Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:23][O:24][C:25]([C:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>CO>[CH3:23][O:24][C:25]([C:27]1([CH2:33][NH:34][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)C1(CN)CCOCC1
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: COC(=O)C1(CNC(=O)c2ncc3cc(Oc4ccccc4)ccc3c2O)CCOCC1

Procedure:
After a mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (121 mg), 4-aminomethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (177 mg; commercially available) in MeOH (3 mL) was microwaved at 150° C. for 650 min; cooled, concentrated, the residue was partitioned between EtOAc and diluted HCl solution, EtOAc phase was washed with water and diluted NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated and column purified to give product (48 mg). LC MS ESI+: 437 (M+1)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([O:9][C@H:10]1[CH2:28][C@H:27]([O:29][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[C@@:26]2([CH3:37])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:38])[C@H:16]3[CH2:17][CH2:18]/[C:19]/2=[CH:20]/[CH3:21])[CH2:11]1)[C:3]([CH3:8])([CH3:7])[CH:4]([CH3:6])[CH3:5].[CH3:40][C:41]([Si:44]([CH3:54])([CH3:53])[O:45][C:46]([CH3:52])([CH3:51])[C:47]#[C:48][CH:49]=[O:50])([CH3:43])[CH3:42].[Cl-].C[Al+]C.C(N(CC)CC)C.[OH-].[NH4+]>CCCCCC>[CH3:43][C:41]([Si:44]([CH3:54])([CH3:53])[O:45][C:46]([C:47]#[C:48][CH:49]([OH:50])[C@H:20]([C:19]1[C@:22]2([CH3:38])[C@H:16]([C:15]3[C@H:25]([CH2:24][CH2:23]2)[C@:26]2([CH3:37])[C:12]([CH2:11][C@@H:10]([O:9][Si:2]([CH3:1])([CH3:39])[C:3]([CH3:7])([CH3:8])[CH:4]([CH3:6])[CH3:5])[CH2:28][C@@H:27]2[O:29][Si:30]([CH2:35][CH3:36])([CH2:31][CH3:32])[CH2:33][CH3:34])=[CH:13][CH:14]=3)[CH2:17][CH:18]=1)[CH3:21])([CH3:52])[CH3:51])([CH3:40])[CH3:42]
Reactant: CC(C)(C#CC=O)O[Si](C)(C)C(C)(C)C
Reactant: C/C=C1/CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C(C)C)C[C@H](O[Si](CC)(CC)CC)[C@]4(C)[C@H]3CC[C@]12C
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C(C)C)CC2=CC=C3[C@H](CC[C@]4(C)C([C@H](C)C(O)C#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]34)[C@]21C
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
A 3-L three-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, and Ar-inlet tube was charged with 91.9 g (160 mmol) of (1α,3β,17Z)-dimethyl[[1-[(triethylsilyl)oxy]pregna-5,7,17(20)-trien-3-yl]oxy](1,1,2-trimethylpropyl)silane, 62.8 mL (240 mmol) of 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy-4-methyl-2-pentynal, and 480 mL of hexane. After cooling to -75° C., 480 mL (480 mmol) of a 1M dimethylaluminum chloride solution in hexane was added over 1 hr. After stirring at -75° C. for 1.5 hr., 66.9 mL (480 mmol) of triethylamine was added followed by 147 mL of ammonium hydroxide over 5 min. After 5 min, the cold-bath was removed, and the mixture was stirred for 2 hr (Gas evolved). Then, 147 g of powder Na2SO4 was added, and the stirring was continued for 30 min. The solid was removed by filtration and washed with a total of 720 mL of hexane. The combined hexane solutions were washed with 480 mL of 95% methanol. The methanol layer was extracted with 240 mL of hexane. The combined hexane solutions were dried over Na2SO4 and concentrated. The residue was then dried under high vacuum overnight to give 153 g (overweight) of crude (1α,3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]-1-[(triethylsilyl)oxy]cholesta-5,7,16-trien-23-yn-22-ol as a brown viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][C:13]=2[N+:19]([O-])=O)[N:4]=1.[C:22](O)(=O)C>C(OCC)(=O)C.O.[Fe]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]2[C:13]([NH2:19])=[CH:14][CH:15]=[C:16]([CH3:22])[CH:17]=2)[N:6]=1
Reactant: CC(=O)O
Reactant: COc1nc(Nc2ccc(C)cc2[N+](=O)[O-])nc(OC)n1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(Nc2cc(C)ccc2N)nc(OC)n1

