Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=2)[N:9]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Yield: 95.4 %

Procedure:
tert-Butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (15.1 g, 36 mmol) was treated with trifluoroacetic acid (50 mL) in dichloromethane (100 mL) at room temperature for about three hours. The solution was evaporated to dryness and the residue was stripped with toluene (100 mL). 10% aq. sodium carbonate solution (300 mL), CH2Cl2 (400 mL), and methanol (100 mL) [methanol is added because 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol is not very soluble in pure CH2Cl2] were added to the residue and stirring was continued until all solids were dissolved. The layers were separated and the aqueous layer was extracted with a mixture of CH2Cl2 (400 mL) and methanol (100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (200 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (11.0 g, 95%) as a yellow solid with 98+% purity.
Reaction SMILES: N1[CH2:6][CH2:5]OCC1.[C:7](O)(=O)C.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1>CC(C)=O>[C:5](=[C:15]1[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]1=[O:19])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: CC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(C)=O
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Morpholine (261 mg, 261 μL, 2.99 mmol) and acetic acid (200 mg, 191 μL, 3.32 mmol) were added to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (24.0 g, 166.17 mmol) in acetone (120 g) at room temperature under argon atmosphere, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogencarbonate solution (200 mL), and the mixture was extracted with toluene (200 mL). The organic layer was washed with 10% brine (200 mL), and the solvent was evaporated under reduced pressure to give 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid. The obtained white solid was subjected to azeotropy with toluene (100 mL) (×2).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:13][C:12]2[C:5](=[C:6]([CH:9]=[CH:10][CH:11]=2)[CH:7]=O)[O:4]1.[OH2:14].[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH2:3]1[O:13][C:12]2[C:5](=[C:6]([CH:9]=[CH:10][CH:11]=2)[CH:7]=[CH:17][C:16]([O:15][CH2:19][CH3:18])=[O:14])[O:4]1
Reactant: C1CCOC1
Reactant: O=Cc1cccc2c1OCO2
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1cccc2c1OCO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Triethyl phosphonoacetate (4.05 mL, 202 mmol) was added dropwise to a stirred suspension of sodium hydride (0.80 g, 20 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 20 minutes. A solution of 2,3-methylenedioxybenzaldehyde (2.50 g, 16.7 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0° C. The mixture was stirred for 2 hours during which time it was allowed to warm to room temperature. The mixture was poured into water (250 mL), and extracted with ethyl acetate (3×250 mL). The combined organic extracts were then washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:10) gave ethyl 2,3-methylenedioxycinnamate as a colourless solid (3.50 g, 92%).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH2:10][C:11]1[C:19]([C:20](=[O:23])[NH:21][CH3:22])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.O>CC(N(C)C)=O>[CH3:22][N:21]1[C:20](=[O:23])[C:19]2[C:11](=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][CH:18]=2)[N:10]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=1
Reactant: CNC(=O)c1cccc(C(=O)O)c1N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 21 h
Yield: 85.9 %

Procedure:
Sodium metabisulfite (3.56 g, 18.7 mmol) was added to a solution of 2-amino-3-(methylcarbamoyl)benzoic acid 31 (2.80 g, 14.4 mmol) and 3-(trifluoromethyl)benzaldehyde 32 (2.51 g, 14.4 mmol) in DMAC (45 mL). The reaction mixture was stirred at 100° C. for 21 h. H2O (150 mL) was added and the resulting precipitate was collected by filtration, rinsed with H2O and dried to give 33 (4.31 g, 84% yield).
