Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:27][C:28]1[C:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][OH:45])=[CH:37][C:36]=2[O:46][CH3:47])=[C:32]([CH3:48])[N:31]=[C:30]([NH2:49])[N:29]=1)(=[O:26])=[O:25]>C1COCC1.O>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:27][C:28]1[C:33]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][O:45][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:37][C:36]=2[O:46][CH3:47])=[C:32]([CH3:48])[N:31]=[C:30]([NH2:49])[N:29]=1)(=[O:25])=[O:26]
Reactant: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(OCCCOS(C)(=O)=O)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.293 mL) was added to a solution of diisopropylethylamine (0.988 mL) and the product from step (vii) (0.95 g) in THF (9.5 mL). The mixture was stirred at RT for 2 h, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to afford the crude product as a pale yellow oil, which was used for next reaction without further purification; 1H NMR (300 MHz, CDCl3); 6.93 (2H, s), 6.73 (1H, d), 6.39 (1H, d), 6.31 (1H, dd), 4.76 (2H, br s), 4.43 (2H, t), 4.03 (2H, t), 3.77 (3H, s), 3.73 (2H, s), 2.98 (3H, s), 2.57 (6H, s), 2.29 (3H, s), 2.25 (3H, s), 2.24-2.16 (2H, m); LC-MS: m/z 580.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([CH2:24][O:25]C(=O)C1C=CC=CC=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][C:12]([CH2:24][OH:25])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2ccc(COC(=O)c3ccccc3)cc2c1Nc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(=O)c1cnc2ccc(CO)cc2c1Nc1ccccc1C

Procedure:
3-Butyryl-4-(2-methylphenylamino)-6-benzoyloxymethyl-quinoline (3.0 g, 6.8 mmol) was dissolved in methanol (50 ml) and 2M sodium hydroxide solution (50 ml) was added. The mixture was heated under reflux for 45 minutes until a clear solution was obtained. The mixture was partitioned between chloroform and water, the aqueous layer re-extracted with chloroform and the combined organic solutions washed with brine, dried, filtered and evaporated. Crystallisation from ether afforded 3-butyryl-4-(2-methylphenylamino)-6-hydroxymethylquinoline; (1.9 g, 83%), m.p. 139°-41° C.
Reaction SMILES: O=C1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=C1O.C(=O)([O-])[O-:14].[Ca+2:17].C.O=O>OO>[Ca:17].[O:14]=[C:5]([O-:6])[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: [Ca+2]
Reactant: O=C([O-])[O-]
Agent: O=O
Agent: OO
Product: O=C([O-])[C@H](O)[C@@H](O)CO
Product: [Ca]
Temperature: 25 °C

Procedure:
Into a 12-L flask equipped with stirrer, thermometer, additional funnel was charged 528 g L-ascorbic acid (3.0 moles) and 7500 mL distilled water. The batch was stirred at room temperature to form a clear solution and added 600 g calcium carbonate. The slurry was stirred and cooled to 15° C. Then 1200 mL hydrogen peroxide (30% w/w) was added at 12°-15° C. over 60 min. The mixture was stirred at room temperature for 16 h. Then 120 g charcoal was added. The mixture was heated to 75° C. while stirring was continued until no more oxygen was evolved (as indicated by bubbling in a water trap). The batch was filtered at 70°-75° C., and the filter cake washed with 2×100 mL distilled water. The combined filtrate was concentrated to about 2-L at less than 50° C. under vacuum. Then 1500 mL methanol was added until the solution became cloudy. The mixture was then stirred at room temperature for 16 h, filtered, and washed with 2×100 mL methanol. The solids were dried at 60° C. under vacuum to constant weight to obtain Calcium-L-threonate having a dry weight of 436.5 g and a melting point 300+° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12]([C:14]2[CH:36]=[CH:35][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([O:31]C)=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:16][CH:15]=2)=[O:13])[CH2:2]1.O[Li].O.O1CCOCC1.Cl>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]4)=[CH:21][C:20]=3[C:33]#[N:34])=[CH:35][CH:36]=2)=[O:13])[CH2:2]1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4COc5ccccc5C4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3COc4ccccc4C3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.1 %

Procedure:
