Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:53][C:54]1[N:59]=[CH:58][N:57]=[C:56]2[N:60]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([C:69]#[N:70])[C:64]=3[CH3:71])[N:61]=[CH:62][C:55]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:69]([C:65]1[C:64]([CH3:71])=[C:63]([N:60]2[C:56]3=[N:57][CH:58]=[N:59][C:54]([O:53][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=4)=[O:43])=[C:55]3[CH:62]=[N:61]2)[CH:68]=[CH:67][CH:66]=1)#[N:70]
Reactant: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(C#N)cn3)ncnc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.346 mL, 0.35 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide (Intermediate AT1) (250 mg, 0.35 mmol) in THF (2 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was quenched with saturated NH4Cl, diluted with DCM and poured onto a phase separator. The organic layer was evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (69.0 mg, 41.2%, 92% ee). 1H NMR (400 MHz, CDCl3) δ 2.37-2.44 (4H, m), 3.73-3.86 (4H, m), 4.15-4.26 (2H, m), 6.07 (1H, t), 7.49 (1H, t), 7.63-7.68 (1H, m), 7.77-7.82 (1H, m), 7.94-8.00 (1H, m), 8.34-8.38 (1H, m), 8.43 (1H, s), 8.55-8.60 (2H, m), 9.34 (1H, s); m/z (ES−) (M−H)−=483.52; HPLC tR=1.95 min.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[NH2:16][C:17]1[C:18]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[CH:24][N:23]([CH:39]3[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]3)[C:19]=2[N:20]=[CH:21][N:22]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[NH2:16][C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)=[CH:24][N:23]([CH:39]3[CH2:40][CH2:41][C:42]([CH2:2][C:1]#[N:4])([OH:45])[CH2:43][CH2:44]3)[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCC1(O)CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15200 %

Procedure:
A solution of diisopropylamine (0.649 g, 0.0050 mol) in tetrahydrofuran (10 mL) was cooled to 0° C. A solution of 1.6 M n-butyl lithium (3.14 mL, 0.0050 mol) in hexanes was added dropwise, keeping the temperature less than 5° C. After the addition was complete, the mixture was stirred for 20 minutes at 0° C. The mixture was cooled to −78° C., and dry acetonitrile (0.175 g, 0.0043 mol) was added, keeping the temperature less than −70° C. After the addition was complete, the mixture was stirred for 20 minutes at −78° C., and a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (1.000 g, 0.0025 mmol) in tetrahydrofuran (10 mL) and hexamethylphosphoramide (10 mL) was added, keeping the temperature less than −70° C. After the addition was complete, the mixture was stirred for 30 minutes at −78° C., then stirred at ambient temperature for 18 hours. The mixture was partitioned between dichloromethane and saturated ammonium chloride (aq). The organic phase was washed with water and saturated sodium bicarbonate (aq), and dried over magnesium sulfate. The solvent was removed in vacuo and the cis and trans isomers were separated by flash column chromatography on silica using dichloromethane/methanol (95:5) as an eluent to give less polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0.120 g, 0.00027 mol) and more polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0.170 g, 0.00038 mol):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(C)C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:6](=[O:7])/[C:5](/[CH:10]([CH3:11])[CH3:12])=[C:4](/[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:18][CH:19]=1)\[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccc(C/C(C(=O)OC)=C(/C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester (44.1 mg, 0.151 mmol) in (880 μL) were added potassium carbonate (34.7 mg, 0.251 mmol) and methyl bromoacetate (138.4 mg, 0.904 mmol) with stirring at room temperature. After stirring at room temperature for 20 h, the reaction mixture was diluted with toluene and water to separate the phases. The aqueous layer was extracted again with toluene, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 10:1) to give 45.2 mg of the title compound as oil (yield: 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:21]1[N:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:24]=[C:23]([CH:30]=O)[CH:22]=1)[CH2:19][CH3:20]>>[C:26]([N:25]1[C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][C:23]([CH2:30][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(c3ccc(OC)cc3)CC2)nn1C(C)(C)C
Yield: 34.2 %

Procedure:
Compound 38 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccc2n1)C1CC1
Yield: 44.5 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.486 mmol), N,N-dimethylacetamide (3.0 mL), 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (163 mg, 0.730 mmol), HATU (277 mg, 0.730 mmol) and N,N-diisopropylethylamine (127 μL, 0.730 mmol) and in the same manner as in Example 8, the title compound (111 mg, 44%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N+:23]([O-])=O)=[CH:6][C:7]([CH3:22])=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:9]=1)[CH3:2]>CCOC(C)=O.CO.[Pt]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:15]2)[C:7]([CH3:22])=[CH:6][C:5]=1[NH2:23])[CH3:2]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Yield: 89.9 %

