Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:21]4[CH2:30][C@H:29]([F:31])[CH2:28][C@H:22]4[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=4)[NH:12][C:11]3=[O:20])[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[S:44](Cl)(=[O:46])=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:21]4[CH2:30][C@H:29]([F:31])[CH2:28][C@H:22]4[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=4)[N:12]([S:44]([C:37]4[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:36]=4[O:35][CH3:34])(=[O:46])=[O:45])[C:11]3=[O:20])[C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C1(c2cccc3c2OCO3)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cccc4c3OCO4)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 0.33 h

Procedure:
353 mg of the compound obtained in step 18-1 (mixture of diastereoisomers) was added under ice cooling and a nitrogen atmosphere to a suspension of 35 mg of sodium hydride in 3 mL of tetrahydrofuran, and the reaction mixture was stirred for 20 minutes. After this, a 2 mL tetrahydrofuran solution of 219 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise. The reaction mixture was stirred for 2 hours at the same temperature, after which 5 mL of ethyl acetate and 10 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (10 mL×3), and the combined organic layer was dried with sodium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain two kinds of diastereoisomer of the titled compound in amounts of 191 mg (isomer A: colorless, amorphous) and 75 mg (isomer B: colorless, amorphous).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared in an analogous manner to the preparation of example 381 by combining 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (48%). LCMS: m/z=483.24 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.08 (s, 1H), 8.01 (m, 2H), 7.45 (s, 1H), 7.33 (m, 3H), 7.23 (d, 1H, J=8.6 Hz), 6.92 (d, 1H, J=8.6 Hz), 6.57 (m, 1H), 2.93 (d, 3H, J=4.8 Hz), 2.37 (m, 2H), 2.07 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:32]([O:31][C:29]([C:28]([CH3:34])=[CH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:22][CH:23]=1)=[O:30])[CH3:33]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CCOC(=O)C(C)=Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccc(Cn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.08 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF under nitrogen at 10°-15°. After complete addition the mixture is stirred at room temperature for 0.5 hour and is treated with a solution of 2.39 g of ethyl 3-(p-chloromethylphenyl)-2-methylacrylate in 5 ml of DMF dropwise. The resulting mixture is stirred at room temperature overnight and poured in 100 ml of water. The resulting mixture is extracted with ethyl acetate (2×50 ml) and the organic layer is washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 1-[p-(2-ethoxycarbonylpropen-1-yl)benzyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]1=[O:20])[CH3:2].[H][H]>[Pd]>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH2:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]1=[O:20])[CH3:2]
Reactant: CCOC(=O)C1C(=O)N(CC)c2cc3ccoc3cc21
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C1C(=O)N(CC)c2cc3c(cc21)OCC3
Yield: 63 %

Procedure:
A mixture of 20 g. (73.3 mmoles) of ethyl 5-ethyl-6-oxo-6,7-dihydro-furo[2,3-f]indole-7-carboxylate and 4 g. of 10% palladium-on-carbon was shaken in a hydrogen atmosphere at an initial pressure of 50 psi. After 2 hours the catalyst was filtered and the filtrate evaporated. The residue was recrystallized from diethyl ether, 12.6 g. (63% yield), m.p. 82°-84° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[OH:45])[CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccnc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
3-Aminopyridine (0.151 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.065 g, 0.159 mmol, 30%).
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(CCCCN2CCN(N=Cc3ccccc3)C2=O)CC1
Yield: 86.6 %

