Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([C:24]#[N:25])[CH:3]=1.[CH3:26]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:7]1[C:2]([CH3:26])=[CH:3][C:4]([C:24]#[N:25])=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1Nc1cc(Cl)c(Br)cc1C#N
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)cc1Cl
Temperature: 110 °C
Reaction time: 24 h

Procedure:
tert-Butyl {(1S,2S)-2-[(4-bromo-5-chloro-2-cyanophenyl)amino]cyclohexyl}carbamate, trimethyl boroxine and potassium carbonate were suspended in a mixed solvent of 1,4-dioxane (16 ml) and water (4 ml), tetrakis(triphenylphosphine)palladium was added thereto, followed by stirring at 110° C. for 1 day. By post-treating the reaction liquid, tert-butyl {(1S,2S)-2-[(5-chloro-2-cyano-4-methylphenyl)amino]cyclohexyl}carbamate was obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:24](C1C=CC=CC=1)=[O:25])C1C=CC=CC=1.[Br:32]C1C=CC=CN=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:32][C:14]1[C:9]([OH:8])=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:24]=[O:25]
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2cccc(C(=O)c3ccccc3)c2OCc2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
A mixture of 11 (3.7 g, 8.94 mmol, 1.0 equiv), 2-bromopyridine (1.6 g, 0.95 mL, 10 mmol, 1.12 equiv), K2CO3 (3.7 g, 26.8 mmol, 3.0 equiv), dioxane (60 mL) and H2O (10 mL) was degassed with N2 for 5 min. Pd(Ph3P)4 (0.5 g, 0.43 mmol, 4.8 mole %) was added and the mixture refluxed for 8 hr, cooled to room temperature and stirred for 48 hr. The reaction suspension was diluted with EtOAc (100 mL) and the mixture filtered through Celite, washing the Celite pad with EtOAc (100 mL). The filtrate was concentrated under reduced pressure giving a yellow oil. The oil was partitioned between 1:1 EtOAc/heptanes (100 mL) and H2O (50 mL). The organic phase was washed with H2O (3×50 mL), brine (50 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a colorless oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (50 g) packed in hexanes. The column was eluted with hexanes (800 mL), 3% EtOAc/hexanes (500 mL), 6% EtOAc/hexanes (500 mL), 10% EtOAc/hexanes (500 mL), and 15% EtOAc/hexanes (500 mL). Product fractions (eluted with 15% EtOAc/hexanes) were concentrated under reduced pressure yielding an oil that crystallized on pumping under high vacuum to give 1.46 g (42%) of 7 as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6](=[O:12])[CH:5]=1.[H][H].[C:15]([O:18][C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23]Cl)(=[O:17])[CH3:16].[Cl-].[Na+]>CS(C)=O>[C:15]([O:18][C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][N:7]1[C:6](=[O:12])[CH:5]=[C:4]([NH2:3])[N:9]([CH3:10])[C:8]1=[O:11])(=[O:17])[CH3:16]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: [H][H]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A 1 liter round bottomed flask was charged with 95% sodium hydride (5.5 g, 220 mmol), dry dimethylsulfoxide (400 ml), and was cooled in an ice bath. 6-Amino-1-methyluracil (28.2 g, 200 mmol) was added slowly in portions. After evolution of hydrogen gas had subsided, the mixture was warmed to room temperature and stirred until the solid had completely dissolved (1 hour). (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol), prepared as described by Klein, J. P.; Leigh, A. J.; Michnick, J.; Kumar, A. M.; Underiner, G. E. Asymmetric Synthesis of Chiral Secondary Alcohols, U.S. Pat. No. 5,629,423 (May 13, 1997), was added slowly. The mixture was heated at 80° C. for 18 hours, and after cooling to room temperature, was treated with saturated aqueous sodium chloride solution (1 L) and extracted with ethyl acetate (4×200 ml). The combined extracts were washed again with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was treated with diethyl ether (100 ml) and stirred for 18 hours. The solid was filtered, rinsed with diethyl ether, and dried under vacuum to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (37 g, 65% yield) as a beige powder. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), (t, 2H), 4.75-4.90 (m, 3H), 4.95 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:15]=[C:16]([C@@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[CH2:17][CH2:18][C@H:19]1[NH:22][C:21](=[O:23])[C@H:20]1[NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCCl>[OH:3][CH:2]([N:22]1[C@H:19]([CH2:18][CH2:17][C:16](=[O:15])[C@@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[C@H:20]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]1=[O:23])[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C=O)cc1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1CCC(=O)[C@@H]1CCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
