Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[NH:19][N:20]=[C:21]([Cl:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[N:19]([CH3:28])[N:20]=[C:21]([Cl:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(Cl)n[nH]c(=O)c32)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.7 %

Procedure:
In DMF (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4-chloroimidazo[4,5-d]pyridazin-7(6H)-one (963 mg) followed by addition of potassium carbonate (985 mg). Then, methyl iodide (0.45 ml) was added and the mixture was stirred at room temperature for 65 hours. To this reaction mixture was added water (50 ml) and the resulting crystals were harvested by filtration. This crystal crop was purified by silica gel column chromatography (stationary phase 30 g; dichloromethane: ether=1:0-3:1) to provide 655 mg (66%) of the title compound. 1H-NMR (CDCl3) δ: 3.86(3H,s), 5.81(2H,s), 7.45(2H,d,J=7.8Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
Reaction SMILES: FC1C=C(C2SC(N[C:18](NCCO)=[O:19])=NC=2C)C=CC=1S(C)(=O)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([NH2:37])=[N:34][C:33]=2[CH3:38])=[CH:28][C:27]=1[S:39]([CH3:42])(=[O:41])=[O:40].[O:43]1[CH2:48][CH2:47][N:46]([C:49]2[N:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([NH:37][C:18]([NH:55][C:52]3[CH:53]=[N:54][C:49]([N:46]4[CH2:47][CH2:48][O:43][CH2:44][CH2:45]4)=[CH:50][CH:51]=3)=[O:19])=[N:34][C:33]=2[CH3:38])=[CH:28][C:27]=1[S:39]([CH3:42])(=[O:40])=[O:41]
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: Cc1nc(NC(=O)NCCO)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Product: Cc1nc(NC(=O)Nc2ccc(N3CCOCC3)nc2)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1

Procedure:
The title compound is prepared by the same procedure as 1-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea (Example 88) replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and by replacing 2-aminoethanol (part 88b) with 6-morpholinopyridin-3-amine.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[S:6][CH:7]=[C:8]([CH3:18])[C:9]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1scc(C)c1C(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1scc(C)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 2-acetylamino-3-benzoyl-4-methylthiophene in 20 ml of dimethylformamide is added 0.207 g of 63% sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 1.64 g of methyl iodide in 4.9 ml of dimethylformaide is added thereto. The mixture is stirred at room temperature for 3 hours, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure to give crystals, which are recrystallized from ether to give N-methyl-2-acetylamino-3-benzoyl-4-methylthiophene as crystals having a melting point of 121.5° - 122.5°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](O)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:18])=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Yield: 100 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.300 g, 1.3 mmol, 1.0 eq.), thionyl chloride (5 ml), and DMF (1 ml). The mixture was refluxed for 4 hour at which time the reaction was poured onto ice and NaHCO3. The aqueous layer was then extracted with ethyl acetate (2×). The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to give 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a brown solid (0.35 g 100% yield). MS (ESI, negative) for C9H8ClN3O2: 224 (M-H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH3:25][C:26]1([O:29][CH2:28]1)[CH3:27]>C1COCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:25][C:26]([CH3:28])([OH:29])[CH3:27])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Reactant: CC1(C)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol (60 g, 0.2 mol) in THF/H2O (1 L, THF/H2O=1:1, v/v) was added NaOH (24 g, 0.6 mol) at room temperature, followed by isobutylene oxide (144 g, 2 mol). The reaction was stirred at 45° C. for 10 hours, and then diluted with EtOAc (1 L). The resulted solution was washed with 1 M NaOH aqueous solution (500 mL×4). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 500 mL of petroleum ether, and collected through filtration to give the title compound as a light yellow solid (31.6 g, 42.5%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Reaction time: 18 h

Procedure:
A solution of ethyl 4-{3-[3-[2-(1-cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoate (Example 4, Step B) (4.0 g., 0.01 mole) and sodium hydroxide (1.2 g., 0.003 mole) in methanol (50 ml.) and water (5 ml.) is allowed to stand at 25° C. for 18 hours. The methanol is distilled at reduced pressure. The residual solution is treated with water (50 ml.) and acidified with 2 N hydrochloric acid. The title compound precipitates as an oil that gradually crystallizes. It is collected, washed with water, and air dried.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].ClCCl.[CH2:18]([O:25][CH2:26][N:27]1[C:32](=[O:33])[C:31]2=[N:34][CH:35]=[N:36][C:30]2=[CH:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:8][N:9]([CH3:14])[S:10]([N:36]1[C:30]2[CH:29]=[N:28][N:27]([CH2:26][O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:32](=[O:33])[C:31]=2[N:34]=[CH:35]1)(=[O:12])=[O:11]
Reactant: O=c1c2ncnc-2c[nH]n1COCc1ccccc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cnc2c(=O)n(COCc3ccccc3)ncc21
Yield: 66.3 %

