Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][C:12]3([CH3:17])[CH3:16])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:21]=[C:2]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:18]([NH2:20])=[O:19]
Reactant: O=C1CCCN1
Reactant: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Product: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(N3CCCC3=O)cc12

Procedure:
4-(((1R)-2,2-dimethylcyclopentyl)amino)-6-(2-oxo-1-pyrrolidinyl) pyrrolo[1,2-b]pyridazine-3-carboxamide was prepared from Intermediate 50 and pyrrolidin-2-one using a similar procedure as described for the preparation of Example 312 LCMS: 356.18 (M+H)+; HPLC (condition L): retention time=7.44 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]1[N:25]([CH3:34])[C:26](=[O:33])[N:27]([CH3:32])[C:28](=[O:31])[C:29]=1[CH3:30]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:20][CH2:21][CH2:22][NH:23][C:24]2[N:25]([CH3:34])[C:26](=[O:33])[N:27]([CH3:32])[C:28](=[O:31])[C:29]=2[CH3:30])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Product: Cc1c(NCCNCC(O)COc2ccc(OCc3ccccc3)cc2)n(C)c(=O)n(C)c1=O
Yield: 30 %

Procedure:
Yield 30% of theory; colorless oil from 4-benzyloxyphenyl glycidyl ether and 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione.
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.Br.[NH2:12][CH2:13][CH2:14]Br.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1sccc1S
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1NCCSc2ccsc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
aca) Method A: 17.4 g of methyl 3-mercapto-thiophene-2-carboxylate were dissolved in 350 ml of toluene under an inert gas atmosphere, whereupon the solution was treated with 20.5 g of 2-aminoethyl bromide hydrobromide and then with 100 ml of 3N sodium methylate solution in methanol. The mixture was stirred at room temperature for 30 minutes and thereafter heated under reflux until the reaction finished. The mixture was evaporated in vacuo, the residue was taken up in 300 ml of water, acidified with 2N hydrochloric acid and the crystals were removed by filtration. By recrystallization from chloroform there was obtained 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5-(2H)-one as white crystals of m.p. 186°-188°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:19][C:17]1[C:16]([C:20]([F:22])([F:21])[F:23])=[CH:15][N:14]=[C:13]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 494 %

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, was allowed to stirred at room temperature for 15 minutes until a clear solution was obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) was added in four portions over 5 minutes. The reaction mixture was stirred at 60 degrees for 1 hour. The reaction mixture was cooled to room temperature and filtered to obtain a white solid. The white solid was washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid was dried under vacuum to yield desired product (3.8 g, 49% yield). MS ES+: m/z=350.
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)C.Cl.[CH3:27][C:28]1[O:29][C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:35]=2[N:36]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=[C:6]2[CH2:5][C:4]([N:32]2[CH2:33][CH2:34][C:35]3[N:36]=[C:28]([CH3:27])[O:29][C:30]=3[CH2:31]2)=[O:25])=[CH:23][CH:22]=1
Reactant: Cc1nc2c(o1)CNCC2
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)CN(C(=O)Cc1nc(-c3ccc(F)cc3)cn1-c1ccc(F)cc1)CC2
Yield: 19.1 %

Procedure:
70 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester, 55 mg 2-methyl-4,5,6,7-tetrahydro-oxazolo[5,4-c]pyridine hydrochloride and 0.1 mL DIPEA in 2 mL NMP was stirred 50 min at 180° C. under microwave condition. The reaction was poured into water and extracted with EtOAC. The organic layer was dried with magnesium sulfate and evaporated the residue was purified by HPLC (Waters Symmetry 50×140 mm water+0,3% HCOOH/methanoll 10% until 90% in 14 min) to yield 17 mg desired product. Rt: 1.10 (method A), (M+H)+: 435
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1B(O)O.[NH2:16][C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:16])[CH:22]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1-c1ccnc(N)c1
Temperature: 85 °C
Yield: 120 %

