Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1C=C2[N:27]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:27])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N[C@@H](C(=O)O)c2ccccc2)cc1Br
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](C(N)=O)c2ccccc2)cc1Br
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of (R)-2-(3-bromo-4-cyanophenylamino)-2-phenylacetic acid (90 mg, 0.27 mmol) and HOBt hydrate (62 mg, 0.40 mmol) in DMF (2 mL), EDC (74 mg, 0.38 mmol) was added. The mixture was stirred for 60 min. Then conc. NH4OH (0.100 mL, ˜1.40 mmol) was added. It was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(3-bromo-4-cyanophenylamino)-2-phenylacetamide (78 mg).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].[F:8][C:9]([F:17])([F:16])[C:10]([C:12]([F:15])([F:14])[F:13])=[O:11].[OH-].[K+]>>[F:8][C:9]([F:17])([F:16])[C:10]([OH:11])([C:12]([F:15])([F:14])[F:13])[CH2:4]/[CH:3]=[CH:2]/[C:1]([O:6][CH3:7])=[O:5]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=CCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COC(=O)/C=C/CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a nitrogen-flushed, 150 mL steel reaction vessel with teflon-coated magnetic stirbar was added 30.0 g methyl 3-buteneoate (300 mmol, 1 eq.). Hexafluoroacetone (55.8 g, 336 mmol, 1.1 eq.) was condensed into the vessel at −78° C. The reaction vessel was sealed under 1 atmosphere of nitrogen and warmed to room temperature slowly. The reaction was heated at 160° C. for 16 hours after which the pressure had decreased dramatically. The vessel was cooled in an ice bath and the excess hexafluoroacetone was carefully vented through a saturated potassium hydroxide solution. The crude reaction mixture was vacuum distilled using a 6-inch, vacuum-jacketed vigereaux column with a short-path distillation head. The product was isolated at 75-80° C. (6 Torr) as a colorless liquid. A second distillation of the prefraction resulted in a total isolated yield of 55.4 g (69%) of E-methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-2-enoate (I).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C@@H:13]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C:14](=O)[C@H:15]([CH3:16])[C@@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([SH:37])[CH2:34][C@H:33]1[CH2:38][OH:39])=[O:31])[CH:27]=[CH2:28]>>[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([S:37][C:14]2[C@H:15]([CH3:16])[C@@H:11]3[C@@H:10]([C@H:8]([O:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:9])[C:24](=[O:25])[N:12]3[C:13]=2[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:34][C@H:33]1[CH2:38][OH:39])=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2[C@@H](C(=O)OCC=C)C(=O)[C@H](C)[C@@H]12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CO)N(C(=O)OCC=C)C3)[C@H](C)[C@H]12
Yield: 37 %

Procedure:
The same operation as in Reference Example 9 was carried out by using allyl (1R,3R,5S,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate (700 mg, 2 mmol) and (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-mercaptopyrrolidine (the compound obtained in Reference Example 1; 470 mg, 1.8 mmol) to obtain the title compound (410 mg, 37% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:25]#[C:26]Br.CO>C1COCC1>[NH2:25][C:26]1[O:4][CH2:3][C@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCN(C[C@H](N)CO)c1ccnc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C[C@H]1COC(N)=N1)c1ccnc(C(F)(F)F)n1
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a stirred mixture of (S)-2-amino-3-[ethyl-(2-trifluoromethyl-pyrimidin-4-yl)-amino]-propan-1-ol (0.185 g, 0.7 mmol) and K2CO3 (0.145 g, 1.05 mmol) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.111 g, 1.05 mmol) in THF (1 ml). The mixture was stirred for 2 hours, then methanol (1 ml) was added. The solution was evaporated over Isolute® Flash-NH2 silicagel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) yielded the title compound as light yellow oil, (0.084 g, 42%); MS (ISP): 290.0 ((M+H)+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][C@@H:7](Br)[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2].[CH3:37][OH:38]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][C@H:7]([O:38][CH3:37])[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@@H](Br)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: 70 °C
Yield: 78 %

Procedure:
Crude bromide from step B (8.4 g, 14.4 mmol) and ZnO (1.2 g, 14.4 mmol) were dissolved in MeOH (144 ml) and heated at 70° C. for 1 hour. The reaction was cooled to room temperature, filtered through celite with EtOAc, and concentrated under vacuum. The residue was recrystallized from MeOH in two batches to give acetic acid (2S,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester (5.98 g, 11.2 mmol, 78%) as the pure β-anomer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[C:14](=[S:15])[NH:13][N:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH3:17].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH:11]=[N:12][N:13]=[C:14]2[S:15][CH3:19])[CH:7]=[CH:6][C:5]=1[O:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-n2cn[nH]c2=S)ccc1OC
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(-n2cnnc2SC)ccc1OC
Yield: 72 %

