Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Cl-].[Al+3].[N+](C)([O-])=O.[F:19][C:20]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25]([F:32])[C:21]=1[C:22](Cl)=[O:23]>C(OCC)(=O)C.O.Cl.CO>[F:19][C:20]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25]([F:32])[C:21]=1[C:22]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][CH:9]=1)=[O:23]
Reactant: Cc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: Cc1cnc2[nH]cc(C(=O)c3c(F)ccc([N+](=O)[O-])c3F)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
To 5-methyl-1H-pyrrolo[2,3-b]pyridine (15, 2.00 g, 15.1 mmol) and aluminum trichloride (11.6 g, 87.2 mmol), nitromethane (63.1 mL, 1.16 mol) was added, followed by the addition of 2,6-difluoro-3-nitro-benzoyl chloride (14, 3.22 g, 14.5 mmol). The reaction was placed in an oil bath at 45° C. and stirred for 3 days, then cooled to room temperature and 30 mL of methanol was added. The reaction was then diluted with 200 mL of ethyl acetate and 100 mL each of water and 1N hydrochloric acid, resulting in a precipitate that was collected to provide the desired compound (16, 2.761 g). Additional compound was recovered from the organic layer, removing the solvent and purifying by silica gel column chromatography eluting with a gradient of 5 to 70% ethyl acetate in hexanes to provide another 126 mg of compound. MS (ESI) [M+H+]+=317.9.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH:15][CH3:16]>CN(C1C=CN=CC=1)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CNC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: CN(C)c1ccncc1
Product: CN(C)C(=O)c1cc(Br)ccc1N
Reaction time: 8 h
Yield: 106.1 %

Procedure:
Into an 15 mL high pressure glass vial (with Teflon screw cap) were added 5-bromoisatoic anhydride (0.401 g, 1.66 mmol), DMAP (20 mg, 0.16 mmol), and dimethylamine (2 M in THF; 5.0 mL, 10.0 mmol). The vial was sealed and placed in an oil bath at 70° C. for 8 h after which it was concentrated under vacuum. The crude product was dissolved in EtOAc and washed 2× with water followed by brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford 0.428 g of 2-Amino-5-bromo-N,N-dimethyl-benzamide as a pink solid, which was used directly for the next step. 1H-NMR (500 MHz, d6-DMSO) δ=7.19 (dd, J=2.0, 8.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 5.31 (br. s, 2H), 2.89 (br. s, 6H). MS: m/z 198/200 [C═O+].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:27]([C:28]#[N:29])=[C:26]([CH3:30])[N:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[C:24](=[O:41])[NH:23]1)(=[O:13])=[O:12])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.C(#N)C.O>ClCCl>[C:20]([C:18]1[CH:17]=[CH:16][C:15]([CH:22]2[C:27]([C:28]#[N:29])=[C:26]([CH3:30])[N:25]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[C:24](=[O:41])[NH:23]2)=[C:14]([S:11]([CH2:10][CH2:9][OH:8])(=[O:13])=[O:12])[CH:19]=1)#[N:21]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)CCO[Si](C)(C)C(C)(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The reaction was carried out under argon. 4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (550 mg, 0.909 mmol) was initially charged in dichloromethane (30 ml), trifluoroacetic acid (30 ml) was added and the mixture was stirred at RT for 5 h (HPLC control). The mixture was then concentrated without heating, and the residue was taken up in dichloromethane (200 ml). The organic phase was washed with saturated sodium bicarbonate solution (2×50 ml) and with saturated sodium chloride solution (50 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The oil obtained was taken up in a little acetonitrile, water was added and the mixture was lyophilized. The title compound was obtained as a solid (450 mg, quant.).
Reaction SMILES: [C:1]([O:10][CH2:11][P:12]([CH3:15])([CH3:14])=[O:13])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:17]1[C:26]2[C:21](=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)(C)C.Cl>[F:30][C:27]([F:28])([F:29])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH2:11][P:12]([CH3:15])([CH3:14])=[O:13])=[O:9]
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: CP(C)(=O)COC(=O)c1ccccc1N
Agent: Cl
Solvent: CC(C)O
Product: CP(C)(=O)COC(=O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
4.6 grams (0.02 mol) of dimethylphosphinylmethyl anthranilate and 4.6 grams (0.02 mol) of 4-chloro-8-trifluoromethylquinoline are kept at 80° C. for about three and a half hours in 15 ml of isopropanol and 2.3 ml of concentrated aqueous hydrochloric acid. After removing the solvents and excess hydrochloric acid, the free base of the ester is liberated at 0° C. The dimethylphosphinyl-methyl N-(8-trifluoromethyl-4-quinolyl)-anthranilate obtained is identical to that prepared in Example 2a). Yield: 7.6 grams (90% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23]CC(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36]C[CH2:38][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.Cl>>[ClH:36].[ClH:35].[N:39]1([CH2:38][CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: ClCCn1ccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCCn3ccnc3)cc2OCc2ccccc2)n1
Yield: 33.3 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(2-chloroethyl)-1H-imidazole hydrochloride (28.1 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(2-(1H-imidazol-1-yl)ethylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine dihydrochloride (28.1 mg, 33.6% yield) as a tan solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.16 (t, 1H), 7.96 (d, 1H), 7.75 (t, 1H), 7.66 (t, 1H), 7.64-7.59 (m, 3H), 7.45-7.33 (m, 3H), 6.77 (s, 1H), 5.34 (s, 2H), 4.35 (t, 2H), 3.47 (t, 2H), 2.29 (d, 3H); Mass spectrum (apci) m/z=424.0 (100) 328.0 (75) 238.0 (35).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N[C:6]1[CH:19]=[CH:18][C:9]2[C:10](=O)O[C:12]([O:14][CH2:15][CH3:16])=[N:13][C:8]=2[CH:7]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>O>[S:20]([OH:24])([OH:23])(=[O:22])=[O:21].[CH2:15]([O:14][C:12]1[O:3][C:1](=[O:4])[C:2]2[C:18]([CH2:9][CH3:10])=[CH:19][CH:6]=[CH:7][C:8]=2[N:13]=1)[CH3:16]
Reactant: CC(=O)O
Reactant: CCOc1nc2cc(N)ccc2c(=O)o1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1nc2cccc(CC)c2c(=O)o1

