Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 73 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (60 mg, 0.19 mmol), glycine (726 mg, 9.68 mmol) and NaOMe solution (14.5 mL, 7.26 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes) to give 49 mg of the title compound as a light yellow solid. MS: (+) m/z 354.07 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[C@H:14]([N:16]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21](=[O:27])[O:20]1)=[O:18])[CH3:15].C(O)=O.[CH2:51](O)[CH3:52].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[C@H:14]([N:16]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([O:26][CH2:51][CH3:52])=[O:25])[CH2:22][C:21](=[O:27])[O:20]1)=[O:18])[CH3:15]
Reactant: C[C@H]([C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)[C@H]1OC(=O)C[C@@H]1C(=O)O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: O
Product: CCOC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
155 mg of (2S,3S)-2-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylic acid prepared by deprotecting the ester of the compound of Example 67(1) with formic acid, 13.5 mg of ethanol and 36.0 mg of 4-dimethylaminopyridine, were dissolved in 2 ml of chloroform, and 57.0 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, followed by stirring at room temperature overnight. The reaction solution was poured into water and extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 123 mg (yield: 76%) of the above-identified compound as slightly yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.O>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
25 Grams (133 mmol) of 6-hydroxy-2-naphthoic acid and 68 g (265 mmol) of acetic anhydride were placed in a reactor, and while the mixture was stirred, 0.05 g of concentrated sulfuric acid was added. The mixture was stirred until heat generation ceased, and the mixture was further heated and stirred at 80° C. for 1 hour and then gradually cooled to room temperature. While the reaction mixture was cooled in an ice bath, 500 g of water was gradually added, and the mixture was stirred at room temperature for 3 hours to quench unreacted acetic anhydride. A precipitated white solid was recovered by filtration, washed with water to remove acetic acid, and dried with a vacuum dryer, to give 30.3 g of an end compound (yield 99%)
Reaction SMILES: C(C[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]=[CH:9][C:10]([OH:12])=[O:11])(O)=O.C[N:17](C)[CH:18]=[O:19]>N>[NH2:17][C:18]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)C=Cc1cccc(CC(=O)O)c1
Agent: N
Product: NC(=O)c1cccc(C=CC(=O)O)c1

Procedure:
A solution of 3-carboxymethylcinnamic acid (427 g) (Example 2(a)) in dimethyl formamide (4.25 l) and aqueous ammonia (specific gravity 0.88, 8.5 l) was stored at room temperature for 4 days, concentrated to call 11 l, and then treated with ice (8 kg) and concentrated hydrochloric acid (1 l). The precipitated title product was washed with water and dried, m.p. >260° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([S:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (500 mg, 1.52 mmol), 3-aminobenzenethiol (381 mg, 3.04 mmol), potassium carbonate (630 mg, 4.56 mmol) and N,N-dimethylformamide (5.0 mL) was stirred at 80° C. for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and precipitated from ethyl acetate to give the title compound (396 mg, 80%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]=[N+:24]=[N-:25])[O:19][C:18]4=[O:26])=[CH:13][C:12]=3[F:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:28]12CC(CC1)=C[CH:29]=2>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]5[CH:29]=[CH:28][N:25]=[N:24]5)[O:19][C:18]4=[O:26])=[CH:13][C:12]=3[F:27])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1=C2CCC(=C1)C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Yield: 57.5 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5-azidomethyloxazolidin-2-one (2.44 g, 6.5 mM) was dissolved in dioxane (50 ml), treated with norbornadiene (2.98 g, 32.3 mM) and heated under reflux for 20 hours. After removal of the solvent, the residue was dissolved in dichloromethane (350 ml) washed with water (3×200 ml), and dried over magnesium sulfate. After filtration and evaporation the residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (1.5 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]=[CH:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC/C=C\C1=CCCC1=O

