Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[S:34][C:35]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[C:36]([CH3:38])[N:37]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:35]3[S:34][C:33]([CH3:32])=[N:37][C:36]=3[CH3:38])([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.47 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (9 mL) at −78° C. After 5 minutes, a solution of (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (259 mg, 1.2 mmol, Intermediate 23: step b) in tetrahydrofuran (2 mL) was added dropwise. After 2 minutes, the flask was placed into an ice-water bath. After 90 minutes, water (4 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (20 mL) and ethyl acetate (50 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 40% ethyl acetate-hexanes initially, grading to 90% ethyl acetate-hexanes provided the title compound as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.41-7.34 (m, 2H), 7.23 (s, 1H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.11 (s, 3H), 3.91 (s, 3H), 3.71 (s, 1H), 2.58 (s, 3H), 2.15 (s, 3H); MS (ESI): mass calcd. for C29H26ClN7O2S, 571.2. m/z found, 572.1 [M+H]+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:47][C:48](OC2C=CC=CC=2)=[O:49])[C:34](=[CH:45][CH:46]=1)[C:35](OCC1C=CC=CC=1)=[O:36]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:34]([C:35](=[O:36])[N:28]([S:25]([C:14]3[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=3)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:48](=[O:49])[NH:47]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(C(=O)OCc2ccccc2)c(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C(=O)O)c(N)c3)c(=O)[nH]c2c1
Yield: 3.1 %

Procedure:
500 mg (1.23 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 460 mg (1.22 mmol) of benzyl 4-methoxy-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 15 mg (yield 3.1%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.82 (3H, s), 6.58 (1H, s) 6.80 (1H, d), 7.16 (1H, d), 7.56 (1H, s), 7.80 (1H, d) 7.90 (1H, d), 11.49 (1H, s).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[C:3]#[C:2][CH2:1][OH:4]
Reactant: Ic1ccc2ccccc2c1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1ccc2ccccc2c1
Temperature: 35 °C
Reaction time: 12 h
Yield: 11 %

Procedure:
Bis(triphenylphosphine)palladium (II) chloride (0.18 g, 0.26 mmol, 0.18 mol %) was added to a stirred solution of propargyl alcohol (8.43 mL, 144.8 mmol, 1 eq.), 2-iodonapthalene (36 g, 142 mmol), triethylamine (39.6 mL, 284 mmol, 2 eq.) and copper iodide (0.09 g, 0.49 mmol, 0.3 mol %) in tetrahydrofuran (750 ml). The mixture was stirred at 35° C. for 12 h under nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate (200 ml). The filtrate was then concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent afforded the desired compound (2.85 g, 11%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.54 (2H, s, CH2), 7.45-7.49 (3H, m, ArH), 7.75-7.81 (3H, m, ArH), 7.95 (1H, s, ArH).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[N:15]=1.[C:23](=[O:25])=[O:24].[Cl-].[NH4+].Cl>O1CCCC1>[Cl:22][C:16]1[N:15]=[C:14]([Cl:13])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[C:23]([OH:25])=[O:24]
Reactant: COc1cc(Cl)nc(Cl)c1
Reactant: O=C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)c1C(=O)O
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
To a solution of diisopropylamine (1.83 mL) in tetrahydrofuran (40 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 4.52 mL) at −78° C., and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2,6-dichloro-4-methoxypyridine (1.93 g) in tetrahydrofuran (10 mL) in a dropwise manner, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (5 g), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added a saturated aqueous ammonium chloride solution and 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give the title compound (1.2 g).
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[N:8][C:7]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[C:16]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[N:8][C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nnc2ccc(-c3ccccc3)cc2c1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2nn1

Procedure:
Thionyl chloride (15 ml.) and dimethylformamide (1 drop) were added to ethyl 4-hydroxy-6-phenylcinnolin-3-yl carboxylate (0.30 g.). The mixture was gradually heated to boiling point and then heated under reflux until the evolution of gases ceased. The solution was evaporated under reduced pressure. The residue was dissolved in dry toluene (20 ml.) and the solution evaporated; this operation was then repeated. The residue was dissolved in a mixture of dimethylformamide (5 ml.) and ethyl acetate (30 ml.). The solution was stirred and sodium borohydride (0.25 g.) was added. The mixture was stirred for 2 hours and then added to a mixture of N-hydrochloric acid (10 ml.) and ethyl acetate (50 ml.). The mixture was separated and the ethyl acetate layer was washed with water (3 × 20 ml.), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure. The residue (which comprised ethyl 6-phenyl-1,4-dihydrocinnolin-3-yl carboxylate) was dissolved in dry toluene (50 ml.). Lead tetraacetate (1 g.) was added, and the mixture was stirred for 2 hours. The mixture was shaken with water (50 ml.), and separated. The organic layer was washed with water (3× 50 ml.), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure. The residue was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give ethyl 6-phenylcinnolin-3-yl carboxylate, m.p. 160°-2° C.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].C[O:16][C:17](=O)[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:10]3[C:8](=[C:7]([CH3:6])[C:13]([OH:14])=[CH:12][CH:11]=3)[O:9][C:17](=[O:16])[CH:18]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(O)cccc1O
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)ccc2c(-c3ccc(F)cc3)cc(=O)oc12
Reaction time: 40 h