Procedure:
7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one acetate (1.0 g) is dissolved in 50 ml water containing a stoichiometric equivalent of sulfuric acid, and the solution evaporated to dryness. The product is suspended in ether and filtered, air dried and recrystallized from methanol/acetone to yield 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one sulfate.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:6][C:5]([C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:22])=[CH:4][C:3]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]2=[N:30]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[OH:1][C:2]1[C:7]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])(=[O:19])=[O:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:6][C:5]([C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:22])=[CH:4][C:3]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]2=[N:30]1
Reactant: CN(C)CCN
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)c2ccc(S(=O)(=O)Cl)cc2)c1
Product: CN(C)CCNS(=O)(=O)c1ccc(C(C)(C)c2cc(C(C)(C)CC(C)(C)C)cc(-n3nc4ccccc4n3)c2O)cc1

Procedure:
The title compound is prepared according to the procedure given in instant Example 35 using 8.0 g of the intermediate compound prepared in Example 34a and 1.4 g of 2-dimethylaminoethylamine. After several recrystallizations from ethyl acetate and ethyl acetate/heptane mixtures, 5.6 g of the title compound is prepared as a near white solid melting at 118-120° C. The structure of the compound is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35]O[CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5].N1CCCC[CH2:41]1>>[CH3:39][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:32][CH2:33][CH2:41][CH2:35][CH2:36]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCOCC5)nc4)cc3)cc2C1=O
Reactant: C1CCNCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCCCC5)nc4)cc3)cc2C1=O
Yield: 91 %