Methyl 7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (27.6 mg, 0.0570 mmol) was dissolved in THF (3 ml) and 1M solution of LiOH—H2O (114 μL, 0.114 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (42.7 μL, 0.171 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 21.2 mg of the title compound as white a solid (79%). MS (apci) m/z=471.0 (M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12.C(=O)([O-])[O-].[Na+].[Na+].[NH2:29][C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>ClCCl.CN(C)C=O.CO>[CH2:14]1[N:19]([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH:29][C@@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:31][OH:32])(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(S(=O)(=O)N[C@H](CO)c2ccccc2)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (40 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 min at room temperature. Then sodium carbonate (0.48 g, 4.52 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-2-amino-2-phenylethanol (0.274 g, 2.0 mmol) in N,N-dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 4 days. Then methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/dichloromethane=1:12) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.60-2.10 (m, 6H), 2.80-3.10 (m, 4H), 3.40 (m, 3H), 4.25 (m, 1H), 4.40-4.60 (m, 1H), 4.82 (t, 1H, J=4 Hz), 7.10 (m, 5H), 7.44 (m, 2H), 7.60 (s, 1H), 7.65 (m, 1H), 8.30 (d, 1H, J=7 Hz); MS (ESI) m/z 430 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].C([Li])CCC.CN1CCN(C)C1=O.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCCCCC.C1COCC1>[C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:7](=[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC1=CC(C(C)(C)C)=CC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CCC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
A 300-ml three-necked flask equipped with a magnetic stirrer and a three-way cock in a nitrogen atmosphere was charged with 5.11 g (23.9 mmol) of 1-ethyl-3-tert-butylcyclopentadiene (GC purity: 75%) and 150 ml of THF. In a dry ice/methanol bath, 16 ml of a 1.56 M hexane solution of n-butyllithium (25.2 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 20 hours, and 3.1 ml (28.8 mmol) of 1,3-dimethyl-2-imidazolidinone was added and 5.3 g (28.8 mmol) of benzophenone was further added. The mixture was stirred under reflux for 48 hours, and the resultant reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with 50 ml of hexane two times. The organic phases were combined and washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. The product was dried over magnesium sulfate and the solvent was distilled off. The distillate was purified by column chromatography to give 4.2 g of an orange solid. The yield was 56%. The compound was identified by 1H-NMR spectroscopy. The results are as follows.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[O:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1cc2cc[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Yield: 47.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (282 mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was heated at 95° C. for 3 hours. After cooling, the residue was poured in water (12 ml) and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by preparative column chromatography on C18 silica eluting with 60% methanol in aqueous ammonium carbonate (2 g ammonium carbonate/liter saturated with CO2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether and the solid was filtered, dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (147 mg, 48%).
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:32]=[CH:31][C:27](C(O)=O)=[CH:26][N:25]=1.FC(F)(F)C(O)=O.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][C:45]([O:46][C:47]2[CH:60]=[CH:59][C:50]([CH2:51][NH:52][C:53]([C:55]3([NH2:58])[CH2:57][CH2:56]3)=[O:54])=[CH:49][CH:48]=2)=[C:44]([C:63]([F:66])([F:65])[F:64])[CH:43]=1>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]([CH:27]=[CH:26][N:25]=1)[C:4]([NH:58][C:55]1([C:53](=[O:54])[NH:52][CH2:51][C:50]2[CH:59]=[CH:60][C:47]([O:46][C:45]3[CH:61]=[CH:62][C:42]([O:41][CH3:40])=[CH:43][C:44]=3[C:63]([F:64])([F:65])[F:66])=[CH:48][CH:49]=2)[CH2:56][CH2:57]1)=[O:8]
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc(F)nc1
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4ccnc(F)c4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