Procedure:
Argon was bubbled through a suspension of 2-methoxy-5-trifluoromethylphenylboronic acid (2.3 g, 10 mmol), 2-amino-4-bromopyridine (2.0 g, 12 mmol), and sodium carbonate (4.4 g, 42 mmol) in 1,4-dioxane (30 mL) and water (9 mL) for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was added. The resulting mixture was heated at 85° C. for 18 hours. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate then choloroform. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 10% methanol in chloroform gradient elution) to afford the title compound as yellow oil (3.22 g).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[C:25]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:17][CH:16]=1)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Yield: 99.5 %

Procedure:
Sodium hydroxide (10 g, 0.25 m) is dissolved in water (300 ml). To this solution 4-nitrophenylalanine (50.3 g, 0.22 m) is added and stirred until complete dissolution. To the resulting solution the sodium carbonate (28.8 g, 0.26 m) is added and stirred suspension is cooled in an ice bath to +8° C. Benzyl chloroformate (44.7 g, 0.26 m) is added dropwise with vigorous stirring, maintaining internal temperature in +6° to +9° C. range. The mixture is stirred at +6° C. for additional 1 hr, transferred to the separatory funnel and washed with ether (2×150 ml). Aqueous phase is placed in a large Erlenmeyer flask (2 L) and is cautiously acidified with dil. aq. HCl to pH=2 and extracted with ethyl acetate (4×500 ml). The combined extracts are washed with water and dried with MgSO4. The solution is filtered and filtrate evaporated, residue is dissolved in ethyl acetate (150 ml) and diluted with hexane (500 ml). Crystalline material is filtered off and rinsed with cold solvent, air dried to give Cbz-4-nitrophenylalanine, 75 g (99.5% yield).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:16]2S(C2C=CC=CC=2)(=O)=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:1]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(OC(=O)c3ccccc3)cc2n1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc(OC(=O)c3ccccc3)cc2[nH]1
Temperature: 0 °C
Yield: 99 %

Procedure:
To a dry 100 mL and stir bar was charged with 4.70 g ethyl 6-(benzoyloxy)-1-(phenylsulfonyl)indole carboxylate (Example 210) and dissolved in 12.5 mL of anhydrous tetrahydrofuran then cooled to 0° C. To this rapidly stirring solution was added 35.0 mL 1.0 M tetrahydrofuran solution of potassium tert-butoxide dropwise via syringe. Upon complete addition the contents were warmed to room temperature and stirred an additional ½ hour then quenched with 10 mL of 3N HCl solution followed by addition of 30 mL of water. The reaction was extracted with 3×50 mL of ethyl acetate then dried over Na2SO4 and concentrated in vacuo. The crude material was purified via column chromatography to yield 3.28g (99.0% yield) of an off white solid. The product had a Rf of 0.42 20% ethyl acetate/hexane; 1H NMR (300 MHz, Acetone-D6); 8.80 Hz, (s, 1H), 8.02 Hz, (dd, 1H), 7.95 Hz, (dd, 1H), 7.68 Hz, (dd, 1H), 7.58 Hz, (m, 2H), 7.46 Hz, (d, 2H), 7.21 Hz, (d, 1H), 6.87 Hz, (dd, 1H), 4.31 Hz (q, 2H), 1.31 Hz (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21]N(C)C=O.C(O[CH2:29][CH3:30])C>C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>[CH2:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]2[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH:29]=[CH2:30]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(O)cccc32)cc1
Reactant: CCOCC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Product: C=CCOc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1

Procedure:
Treatment of 1-[(4-methylphenyl)sulfonyl]-1H-indol-4-ol with potassium carbonate and allyl bromide in N,N-dimethylformamide (29.24 g, 0.242 mol) followed by aqueous workup and extraction with diethyl ether provides 4-(allyloxy)-1-[(4-methylphenyl)sulfonyl]-1H-indole.
Reaction SMILES: [C:1](Cl)(=O)C.[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6]1>CO>[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:1])=[O:12])=[CH:6]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1ccsc1
Reaction time: 8 h