Procedure:
N-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-2-nitroaniline (10 g) was dissolved in ethyl acetate (50 ml) and water (50 ml), and 10 g of iron power and acetic acid (2 ml) were added thereto, followed by reflux for 2 hours. Insoluble matters were removed by filtration, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 8.8 g of the desired product as a white powder (m.p. 180-183° C.).
Reaction SMILES: C(OO)(C)(C)C.[Cl-].[Na+].[C:9]([O:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([OH:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>[Mo](=O)(=O)=O>[C:9]([O:17][CH:18]1[CH2:19][C:20]([CH3:28])([CH3:27])[N:21]([O:26][C:30]2([CH3:29])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:22]([CH3:24])([CH3:25])[CH2:23]1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC1CCCCC1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Agent: [Cl-]
Product: CC1(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CCCCC1
Temperature: 25 °C
Yield: 89 %

Procedure:
t-Butyl hydroperoxide (70%, 65.2 g, 507 mmol), methylcyclohexane (150 ml), and sodium chloride (10 g) are agitated in a separatory funnel. The organic layer is dried over magnesium sulfate. The t-butyl hydroperoxidemethylcyclohexane solution is mixed with 35.0 g (127 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 2.0 g of molybdenum trioxide, and 50 ml of methylcyclohexane. The reaction mixture is heated at reflux for 5 hours, then cooled to room temperature, filtered, and concentrated at reduced pressure. The crude product is diluted with heptane and passed through a short column of silica gel with heptane as the eluent to afford, after evaporation of solvent, 42.4 g (89% yield) of a clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a glass bomb were charged with 5-bromopyridin-2-amine (10.0 g, 57.8 mmol), ethyl acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144 mmol) in DMF (40 mL). The mixture was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2.89 mmol) and (o-Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was sealed, and heated with 100° C. oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates were removed by filtering through a thin layer of Celite. The filtrate was concentrated as much as possible via rotavap, and the residue was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with water (2×100 mL), dried over Na2SO4, and concentrated. A brown slid was obtained as crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid was collected via filtration. The filter cake was rinsed with small amount of EtOAc and dried under vacuum as the first crop of product (5.0 g). The mother liquor from trituration was stripped by dilute aqueous 1 N HCl (30 mL) and water (70 mL). Aqueous layer was transferred to a clean separate funnel, basicified with 20 mL sat. Na2CO3, and extracted with EtOAc (60 mL). EtOAc layer was dried over Na2SO4, concentrated and provided the second portion of product (4.0 g). The two crops of product were combined to afford 81% yield. LCMS (m/z) 193.2 (MH+), 0.39 min.
Reaction SMILES: C1CO[CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH2:20][CH2:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1.[BH4-].[Na+]>CO.O>[O:2]=[C:3]1[CH2:17][CH2:16][C@H:15]([CH2:20][CH2:21][CH:22]([OH:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1CCC(=O)C(C)(C)CC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCC[C@H]1C(=O)CC[C@@H]1CCC(O)C(C)(C)CC=C(C)C
Reaction time: 0.5 h

Procedure:
To the solution of 2.4 g of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prost-18-enoic acid, methyl ester in methanol (20 ml.) 0.4 g of sodium borohydride are gradually added while the temperature is kept under 35° C. The mixture is stirred for 30 minutes, then diluted with water (150 ml.) and extracted with ethyl acetate (3×70 ml.). The organic layer is washed with water to neutrality, dried over sodium sulphate and the solvent is removed in vacuo. The oily residue (2.2 g) is suspended in 65% acetic acid (30 ml.) and stirred at room temperature for 60 minutes. The obtained solution is diluted with water (100 ml.) and extracted with diethyl ether (3×70 ml). The organic layer is washed with aqueous saturated NaHCO3 solution to neutrality, dried over sodium sulphate and the solvent is evaporated. From the oily residue (1.8 g), by chromatography on silica (200 g) and elution with benzene/ethyl acetate (4:1), 0.48 g of 9 -keto-15β-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester, 0.40 g of 9-keto-15α-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester and 0.48 g of a mixture of 15α and 15β are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([C:26]#[N:27])=[N:14]1.S(=O)(=O)(O)[OH:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([S:21][C:22]([F:25])([F:23])[F:24])[C:15]([C:26]([NH2:27])=[O:29])=[N:14]1
Reactant: CCOc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(O)O
Product: CCOc1c(SC(F)(F)F)c(C(N)=O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 73 %