Procedure:
A solution of 3 g. of crude 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene-1-one (Example 1133) in 100 ml. of 2% sodium hydroxide is stirred at 80° C. under nitrogen for 1.5 hours. The cooled solution is acidified to Congo Red and extracted into ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.COC[C@@H](O)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:16]([CH3:17])[CH2:15][O:14][CH3:18])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: C1CCOC1
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-fluoro-2-methylquinolin-8-ol (0.50 g, 2.8 mmol) in tetrahydrofuran (2.4 mL, 2.8 mmol) was added triphenylphosphine (2.6 g, 9.9 mmol), diisopropyl azodicarboxylate (0.91 mg, 4.5 mmol), and (S)-1-methoxypropan-2-ol (0.33 mg, 3.7 mmol) and the resultant mixture allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by normal phase chromatography on silica gel (0-2% methanol/dichloromethane) afforded the title compound which was taken on to the subsequent step without further purification, assuming theoretical yield (0.70 g, 100%) was obtained, despite being contaminated with residual triphenylphosphine oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15](I)[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=4)[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ncnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of Example 3C (3.07 g, 6.03 mmol) in 70 mL 1,2-dimethyoxyethane/ethanol (50:20) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.80 g, 9.04 mmol), 2M sodium carbonate (12.06 mL, 24.11 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.423 g, 0.603 mmol). The mixture was stirred at 100° C. for 3 hours, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (Analogix 280) eluting with a gradient of 20% to 80% ethyl acetate/hexane gave the title compound. MS (ESI+) m/z 565.43 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:22](=[O:23])[NH:21][C:20](=[O:24])[C@@:5]21[O:9][C@@H:8]([CH2:10]I)[C@H:7]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]2[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2].[C:25]([O-:28])(=[S:27])[CH3:26].C[N+](C)(C)C>COCCOC.ClCCl>[C:1]([N:4]1[C:22](=[O:23])[NH:21][C:20](=[O:24])[C@@:5]21[O:9][C@@H:8]([CH2:10][S:27][C:25](=[O:28])[CH3:26])[C@H:7]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]2[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](CI)O[C@]2(C(=O)NC(=O)N2C(C)=O)[C@@H]1OC(C)=O
Reactant: CC([O-])=S
Agent: C[N+](C)(C)C
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](CSC(C)=O)O[C@]2(C(=O)NC(=O)N2C(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Yield: 94.4 %

Procedure:
To a solution of (2R, 3R, 4R, 5S)-6-acetyl-2-iodomethyl-3, 4-diacetoxy-1-oxa-6,8-diazaspiro (4,4) nonane-7, 9-dione (598 mg, 1.32 mm) in anhydrous DME (10 ml) is added, under N2, tetramethylammonium thioacetate (353 mg, 2.37 mm) in one portion. The resulting mixture is heated at 45° C. for 4 hours, then diluted with dichloromethane and washed with brine, dried, and evaporated for dryness. The crude product is purified by thin-layer chromatography to give (2R, 3R, 4R, 5S)-6-acetyl-2-acetylthiomethyl-3, 4-diacetoxy-1-oxa-6, 8-diazaspiro (4,4) nonane-7, 9-dione (500 mg) as a hygroscopic foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 3-tert-butoxycarbonylaminopropanoic acid (2 g, 10.6 mmol.) and HOSu (1.22 g, 10.6 mmol.) in 40 mL DCM/Dioxane (2:1) was cooled in an ice bath. To this solution was added DCC (2.4 g, 11.6 mmol.), and the mixture was stirred at room temperature for 1 h. To the resulting mixture was added benzylamine (1.7 g, 15.8 mmol.), the mixture was stirred for 4 h at room temperature. The solid that formed in the mixture was removed by filtration and washed with EtOAc. The filtrate and washings were combined and washed with 1N HCl and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford 3-tert-butoxycarbonylamino-N-benzylpropionamide (2.4 g, 82%). 3-tert-Butoxycarbonylamino-N-benzylpropionamide was dissolved in cooled HCl/MeOH (20 mL) and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed to afford 3-amino-N-benzylpropionamide hydrochloride (1.8 g, 100%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2F)[CH2:7]1.O.C(OCC)(=O)C>CN(C)C=O>[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2[C:1]#[N:2])[CH2:7]1
Reactant: [C-]#N
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1C#N
Temperature: 50 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
0.30 g (6.0 mmoles) of sodium cyanide was added, at room temperature, into a solution of 1.08 g (3.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 10 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.10 g (yield: quantitative) of 5-chloromethyl-3-(5-cyano-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].C[Si]([N:20]=[C:21]=[O:22])(C)C.ClCCl>CN(C)C=O>[NH2:20][C:21]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:22]
Reactant: NC(=O)c1sc(-c2ccccc2)cc1N
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2ccccc2)sc1C(N)=O

