Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2=[CH:25][S:24][CH:23]=[C:20]2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by suspending the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (2.0 g, 5 mmol) of Example 10 in CH2Cl2 and treating it with acetyl chloride (469 mg, 6 mmol) and triethylamine (1 equivalent). After stirring at room temperature for 24 hours, the organic phase was washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using EtOAc/hexane (1/1). The title compound was crystallized from CH2Cl2 /hexane to give a white solid (337 mg, 15% yield), mp 150°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C[C:25]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([O:37][CH2:38][CH2:39][NH2:40])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].CCN(CC)CC.Cl>CN(C=O)C>[N+:34]([C:33]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]([OH:29])=[O:28])([O-:36])=[O:35]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: Cc1c(C(=O)O)ccc(OCCN)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2[N+](=O)[O-])ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy)benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The crude solid was recrystallized from CHCl3—EtOH to give 60 mg (3% for 2 steps) 3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 257 as a yellow crystalline solid. mp 112-115° C.; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37-3.66 (m, 7 H), 3.84 (s, 3 H), 4.27-4.30 (m, 1 H), 6.74-8.56 (series of m, total 12 H); MS (FAB) m/z 523 (M++1); Anal. Calcd. for C26H26N4O8.3/2H2O: C, 56.83; H, 5.32; N, 10.20. Found: C, 56.66; H, 4.90; N, 9.33.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:38])[C@@H:29]([NH2:37])[CH2:30][C:31]1[S:32][C:33]([Br:36])=[CH:34][CH:35]=1>>[CH3:26][O:27][C:28](=[O:38])[C@@H:29]([NH:37][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][S:12]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[CH:22]=[CH:23][CH:24]=1)(=[O:14])=[O:13])[CH2:30][C:31]1[S:32][C:33]([Br:36])=[CH:34][CH:35]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)s1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid was coupled with (S)-2-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.34 min. MS (ESI−): mass calcd. for C23H18BrClN4O5S2, 607.96; m/z found, 607/609 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.94 (d, J=1.8, 1H), 8.91 (d, J=1.8, 1H), 8.59 (dd, J=7.4, 1.4, 1H), 8.32 (dd, J=8.4, 1.3, 1H), 7.89 (dd, J=8.4, 7.4, 1H), 7.80 (d, J=2.0, 1H), 7.27 (d, J=8.4, 1H), 6.96 (dd, J=8.4, 2.0, 1H), 6.86 (d, J=3.7, 1H), 6.57 (br d, J=6.8, 1H), 6.48 (d, J=3.6, 1H), 4.92 (dt, J=7.0, 4.6, 1H), 3.83 (s, 3H), 3.40 (d, J=4.6, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[NH2:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CCOC(=O)c1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Temperature: 150 °C
Reaction time: 6 h
Yield: 39.1 %

Procedure:
A mixture of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (951 mg, 3.00 mmol), 3-aminophenol (655 mg, 6.00 mmol), potassium carbonate (622 mg, 4.50 mmol) and N,N-dimethylformamide (9.0 mL) was stirred at 150° C. for 6 hr. After allowing the reaction mixture to cool to room temperature, ethyl acetate and water were added to the mixture and the insoluble material was filtered through celite. The organic layer was collected from the filtrate, washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) to give the title compound (350 mg, 39%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt as a white crystalline solid, m.p. 216°-220° C. (uncorr.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[OH:17].[S:18]1[CH:22]=[CH:21][C:20](Cl)=[CH:19]1.[CH3:24]S(O)(=O)=O.O>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]2[O:17][C:24]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: CS(=O)(=O)O
Reactant: Clc1ccsc1
Reactant: Nc1cc(Cl)cc(CCc2ccccn2)c1O
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(CCc2ccccn2)c2oc(-c3ccsc3)nc2c1
Yield: 30 %

Procedure:
This compound is prepared from 2-amino-4-chloro-6-[2-(pyridin-2-yl)ethyl]phenol, and 3-thienyl chloride using method A with 1,4-dioxan as solvent to give the crude amide in a 100% yield. This is treated with methanesulphonic acid in toluene at reflux, with azeotropic removal of water. Purification by flash chromatography (SiO2, EtOAc:hexanes 1:1), gave the title compound, (30%) as a white crystalline solid, m.p. 126-127° C. TLC (SiO2, EtOAc:hexanes 1:1, Rf=0.46). CI Mass Spectrum (methane), m/z=341 [M+H]+.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:15]=[C:14]2[N:16]([CH3:19])[CH:17]=[N:18][C:13]2=[C:12]([F:20])[C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:9])=C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:15]=[C:14]2[N:16]([CH3:19])[CH:17]=[N:18][C:13]2=[C:12]([F:20])[C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:9]