Procedure:
A stirred mixture of 1-(2,6-dichloro-4-trifluoromethylpheny)-5-ethoxy-4-trifluoromethylthio-1 H-pyrazole-3-carbonitrile (0.55 g, 1.22 mmol) and concentrated sulfuric acid (0.55 ml) was heated at 100° C. for 3 hours. The cooled mixture was added to ice water and the precipitate filtered off, washed with water and air-dried. The crude product was dissolved in heptanes/ethyl acetate (1:1) and filtered. The filtrate was evaporated to give the title compound (0.42 g, yield 73%) as yellowish crystals, mp 161° C., 1H NMR (CDCl3): 1.32 (t, 3H, CH3), 4.68 (q, 2H, OCH2), 5.54 and 6.69 (bs, 2H, C(O)NH2), and 7.77 (s, 2H, Ar—H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([C:16]([C:20]([OH:22])=[O:21])([CH2:18][OH:19])[NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.C=O>>[CH2:9]([C@@:16]([C:20]([OH:22])=[O:21])([CH2:18][OH:19])[NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(CO)(Cc1ccccc1)C(=O)O
Agent: C=O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Product: N[C@](CO)(Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
A reaction mixture in a total amount of 0.1 mL obtained by adding 0.03 mL of the cell-free extract solution to a reaction solution A having a composition of 50 mM potassium phosphate buffer (pH 7.4), 10 mM α-benzyl-DL-serine and 0.1 mM pyridoxal phosphate was reacted at 30° C. for 10 minutes. After 10 minutes, the reaction was stopped by mixing 0.1 mL of an alkali reagent (5 N potassium hydroxide) attached in a formaldehyde kit, Test Wako (Wako Pure Chemicals Industries Ltd.).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 188 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-83° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.82-7.76 (m, 3H), 7.29-7.21 (m, 4H), 7.19-7.14 (m, 1H), 4.47-4.44 (m, 1H), 3.89-3.82 (m, 1H), 3.08 (s, 2H), 2.82-2.69 (m, 3H), 2.63-2.54 (m, 1H), 2.42-2.27 (m, 4H), 2.20-1.94 (m, 2H), 1.86-1.77 (m, 2H); LCMS: 514 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1C(=O)c1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Under argon, 4-hydroxyphenyl 2-methylphenyl ketone (1.334 g) obtained in Example 126 and 4-dimethylaminopyridine (845 mg) were added to xylene (15 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (1.406 g) was added, and the admixture was refluxed with heat for 23 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by thin layer chromatography on silica gel eluting with hexane/acetone (2/1), to obtain 1.258 g of the title compound (yield: 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: ClCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)c(F)c2)cc1
Product: N#Cc1ccc(-c2ccc(OCCCCl)c(F)c2)cc1
Yield: 99 %

Procedure:
The product from Example 167A and 1-bromo-3-chloropropane were processed as described in Example 164C to provide the title compound (99% yield). 1HNMR (300 MHz, CDCl3) δ2.30 (m, 2H), 3.80 (m, 2H), 4.25 (m, 2H), 7.12-7.75 (m, 7H); MS (DCI) m/z 290 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([NH:10][CH3:11])=O)[N:5]=[N:4][N:3]=1.C(Cl)Cl.C(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].CN(C)C(=[NH2+])N(C)C>N1C=CC=CC=1>[CH3:11][N:10]1[C:8]([CH2:7][N:6]2[C:2]([Cl:1])=[N:3][N:4]=[N:5]2)=[N:21][N:20]=[N:19]1
Reactant: CNC(=O)Cn1nnnc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnnc1Cn1nnnc1Cl
Reaction time: 0.17 h

Procedure:
To a suspension of 1.75 g. (10 mmole) of 5-chloro-N-methyl-1H-tetrazol-1-acetamide, prepared as described under A above, in 50 ml. of methylene chloride containing 0.8 g. of pyridine and maintained at a temperature of about 0° C. was added with stirring excess phosgene. After addition was complete, the reaction mixture was stirred for 10 minutes without further cooling. The clear solution obtained on reaction was evaporated to dryness at a temperature of about 30° C. under reduced pressure. The residue containing the reaction product was suspended in 50 ml. of dioxane, and 2.4 g. (15.2 mmole) of tetramethylguanidinium azide were added to the suspension. The mixture was heated for 2 hours at the reflux temperature and after stirring overnight at room temperature, the reaction mixture was concentrated to near dryness under reduced pressure. The concentrate was dissolved in 30 ml. of water forming a pale yellow solution from which the product crystallized as colorless needles. The product was filtered and 0.4 g. of the crystalline product melting at about 138° C. to about 140° C. were obtained. A second crop of 0.5 g. of the product melting at about 136° C. to about 139° C. was isolated from the filtrate.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[CH2:5][O:4][N:3]=1.[NH2:13][NH2:14]>C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][O:4][N:3]=[C:2]([NH:13][NH2:14])[C:7]=2[CH:8]=1
Reactant: NN
Reactant: ClC1=NOCc2ccc(Cl)cc21
Solvent: CCO
Product: NNC1=NOCc2ccc(Cl)cc21
Yield: 60 %