p-Methoxybenzyl glyoxylate (3.20 g, 16.5 mmol) in 1,2-dichloroethane (50 ml) was heated at reflux for 1h. using Dean and Stark apparatus. The solution was cooled in ice and treated successively with (3S,4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phenylacetamidoazetidin-2-one (4.10 g, 12.4 mmol) and triethylamine (170 μl, 1.22 mmol). After stirring at 0° C. for 30 min., the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexane, then ethyl acetate to yield the title compound as a yellow foam (4.53 g, 70%); νmax (CH2Cl2) 3420, 3226, 1769, 1743, 1681, 1613 and 1516 cm-1 ; m/z (FAB, +ve ion, 3-nitrobenzyl alcohol/sodium acetate) 547 (MNa+).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.[CH3:31][O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][N:28]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:36]5[CH2:37][CH2:38][CH:33]([O:32][CH3:31])[CH2:34][CH2:35]5)[CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1
Reactant: COC1CCNCC1
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: O=C(O)/C=C/CBr
Agent: Cl
Product: COC1CCN(C/C=C/C(=O)N2CCc3c(sc4ncnc(Nc5cc(O)cc(Cl)c5)c34)C2)CC1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and 4-methoxypiperidine (50 mg, 0.43 mmol) to yield 33 mg (23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][C:15]3[C:20]([CH2:21][C@@H:9]12)=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]2[C@H:9]1[CH2:21][C:20]1[C:15]([CH2:14]2)=[C:16]2[O:23][CH2:24][O:22][C:17]2=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2Cc3c(ccc(O)c3O)C[C@H]21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H]2Cc3c(ccc4c3OCO4)C[C@H]21
Temperature: 110 °C

Procedure:
Intermediate VI (60 mg), Cs2CO3 (33 mg) and CH2BrCl (48 mg) and DMF (1 mL) were heated to 110° C. for 0.5 h in a sealed microwave reactor vial. More CH2BrCl (33 mg in 0.2 mL DMF) was added and the mixture was heated 110° C. for 0.5 h. The reaction mixture was purified by silica gel chromatography (EtOAc/heptane). Yield: 18 mg of intermediate VII.
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].[N-:19]=[N+:20]=[N-:21].CN(C)C(=[NH2+])N(C)C>CN(C)C=O>[CH2:1]([C:4]1[C:5]([OH:6])=[CH:7][CH:8]=[CH:9][C:10]=1[O:11][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[NH:18][N:21]=[N:20][N:19]=1)[CH2:2][CH3:3]
Reactant: N#CCCCCBr
Reactant: CCCc1c(O)cccc1O
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OCCCCc1nnn[nH]1

Procedure:
Six grams of 2-propylresorcinol and 6.4 g. of 5-bromovaleronitrile were reacted following cedure of Example 2A to provide 3.4 g. of the desired nitrile intermediate. This intermediate was heated to 125° C. overnight with 40 mmoles of tetramethylguanidinium azide in 10 ml. of dimethylformamide. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with water adjusted to pH 6. The organic layer was dried and evaporated to yield the desired subtitle tetrazole intermediate which crystallized after evaporation of the solvent. NMR.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][OH:31])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH:30]=[O:31])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: CCCCCCCCCCN(CCO)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (12.24 mL) and methylene chloride (50 mL) at −35 to −45° C. was added DMSO (14.75 g) in methylene chloride (25 mL) over 20 minutes. The reaction mixture was stirred for 10 minutes at −35 to −45° C. A solution of N-Fmoc-2-(n-decylamino)ethanol (20.0 g) in methylene chloride (70 mL) was added over 25 minutes and then stirred 40 minutes at −35 to −45° C. Triethylamine (21.49 g) was then added and the mixture stirred for 30 minutes at −10 to −20° C. The reaction mixture was quenched with water (120 mL) followed by concentrated sulfuric acid (20.0 g) while maintaining the internal temperature at 0-5° C. The organic layer was isolated and washed with 2% sulfuric acid (100 mL) followed by water (2×100 mL). The organic solution was distilled under vacuum at 60° C. to about 100 mL. Heptane (100 mL) was added, the temperature of the oil bath raised to 80° C. and the distillation was continued until the residual volume was 100 mL. More heptane (100 mL) was added and the distillation repeated to a volume of 100 mL. The heating bath was replaced with a cold water bath at 15° C. The bath was cooled slowly to 5° C. over 20 minutes to start the precipitation of the product. The slurry was then cooled to −5 to −10° C. and the slurry was stirred for 2 hours. The solid was then collected on a Buchner funnel and washed with cold (−5° C.) heptane (2×15 mL). The wet solid was dried in vacuo to yield the title aldehyde.