Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:21])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[S:29])=[CH:26][CH:25]=1>>[C:3]([C:2]([NH:1][C:28](=[S:29])[C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:32][CH:31]=1)([CH3:21])[CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[C:10]([C:17]([F:19])([F:20])[F:18])[CH:11]=[CH:12]2)=[N:7]1)#[N:4]
Reactant: COc1c2ccc(C(F)(F)F)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2ccc(C(F)(F)F)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(3-methoxy-6-trifluoromethyl-2H-indazol-2-yl)-2-methylpropionitrile (50 mg, described in Example 131) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (66 mg, 78%). MS (ES): M/Z [M+H]=503. 1H NMR: (400 MHz, DMSO-d6): 1.72 (s, 3H), 4.24 (s, 3H), 4.84 (d, J=13.8 Hz, 1H), 4.96 (d, J=13.9 Hz, 1H), 7.08 (dd, J=9.0, 1.4 Hz, 1H), 7.85 (s, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.94-7.99 (m, 2H), 8.09 (d, J=9.0 Hz, 1H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F) and −61.8 (s, 3F).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:22])[N:9]=1
Reactant: NCC(O)CO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCC(O)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.4 g of (±)3-amino-1,2-propanediol are heated at 60° C. for 2 h in 10 ml of ethanol. The crystals precipitating on cooling are filtered off and washed with ethanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2,3-dihydroxypropyl)acetamide remains as colorless crystals of m.p. 180-181° C.
Reaction SMILES: C([Si]([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])(C)C)(C)(C)C.C(Cl)(=O)C([Cl:30])=O>ClCCl.CN(C)C=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:9]([Cl:30])=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=CC(=O)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 10.01 g 3-[2-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid tert-butyl-dimethyl-silanyl ester in 25 ml of dichloromethane, three drops of dimethylformamide were added and 4.14 g oxalyl chloride was dropped in at 0° C. After stirring at 0° C. for 90 minutes and then at room temperature overnight, the mixture was evaporated to dryness. The resulting brown solid (7.52 g) was not further purified.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (580 mg, 1.243 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5.00 ml) was added. Lithium hydroxide (78 mg, 1.865 mmol) was added and the mixture stirred under argon at room temperature overnight. The THF was evaporated off and the aqueous residue was adjusted to ˜pH of 6 with 1N HCL. A white solid slowly formed. The white solid was filtered and washed 2× with water (5 mL). The pH of the filtrate was checked and was found to be 8. The pH was gradually lowered to 4 with 1N HCl. At this point no additional solid appeared to be forming. The solid was filtered and washed 2× with water (5 mL). The combined solid was dried at 50° C. in a vacuum oven for 6 hours to give 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (533 mg, 1.178 mmol, 95% yield) as a white solid. LC-MS m/z 453 (M+H)+, 0.71 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([Br:21])=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Br)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To a pre-cooled solution (0° C.) of the compound from Step F of Example 62 (28 mg, 0.10 mmol) in DMF (0.5 mL) was added N-bromosuccinimide (0.018 g, 0.10 mmol) in DMF (0.5 mL) dropwise. The solution was stirred at 0° C. for 20 min, then at rt for 10 min. The reaction was quenched by addition of methanol (4 mL) and evaporated in vacuo. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (13.0 mg) as a colorless solid.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[F:15][C:16]([F:20])([F:19])[CH2:17]I.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:17][C:16]([F:20])([F:19])[F:15]
Reactant: FC(F)(F)CI
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 130 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To dry N,N-dimethylformamide (10 ml) were added 2-methoxyphenol (150 mg), 2,2,2-trifluoroethyl iodide (584 mg) and potassium carbonate (400 mg), and the mixture was stirred vigorously at 130° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and chloroform (5/2) as eluent to give 179 mg of 1-methoxy-2-(2,2,2-trifluoroethoxy) benzene as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[NH:14]1[CH2:19][CH2:18]N[CH2:16][CH:15]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[CH2:26](N(CC)CC)C.[ClH:33]>O1CCOCC1>[ClH:33].[N:14]1[CH:19]=[CH:18][CH:26]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=2)[CH2:22][CH2:21]1