68 μL (0.48 mmol) of TEA and 57 mg (0.19 mmol) of TBTU were added to a solution of 23 mg (0.16 mmol) of 6-fluoro-nicotinic acid in 2 mL DMF and the mixture was stirred for 5 min at RT. Then 80 mg (0.16 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) was added and the mixture was stirred for 2 h at ambient temperature. A further 57 mg (0.19 mmol) of TBTU, 68 μL (0.48 mmol) of TEA and 23 mg (0.16 mmol) of 6-fluoro-nicotinic acid were added and the mixture was stirred overnight at RT. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Br.CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1>>[Br:13][C:9]1[CH:10]=[C:11]([F:12])[C:2]([NH:1][C:34]2[C:35]([Cl:39])=[CH:36][N:37]=[C:32]([Cl:31])[N:33]=2)=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cc(Br)cc(F)c1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
2-Amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide (2.00 g, 6.10 mmol) was placed in N-methylpyrrolidinone (20.0 mL, 207 mmol) and N,N-diisopropylethylamine (3.19 mL, 18.3 mmol) was added. The reaction was stirred for 5 minutes and then 2,4,5-trichloro-pyrimidine (3.50 mL, 30.5 mmol) was added. The reaction was heated at 100° C. for 24 hours and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed twice with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent to obtain 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a tan solid (1.19 g, 50%). m.p.=246-249° C.; LCMS (m/e) 393 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.73 (s, 1H), 8.68-8.57 (m, 1H), 8.43 (s, 1H), 7.87 (d, 1H, J=9.6 Hz), 7.66 (s, 1H), 2.69 (d, 3H, J=3.9 Hz); 19F-NMR (d6-DMSO, 400 MHz) δ −113.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].[Br:27][CH2:28][C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C>O>[Br:27][CH2:28][C:29]([NH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[O:30]
Reactant: O=C(O)CBr
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred slurry of 4.27 g. (10 mmole) of 6-(2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water, at 0° C., is added 1.39 g. (10 mmole) of bromoacetic acid in 6 ml. of water. The pH is adjusted to 6.0, and then 1.9 g. (10 mmole) of 1-ethyl-3-(dimethylaminopropyl)-carbodimide hydrochloride in 9 ml. of water is added. The mixture is stirred for 3 hours at pH 6. At this point, the pH is raised to 7.0, and the reaction mixture is washed with ethyl acetate. The pH is then lowered to 2.0, and the product is extracted into ethyl acetate. The dried extracts are concentrated to dryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p. 128°-135° C. IR (KBr disc): 1800 cm-1 (β-lactam) and 1653 cm-1 (amide I). NMR (in DMSO-d6 /D2O): 7.43 ppm (s, 5H), 5.73 ppm (s, 1H), 5.63 ppm (m, 2H), 5.23 ppm (s, 1H), 4.02 ppm (s, 2H), 1.60 ppm (s, 3H), 1.00 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.00 g, 25.2 mmol, Ark Pharm) in DMF (150 mL) was cooled in an ice bath to about 0° C. and then NaH (60% dispersion in mineral oil, 1.21 g, 30.3 mmol) was added. After about 15 min, 4-tert-butylbenzene-1-sulfonyl chloride (6.46 g, 27.8 mmol) was added. The reaction was maintained between about 0-10° C. for about 2 h. Then, the reaction was diluted with water (200 mL) to give a yellow suspension. The solid was collected by vacuum filtration, while washing with additional water (100 mL), and dried in a vacuum oven at about 70° C. to give 2-bromo-5-(4-tert-butylphenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (9.05 g, 91%): LC/MS (Table 2, Method a) Rt=3.05 min; MS m/z: 394/396 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:15])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:15][C:16](=[O:18])[CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(OCc2cccs2)ncc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)Nc1nc(OCc2cccs2)ncc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a 2 dram screw cap vial, a solution of 5-fluoro-2-(thiophen-2-ylmethoxy)-pyrimidin-4-ylamine (0.10 g, 0.4 mmol) in CH2Cl2 was treated with acetyl chloride (0.032 g, 0.4 mmol,) and PS-NMM (0.42 g, 0.8 mmol), a resin-bound equivalent of N-methyl morpholine (NMM). The mixture was shaken at RT for 12 h. The reaction mixture was filtered and the solvent evaporated to yield 0.084 g (75%) of the title compound as white solid: mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.6 Hz, 1H), 7.86 (bs, 1H), 7.31 (m, 1H), 7.23 (m, 1H), 7.00 (m, 1H), 5.54 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.Cl.Cl.[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH2:40])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClC(Cl)C>[CH3:28][O:29][C:30](=[O:41])[C@@H:31]([NH:40][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:15])[CH2:32][CH2:33][N:34]([CH2:36][CH2:37][O:38][CH3:39])[CH3:35]