Procedure:
An amount of 3.6 g. of 4,6-dichloro-1H-2,3-benzoxazine and 1.8 ml. of anhydrous hydrazine are dissolved in 18 ml. of absolute ethanol and refluxed for 30 minutes. The mixture is allowed to cool, then is distilled in vacuo. The residue is taken up with methylene chloride and filtered from precipitated hydrazine hydrochloride. The filtered solution is distilled to dryness and the residue crystallized from ethanol. An amount of 2.10 g. of 6-chloro-4-hydrazino-1H-2,3-benzoxazine is obtained.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.Br[C:23]1[S:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=1>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:23]2[S:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1ccc(Br)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cc2ccc(C#N)s2)cc1
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A mixture of sodium ethoxide (0.7 g), 1-(4-methoxyphenyl)acetylene (0.5 g), and toluene (40 cm3) is stirred for 2 h, 2-bromo-5-cyanothiophene (0.7 g), is added and the resultant mixture heated under reflux for 3 h. The reaction mixture is poured into water (500 cm3) and the organic layer separated off. The aqueous layer is then extracted with toluene (2×50 cm3). The combined organic layers are washed with water (2×200 cm3), dried (MgSO4), filtered and then evaporated down. The residue is purified by column chromatography on silica gel using a 95:5 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 0.3 g of 1-(4-methoxyphenyl)-2-(2-cyanothiophen-5-yl)acetylene.
Reaction SMILES: Br[C:2]1[C:3]([C:19](=[O:21])[NH2:20])=[C:4]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]2[C:17]=1[Cl:18].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:19]([C:3]1[C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:17]([Cl:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]=12)(=[O:21])[NH2:20]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(Br)c(C(N)=O)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1
Temperature: 100 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
To a solution under nitrogen of 3.78 g (9.98 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 160 ml of tetrahydrofuran are added 1.34 g (11.0 mmol) of benzeneboronic acid (CAS 98-80-6), 8 ml of water, 9.76 g (30.0 mmol) of caesium carbonate and 0.98 g (1.20 mmol) of a complex of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdCl2(dppf).CH2Cl2—CAS 95464-05-4). The mixture is stirred for 6 hours at 100° C. and then for 15 hours at 80° C., then cooled to room temperature and filtered through Celite™. The Celite is rinsed with 100 ml of ethyl acetate and 30 ml of water are added to the combined filtrates. The organic phase is separated out by settling, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 1.50 g of tert-butyl 8-carbamoyl-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after recrystallization from ethyl acetate and drying at 60° C. under reduced pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16](=[O:38])[CH2:17][C:18]1[C:27]([CH3:28])=[C:26](OS(C(F)(F)F)(=O)=O)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:37])[CH:24]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[Cl-].[Na+].O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:15][C:16](=[O:38])[CH2:17][C:18]1[C:27]([CH3:28])=[C:26]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:37])[CH:24]=2)[CH:19]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a mixture of 4-(methanesulfonyl)benzeneboronic acid (146 mg, 0.734 mmol), (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (93 mg, 0.244 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (36 mg, 0.048 mmol), and cesium carbonate (239 mg, 0.734 mmol) was added anhydrous DMF (5 mL) at room temperature. The resulting light brown suspension was heated to reflux for 15 hours. The reaction mixture was cooled to room temperature and diluted with brine and ethyl acetate. The two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined extracts were washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude residue. Flash chromatography (80 g ISCO column, 0-45% ethyl acetate in hexanes) gave 80 mg (85%) of [6-fluoro-4-(4-methansulfonyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ ppm 8.11 (d, J=8.2 Hz, 2 H), 7.82 (dd, J=8.7, 5.9 Hz, 1 H), 7.77 (s, 1 H), 7.49 (d, J=8.2 Hz, 2 H), 7.21 (td, J=8.7, 2.3 Hz, 1 H), 6.77 (dd, J=11.2, 2.3 Hz, 1 H), 3.87 (s, 2 H), 3.74 (s, 3 H), 3.20 (s, 3 H), 2.13 (s, 3 H). HRMS cald. for C21H20FO4S [(M+H)+] 387.1061, obsd. 387.1059.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([NH:8][C@@H:6]2[CH2:5][N:4]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:7]2)=[O:10])=[N:12]1)([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CNS(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 17 from tert-butyl (2S,4S)-2-(aminomethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (step 2 of Example 17) and methanesulfonyl chloride.