Procedure:
Treat a stirred mixture of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid methyl ester (3.80 g, 14.38 mmol), potassium carbonate (2.19 g, 15.8 mmol) and anhydrous acetone (60 mL) with methyl iodide (1.07 mL, 17.25 mmol) added dropwise via syringe. Reflux the stirred mixture for 2.5 hours, cool, filter and wash the filter cake twice with acetone. Combine the acetone phases, concentrate in vacuo, dissolve the residue in ethyl acetate and wash with NaHCO3 solution. Extract the combined aqueous phases three times with ethyl acetate. Combine the ethyl acetate phases, wash with saturated NaHCO3 and brine, dry (MgSO4), filter and concentrate in vacuo to afford an oil. Purify the oil by flash chromatography (silica gel, 5.5×15.2 cm) eluting with ethyl acetate and then with 5% methanol in dichloromethane after elution of the starting material. Concentrate the appropriate fractions to afford 2.89 g of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].C[O:9][C:10]([C:12]1([CH3:33])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[NH:13]1)=O>>[Cl:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[N:13]3[C:6](=[O:7])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:10](=[O:9])[C:12]3([CH3:33])[CH2:24][C:23]2=1
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Cl)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCCCl
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-chloro-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=457.9
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].Cl.C(NCC)C.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CCNCC
Product: O=P(Cl)(Cl)Oc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of 225 g. phosphoryl chloride and 2 g. diethylamine hydrochloride there is added 94 g. phenol over a two-hour period at a temperature of 105°-110°C. The temperature is held for two hours at 110°-115°C. to afford phenyl phosphorodichloridate.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-])=O)=[O:7]>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])=[O:7]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2[N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2N)s1
Yield: 59.4 %

Procedure:
Ammonium chloride (118 mg) and iron powder (1.0 g) were dissolved in a mixed solvent of ethanol (15 ml) and water (5 ml). trans-N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-nitrophenyl)propenamide (1.07 g) was carefully added under reflux to the reaction mixture, and the mixture was refluxed for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 0.60 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-aminophenyl)propenamide.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][C:4]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl.ClCCl>[CH3:1][C:2]1([CH3:17])[C:16]2[C:7](=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][CH:15]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: COC(=O)c1ccccc1NC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1cccc2c1NC(=O)CC2(C)C
Temperature: 25 °C

Procedure:
A solution of 15.18 g of methyl 2-(3-methyl-but-2-enoylamino)benzoate and 35.07 g of aluminium trichloride in 250 ml of 1,2-dichloroethane is stirred at reflux over 30 minutes. The reaction mixture is cooled to room temperature, diluted with dichloromethane, washed with 1N HCl (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (3:7 EtOAc-heptane); Rt=3.98.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2[N+](=O)[O-])CC1
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+](=O)[O-])CC1

Procedure:
A solution of 64.0 g (0.19 mole) of 4-[6-(cyclopropylamino)-3-nitro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 115 ml of acetic anhydride and 115 ml of acetic acid was heated on a steam bath for 36 hours. The solvents were removed in vacuo, the residue was triturated with a mixture of ethanol and toluene which was also evaporated in vacuo to give 68.3 g of the title compound, mp 90°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[S:7].[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1cccc(C(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of 3-methoxy-thiobenzamide (1.99 g, 11.88 mmole) and 2-chloro-3-oxo-butyric acid ethyl ester (1.7 ml, 12.11 mmole) in ethanol (20 ml) was refluxed for 18 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (3.02 g). MS: (+) m/z 277.93 (M+1).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:18])[CH2:16]Cl.O>CO.CN(C)C=O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:18])[CH2:16][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 40 °C
Yield: 66.3 %

Procedure:
30 g of sodium were added to a solution of 88.5 g of imidazole in 600 ml of methanol; the solvent was then evaporated off. The residue was dissolved in 300 ml of dimethylformamide and heated to 115°-120° C. To the solution so obtained was added, dropwise and under stirring, a solution of 225 g of 1-(2',4'-dichlorophenyl)-2-chloro-ethanol in 400 ml of dimethylformamide. The mixture was heated to 115°-120° C. and maintained at that temperature for 20 minutes and, after subsequent cooling to 40° C., 2500 ml of iced water were added under vigorous stirring. The product precipitated under stirring over a period of about two hours, the upper liquid was then decanted off, a further 2500 ml of water were added and, after standing, the whole was filtered. The precipitate thus obtained was dried and crystallized from toluene. 170 g of the desired product, melting at 134°-135° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.[C:13]([O:17][C:18]([NH:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:24](=[O:25])[NH:12][CH:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][C:9]=3[F:11])[CH2:5][CH2:6]2)[CH2:22][CH2:23]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: NC1CCc2cc(Br)cc(F)c21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CCc3cc(Br)cc(F)c32)CC1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B] and for the preparation of example 12, (rac)-5-bromo-7-fluoro-indan-1-ylamine (intermediate A-7 [C]) has been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((rac)-5-bromo-7-fluoro-indan-1-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester, which was then reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) and (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and subsequently with 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) to give the title compound as light brown solid. MS: 545.2 (MH+, 1Cl).
Reaction SMILES: C([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)[OH:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[OH:11][C@H:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:8][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)cc1
Yield: 92.3 %