Reaction SMILES: [CH3:1][C@@:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3](O)=[O:4].CN1CCOCC1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:41][NH2:42].O>CC1CCCO1>[CH3:1][C@@:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3]([NH:42][O:41][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)O)S(C)(=O)=O
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Solvent: O
Product: C[C@@](CCn1cc(-c2ccc(-c3ncco3)cc2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}butanoic acid (0.125 g, 0.321 mmol) in 2-methyltetrahydrofuran (20 mL) was added n-methyl morpholine (0.046 g, 0.449 mmol, 1.4 eq), followed by CDMT (0.068 g, 0.385 mmol, 1.2 eq). The reaction was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.045 g, 0.385 mmol, 1.2 eq) was added, and the reaction mixture was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with 50%-100% ethyl acetate/heptane to yield (2R)-2-methyl-2-(methylsulfonyl)-4-{4-[4-(1,3-oxazol-2-yl)phenyl]-1H-pyrazol-1-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (31 mg, 20% yield) as a colorless oil. LC-MS M−H 487.5.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=3)[CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[Li+].[OH-].O.Cl>CO.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=3)[CH:20]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Yield: 14.2 %

Procedure:
The title compound 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylic acid (28) was prepared by the following procedure: A mixture of ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E) (22 mg, 0.05 mmol) and LiOH (12 mg, 0.49 mmol) was stirred in MeOH (2 mL) and water (1 mL) for 20 h. The mixture was diluted with EtOAc (5 mL) and acidified with 1M HCl. The organic layer was isolated, washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC, to provide 3.0 mg (14%) of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylic acid (28). LC/MS (APCI): m/z 423.1 (M+H), 844.8 (2M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:7]
Reactant: NCc1ccccc1
Reactant: Nc1cc(C(=O)O)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)NCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 2-aminoisonicotinic acid (2.76 g, 20.0 mmol) in N,N-dimethylformamide (60 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 g, 26.0 mmol) and N,N-diisopropylethylamine (10 mL, 57.7 mmol). The resulting solution was stirred for 30 minutes at ambient temperature followed by the addition of 1-hydroxybenzotriazole (3.24 g, 24.0 mmol) and benzylamine (3.2 mL, 29.3 mmol). The reaction mixture was stirred for 72 hours at ambient temperature, diluted with water (30 mL) and extracted with ethyl acetate (200 mL×4). The combined organic layers were washed with brine (30 mL), dried over anhydrous sulphate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and hexanes (in a 1:10 ratio), filtered and dried in vacuo to give 2-amino-N-benzylisonicotinamide as a colorless solid (1.97 g, 43%): NMR (300 MHz, CDCl3) δ 8.11-8.09 (m, 1H), 7.37-7.27 (m, 5H), 6.88-6.82 (m, 2H), 6.42 (br s, 1H), 4.60 (d, J=5.7 Hz, 2H); MS (ES+) m/z 228.5 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:28]=[CH:27][C:20]3[S:21][C:22]([C:24](O)=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:28]=[CH:27][C:20]3[S:21][C:22]([C:24]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:25])=[CH:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2sc(C(=O)NCC(=O)O)cc2c1
Yield: 42.9 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (310 mg, 0.686 mmol), DMAP (167 mg, 1.37 mmol), EDC (197 mg, 1.03 mmol), and glycine methyl ester hydrochloride (172 mg, 1.37 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (150 mg, 43%).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:38][CH2:39][N:40]=[C:41]=[O:42].CC([O-])(C)C.[Na+].C(O)=O>C1COCC1>[CH3:2][CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:27]=[CH:26][C:24]([N:25]4[CH2:38][CH2:39][NH:40][C:41]4=[O:42])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N)cc3)CC2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N4CCNC4=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)aniline (82 mg, 0.221 mmol) in THF (2.5 ml) at room temperature under nitrogen was added DIPEA (0.155 ml, 0.885 mmol), followed by 2-chloroethyl isocyanate (0.038 ml, 0.443 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was then cooled to 0° C. and NaOtBu (2M solution in THF) (0.443 ml, 0.885 mmol) was added dropwise. The ice bath was removed and the mixture was stirred for 30 minutes at room temperature. The mixture was quenched with formic acid (0.068 ml, 1.771 mmol) and then concentrated under reduced pressure. The residue was dissolved in DMF and filtered. The residue in DMF was then purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate. The fractions containing product were combined, frozen and then lyophilized from MeCN/water to afford the title compound.