Procedure:
2.08 g of triethylamine, 2.80 g of N,N-dimethyl sulfamoyl chloride, and 0.22 g of 4-dimethylaminopyridine were added to 50 ml of a dichloromethane solution of 3.04 g of 5-benzyloxymethylimidazo[4,5-d]pyridazin-4-one [CAS NO. 82137-50-6] (R. Paul Gagnier, Michael J. Halat, and Brian A. Otter Journal of Heterocyclic Chemistry, 21, p 481, 1984), and the mixture was heated under reflux for 4 hours. 250 ml of ethyl acetate was added to the solution, and the mixture was washed successively with 50 ml of an aqueous solution of 1N hydrochloric acid, 50 ml of a saturated sodium bicarbonate solution, and 50 ml of a saturated sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.86 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: C(S[C:4]1[N:5]=[CH:6][C:7]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH:18]3[CH2:20][CH2:19]3)[C:8]=2[N:9]=1)C.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:4]2[N:5]=[CH:6][C:7]3[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH:18]4[CH2:19][CH2:20]4)[C:8]=3[N:9]=2)[CH2:24][CH2:23]1
Reactant: CCSc1ncc2c(=O)c(C(=O)O)cn(C3CC3)c2n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ncc3c(=O)c(C(=O)O)cn(C4CC4)c3n2)CC1

Procedure:
A solution of 2.91 g of 2-ethylmercapto-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid and 2.2 l g of N-methylpiperazine in 30 ml of N-dimethylformamide is heated at 110° for 2.5 hours. The solvent is distilled off in vacuo and the residue is recrystallised from ethanol. 2.4 g (73% of the theoretical yield) of 2-(4-methyl-piperazino-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid with a melting point of 209°-210° C. are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7].[C:17]([N:21]1[C:25](=[O:26])[C:24](Cl)=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:22]1(=[O:35])=[O:34])([CH3:20])([CH3:19])[CH3:18].C(OCC)C>CC#N.CN(C=O)C>[C:17]([N:21]1[C:25](=[O:26])[C:24]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:22]1(=[O:34])=[O:35])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1cccc(C)c1OC(=O)CCCN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cccc(C)c1OC(=O)CCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.9 %

Procedure:
2,6-Dimethylphenyl 4-aminobutanoate hydrochloride (80.4 mg, 0.33 mmol) and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (89.9 mg, 0.91 mmol) were dissolved in a mixture of MeCN/DMF (4:1, 5 ml, dry). TEA (0.134 ml) was added and the reaction mixture was stirred at rt for 15 h. Diethyl ether (30 ml) was added and the resulting mixture was extracted with water (2×10 ml). The organic layer was dried (MgSO4), evaporated and the residue was purified by column chromatography on silica, using n-heptane/EtOAc (7:3) as eluent. The obtained product was further purified by re-chromatography, using the same conditions as before, to give the title compound (17 mg, 11%) as colorless oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 1.73 (s, 9H), 1.78-1.85 (m, 2H), 2.06 (s, 6H), 2.38 (t, 2H), 2.96-3.01 (m, 2H), 5.37 (bt, 1H), 7.04 (s, 31), 7.42-7.44 (m, 3H), 7.50-7.52 (m, 2H).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C([C:18]1C=C(C)C=C(C(C)(C)C)[C:19]=1[OH:29])(C)(C)C.OCC[O:33][C:34](=[O:37])[CH:35]=[CH2:36]>>[C:34]([OH:37])(=[O:33])[CH:35]=[CH2:36].[NH2:8][C:9]([O:29][CH2:19][CH3:18])=[O:10]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCO
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 1 h