Reactant: CCN(CC)CC
Reactant: C1CN(C2CNCCN2)CCN1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(CN2CCN(c3ccccn3)CC2)cc1

Procedure:
Using 2.2 g of methyl 4-bromomethylphenylacetate, 1.5 g of 1-(2-piperazinyl)piperazine, 1.9 ml of triethylamine, and 70 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from ethanol-ether to provide 1.1 g of the title compound melting at 214° C.-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)=[N:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[N:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)=[N:23][CH:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc(-c5cccc(Cl)c5)nc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1cnc(-c2cccc(Cl)c2)nc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 35 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(3-chlorophenyl)pyrimidin-5-ylcarbamoyl)phenoxy)chroman-4-carboxylate (45 mg, 0.080 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (399 μl, 0.40 mmol) and ethanol (500 uL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a 0.5 mm preparative TLC plate eluting with 10% methanol/DCM to yield the desired compound (15 mg, 0.028 mmol, 35% yield) MS (ESI)=536.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:36][CH:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]([OH:37])[C:26]([O:25][CH2:23][CH3:24])=[O:38])=[O:11])[CH:6]=1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-chloro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 505.15
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([C:31](=[O:43])[CH2:32][CH2:33][C:34]2[C:35]([CH3:42])=[C:36]([CH:40]=O)[NH:37][C:38]=2[CH3:39])[CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:40]\[C:36]1[NH:37][C:38]([CH3:39])=[C:34]([CH2:33][CH2:32][C:31]([N:26]2[CH2:27][C@H:28]([CH3:30])[NH:29][C@H:24]([CH3:23])[CH2:25]2)=[O:43])[C:35]=1[CH3:42])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 4-[3-((3R, 5S)-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (139 mg, 1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark brown orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].C[N+]1([O-])CC[O:20]CC1.[OH2:24].OS([O-])=O.[Na+]>[Os](=O)(=O)(=O)=O.C(O)(C)(C)C.CC(C)=O>[OH:24][CH:11]([CH:10]([OH:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:12]([O:14][CH3:15])=[O:13]
Reactant: O
Reactant: COC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: COC(=O)C(O)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 2,3-dihydroxy-3-(2-nitrophenyl)propionate (Compound IIa) was prepared by adding 250 mg of osmium tetroxide (0.984 mmol) in one portion to a 0° C. solution of 15 g of methyl trans-3-(2'-nitrophenyl)propenoate (72.4 mmol) (Compound Ia) and 12.7 g of N-methylmorpholine-N-oxide (0.108 mol) in a solution containing 25 ml each of H2O, acetone and t-butanol (1:1:1). The reaction was warmed to room temperature, then stirred for 6 hr. Then, 50 ml of a freshly prepared solution of 20% (v/v) NaHSO3 was added slowly over 30 min to destroy excess oxidant. Several scoops of NaCl were added to the resulting reaction mixture, and then the product was extracted 3 times, each with 200 ml of ether. The combined extracts were washed with 150 ml of a saturated NaCl solution (brine), dried over MgSO4, and then concentrated in vacuo. The crude product, a light brown solid, was purified by recrystallization from ethanol to give 15.3 g (87% yield) of Compound IIa. M.p. 125.6-127.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br>[OH-].[Na+]>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH:10]=1
Reactant: BrCCCBr
Reactant: Cc1coc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1coc2cc(OCCCBr)ccc12
Temperature: 80 °C
Yield: 169.6 %

Procedure:
To a solution of 3-methyl-1-benzofuran-6-ol (0.20 g, 1.35 mmol) in NaOH (6 M aqueous solution, 0.25 mL) was added 1,3-dibromopropane (0.48 mL, 0.46 mmol), and the mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to rt, and NaOH (6 M aqueous solution, 0.11 mL) was added. The reaction mixture was heated at 80° C. for 1 h, cooled to rt, and partitioned between CH2Cl2 and NaHCO3 (saturated aqueous solution). The organic layer was dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexane (v/v)=1:19) to give 210 mg (58%) of the title compound containing minor impurities. This material was used in next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 1H), 7.32 (s, 1H), 7.0 (s, 1H), 6.88 (dd, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 2.40-2.28 (m, 2H), 2.20 (s, 3).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:15][C:16]([C:18]2(CC(Cl)=C)[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[CH:3][CH:2]=1.[C:33]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:38]=[CH:37][C:36]([CH2:39][C@H:40]([NH:47][C:48]([C:50]2(CC(Cl)=C)[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[C:41]2[N:42]=[N:43][N:44]([CH3:46])[N:45]=2)=[CH:35][CH:34]=1.C[C:66]([CH3:68])=[O:67]>>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:15][C:16]([C:18]2([CH2:68][C:66]([OH:49])=[O:67])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[CH:3][CH:2]=1.[C:33]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:38]=[CH:37][C:36]([CH2:39][C@H:40]([NH:47][C:48]([C:50]2([CH2:68][C:66]([OH:17])=[O:67])[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[C:41]2[N:42]=[N:43][N:44]([CH3:46])[N:45]=2)=[CH:35][CH:34]=1
Reactant: CC(C)=O
Reactant: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)c2nnnn2C)CCCC1
Reactant: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)c2nnn(C)n2)CCCC1
Product: Cn1nnc([C@H](Cc2ccc(-c3ccccc3)cc2)NC(=O)C2(CC(=O)O)CCCC2)n1
Product: Cn1nnnc1[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)O)CCCC1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a mixture of (S)—N-(2-(biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-yl)ethyl)-1-(2-chloroallyl)cyclopentanecarboxamide and (S)—N-(2-(biphenyl-4-yl)-1-(2-methyl-2H-tetrazol-5-yl)ethyl)-1-(2-chloroallyl)cyclopentanecarboxamide in acetone at −7° C. was bubbled ozone for 30 seconds using ozone generator. The mixture became a persistent pale blue color. The mixture was stirred at −78° C. for 1 minute. To the mixture was bubbled oxygen gas for 10 minutes and was added dimethyl sulfide (0.5 mL) followed by water (1 mL). The cooling bath was removed and stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure and diluted in EtOAc. The mixture was acidified with 1 M HCl until pH=1. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN gradient) to give two isomers, (S)-2-(1-(2-(biphenyl-4-yl)-1-(1-methyl-1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetic acid and (S)-2-(1-(2-(biphenyl-4-yl)-1-(2-methyl-2H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetic acid (11 mg, regioisomer 1, 7.6 mg regioisomer 2). Regioisomer 1: HPLC retention time=1.57 minutes (condition D); MS (m+1)=434.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.85 (m, 6H), 1.89-2.19 (m, 2H), 2.73 (q, J=16.4 Hz, 2H), 3.18-3.41 (m, 1H), 3.48 (dd, J=13.3, 6.4 Hz, 1H), 3.69 (s, 3H), 5.42-5.65 (m, 1H), 7.03 (br. s., 1H), 7.08-7.24 (m, 2H), 7.34-7.41 (m, 1H), 7.42-7.65 (m, 6H). Regioisomer 2: HPLC retention time=1.66 minutes (condition D); MS (m+1)=434.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44-1.73 (m, 6H), 1.73-1.99 (m, 2H), 2.59 (s, 2H), 3.15-3.38 (m, 2H), 4.24 (s, 3H), 5.50-5.79 (m, 1H), 6.60 (br. s., 1H), 7.06 (d, J=8.1 Hz, 2H), 7.19 (s, 2H), 7.22-7.30 (m, 1H), 7.30-7.56 (m, 4H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[CH2:16]([NH:24][C:25]([NH2:27])=[S:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[BrH:1].[N+:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:27]=[C:25]([NH:24][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:26][CH:2]=2)[CH:6]=[C:7]([OH:15])[C:8]=1[OH:14])([O-:13])=[O:12]
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NC(=S)NCCc1ccccc1
Solvent: CCCCO
Product: Br