Procedure:
The compound of example 214 was prepared analogous to compound of example 212 by reaction of compound of example 211 with piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1.[Cu].O.C(O)(=O)C>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:28]2[CH:29]=[CH:30][C:25]([C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Ic1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In a 500 milliliter round bottomed flask equipped with mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 12.39 grams (0.055 mole) of bis(3,4-dimethylphenyl)amine, 14 grams (0.050 mole) of 4-iodobiphenyl, 0.50 gram (0.0025 mole) of cupric (copper II) acetate monohydrate, 0.45 gram (0,0025 mole) of 1,10-phenanthroline, 22.44 grams (0.4 mole) of flake potassium hydroxide and 20 milliliters of toluene solvent. The reaction was heated quickly to a reflux temperature of 120° C. and maintained at this temperature for 4 hours after which time chromatographic analysis revealed the reaction to be complete. The reaction was cooled to room temperature, about 25° C., and partitioned between 200 milliliters of toluene and 150 milliliters of deionized water. The resulting organic layer was separated and water removed by azeotropic distillation of the solvent under a Dean-Stark trap. The product was decolorized by slurry treating the toluene solution with 10 grams of FILTROL-24™, an acid washed clay, and 10 grams of Alcoa CG-20 alumina. After 3 hours stirring at reflux, the solution was hot filtered to remove the clay and alumina, and cooled to room temperature. Evaporation of the solvent and recrystallization from octane provided the above product compound in a yield of 10.2 grams (76 percent) and which product melted at 113.8° C. This product of N,N-bis(3,4-dimethylphenyl)-4-biphenylamine was suitable for further purification by conventional means to afford electronic grade, about 99 percent pure, product. The above total reaction time was an accelerated 4 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-:24])=[O:23])[C:17]([CH3:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH3:21][C:17]1[C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N:12][CH:13]=[CH:14]2
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 89.6 %

Procedure:
A mixture of 4-aminobenzonitrile (4.0 g, 34 mmol), isopropanol (50 mL) and 1-chloro-6-methyl-5-nitroisoquinoline (5.0 g, 22 mmol) was stirred at RT (22° C.) and treated with TFA (5.0 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 17 h, and allowed to cool to RT. The thick slurry was diluted with isopropanol (100 mL) and the solid precipitate was collected by suction filtration. The solid was washed with saturated NaHCO3 (2×100 mL), water (50 mL), Et2O (50 mL), and hexane (100 mL) and dried in a vacuum oven at 70° C. overnight to provide 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (6.0 g, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 305 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]3)=[CH:14][C:13]=2[N+:27]([O-])=O)=[N:2]1.[Sn].Cl.[OH-].[Na+]>C(O)C>[NH2:27][C:13]1[CH:14]=[C:15]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][OH:26])[CH2:22][CH2:23]2)[CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=[N+]([O-])c1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(N2CCN(CCO)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(E)-2-(4-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}piperazin-1-yl)ethanol (0.26 g, 0.66 mmol) obtained in Step 2 was dissolved in ethanol (3.0 mL), and the solution was added with tin (0.17 g, 1.4 mmol) and concentrated hydrochloric acid (1.5 mL) under ice-cooling, followed by stirring at 40° C. for 1 hour. To the reaction mixture under ice-cooling, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture. Then the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain (E)-2-(4-{3-amino-4-[2-(1H-indazol-3-yl)vinyl]phenyl}piperazin-1-yl)ethanol (0.24 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].C1(C)C=CC=CC=1>[NH:1]([C:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: NCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)CCNC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
6.0 g of β-alanine are taken up in 33.7 ml of 2N NaOH and cooled to +5°. At this temperature there are then added dropwise, simultaneously, 22.5 ml of a 50% solution of chloroformic acid benzyl ester in toluene and 16.8 ml of 4N NaOH. The emulsion is subsequently stirred in an ice bath for 3 hours. After separating off the organic phase, the aqueous phase is extracted once more with ether and then, while cooling with an ice bath, the pH is adjusted to 1 with 44 ml of 2N HCl. By filterirg off the precipitate and drying in a high vacuum at 50°, Z-β-Ala-OH is obtained in the form of a white powder; Rf (CH2Cl2 /MeOH/concentrated aqueous ammonia solution [5:3:1])=0.37.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@:11]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:15][O:14][C@@H](C(C)(C)C)[N:12]1C=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[CH2:1]([O:8][C:9](=[O:10])[C@:11]([NH2:12])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:15][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H]1OC[C@](Cc2cccc(C#N)c2)(C(=O)OCc2ccccc2)N1C=O
Agent: Cl
Solvent: CO
Solvent: O
Product: N#Cc1cccc(C[C@](N)(CO)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
A 1L round bottom flask equipped with a reflux condenser and a Teflon-coated magnetic stirring bar was charged with compound 2 (30 g, 73.8 mmol) and MeOH (1 L). 6N HCl (45 mL) was added and the slightly cloudy reaction mixture was heated to a gentle reflux with stirring for 48 hours. The reaction mixture was cooled to ambient temperature and concentrated to dryness to give a white colorless solid, which was dissolved in H2O (300 mL) and extracted with CH2Cl2 (50 mL). The aqueous phase was concentrated to give the title compound as a white colorless solid (22.7 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC1CCCC1
Yield: 46.8 %