Procedure:
To a reaction vessel equipped with a stirrer, 109.8 gm of 2,4-tolylene diisocyanate, 1 gm of dibutyltindilaurate, and 0.3 gm of 2,6-di-t-butyl-4-methylphenol as a polymerization inhibitor were added. To this, 48.8 gm of 2-hydroxyethylacrylate was added while controlling the temperature to 20° C. or less. After the addition was completed the mixture was continuously stirred for an additional one hour at 10° to 20° C. Following this, 841.4 gm of polypropylene glycol of a number average molecular weight of 2,000 (commercial product PPG2000 manufactured by Asahi-Olin) was added while maintaining the temperature in the 40° to 50° C. range, after which the mixture was continuously stirred for 5 hours at 50° to 60° C. to complete the reaction. A urethane acrylate [B-1] of a number of average molecular weight of about 4,750 was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:25][C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]>>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:33]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]([CH3:23])([CH3:22])[C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:24])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:34])[CH:29]=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Yield: 53 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3,3-dimethyl-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 28) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethoxy-benzene (intermediate 17) gave the titled compound in 53% yield as light yellow foam. MS: 575.22 (MH+, Cl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.CCN(CC)CC>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=4)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cn1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(c5ccc(C#N)cn5)CC4C3)n2)cn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (377.4 mg, 1.13 mmol) and 6-chloronicotinonitrile (318.8 mg, 2.31 mmol) in a mixture of DCM and MeOH (10 mL/10 mL) was added Et3N (235.0 mg, 2.32 mmol). The reaction mixture was stirred at 45° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/80) to give the title compound as a beige solid (304.4 mg, 61.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16](C)(C)C)=O)[C@H:10](CO)[CH2:9]2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:40])[NH:29][C@@H:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH2:31][OH:32])=[C:24]([F:41])[CH:23]=1.CCN(C(C)C)C(C)C.C(C1NC=CN=1)(C1NC=CN=1)=[S:52]>C(#N)C.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:29][C@@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:31][OH:32])=[O:40])=[C:24]([F:41])[CH:23]=2)=[CH:4][C:5]([C@@H:8]2[CH2:12][N:11]3[C:13](=[S:52])[O:15][CH2:16][C@@H:10]3[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)C[C@H]1CO
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1ncc([C@H]2C[C@H]3COC(=S)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (45 mg, 0.063 mmol) (see Example 7) in acetonitrile (0.75 mL) and DMF (0.5 mL) was added DIEA (42 μL, 0.240 mmol) and thiocarbonyl diimidazole (15.6 mg, 0.088 mmol). After 2 h, the reaction was quenched with 1 N aqueous solution. NaOH (1 mL) and stirred vigorously to effect decomposition of a mixed thiocarbamate byproduct. The reaction was then diluted with ethyl acetate (10 mL), washed with water (5 mL) and brine (5 mL), then dried over sodium sulfate and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-thioxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (3.2 mg, 11% yield). LCMS (m/z): 527.3, 529.3 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J=3.91, 7.04 Hz, 1H), 7.85 (d, J=1.96 Hz, 2H), 7.83-7.77 (m, 3H), 7.39-7.32 (m, 5H), 7.30-7.26 (m, 3H), 7.25-7.19 (m, 2H), 5.15-5.07 (m, 2H), 4.73-4.69 (m, 2H), 4.45-4.35 (m, 3H), 3.85-3.65 (m, 8H), 2.38 (td, J=5.58, 11.54 Hz, 2H), 1.80-1.70 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:14][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[NH:11][C:10]2=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(C)[nH]c(=O)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: Cc1nc2ccc(CBr)cc2c(=O)[nH]1
Yield: 65.4 %

Procedure:
According to example 4, 1.00 g of 3,4-dihydro-2,6dimethyl-4-oxoquinazoline (Sen, A. B.; Gupta, J. K. J. Indian Chem. Soc., 1962, 31, 369) was subjected to bromination using 1.05 g of N-bromosuccinimide (Aldrich) and 0.17 g of benzoyl peroxide in 50 mL of 1,2-dichloro-ethane for 30 min to afford 0.95 g (64%) of 6-bromomethyl-3,4-dihydro-2-methyl4-oxoquinazoline as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH2:50])=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:41][CH2:42][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:44][CH2:45]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 40.3 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2,5-bis(methyloxy)aniline (0.166 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina. The desired combined fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and air dried to give the title compound (0.130 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (br. s., 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.36-7.42 (m, 1H), 7.34 (s, 1H), 7.20 (t, J=8.1 Hz, 2H), 6.94-7.00 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.43 (d, J=11.7 Hz, 2H), 2.51-2.58 (m, 2H), 2.26-2.35 (m, 1H), 1.77 (d, J=13.6 Hz, 2H), 1.53-1.64 (m, 2H), 1.48 (s, 4H), 1.38 (s, 2H). MS (M+H, ES+) 745.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CO.[OH-].[K+:31]>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+:31]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)[O-])cc3)no2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (16.4 kg), tetrahydrofuran (164 L), methanol (25 L) and 19% aqueous potassium hydroxide (25 L) were put into a 1500 L glass-lined reaction chamber, heated to 50 to 60° C., and stirred for 2 hours. Tetrahydrofuran (328 L) was added to this reaction mixture for 30 minutes to 1 hour. The mixture was then cooled to 35 to 40° C. and stirred further for 1 hour. The product was isolated by a centrifugal separator and washed with tetrahydrofuran (164 L) to obtain rough potassium 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (which was used in the next step in a wet state).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:44][CH2:45][C:46](Cl)=[O:47]>C1COCC1.CCOC(C)=O>[Cl:44][CH2:45][C:46]([NH:15][NH:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)[C:10](=[O:28])[N:11]([CH2:16][C:17]2[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)[N:12]=1)=[O:47]
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NNC(=O)CCl)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (500 mg, 0.977 mmol) in THF (7 ml), Et3N (197 mg, 1.953 mmol) was added chloroacetyl chloride (110 mg, 0.977 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (50 ml) and the resulting solution was washed with water (2×20 ml) and saturated NaCl (20 ml). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified using an ISCO automated chromatography system (12 g silica gel, 20-40% EtOAc/CH2Cl2) to give the product 2-chloro-N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetohydrazide as a light yellow solid (410 mg, 72% yield). HPLC retention time 2.920 min (Method A); LCMS (M+H)=587.0.