Reactant: C=COCCONC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3 -methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy)-amide (1.00 equivalent) in THF-EtOH is added 1 N aqueous HCl (2.0 equivalents) at room temperature. After stirring for 1 hour at room temperature, the reaction mixture is neutralized with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@@H:32]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][C@@H:35]4[CH3:47])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.CCN(CC)CC.[CH3:73][S:74](Cl)(=[O:76])=[O:75]>C(Cl)Cl>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=3)=[CH:17][C:18]([C@@H:32]([N:34]3[CH2:39][CH2:38][N:37]([S:74]([CH3:73])(=[O:76])=[O:75])[CH2:36][C@@H:35]3[CH3:47])[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ncc(Nc2ncc([C@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of (S)-tert-butyl 4-((S)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.101 g, 0.127 mmol) (the first-eluting diastereomer from Example 271, Step 4) in DCM (3.00 mL, 46.6 mmol) was treated with TFA (3.00 mL, 38.9 mmol) and the resulting mixture was stirred at room temperature for 30 min before being concentrated to give a brown oil. This oil was re-dissolved in DCM (3.00 mL) and sequentially treated with Et3N (0.089 mL, 0.636 mmol) and methanesulfonyl chloride (0.030 mL, 0.382 mmol) (slow addition) at −15° C., and the resulting mixture was stirred for 1 h. The reaction mixture was then quenched with saturated aqueous NaHCO3 and water. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was treated with TFA (2.00 mL) and heated at 80° C. overnight. The resulting mixture was allowed to cool to room temperature and was then concentrated in vacuo. The crude product was adsorbed onto silica gel and chromatographically purified (silica gel, 0% to 5% MeOH/DCM) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((S)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (29 mg, 0.055 mmol, 42.9% yield) as a yellow solid. m/z (ESI, +ve ion) 532 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H); 8.74 (d, J=2.54 Hz, 1H); 8.27-8.46 (m, 3H); 7.90 (br. s., 1H); 7.77 (br. s., 1H); 3.99-4.09 (m, 1H); 3.93 (s, 3H); 3.20-3.30 (m, 1H); 2.94-3.11 (m, 2H); 2.84 (s, 3H); 2.75-2.84 (m, 2H); 2.45 (s, 3H); 2.40 (dd, 1H); 2.29-2.35 (m, 1H); 1.28 (d, J=6.65 Hz, 3H); 1.15 (d, J=6.26 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:12]([OH:14])=[O:13].C(N(CC)C1C=CC=CC=1)C.C(C1[C:46]([OH:47])=[C:45]([C:48](C)(C)C)C=C(C)C=1)(C)(C)C.[C:53](Cl)(=[O:56])[CH:54]=[CH2:55]>O1CCOCC1>[C:53]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:46](=[O:47])[CH:45]=[CH2:48])[C:12]([OH:14])=[O:13])(=[O:56])[CH:54]=[CH2:55]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Reactant: O=C(O)c1ccc(OCCCCCCO)c(OCCCCCCO)c1
Solvent: C1COCCO1
Solvent: CCN(CC)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCOC(=O)C=C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
13.6 g (0.04 mol) of 3,4-di-(6-hydroxyhexyloxy)benzoic acid, 9.6 ml (0.06 mol) of N,N-diethylaniline and 100 mg of 2,6-di-tert-butyl-p-cresol as stabilizer are added to 150 ml of 1,4-dioxane and heated to 60° C. At 60° C., 6.9 ml (0.085 mol) of acryloyl chloride are added slowly such that the reaction temperature does not exceed 65° C. The reaction mixture is stirred for 2.5 h at 60° C. The solution is cooled to room temperature and poured onto ice water with stirring. A precipitate of 3,4-di-(6-acryloyloxyhexyloxy)benzoic acid is obtained which is separated by filtration, dried and recrystallized from 300 ml of isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])C(OC)=O.Cl.[C:21](O)(=O)C>>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[CH3:21]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: Cl
Product: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a suspension of 2-(4-bromo-2-nitro-phenyl)-malonic acid dimethyl ester (crude, 8.1 mmol) in acetic acid (10 mL) is added 6N HCl (10 mL). The mixture is heated at 110° C. overnight (about 15 hr). The reaction mixture is evaporated to dryness. The crude is used in the next step without further purification. To a solution of the crude in ethanol (40 mL) is added concentrated H2SO4 (3 drops) and the resulting reaction mixture is heated at reflux over night. Solvent is removed under reduced pressure. It is purified by flash column chromatography. 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 7.72-7.7 (m, 1 H), 7.26-7.22 (m, 1 H), 4.23-4.13 (q, 2 H), 3.97 (s, 2 H), 1.29-1.23 (t, 3 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:24][N:25]([C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1)C(=O)OC(C)(C)C>>[CH3:24][NH:25][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)C1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCC(O)C4)sc3n2)cn1