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[C:22]1([C:28]#[C:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](O[C:42](=O)[CH3:43])OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:30][C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1.[C:22]1([C:28]#[C:29][CH2:30][N:1]([CH2:19][C:14]#[C:15][C:42]2[CH:43]=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=CC#Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(N(CC#Cc2ccccc2)CC#Cc2ccccc2)CC1
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCC#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10 mL of a chloroform solution containing 404 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 180 mg of phenylpropargylaldehyde, 80 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 474 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 224 mg of 7-fluoro-1-(2-(4-(3-phenyl-2-propyn-1-ylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as brown solid and 158 mg of 1-(2-(4-(bis(3-phenyl-2-propyn-1-yl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as yellow oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[CH3:15][N:16]1[C:20]([C:21]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Product: Cc1cc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)n(C)n1

Procedure:
(2,5-Dimethyl-2H-pyrazol-3-yl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 1,3-dimethylpyrazole-5-carbonyl chloride, and indole according to GP 2. Yield, 7%. 1H-NMR (DMSO-d6): δ=1.97 (s, 3H), 3.77 (s, 3H), 5.56 (s, 1H), 6.20 (s, 1H), 6.63 (s, br., 1H), 6.95 (t, J=7.5 Hz, 1H), 6.99-7.10 (m, 2H), 7.14-7.30 (m, 3H), 7.42 (t, J≈7.2 Hz, 1H), 7.49-7.58 (m, 2H), 7.83 (d, J=6.7 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H), 10.72 (s, 1H); (+)-ESI-MS: m/z=419 [M+H]+, 302 [M-indole+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][S:9](=[O:18])(=[O:17])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]([CH3:21])[S:9](=[O:17])(=[O:18])[C:10]2[CH:16]=[CH:15][S:14][C:11]=2[C:12]=1[OH:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=C(O)c2sccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.93 G. (7 mmol) of 3-ethoxycarbonylmethyl-4-hydroxy-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide are dissolved in 4 ml. of absolute dimethylformamide and added dropwise during 30 minutes at 0° C. to a stirred suspension of 0.185 g. (7.7 mmol) of sodium hydride in 2 ml. of absolute dimethylformamide. The mixture is stirred for a further 1 hour at room temperature. There are then added firstly 0.53 ml. (1.2 g.; 8.45 mmol) of methyl iodide and, after 30 minutes, a further 0.25 ml. (0.565 g; 4 mmol) of methyl iodide and the mixture is allowed to react for 1 hour. After distillation of the solvent, the residue is taken up in 30 ml. of 0.5-N hydrochloric acid and 30 ml. of methylene chloride, the organic phase is separated and the aqueous layer is back-extracted twice with a small amount of methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol. There is obtained 3-ethoxycarbonylmethyl-4-hydroxy-2-methyl-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide of melting point 161°-163° C. (crystal transformation at 151°-152° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]=[C:14]=S)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C1(C([O-])=O)C=C(C)C=C(C)C=1.[NH2:27][N+:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[NH2:34].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[ClH:55]>ClCCl>[Cl:55][C:30]1[C:29]2[N:28]([N:27]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[N:34]=2)[CH:33]=[CH:32][N:31]=1
Reactant: S=C=Nc1ccc(N2CCOCC2)cc1
Reactant: Nc1cncc[n+]1N
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1cc(C)cc(C(=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nccn2nc(Nc3ccc(N4CCOCC4)cc3)nc12
Reaction time: 6 h
Yield: 84.1 %

Procedure:
To a solution of 4-morpholinophenylisothiocyanate (2 g, 8.99 mmol) in dry dichloromethane (200 ml), 1,2-diamino-pyrazinium mesitylenate (3.86 g, 11.24 mmol), diisopropylethylamine (5.81 g, 44.99 mmol) and EDCl (3.44 g, 17.98 mmol) are added and stirred for 6 hours. The reaction mixture is concentrated and the residue is taken in water (100 ml), triturated and filtered, washed with water (50 ml×2) and dried, the crude solid is purified by silica column using (60-120) mesh to get the titled product as light brown solid (2.5 g, 84.17%); TLC: chloroform/methanol (9.5/0.5) Rf-0.3; HPLC purity (method A) 98%; Rt (min): 2.21; LCMS: mass found (M+, 331.0), Rt (min): 2.08;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:18])([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[C:6]([F:19])[C:5]([F:20])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:28][C:29](Br)=[O:30]>CCOCC>[F:19][C:6]1[C:7]2[C:8]([C:13]#[C:14][CH:15]([CH3:17])[CH3:16])([C:9]([F:10])([F:11])[F:12])[O:18][CH2:28][C:29](=[O:30])[NH:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:20]
Reactant: CC(C)C#CC(O)(c1c(N)ccc(F)c1F)C(F)(F)F
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C#CC1(C(F)(F)F)OCC(=O)Nc2ccc(F)c(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled soliution of 81 mg of 6-Amino-2,3-difluoro-α-(isopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 8 mL of dry ether was added 0.55 mL of dry pyridine and 0.032 mL of bromoacetyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 10 mg of 100% sodium hydride for 20 min. The cooling bath was removed, and the reaction was allowed to proceed at ambient temperature for 1 h. The reaction was quenched with one drop of acetic acid and then the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and this solution vas washed with water and brine, dried and evaporated to a solid which was crystallized from ethyl acetate/hexanes affording 28 mg of the title compound as colorless crystals: mp 192.5-193.5°; HRMS: Calcd. for C15H13NO2F5 (M+H)+ : 334.086645. Found: 334.084917.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)(O)=[O:2].[OH2:21]>>[O:2]=[C:1]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:14][C:15]([NH2:16])=[O:21])=[CH:9][C:8]=2[CH2:7][CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2
Reactant: N#CCc1cccc(CCc2ccccc2C(=O)O)c1
Reactant: O
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C

Procedure:
3-(2-Carboxyphenethyl)phenylacetonitrile (2 g.) is added to polyphosphoric acid (20 g.) [prepared from orthophosphoric acid (d = 1.7; 1,120 g.) and phosphorus pentoxide (1,300 g.)], and the mixture is heated for 2 hours at 100°C. After cooling, the reaction mixture is poured into water (250 cc.); the oil which separates out is extracted twice with methylene chloride (total 150 cc.). The combined organic extracts are washed and dried over anhydrous sodium sulphate (10 g.) and the solvent is evaporated under reduced pressure (20 mm.Hg) at 60°C. to give (5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)acetamide (1.8 g.) melting at 174°C. After recrystallisation from ethanol, the product melts at 185°C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH:14]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>ClCCl>[CH:27]([C:29]1[CH:34]=[C:33]([N:16]2[CH2:15][CH:14]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH2:17]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(c1cccc(C=O)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Copper acetate Cu(OAc)2 (960 mg; 5 mmol) and triethylamine (1.5 ml; 10.5 mmol) are suspended in 60 ml of dichloromethane. The compound of Example 4 (1 g; 3.5 mmol), 3-formylphenylboronic acid (1.05 g; 7 mmol) and molecular sieve are then added in succession and progressively to the solution. The reaction mixture is stirred at ambient temperature for 2 hours. The mixture is filtered, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached) to yield the title product in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:30])[CH2:28]Br)[CH:22]=1>CN(C)C=O.[Cl-].[Na+].O>[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH2:28][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:30])[CH:22]=1
Reactant: Nc1c(C(=O)c2cccc(C(=O)CBr)c2)cnn1-c1ccc(F)cc1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)c2cccc(C(=O)CN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of morpholine (0.25 ml, 2.79 mmol) in dimethylformamide (5 ml) was added a solution of 5-amino-4-[3-(2-bromoacetyl)benzoyl]-1-(4-fluorophenyl)pyrazole (0.22 g, 0.56 mmol) in dimethylformamide (5 ml). After 16 h, the reaction mixture was poured into brine and the product was extracted into ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: ethyl acetate—10% methanol/ethyl acetate) to give 5-amino-1-(4-fluorophenyl)-4-[3-(morpholin-4-ylmethylcarbonyl)benzoyl]pyrazole (0.05 g) as a solid.