Procedure:
To 1-[5-(ethyloxy)-2-methyl-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (33.1 g, 89.0 mmol) in EtOAc (800 mL) and MeOH (200 mL) was added platinum on carbon (sulfided) (17.5 g, 4.47 mmol). The mixture was stirred under H2 (1 atm.) over the weekend. The mixture was filtered through Celite®, washed with DCM, and rotovapped down. The resultant solid was triturated with diethyl ether to provide the title compound of Step G (27.3 g, 80 mmol, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 6.44 (s, 1H), 4.28 (s, 2H), 3.94 (q, J=6.9 Hz, 2H), 3.11-3.22 (m, 2H), 2.97 (s, 3H), 2.87 (d, J=11.5 Hz, 2H), 2.44-2.56 (m, 2H), 2.06 (s, 3H), 1.59-1.80 (m, 4H), 1.43 (ddd, J=14.2, 7.0, 3.5 Hz, 1H), 1.21-1.36 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH:16][C:17](=[O:19])[CH3:18].[C:20](Cl)(=[O:25])[CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[C:17]([N:16]1[C:22](=[O:23])[CH2:21][C:20](=[O:25])[N:15]1[C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])(=[O:19])[CH3:18]
Reactant: CC(=O)NNc1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)CC(=O)N1c1cc(SCC(F)(F)F)c(C)cc1F
Yield: 70.9 %

Procedure:
2.0 g of N′-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}acetohydrazide was dissolved in 100 mL of tetrahydrofuran, 0.95 g of malonyl chloride was added under cooling with ice, stirring was carried out under cooling with ice for one hour, and then stirring was carried out under reflux with heating for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with isopropyl ether to obtain 1.74 g of 1-acetyl-2-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazolidine-3,5-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]O.S(Cl)(Cl)=O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1/[CH:5]=[CH:6]/[CH2:7][N:17]1[CH2:22][CH2:21][N:20]([CH2:7]/[CH:6]=[CH:5]/[C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:19][CH2:18]1
Reactant: COc1ccccc1C=CCO
Reactant: C1CNCCN1
Solvent: O=S(Cl)Cl
Product: COc1ccccc1/C=C/CN1CCN(C/C=C/c2ccccc2OC)CC1

Procedure:
2-Methoxy-cinnamylalcohol (1.44 g) was chlorinated using thionylchloride. Subsequently, reaction with piperazine and other treatments were performed as described in Preparation Example 2, to thereby obtain 314 mg of a salt as colorless prisms.
Reaction SMILES: C(OCN1N=NC(C2C=CC(CCCC3C=CC=CC=3O)=CC=2)=N1)(=O)C(C)(C)C.C(OC[N:38]1[N:42]=[N:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:45][CH:44]=2)=[N:39]1)(=O)C(C)(C)C.OC1C=CC=CC=1CCCC1C=CC(C([O-])=O)=CC=1.C(OC1C=CC=CC=1CCCC1C=CC(C(OC)=O)=CC=1)C1C=CC=CC=1>>[CH2:59]([O:58][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[CH2:51][CH2:50][CH2:49][C:46]1[CH:45]=[CH:44][C:43]([C:40]2[NH:41][N:42]=[N:38][N:39]=2)=[CH:48][CH:47]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2ccc(CCCc3ccccc3OCc3ccccc3)cc2)n1
Agent: CC(C)(C)C(=O)OCn1nnc(-c2ccc(CCCc3ccccc3O)cc2)n1
Agent: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: O=C([O-])c1ccc(CCCc2ccccc2O)cc1
Product: c1ccc(COc2ccccc2CCCc2ccc(-c3nnn[nH]3)cc2)cc1

Procedure:
2-(Pivaloyloxymethyl)-5-{-4-[3-(2-hydroxyphenyl)propyl]-phenyl}tetrazole was converted to 2-(pivaloyloxymethyl)-5-{-4-[3-(2-benzyloxyphenyl)propyl]phenyl}tetrazole by the process described in Example 1 for the conversion of 4-[3-(2-hydroxyphenyl)propyl]benzoate to methyl 4-[3-(2-benzyloxyphenyl)propyl]benzoate.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.[Pd]>[OH:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccccc1-c1nncn1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1nncn1O