Reaction SMILES: [BH4-].[Na+].[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([C:6]3=[O:13])[CH2:4]1)[CH2:10]2>CO.[Cl-].[Na+].O>[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH:6]3[OH:13])[CH2:4]1)[CH2:10]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1C2CC3CC1CN(C3)C2
Temperature: 0 °C

Procedure:
Sodium borohydride (0.7 g) is added to 20 ml of ice-chilled MeOH. Then 1.88 g (0.012 mole) of 1-azatricyclo[3.3.1.13,7 ]decane-4-one, in 20 ml MeOH, is added dropwise over 5 minutes. A further 0.8 g NaBH4 (total 1.5 g, 0.04 mole) is added portionwise over 5 minutes. The reaction is stirred in ice one-half hour more, and then 1 hour at room temperature. The reaction is diluted with 20 ml brine, and extracted into ether. The ether is dried over MgSO4 and stripped to dryness, to give 1 -azatricyclo-[3.3.1.13,7 ]decane-4-ol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[C:20]([F:23])[C:21]=1[F:22].Cl>O1CCCC1>[O:1]=[C:2]([C:18]1[CH:17]=[C:16]([F:15])[C:21]([F:22])=[C:20]([F:23])[CH:19]=1)[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of tert-butyl 2-oxopiperidine-1-carboxylate (0.30 g, 1.51 mmol) in tetrahydrofuran (8 mL) cooled to −78° C. was added slowly over 15 minutes 0.3 M 3,4,5-trifluorophenylmagnesium bromide in tetrahydrofuran (3.30 mL, 1.66 mmol) and the mixture was then allowed to warm to 25° C. over 30 minutes. The reaction mixture was poured slowly into an ice cold solution of 0.5 N hydrochloric acid (100 mL), and extracted twice with ethyl acetate (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel column chromatography (diethyl ether/hexanes 1:4) to give tert-butyl 5-oxo-5-(3,4,5-trifluorophenyl)pentylcarbamate (0.18 g, 36% yield). MS (EI) for C16H20F3NO3: 332 (MH+).
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][NH:17][NH2:18])[CH3:13].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][N:17]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:18]1)[CH3:13]
Reactant: N#CCC(=O)c1cccnc1
Reactant: CCOC(CNN)OCC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC

Procedure:
With gentle heating, 125 g (812 mmol, purity 95%) of 3-oxo-3-(pyridin-3-yl)propionitrile [lit. for example: P. Seneci et al., Synth. Commun. 1999, 29 (2), 311-341; also available commercially] were dissolved in 1.25 liters of ethanol. 126 g (853 mmol) of (2,2-diethoxyethyl)hydrazine and 4.1 ml (4.06 mmol) of 1 M hydrochloric acid were then added. The reaction mixture was heated under reflux for 4 h, and all volatile components were then substantially removed on a rotary evaporator. The residue obtained was taken up in ethyl acetate, and the solution was washed with water and dried over anhydrous magnesium sulphate. After filtration, the mixture was evaporated to dryness. The residue that remained was triturated with diisopropyl ether at RT. The resulting solid was then filtered off with suction and dried under high vacuum. This gave 153 g (65% of theory, purity 96%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([NH:33][CH:30]4[CH2:32][CH2:31]4)[CH:4]=3)[C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: O=c1c2cc(F)c(OS(=O)(=O)C(F)(F)F)cc2ccn1-c1ccc([N+](=O)[O-])cc1
Reactant: NC1CC1
Product: Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1

Procedure:
An analogous C—N coupling procedure to that described in Example 7 was performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl ester (Example 6) using cyclopropylamine as the nucleophile. Reduction of the nitro group was effected using the procedure outlined in Example 9. ES-MS (M+H)+=310.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].O>CS(C)=O>[CH3:28][O:29][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
{2-[4-(6-Fluoropyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-ylamine (200 mg, 0.55 mmol) was dissolved in 4 mL dry DMSO and treated with sodium methoxide (300 mg, 5.5 mmol, 10 eq) and stirred for 20 h at 25° C. The mixture was poured into H2O (15 mL) and extracted with CH2Cl2 (2×25 ml). The pooled CH2Cl2 extracts were washed with H2O and brine, dried (Na2SO4), filtered, and evaporated. The gummy residue was dissolved in a minimum quantity of CH2Cl2 and treated with hexane to precipitate the product as a solid that was collected by suction filtration, washed with hexane and dried in vacuo to afford {2-[4-(6-methoxypyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (139 mg) as a tan solid: mp 152-153° C.; 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.0 Hz, 2H), 6.36 (d, J=7.7 Hz, 2H), 3.83 (m, 2H), 3.65 (s, 3H), 3.00 (m, 2H); ESIMS m/z 375 ([M+H]+).