Procedure:
Acteyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of 3-thiopheneacetic acid (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0° C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound as an oil. 1H NMR (400 MHz, CDCl3): □ 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14-7.15 (m, 1H), 7.27-7.29 (m, 1H).
Reaction SMILES: [Br:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:15]=[C:16]([CH3:18])[CH3:17]>CCOCC>[Br:1][C:2]1([C:7]([O:9][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=C(C)C
Reactant: O=C(O)C1(Br)CCCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(Br)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a mixture of 1-bromocyclopentanecarboxylic acid (36.99 g) and anhydrous ether (35 ml) in a 500 ml pressure bottle, containing a magnetic stirrer-bar, was added concentrated sulphuric acid (3.5 ml), followed by precondensed isobutene (150 ml). The bottle was sealed, and stirred at ambient temperature for 20 hours. The bottle was then opened excess isobutene was evaporated, and the residue in ether was washed with aqueous sodium bicarbonate solution and water, dried, and concentrated. The residue was distilled under reduced pressure to give the title ester (b.p. 66°-74°/0.5- 2.0 mm) (33.6 g, 70%); λmax (CHBr3) 1702 cm-1 ; τ (CDCl3) 7.78, 8.20 (cyclopentane protons) and 8.54 (C(CH3)3).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28](ON1C(=O)CCC1=O)=[O:29]>CN(C=O)C.CCN(CC)CC>[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28]([NH:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution at 0° C, of HCl.H-Glu(OBzl)-OBzl (1.82 g, 5 mmol) in DMF (35 ml), Et3N (0.7 ml) was added dropwise followed by Boc-Gly-OSu (1.5 g, 5.5 mmol). The mixture was stirrred at 0° C for 2 hr and at room temperature overnight; pH 8 was maintained by addition of a few drops of Et3N. The reaction mixture was then evaporated to a small volume and H2O was added. The precipitated oil was extracted with EtOAc and the organic phase was washed with 1 M AcOH, water, and dried (Na2SO4). Evaporation provided an oil which was purified on a Silica gel 60 column using CHCl3 :MeOH (5:1) as eluant. The pooled fractions containing (XVIII) were evaporated yielding colorless oil which failed to crystallize, 1.62 g (67%) homogeneous on tlc [α]D25 -15.0° (c 2, MeOH). Anal. Calcd for C26H32N2O7 (484.558): C, 64.45; H, 6.66; N, 5.78. Found: C, 64.23; H, 6.72; N, 5.66. Compound XVIII was also prepared from Boc-Gly-Glu(OBzl)-OH via the cesium salt procedure of Wang et al, supra.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12](Cl)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH2:12][C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)C(F)(F)C3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)CC(F)(F)C3
Yield: 106.3 %