Procedure:
A solution of 4-hydroxy-3-(2-nitrophenyl)-1,2,4-triazole (0.38 g, 1.8 mmol), prepared according H.G.O. Becker in J. Prakt. Chem., 1970, 312, 610, in 96% ethanol was hydrogenated over 5% palladium on charcoal at room temperature for 1 hour. The reaction was filtered through a pad of celite to give desired material on evaporation of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:14]([O:16]C)=[O:15])[C:10]([O:12]C)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl.ClCCl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10]([OH:12])=[O:11])[C:14]([OH:16])=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C(C(=O)O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 1,3-dimethyl 2-(3,5-dichlorophenyl)propanedioate form Step A was taken up in methanol (150 mL) and water (300 mL). To this mixture was added 50% aqueous sodium hydroxide (120 g, 1.5 mol) over 30 min at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 10° C. in an ice bath. The mixture was acidified with concentrated hydrochloric acid (135 mL of 37%) over 30 min while maintaining the temperature of the reaction mixture at less than 17° C. The reaction mixture was extracted with ethyl acetate (600 mL) and the organic phase was concentrated under vacuum to give a viscous oil. The crude oil was treated with dichloromethane (200 mL) and stirred till a thick slurry formed. The slurry was filtered and dried via suction filtration under a nitrogen blanket for 48 hours at room temperature to give a solid (76.0 g, 84% over 2 steps).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:23][C:4]1[C:5]([N+:20]([O-:22])=[O:21])=[CH:6][C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[C:2]([CH:3]=1)[CH:26]=[CH:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (3.06 g), ethyl acrylate (1.64 mL), palladium(II) acetate (84 mg), tris(2-methylphenyl)phosphine (0.23 g) and triethylamine (5.2 mL) in acetonitrile (30 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, and poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−2/1) to give ethyl 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrocinnamate (2.46 g). This material was dissolved in tetrahydrofuran (30 mL). To the solution were added methanol (30 mL) and nickel(II) bromide (63 mg). To the mixture was added sodium borohydride (0.65 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.69 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:47][N:48]([CH3:73])[C:49](=[O:72])[C@@H:50]([NH:59][C:60](=[O:71])[C@H:61]([NH:69][CH3:70])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57].C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[N:69]([C@@H:61]([C:60](=[O:71])[NH:59][C@H:50]([C:49](=[O:72])[N:48]([CH3:47])[CH3:73])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:58])[CH3:57])[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH3:70])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=1)[CH3:21])([CH3:15])([CH3:14])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(C)=O)C(=O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.6 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (594 mg, 3.1 mmol) was added at 0° C. to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (1.02 g, 3.1 mmol) and 1-hydroxy-7-azabenzotriazole (422 mg, 3.1 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the hydrochloride salt of crude (2S)-6-acetylamino-2-(((2R)-2-(methylamino)-3-phenylpropionyl)amino)hexanoic acid dimethylamide (1.28 g, 3.1 mmol) in dichloromethane (20 ml)and N,N-dimethylformamide (10 ml) and ethyidiisopropylamine (1.59 ml, 9.3 mmol) were added subsequently. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a 10% aqueous sodium hydrogen sulfate solution (150 ml). The aqueous solution was extracted wtih ethyl acetate (3×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (120 g), usin dichloromethane/methanol (10:1) as eluent, to give 1.57 g of N-((1R)-1-{N-[(1R)-1-((1S)-5-(acetylamino)-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].[NH3:20]>C(O)C>[NH2:20][C:15]1[N:14]=[C:13]([CH:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:11]#[N:12])[CH:18]=[CH:17][N:16]=1
Reactant: N
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Solvent: CCO
Product: N#CC(c1ccnc(N)n1)c1nc2ccccc2s1
Temperature: 150 °C
Yield: 51 %

Procedure:
A suspension of 1 (0.1 g, 0.35 mmol) in a 2M solution of ammonia in ethanol (10 ml) was heated up to 150° C. in a Parr vessel for 3 h. The solution was cooled down to r.t. and the yellow precipitate formed was filtered off then washed thoroughly with ethanol/water 1:1 and water. The precipitate was dried in vacuum at 40° C. affording 48 mg (51%) of the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10](OCC)([O:14]CC)[O:11][CH2:12][CH3:13])[C:3]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CCO.O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]([O:11][CH2:12][CH3:13])=[O:14])[C:3]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1(c2c(Cl)cccc2C#CC(OCC)(OCC)OCC)CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C#Cc1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
A mixture of ethyl 4-(2-chloro-6-(3,3,3-triethoxyprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (2.42 g, 5.51 mmol) in 50 mL EtOH and 10 mL water was treated with 4-methylbenzenesulfonic acid hydrate (0.105 g, 0.551 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with 100 mL EtOAc, washed with 20 mL saturated NaHCO3, dried over anhydrous Na2SO4 and concentrated. The concentrate was purified by column chromatography (20% EtOAc/hexane) to give 1.19 g pale yellow solid. MS m/e: (M+H)+ 365.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl>CCO>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(N)cc1Br
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
(3-Bromo-5-nitro-pyridin2-yl)-carbamic acid tert-butyl ester (100 mg, 0.31 mmol) and tin chloride (298 mg, 1.57 mmol) were dissolved in EtOH (3 mL), and stirred for 2 h at 40° C. The reaction solution was quenched with 2M NaOH, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated to provide (5-amino-3-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester (85 mg, 94% yield) as a brown solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[S:24][C:25]([CH3:30])=[C:26]([CH2:28][CH3:29])[N:27]=1>C1(C)C(C)=CC=CC=1>[CH2:28]([C:26]1[N:27]=[C:23]([NH:22][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:24][C:25]=1[CH3:30])[CH3:29]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CCc1nc(N)sc1C
Solvent: Cc1ccccc1C
Product: CCc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2)sc1C
Yield: 55 %

Procedure:
N-(4-Ethyl-5-methyl-2-thiazolyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 37 from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino-4-ethyl-5-methyl-thiazole. Yield: 55% of theory; m.p. 268°-270° C (decomp.; from xylene).