Reactant: COCCN(C)CC[C@H](N)C(=O)OC
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCCN(C)CC[C@H](NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (prepared as in Example 110, Steps A-G) (0.094 g, 0.27 mmol), (S)-2-amino-4-[(2-methoxy-ethyl)-methyl-amino]-butyric acid methyl ester dihydrochloride (0.079 g, 0.28 mmol), EDCI (0.057 g, 0.30 mmol) and HOBt (0.045 g, 0.30 mmol) in dichloroethane (2 mL) was added dropwise triethylamine (0.23 mL, 1.62 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure and chromatographed, eluting with ethyl acetate, to afford 0.100 g of product (69% yield).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])O[C:2]1=O.C([O-])([O-])OCC.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[C:4](=[O:11])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH2:32][CH2:33]1)[CH3:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOc1ccccc1N1CCN(CCCCN)CC1
Agent: CCOC([O-])[O-]
Product: CCOc1ccccc1N1CCN(CCCCn2cnc3ccccc3c2=O)CC1
Yield: 37 %

Procedure:
A mixture comprising 1.63 g of 2H-3,1-benzoxazine-2,4(1H)-dione, 1.78 g of ethyl orthoformate and 2.77 g of 4-(2-ethoxyphenyl)-1-(4-aminobutyl)piperazine was heated on a boiling water bath for about 10 minutes and further heated on an oil bath of 120° to 130° C. for about 2 hours. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure and the residue was columnchromatographed over silica gel column and eluted with an ethyl acetatetriethylamine solvent (30:1) to give 1.5 g of 3-{4-[4-(2-ethoxyphenyl)-1-piperazinyl]butyl}-4(3H)-quinazolone as an oil (yield: 66.7%). ##STR15## 1.50 g of this oily free base was dissolved in a small amount of acetone. The obtained solution was added to a saturated solution of 0.857 g of fumaric acid in acetone to precipitate a crude crystal. The crude crystal was recrystallized from ethanol to give 1.65 g of the corresponding monofumarate having a melting point of 197° to 198° C. as a colorless prisms.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:17]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[N:16][C:15]=2[N:14]([CH3:35])[C:13]1=[O:36])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][C:17]1[N:18]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C:19]2[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:36])[N:14]([CH3:35])[C:15]=2[N:16]=1
Reactant: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.55 g, 1.03 mmol) was dissolved in ethanol (10 mL) and 6N HCl (2 mL) was added and the reaction was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined extracted were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a golden oil. The oil was purified using a 24 g silica gel flash column eluted with 50% ethyl acetate/hexanes to give 8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.21 g, 49% yield) as a white solid. LCMS retention time=3.859 min and 98% purity, LCMS MH+=421. 1H NMR (CDCl3) δ 7.35-7.38 (m, 2H), 7.24-7.28 (m, 1H), 7.18-7.25 (m, 1H), 4.27 (t, 2H, J=8 Hz), 4.20 (t, 2H, J=8 Hz), 3.52-3.58 (m, 3H), 3.47 (s, 3H), 1.86-1.94 (m, 2H), 1.70-1.78 (m, 2H), 1.59-1.69 (m, 1H), 0.98 (d, 6H, J=8 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])C)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:16])C.C(O)(=O)C>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
The oxidation of p-acetoxyacetophenone proceeded as in Example I, except that the reaction was run for 30 minutes and a total of 150 g (1.47 moles) of acetic anhydride and 37 g (0.62 mole) of acetic acid was added through the pump. The reaction mixture was concentrated from 772 g to 413 g by evaporation of acetic acid. The slurry was filtered to remove precipitated p-acetoxybenzoic acid. After drying, 128.2 g of p-acetoxybenzoic acid of 95 mole % purity (73% yield) were obtained. Remaining in the filtrate were: p-acetoxybenzoic acid, 8.5 mole % yield, p-acetoxyacetophenone, 1.8 mole % yield, p-hydroxybenzoic acid, 0.6 mole % yield. Analysis of the reactor wash showed 2.6 mole % p-acetoxybenzoic acid. Total reaction yield of p-acetoxybenzoic acid was 84 mole %.