Procedure:
2-Nitrophenol (83.5 g, 0.60 mole), cyclopentyl bromide (98.0 g, 0.66 mole), anhydrous potassium carbonate (82.9 g, 0.60 mole) and dry acetone (600 cc) were refluxed for 72 hours, and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 144°-146° C. at 1.0 mm. Hg to yield 58.2 g of product (46.8%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:20]#[N:21])[CH:16]=[CH:15][C:14]1=2
Reactant: CN(C)C=O
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CCCC2=O
Temperature: 135 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (11.5 g, 39.0 mmol), prepared in the previous step, and zinc cyanide (2.7 g, 23.5 mmol) in dry dimethylformamide (100 mL) was degassed and put under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (1.7 g, 1.5 mmol) was added and the mixture again degassed and put under a nitrogen atmosphere. The mixture was stirred at 135° C. overnight. An additional 171 mg of tetrakis(triphenylphosphine)palladium(0) was added and the reaction stirred for another 4 h. The reaction mixture was filtered through the Celite™ reagent and rinsed with ethyl acetate. The filtrate was washed with water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give 8.1 g of crude product. Purification of the crude product on silica gel using a step-wise gradient of 5% to 15% ethyl acetate: hexane as the eluent gave 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (2.8 g, 41%), MS(ES) m/z 172 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[SH:11][C:12]1[N:17]2[N:18]=[C:19]([C:21](OC)=[O:22])[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=1.Cl>CO>[OH:10][NH:9][C:21]([C:19]1[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=[C:12]([SH:11])[N:17]2[N:18]=1)=[O:22]
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(S)n2nc(C(=O)NO)nc2n1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Triethylamine (1.35 g) (13.37 mmol) are added dropwise at 0° C. to a solution of 0.62 g (8.92 mmol) of hydroxylamine hydrochloride in 15 ml of absolute methanol. The mixture is stirred for 10 minutes and subsequently a solution of 1.0 g (4.46 mmol) of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate (known from EPOS 303,172) in 30 ml of absolute methanol is added dropwise. After stirring at room temperature for 3 days the beige suspension is made acid (pH 4) with 1N aqueous hydrochloric acid and suction filtered. The filter material is washed with water and diethyl ether and crystallized from methanol/dichloromethane. There are obtained 510 mg of N-hydroxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as beige crystals of m.p. 213° C. (dec.).
Reaction SMILES: [CH:1]([S:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[CH:1]([S:4][C:5]([CH3:12])([CH3:11])[C:6]([OH:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)SC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)SC(C)(C)C(=O)O

Procedure:
A mixture of ethyl 2-(isopropylthio)-2-methylpropionate (5.4 g, 30 mmol) and potassium hydroxide (5.0 g, 90 mmol) in ethanol is refluxed for 6 hours, cooled, and concentrated in vacuo to obtain a residue. The residue is diluted with water, washed with ether, acidified with hydrochloric acid, and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. The solid is washed with chloroform and dried under reduced pressure to give the title product as a solid, mp 51.5-52.5° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4].BrC1C=CC([C@@H](O)C(F)(F)F)=C(N2C=CC(C)=N2)C=1>[Ir]>[F:22][C:2]([F:1])([F:21])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)C(F)(F)F)c(-c2ccccc2)c1
Agent: [Ir]
Agent: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Product: CS(=O)(=O)c1ccc([C@@H](O)C(F)(F)F)c(-c2ccccc2)c1

Procedure:
Chiral reduction of 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol, provided (R)-2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as a white solid.