Procedure:
The product from step (b) (21 mg) was dissolved in EtOAc (40 ml) and placed in a parr hydrogenation bottle. To this solution was added 5% Pd—C (10 mg). The mixture was shaken under 50 psi of hydrogen for 2 hours after which LCMS indicated no starting material. The mixture was purged with Nitrogen and filtered thru a bed of celite. The solvent was evaporated in vacuo to give the sub-titled compound (20 mg) as a yellow oil. MS: ESI (positive): 296 (M+H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]([F:35])[CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D139) (330 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E101) (150 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.62 (2H, t), 2.96 (2H, t), 5.43-5.49 (1H, m), 7.35 (1H, d), 7.65-7.69 (2H, m), 8.77 (1H, s), 9.07 (1H, s), 10.99 (1H, s), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −124.9. MS (ES): C21H18ClFN4O4 requires 444. found 445.1 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][S:11]([C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12].C([N:24](CC)C(C)C)(C)C.O1CCCC1.[OH-].[NH4+]>>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][S:11]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:1]([NH2:24])=[S:2])=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: S=C(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Carbonothioic dichloride (2.0E1 uL, 0.00026 mol) was added to a solution of the 6-Amino-pyridine-3-sulfonic acid thiazol-2-ylamide (45 mg, 0.00018 mol) and N,N-Diisopropylethylamine (0.092 mL, 0.00053 mol) in Tetrahydrofuran (1.2 mL, 0.014 mol) at 0° C. under an atmosphere of Argon and was stirred for 40 min at 0° C. Saturated ammonium hydroxide solution was added to the reaction mixture and stirred for a few min, then warmed to ambient temperature. The reaction mixture was concentrated and then dried on a lyophilizer to give the crude product that was used in the next step without purification. Note: The starting material, 6-Amino-pyridine-3-sulfonic acid thiazol-2-ylamide, was TFA salts.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[C:12]([CH:28]([CH3:30])[CH3:29])=[C:11]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH:42]2[CH2:44][CH2:43]2)[CH:32]=1)C1C=CC=CC=1.N.[H][H]>[Pd].C(O)C>[CH:42]1([O:41][C:33]2[CH:32]=[C:31]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:18](=[O:19])[C:13]=4[C:12]=3[CH:28]([CH3:30])[CH3:29])[CH:36]=[CH:35][C:34]=2[O:37][CH:38]([F:40])[F:39])[CH2:44][CH2:43]1
Reactant: [H][H]
Reactant: CC(C)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CC(C)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 60.1 %

Procedure:
To 313 mg (0.500 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isopropyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 7-(a) were added 15 ml of ethanol, 1.6 ml of 28% aqueous ammonia and 39 mg of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at 30° C. for 7 days. After completion of the reaction, the reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 152 mg of the title compound as a white foam. (Yield: 60%)
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[NH:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH:25][C:23](=[NH:24])[C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Nitrostyrylsulfonyl chloride (2.5 g., 0.01 mole) is added portion-wise to a solution of 4-nitrobenzamidine (1.65 g., 0.01 mole), prepared according to the procedure of L. Weintraub, et al., J. Org. Chem., 33, 1679 (1968), and triethylamine (1.01 g., 0.01 mole) in 50 ml. of acetone at 10° C. After stirring for a period of 1 hr. at 25° C., the mixture is concentrated under reduced pressure and the residual material stirred with water and collected. Triturating the filter cake with acetone provides N-(4-NITROSTYRYLSULFONYL)-4-NITROBENZAMIDINE, m.p. 173°-177° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[C:3]1([CH:9]([O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: C#CC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(OCC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a stirred suspension of NaH (60%, 76 mg, 1.89 mmol) in 5 mL of anhydrous N,N-dimethylformamide was added 1-phenylprop-2-yn-1-ol (250 mg, 1.89 mmol). After 15 min at room temperature, methyl bromoacetate (179 μL, 1.89 mmol) was added. The resulting mixture was stirred at room temperature for 90 min before it was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatography oh silica gel, eluting with ethyl acetate:hexane (1:9), to provide the title compound as a colorless oil (160 mg, 41% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:5]([C:24]#[N:25])=[CH:4][N:3]=1>C(O)(=O)C.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:24][N:25]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]3[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=3[C:6]=2[N:7]=1
Reactant: N#Cc1cnc(N)nc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Ni]
Solvent: CC(=O)O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 2.5 h

Procedure:
A solution of 50 mg (0.142 mmole) of the end product of Example 10 in 10 ml of acetic acid was treated with 1/4 spatula of Raney nickel, and hydrogenated for 2.5 hrs. The reaction was filtered through celite, evaporated, and partitioned between 30 ml of dichloromethane and 15 ml of dilute ammonium hydroxide. The organic layer was dried with sodium sulfate, evaporated and the residue was refluxed in ethanol for 1 hr, and then evaporated to dryness. The solid was dissolved in dichloromethane and developed on a thick layer silica gel plate in ethyl acetate/ethanol (20/l). The band of Rf 0.3 was removed and crystallized from ether to give white prisms, mp 243°-248° C., and a mixed mp of 244°-248° C. with authentic material obtained as in Example 2.