Procedure:
Concentrated H2SO4 (27 ml) was added to a mixture of methyl resorcinol (12.41 g, 100 mmol) and methyl-4-fluorobenzoylacetate (21.8 g, 110 mmol) at 0° C. The resulting suspension was set aside for 40 h. Water (1 L) was added and the mixture was stirred for 1 h. The residue was filtered, washed with water (2 L) and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][N:43]([CH3:56])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:31]=1>>[CH3:41][C:37]1([CH3:40])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][CH3:56])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: CN(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Product: CNCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and N-((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)-N-methyl-2-nitrobenzenesulfonamide (reagent preparation 17) in step 3 followed by 2-nitrobenzenesulfonyl-group deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (br s, 1H), 8.06 (br s, 1H), 7.75 (d, 1H), 7.53 (dd, 1H), 7.01 (d, 1H), 4.68 (s, 2H), 4.33-4.27 (m, 2H), 3.91-3.85 (m, 2H), 3.48 (s, 2H), 2.68 (t, 2H), 2.54 (s, 3H), 2.45 (s, 2H), 2.12 (s, 3H), 1.59 (t, 2H), 0.87 (s, 6H); MS (EI) for C28H33N7O: 484 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:26])[N:3]=[CH:4]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Reactant: O=C(O)c1cccnc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1CCCc1ccccc1

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and nicotinic acid instead of 3-pyridylacetic acid hydrochloride to obtain crude 1-(3-phenylpropyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:20]=[C:21]=[O:22])[CH:18]=[CH2:19].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:20][C:21]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:22])[CH:18]=[CH2:19]
Reactant: C=CCN=C=O
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: C=CCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 12 h

Procedure:
4.4 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 20 parts of allyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue was stirred in 100 parts of water for 12 hours. This phase was extracted with chloroform and the extracts washed with brine and dried over magnesium sulphate. Evaporation of the solvent in vacuo afforded an oil which was chromatographed on an alumina column to give 14-allylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one which gave the following elemental analysis by weight:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:26]#[N:27])=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]2[C:20](=[C:26]([NH2:27])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1
Reactant: N#Cc1nc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc2ccccc2c2ccc(Cl)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-chloropicolinonitrile (from step 2) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give a solid, which was then triturated in 10% ethyl acetate in hexane to give 3-chlorobenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 9.10 (d, 1H), 8.45 (d, 1H), 7.89 (d, 1H), 7.58-7.65 (m, 2H), 7.35-7.39 (dd, 1H), 6.67 (br, 2H). LRMS [M+H]=230.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:3]=[C:2]([C:42]2[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=2)[CH:7]=[CH:6][CH:5]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
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+]
Product: CC(C)C(O)(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 76.4 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.01 g), 4-trifluoromethylphenylboronic acid (1.70 g), 2M aqueous sodium carbonate solution (22.4 ml) and tetrakis(triphenylphosphine)palladium(0) (323 mg), the title compound (2.58 g) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 87.6 %

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.23 g, 8.87 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (2.84 g). 1H NMR (CDCl3) δ7.23 (m, 1H), 6.88 (m, 3H), 5.75 (m, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 2.71 (m, 2H), 2.30 (m, 2H), 2.25 (m, 1H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), 0 (s, 3H), −0.2 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:6]([C:18]([O:20]CCC#N)=[O:19])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[OH-].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:6]([C:18]([OH:20])=[O:19])=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)O)C1c1ccc([N+](=O)[O-])cc1
Yield: 64.8 %

Procedure:
A solution of 5-acetyl-2-(4-azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine (1.05 g, 2.32 mmol) in 10 ml of acetone was treated with 20 ml of 1N aqueous KOH solution at 0° C. for 1 hr. The acetone was removed in vacuo and the aqueous layer was acidified to pH=3 by 2N hydrochloric acid, the resulting yellow precipitate was collected by filtration, washed with 10 ml of cold water and dried in vacuo to yield 0.60 g (60% yield) of 5-acetyl-2-(4-azidobuyl)-1,4-dihydro-6-methyl-4-(4-nitrophenyl)pyridine-3-carboxylic acid as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[C:4]([N+:20]([O-])=O)[C:3]=1[NH:23][C@@H:24]1[CH2:29][C@@H:28]2[CH2:30][C@@H:26]([C:27]2([CH3:32])[CH3:31])[C@H:25]1[CH3:33].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:20][C:4]1[C:3]([NH:23][C@@H:24]2[CH2:29][C@@H:28]3[CH2:30][C@@H:26]([C:27]3([CH3:31])[CH3:32])[C@H:25]2[CH3:33])=[C:2]([Br:1])[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:11])[N:5]=1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c([N+](=O)[O-])nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c(N)nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Yield: 43.1 %

Procedure:
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (32 mg, 0.0616 mmol) in ethyl acetate (3 mL) was stirred with tin (II) chloride dihydrate (72 mg, 0.319 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was basified to pH 9-10 with aqueous sodium hydroxide and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=6/1) to give the desired product (13 mg, 43% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14]1[N:15]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[S:17][C:18]=1[C:19]([NH2:21])=[O:20].[C:28]([O:31][CH2:32][C:33](Cl)=O)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([O:31][CH2:32][C:33]1[N:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])[C:14]2[N:15]=[C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[S:17][C:18]=2[C:19](=[O:20])[N:21]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1c(CNc2nc(N3CCOCC3)sc2C(N)=O)cccc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
A solution of 4-({[2-methyl-3-(trifluoromethyl)phenyl]methyl}amino)-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (300 mg, 0.749 mmol), 2-chloro-2-oxoethyl acetate (0.201 mL, 1.873 mmol) in Tetrahydrofuran (THF) (6 mL) was charged into a sealed tube under 0 C. The mixture was warmed up to RT gradually. The reaction was stirred at RT for overnight. The mixture was partitioned between DCM and NaCl, the organic layer was concentrated and the residue was purified on silica column (5% MeOH/DCM) to give product 80 mg (˜20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, step 1) by alkylation with methyl-5-chloro-2-pyrazinecarboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=516.1 [MH+].