Reaction SMILES: C(OC([NH:8][N:9]=[CH:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:9](=[CH:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])[NH2:8]
Reactant: CC(C)(C)OC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of 3-(2-tertiary butoxycarbonylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (247 mg) in methylene chloride (1 ml) are added anisole (0.6 ml) and trifluoroacetic acid (0.6 ml), and the mixture is kept at room temperature for 1 hour. After removing trifluoroacetic acid and methylene chloride, the reaction mixture is diluted with ether. The separated cyrstals are collected by filtration and dried to give 3-hydrazonomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid in nearly quantitative yield. m.p. 164°-169° C (decomposition). IR: νmaxNujol 3260, 1787, 1657, 1542cm-1. UV: λmaxCH3OH 230.5nm(ε=12900); 304nm(ε=6900); 402nm(ε=12400). NMR: δd 6-DMSO (60MHz) 3.79s2H, 3,84d(12Hz)2H, 5.20d(5Hz)1H, 5.84dd(8;5Hz)1H, 6.8-7.5m3H, 7.55s+7.78s1H, 9.12d(8Hz)1H. [α]D23.5 +66.2°(c=0.5022, DMSO).
Reaction SMILES: C([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)=O.[N+:8]([CH2:11][CH3:12])([O-:10])=[O:9].[CH2:13](N)CCC.C(O)(=O)C>>[N+:8]([C:11]([CH3:13])=[CH:12][C:6]1[S:5][CH:4]=[CH:3][CH:7]=1)([O-:10])=[O:9]
Reactant: CC[N+](=O)[O-]
Reactant: CCCCN
Reactant: O=Cc1ccsc1
Solvent: CC(=O)O
Product: CC(=Cc1cccs1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
5.0 g (44.6 mmol) 3-formylthiophene are dissolved together with 8.9 ml (124.8 mmol) nitroethane, 5.3 ml (53.5 mmol) butylamine in 25.1 ml glacial acetic acid (454.7 mmol) and heated to 80° C. After two hours the mixture is cooled and the precipitate formed is suction filtered and washed with copious amounts of water. The crude product thus obtained is dissolved in ethyl acetate, dried on sodium sulphate and evaporated down i. vac.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=4)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:30][CH3:31])=[C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)ccc4F)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)ccc5F)c4)c3c2)cc1NS(C)(=O)=O
Yield: 22.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methanesulfonamide (120 mg, 0.180 mmol) was hydrolyzed by lithium hydroxide 38 mg, 0.904 mmol) in THF/methanol/water (15/7.5/4 ml) to yield 21 mg of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 10.3 (s, 1H), 8.49-8.48 (d, 1H), 8.256-8.252 (d, 1H), 7.85 (s, 1H), 7.81-7.80 (d, 1H), 7.77 (s, 1H), 7.48-7.47 (d, 1H), 7.39-7.37 (dd, 1H), 7.26-6.91 (m, 5H), 5.42 (s, 2H), 3.96 (s, 3H), 3.01 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 96.37% in method B.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[CH2:18]([S:20]SCC)[CH3:19]>C1COCC1>[CH2:18]([S:20][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: CCSSCC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCSc1ccc2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a mixture of potassium hydride (30% wt. in mineral oil, 2.71 g, 20.2 mmol) and THF (30 mL) was added a solution of 6-bromoindole (3.98 g, 20.3 mmol) in THF (10 mL) at 0° C. After 15 minutes the solution was cooled to −78° C., and tert-butyllithium (1.5 M in pentane, 27.07 mL, 40.60 mmol) was added via syringe. The mixture was stirred at −78° C. for 10 min then ethyl disulfide (4.97 g, 40.6 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature, poured into ice-sat.aq. NH4Cl (150 mL), and then extracted with EtOAc (150 mL). The organic phase was washed with water (150 mL), brine (150 mL), dried over Mg2SO4, concentrated, and purified on silica gel (EtOAc/hexane 5% to 15%), to provide 6-ethylsulfanyl-1H-indole (2.75 g, 77%) as a clear liquid.