Product: O=[N+]([O-])c1cc(-c2csc(NCCc3ccccc3)n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A suspension of 13.8 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is treated with 9.0 g of 1-(phenethyl)-2-thiourea in 150 ml of n-butanol and the mixture is heated to boiling under reflux for 3 hours. After cooling to room temperature, the crystals are filtered under suction and crystallized from n-butanol. There is obtained 3-nitro-5-[2-(phenethylamino)-4-thiazolyl]pyrocatechol hydrobromide of m.p. 249°-251°.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]([C@@H:17]([CH:23]3[CH2:25][CH2:24]3)[C:18](OCC)=[O:19])[C@@H:11]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:7]=[CH:8][CH:9]=1>CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:11]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[N:12]([C@@H:17]([CH:23]3[CH2:24][CH2:25]3)[CH2:18][OH:19])[C:13](=[O:16])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@H](C1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1[C@H](CO)C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of lithium borohydride (2M in THF, 15.46 mL, 30.9 mmol) was added to a solution at 0° C. of (S)-ethyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate (Example 249, Step B, 2.3 g, 5.15 mmol) in ether (40 mL). After stirring at ambient temperature for 20 hours, the reaction was quenched with saturated aq. NH4Cl solution and extracted into EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate and concentrated to give the title compound as a solid, which was used without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].C(O)C.[CH3:7][C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([CH3:14])[C:9](OCC)=[O:10].C(OCC)(=O)C>O>[CH3:7][C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([CH3:14])[C:9]([NH:2][NH2:3])=[O:10]
Reactant: CCOC(=O)C(C)(C)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)NN)c1cccs1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Hydrazine monohydrate (2.6 ml) was added to an ethanol (10 ml) solution of ethyl 2-methyl-2-(2-thienyl)propanoate (530 mg), followed by stirring at 70° C. for 48 hours. After the reaction solution and ethyl acetate were added to water, the organic layer was separated. Furthermore, the organic layer washed with saturated brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 447 mg of 2-methyl-2-(2-thienyl)propanohydrazide (colorless oil).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3]([Cl:14])=[O:4]
Reactant: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Product: CC(C(=O)Cl)C(C)[Ge](Cl)(Cl)Cl
Yield: 90.4 %

Procedure:
28.0 g (0.1 mol) of 2-methyl-3-(trichlorogermyl) butanoic acid was treated with 100 ml of thionyl chloride. The reaction mixture was distilled under a reduced pressure to obtain 27.0 g of 2-methyl-3-(trichlorogermyl) butanoyl chloride as a pale yellow portion having a boiling point of 99° to 100° C./6 mm Hg (yield: 90.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]#[N:16])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)([O-:14])=[O:13]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Yield: 66.6 %

Procedure:
A mixture of 10.6 g (45.7 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 8.82 g (54.8 mmol) of 3-(trifluoromethyl)aniline in 270 mL of ethanol was refluxed under N2 for 5 h. The reaction was diluted with ethanol, neutralized with satd sodium bicarbonate and evaporated. The residue was slurried with hexane, collected, washed with hexane and water and dried in vacuo (60° C.) to give 10.9 g of yellow solid. A 2.00 g sample was recrystallized from ethanol to give 1.20 g of bright yellow solid; mp 260-261° C.
Reaction SMILES: [NH2:1][C:2]([CH2:22][F:23])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]CC2C=CC=CC=2)[CH:7]=1)C#N.Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=[O:32].[CH3:38][OH:39]>>[NH2:1][C:2]([CH2:22][F:23])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[C:38]([OH:32])=[O:39]
Reactant: CO
Reactant: COc1ccc(CC(N)(C#N)CF)cc1OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: COc1ccc(CC(N)(CF)C(=O)O)cc1O
Reaction time: 8 h

Procedure:
A solution of 2-amino-2-fluoromethyl-3-(3-benzyloxy-4-methoxyphenyl)propionitrile (0.7 g) in absolute methanol saturated with dry hydrogen chloride (50 ml) is heated at reflux for 12 hours. The methanol is evaporated and the residue dissolved in trifluoroacetic acid (10 ml). The mixture is heated at reflux temperature for 2 hours. Water (4 ml) is then added, and reflux continues overnight. The residue obtained upon evaporation under reduced pressure is passed through Amberlite 120 H+ ion exchange resin column. The ninhydrin positive fractions are pooled and concentrated. The residue is crystallized from water-methanol-ether to afford the desired product.