Yield: 29 %

Procedure:
1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-3-ol (235 mg, 0.67 mmol) was utilized in a Suzuki coupling with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate (311 mg, 0.93 mmol) according to General Procedure Suzuki to provide 380 (83 mg) after reverse phase HPLC purification. MS (Q1) 428 (M)+
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH2:18])[C:8]3[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=3[C:16]=2[CH:15]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%–10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=O)[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[NH2:21][OH:22].Cl>C(OC(O)C)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:21][OH:22])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)c1c-2cnc2ccccc12
Agent: CCOC(C)O
Agent: Cl
Product: COc1ccc2c(c1)C(=NO)c1c-2cnc2ccccc12
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a suspension of compound 5d (0.26 g, 1 mmol) in ethoxyethanol (30 mL) was added NH2OH·HCl (0.20 g, 3 mmol). The reaction mixture was heated with stirring under microwave irradiation (100 W) for 30 min (by TLC monitoring), followed by concentration in vacuo. A solid thus obtained was recrystallized from MeOH to give the title compound 6a (0.20 g, 73% yield).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:12]([CH2:34][CH3:35])[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[CH:18][CH:17]=1)[CH3:11]>O1CCCC1>[CH2:34]([N:12]([CH2:10][CH3:11])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([C:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:20][CH:21]=1)[CH3:35]
Reactant: CCN(CC)CCOc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(N(C(=O)Nc2ccccc2)C2=NN(c3ccccc3)CC2)cc1

Procedure:
Phenylisocyanate (1.05 ml) was added dropwise to a solution of N-[4-(2-diethylaminoethoxy)phenyl]-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (2.4 g) in tetrahydrofuran (30 ml) and the solution heated to reflux for 4 hours. After cooling the solvent was removed and water added to the residue, which was then extracted with ether. The combined ether layer was washed with water and dried. Solvent was removed to give a solid which was recrystallised from ethyl acetate and petroleum ether to give the title compound (1.3 g) mp 140°-1°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1CCCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10](=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Solvent: C1CCCCC1
Product: CCOC(=O)C(=CN(C)C)C(=O)Nc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 21.12 grams (0.07 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 12.58 grams (0.11 mole) of N,N-dimethylformamide dimethyl acetal and 900 milliliters of cyclohexane was heated under reflux for a period of thirty two minutes at which time TLC indicated the reaction to be incomplete. Another 12.58-gram (0.11 mole) portion of the acetal was then added and the reaction mixture stirred overnight at ambient temperature. Solvent was stripped from the mixture under reduced pressure and the resulting solid then crystallized from hexane-ethyl acetate (10:1) to give 12.6 grams (0.035 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-(dimethylaminomethylene)-3-oxopropanoate having a melting point of 88° C.-90° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ncccn1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2-c2ncccn2)cn1
Temperature: 210 °C
Yield: 87.3 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 27 mg 0.10 mmole) and 2-bromopyrimidine (24 mg, 0.15 mmole) were dissolved in DMA (0.7 ml) and potassium carbonate (20 mg, 0.14 mmole) and copper(I) iodide (4.0 mg, 0.022 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. The reaction was taken up in ethyl acetate (25 mL) and the solution washed with water (3×7 mL) and brine. The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound (31 mg). 1H-NMR (CDCl3, 500 MHz): 3.95 (s, 3H), 6.73 (d, J=0.95 Hz), 7.34 (s, 1H) under 7.34 (t, J=5.04 Hz, 1H), 7.53 (s, 1H), 8.11 (t, J=0.95 Hz, 1H), 8.66 (d, J=0.95 Hz, 1H), 8.85 (d, J=5.04 Hz, 2H),
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[N:26]=[CH:27][C:22]([Cl:21])=[CH:23][N:24]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ncc(Cl)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=428.2 [M+H]+.