Procedure:
3-Amino-5-phenyl-2-thiophenecarboxamide (0.5 g), trimethylsilylisocyanate (3 mL), dichloromethane (15 mL) and dimethylformamide (3 mL) were heated at reflux for 3 days.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[C:21]1([CH2:20][CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCc1ccccc1
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Hydroxyphthalimide (15.0 g, 92 mmol) and sodium acetate (7.5 g, 92 mmol) were stirred in dimethylsulfoxide (70 ml) at ambient temperature for 3 h. 2-Chloroethylbenzene (12.5 g, 89 mmol) was added and the reaction mixture was heated at reflux for 2 h. After cooling and standing overnight the reaction mixture was filtered and the flitrate was poured onto ice/water (300 ml). The mixture was extracted with dichloromethane (4×100 ml), the combined extracts were dried (MgSO4) and evaporated in vacuo to a residue. Purification by flash chromatography on a silica gel column eluting with heptane/ethyl acetate (1/1) afforded the title compound as a colourless foam (15.7 g, 33%); 1H NMR (DMSO-d6)γ 3.05 (2H, t, --OCH2 --), 4.39 (2H, t, --CH2Ph), 7.20-7.35 (5H, m, Ar-H), 7.85 (4H, s, Ar-H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].N1C=CC=CC=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:20](=[O:21])[C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:23])[F:12])=[N:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: C#CCNC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
N-methylpropargylamine (95%, 1.0 g, 13.75 mmol) and pyridine (5 mL) in dry dichloromethane (DCM)(50 mL) were cooled with ice-water. 6-(Trifluoromethyl)pyridine-3-carbonyl chloride (97%, 2.83 g, 13.10 mmol) was added drop wise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. DCM (150 mL) was added and the mixture was washed with water (3×100 mL). The organic phase was dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the product (1.96 g, 70.0% yield), LRMS ESI (M+H+) 243, HPLC rt=5.4 min.
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)=[CH:12][N:11]=[CH:10]1)([CH3:8])[CH3:7].CN([CH:30]=[O:31])C>C1COCC1>[NH:20]([C:16]1[N:15]=[C:14]([C:13]2[N:9]([CH:6]([CH3:8])[CH3:7])[C:10]([CH:30]=[O:31])=[N:11][CH:12]=2)[CH:19]=[CH:18][N:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)n1cncc1-c1ccnc(Nc2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
n-Butyllithium (7.2 ml of 1.6 M solution in hexane, 11.2 mmol) was added to a solution of 4-(1-isopropylimidazol-5-yl)-2-anilinopyrimidine (Method 5; 1.25 g, 4.48 mmol) in anhydrous THF (50 ml) cooled to −70° C., and the reaction mixture was then stirred at −70° C. for 30 minutes. Anhydrous DMF (0.7 ml, 9.0 mmol) was added and the mixture was stirred for 18 hour at ambient temperature. The mixture was quenched with water (50 ml), and was extracted with EtOAc (4×75 ml). The organic extracts were combined, washed with brine (2×50 ml), dried and evaporated. The residue was purified by chromatography eluting with EtOAc/Hexane (1:1) to give the title compound (930 mg, 68%) as a pale yellow crystalline solid. NMR (CDCl3): 1.6 (d, 6H), 5.60-5.75 (m, 1H), 6.98 (d, 1H), 7.12 (t, 1H) , 7.30-7.40 (m, 3H), 7.55-7.65 (m, 3H), 8.50(d, 1H), 9.90 (s, 1H); m/z 308.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][C:14]1[C:32]([F:33])=[CH:31][C:17]([C:18]([NH:20][CH:21]2[CH2:28][C@H:27]3[N:29]([CH3:30])[C@H:23]([CH2:24][CH2:25][CH2:26]3)[CH2:22]2)=[O:19])=[C:16]([F:34])[CH:15]=1.Cl[C:36]1[N:46]=[C:45]2[C:39]([N:40]([CH3:53])[C:41](=[O:52])[CH2:42][CH2:43][N:44]2[CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:38][N:37]=1>CC(C)CC(O)C>[CH:47]1([N:44]2[CH2:43][CH2:42][C:41](=[O:52])[N:40]([CH3:53])[C:39]3[C:45]2=[N:46][C:36]([NH:13][C:14]2[C:32]([F:33])=[CH:31][C:17]([C:18]([NH:20][CH:21]4[CH2:28][C@H:27]5[N:29]([CH3:30])[C@H:23]([CH2:24][CH2:25][CH2:26]5)[CH2:22]4)=[O:19])=[C:16]([F:34])[CH:15]=2)=[N:37][CH:38]=3)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CN1[C@@H]2CCC[C@H]1CC(NC(=O)c1cc(F)c(N)cc1F)C2
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4C[C@H]5CCC[C@@H](C4)N5C)cc3F)ncc21
Temperature: 150 °C
Yield: 23.1 %

Procedure:
p-Toluenesulphonic acid monohydrate (338 mg, 1.78 mmol) was added to 4-amino-2,5-difluoro-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 274; 220 mg, 0.71 mmol), and 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (Intermediate 1; 200 mg, 0.71 mmol) in 4-methyl-2-pentanol (4 mL) at 25° C. The resulting mixture was heated by microwave irradiation at 150° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX-3 (5 g) column. The desired product was eluted from the column using 2M NH3/MeOH and product-containing fractions were evaporated to dryness. The residue was further purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (91 mg, 23.%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:19]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:27][CH2:26][CH2:25][CH2:24][C:20]1[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: Cc1ccnc(CCCN)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccnc(CCCNC(=O)/C=C/C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (64 mg, 0.46 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (40 μl, 0.46 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 3-(4-methyl-2-pyridyl)propan-1-amine hydrochloride (56 mg, 0.3 mmol) and EDIPA (240 μl, 1.4 mmol) in anhydrous dichloromethane (5 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 47 mg of a solid (0.17 mmol, 58% yield)