Procedure:
Methyl 4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (470 mg), ammonium formate (296 mg) and palladium on carbon powder (100 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform-methanol) over silica gel to give methyl 4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylate (326 mg) as a colorless foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]1([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[C:5]([C:12]1[CH:13]=[CH:14][C:9]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:10][CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)NCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of aluminum chloride (22.3 g) in dichloroethane (40 ml) was added acetylchloride (7.1 ml). Thereto was added a solution of N-phenylmethylacetamide (10 g) in dichloroethane (20 ml) at 10-15° C. over 20 min. This reaction mixture was stirred at room temperature for 6 hr and poured into ice water (100 ml). The mixture was extracted with chloroform (100 ml×3). The chloroform layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a black brown oil (15.5 g). The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (6.48 g) as a black brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Li+]>C(O)C.O>[CH3:1][C:2]1[N:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:5]2[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2c(=O)n(C)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)c2ccn(C)c(=O)c2n1C(C)c1ccccc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of ethyl 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (500 mg, 1.5 mmol) and lithium hydroxide (50 mg, 2.1 mmol) in ethanol (20 mL) and water (5 mL) was stirred and heated at 80° C. for 12 hours. Once starting material was consumed, the mixture was concentrated and the residue was dissolved into water (50 mL). Then the solution was extracted with ethyl acetate (20 mL×2). The aqueous layer was collected, adjusted to pH 4, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2,6-dimethyl-7-oxo-1-(1-phenylethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (200 mg, 44%) as a light yellow solid which was used directly in the next step without further purification. LRMS (M+H+) m/z: calcd 310.13. found 310.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc[nH]n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc[nH]n3)cc12
Reaction time: 4 h
Yield: 18.6 %

Procedure:
3-(2-Methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (156 mg, 0.350 mmol) was dissolved in methanol (1.0 mL) and dimethylformamide (1.0 mL) and 50% w/v aqueous potassium hydroxide (1.0 mL) was added. After 4 hours, the reaction was quenched by addition of acetic acid (1.0 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 3-(2-methoxy-phenyl)-5-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine (18.9 mg, 18.6%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 3.78 (s, 3H), 6.69 (d, J=2.0 Hz, 1H), 6.99 (dt, J=7.0, J=0.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.23 (dt, J=7.0, J=1.5 Hz, 1H), 7.50 (dd, J=7.5, J=1.5 Hz, 1H), 7.63 (d, J=2.5 Hz, 1H), 7.65 (br s, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.63 (br s, 1H), 11.82 (s, 1H). MS: m/z 291 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:8][C:7]=1[C:20]([F:23])([F:22])[F:21])=[O:5])C.[OH-].[Na+].Cl>CO>[C:16]([O:15][C:13]([O:12][NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:20]([F:22])([F:23])[F:21])[N:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)ONc1nc(C(F)(F)F)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of ethyl-2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylate (6.5 g, 19.1 mmol) in methanol (100 mL) was treated with a 1N aq. NaOH solution (573 mL). The mixture was stirred at rt overnight. The solution was cooled to 0° C. and acidified with a 6 M aq. HCl solution to pH 1 and extracted with chloroform (150 mL, 6×). The chloroform extracts were combined, dried (Na2SO4), filtered and concentrated under reduced pressure and in vacuo to obtain the title acid (5.75 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:19])[NH:14][N:15]=[C:16]([Cl:18])[CH:17]=1)=O.NC1C=C(Cl)C=CC=1NC(C1C(=O)NN=C(Cl)C=1)=O>C(O)(=O)C>[Cl:18][C:16]1[CH:17]=[C:12]([C:10]2[NH:9][C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)[C:13](=[O:19])[NH:14][N:15]=1
Reactant: Nc1ccc(Cl)cc1NC(=O)c1cc(Cl)n[nH]c1=O
Agent: Nc1cc(Cl)ccc1NC(=O)c1cc(Cl)n[nH]c1=O
Solvent: CC(=O)O
Product: O=c1[nH]nc(Cl)cc1-c1nc2ccc(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
A mixture of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (2-amino-5-chlorophenyl)amide and 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (2-amino-4-chlorophenyl)amide (1.0 g; 1.67 mmol) is dissolved in 100 ml of glacial acetic acid and heated at 120° C. for 90 min. A precipitate separates out on cooling and is filtered off with suction and dried in vacuo at 40° C.