product: CCOc1ccc(C(=O)O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A stirred mixture of 6-ethoxy-nicotinic acid (0.23 g, 1.40 mmol) and CDI (0.24 g, 1.50 mmol) in N,N-dimethylformamide (10 mL) was heated to 40° C. under nitrogen. After 1 h, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.5 g, 1.40 mmol) was added and the mixture was heated at 50° C. for 1.5 h. The mixture was cooled to rt and water (20 mL) was added. The solids were isolated by filtration and then triturated in EtOAc (20 mL) for 18 h. The product was filtered and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-ethoxy-nicotinamide as a white solid (0.30 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.12 min (95.33%); mp: 255-257° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H, CH3), 1.84-2.14 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=16.8 Hz, 1H, CHH), 2.80-3.09 (m, 1H, CHH), 4.21-4.52 (m, 4H, CH2, CH2), 4.59 (d, J=5.9 Hz, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.88 (d, J=8.7 Hz, 1H, Ar), 7.47 (d, J=7.9 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.16 (dd, J=2.5, 8.7 Hz, 1H, Ar), 8.71 (d, J=2.3 Hz, 1H, Ar), 9.14 (t, J=5.9 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.40, 22.49, 31.20, 42.60, 47.12, 51.58, 61.80, 110.19, 122.07, 122.94, 123.26, 127.07, 130.39, 138.18, 142.40, 143.80, 147.10, 164.61, 164.91, 167.92, 170.98, 172.85; LCMS: MH=423; Anal Calcd for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.24; H, 5.19; N, 13.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[O:11])[CH:7]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=2)=[O:23])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Reaction time: 1 h

Procedure:
(S,E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: To Intermediate 2 (0.213 g, 0.851 mmol) and 3B (0.3 g, 0.851 mmol) in EtOAc (5 mL), cooled in ice bath, was added DIEA (0.446 mL, 2.55 mmol) and 50% T3P in EtOAc (0.481 mL, 1.702 mmol). After 1 h, the reaction was concentrated and the crude was taken on to next step. MS (ESI) m/z: 585.3 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]2[CH:38]=[N:39][N:40]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=3)[C:41]=2[CH3:42])=[O:36])=[CH:30][C:29]=1[CH3:53]>O1CCOCC1.C(OCC)(=O)C>[CH3:42][C:41]1[N:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][N:44]=2)[N:39]=[CH:38][C:37]=1[C:35]([NH:34][C:31]1[CH:32]=[N:33][C:28]([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:16])([F:17])[F:18])[CH2:11][CH:10]=2)=[C:29]([CH3:53])[CH:30]=1)=[O:36]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1Br
Reactant: CC1(C)OB(C2=CCC(C(F)(F)F)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(C(F)(F)F)CC1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
4,4,5,5-Tetramethyl-2-[4-(trifluoromethyl)cyclohex-1-en-1-yl]-[1,3,2] dioxaborolane (163 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (37 mg), sodium carbonate (144 mg) and water (1.0 ml) were added at room temperature to a solution of N-(6-bromo-5-methylpyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 189 in 1,4-dioxane (3.0 ml), and stirred at 100° C. under radiation of microwave for an hour. After completion of the reaction, water and ethyl acetate were added, filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (146 mg) as a white solid.