Procedure:
A stirred solution of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone (10.0 g, 0.0269 mole), dimethylformamide (150 ml) and 1-methylpiperazine (6.0 ml, 3.4 g, 0.0539 mole) is heated to reflux. Reflux is maintained for 2.5 hours. The solution is concentrated under reduced pressure to a semi-solid residue. This residue is dissolved in CHCl3 (300 ml), then washed with saturated NaHC3 solution. (3×400 ml), H2O (2×100 ml) and dried over MgSO4. The filtered solution is concentrated under reduced pressure to an oily residue. This residue is triturated in hexane (300 ml) by stirring. The solid is collected and air-dried to give 8.0 g (0.0233 mole) of 1-phenylmethyleneamino-3-[4-(4-methyl-1-piperazinyl)butyl]-2-imidazolidinone.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].C1C[O:24][CH2:23]C1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl.C(O)=O>[CH:23]([N:18]1[CH2:19][CH2:20][CH:15]([N:3]([CH3:2])[C:4]([C:6]2[CH:14]=[CH:13][C:9]3=[N:10][O:11][N:12]=[C:8]3[CH:7]=2)=[O:5])[CH2:16][CH2:17]1)=[O:24]
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Reactant: C1CCOC1
Agent: Cl
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.5 g, 1.7 mmol) was suspended in chloroform (20 ml) and THF (20 ml) and triethylamine (6 ml), was added. A mixture of formic acid (1 ml) and acetic anhydride (1 ml) was stirred for 1.5 h at room temperature and then slowly added to the suspension. After stirring the mixture for 1 h, it was washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (2×100 ml) and the combined organics were dried (MgSO4), concentrated under vacuum, and purified by silica gel chromatography, eluting with ethyl acetate/chloroform/methanol (50:45:5) to give a white solid (341 mg). Mp=163-165° C., 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (d, J=9.3 Hz, 1H); 7.86 (s, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.90-4.45 and 3.85-2.60 (m, 5H); 2.88 (sb, 3H); and 1.95-1.60 ppm (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:11].[BH4-].[Na+]>CO>[OH:11][C:3]1[C:2]([Br:1])=[CH:9][C:8]([Br:10])=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)cc(Br)c1O
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a stirred solution of 3,5-dibromosalicylaldehyde (10.6 grams, 38 mmol) in MeOH (70 mL), was added NaBH4 (4.3 grams, 115 mmol) in small portions and the solution was stirred for 1.5 hours. Another batch of NaBH4 (2.0 grams, 52 mmol) was added in small portions and the mixture was stirred for another 2 hours. The solvent was removed under vacuum and the resulting white solid was re-precipitated in water. The product was collected as a white solid by vacuum filtration (10.1 grams, 94% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][C:24]=1[CH2:25][N:26]1[C@@H:30]([CH3:31])[C@@H:29]([C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[O:28][C:27]1=[O:46].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[F:45][C:42]([F:43])([F:44])[C:34]1[CH:33]=[C:32]([C@H:29]2[O:28][C:27](=[O:46])[N:26]([CH2:25][C:24]3[CH:47]=[C:48]([O:51][C:52]([F:53])([F:54])[F:55])[CH:49]=[CH:50][C:23]=3[NH:22][C:12]([C@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:11][CH2:10]3)=[O:14])[C@H:30]2[CH3:31])[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)Nc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of trans-4-(2-ethoxy-2-oxoethyl)-cyclohexanecarboxylic acid (1 g; 4.67 mmol) in anhydrous THF (25 mL) at 0° C. was treated dropwise with oxalyl chloride (1.02 mL; 11.68 mmol) followed by catalytic DMF (50 μL). The reaction was stirred at room temperature for 2 h, concentrated in vacuo, and the residue was redissolved in THF (25 mL). The resultant solution was cooled to 0° C. and treated with (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.58 g; 5.14 mmol) and triethylamine (0.716 mL; 5.14 mmol). The reaction was stirred at room temperature for 1 h, quenched with water and partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAc/hexanes, to afford ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}carbonyl)cyclohexyl]acetate as an off-white solid. LCMS=698.9 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.94 (s, 1 H), 8.23 (d, J=8.9 Hz, 1 H), 7.92 (s, 1 H), 7.73 (s, 2H), 7.27-7.24 (m, 1 H), 7.02 (s, 1 H), 5.71 (d, J=8.4 Hz, 1 H), 4.78 (d, J=15.5 Hz, 1 H), 4.19-4.12 (m, 3H), 4.07 (d, J=15.6 Hz, 1 H), 2.43-2.37 (m, 1 H), 2.21 (d, J=6.9 Hz, 2 H), 2.07-1.98 (m, 2 H), 1.93-1.83 (m, 3 H), 1.67 (q, J=12.6 Hz, 2 H), 1.26 (t, J=7.2 Hz, 3 H), 1.19-1.11 (m, 2 H), 0.88 (d, J=6.6 Hz, 3 H).
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:11])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[Na+].[OH:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][C:17]([O-:19])=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:19][C:17](=[O:18])[CH2:16][CH2:15][CH:14]([OH:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Reactant: CC(C)=CCCC(C)=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCC(O)CCC(=O)OCC=C(C)CCC=C(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
A mixture of 155 g 1-chloro-3,7-dimethyl-octa-2,6-diene, 202 g 4-hydroxy-undecanoic acid sodium salt and 5 g tetrabutylammoniumbromide in 800 ml of dimethylfornamide was heated to 50° C. After stirring for 24 hours, the mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with ether, washed with water, 2N HCl, saturated sodium bicarbonate and brine. The organic phase was dried and evaporated to dryness. The resulting yellow oil was purified by wipe film distillation to yield 96.6 g of a yellow oil.
Reaction SMILES: [BH4-].[Na+].[OH:3][C@H:4]1[C:13](=[O:14])[C:12]2[C:11]([CH2:15][O:16][CH3:17])=[CH:10][N:9]3[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:8]3[C:7]=2[NH:6][C@@H:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[OH:14][C@H:13]1[C:12]2[C:11]([CH2:15][O:16][CH3:17])=[CH:10][N:9]3[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:8]3[C:7]=2[NH:6][C@H:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:4]1[OH:3]
Reactant: COCc1cn2c(C)c(C)nc2c2c1C(=O)[C@H](O)[C@@H](c1ccccc1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCc1cn2c(C)c(C)nc2c2c1[C@H](O)[C@H](O)[C@@H](c1ccccc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
At room temperature, 0.2 g of sodium borohydride are added in small portions to 0.4 g of (8R, 9R)-8-hydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1 ,2-h][1,7]naphthyridin-7-one, dissolved in 20 ml of methanol, and the mixture is stirred at room temperature for 2 hours. The solvent is then removed under reduced pressure and the residue is admixed with water and extracted 3 times with methylene chloride. The organic phases are combined and concentrated to dryness in vacuo. Purification on silica gel (mobile phase: methylene chloride/methanol=100/3) gives 80 mg of the title compound [Rf=0.54 (methylene chloride/methanol=13/1)] of melting point 182-3° C. (decomp.).
Reaction SMILES: [OH:1][CH:2]([C:4]1([OH:27])[CH2:21][CH2:20][CH:19]2[CH:6]([C:7](=[O:26])[C:8]3[C:17]([CH2:18]2)=[C:16]([O:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=3[O:24][CH3:25])[CH2:5]1)[CH3:3]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:2]([C:4]1([OH:27])[CH2:21][CH2:20][CH:19]2[CH:6]([C:7](=[O:26])[C:8]3[C:17]([CH2:18]2)=[C:16]([O:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=3[O:24][CH3:25])[CH2:5]1)(=[O:1])[CH3:3]
Reactant: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)=O)CCC1C2
Yield: 100.5 %

Procedure:
0.1 g of 1,2,3,4,4a,5,12,12a-octahydro-2-(1-hydroxyethyl)-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene, prepared as described in Example 12, in benzene was treated with 1 g of silver carbonate at refluxing temperature. After filtering off the inorganic solids and removing the solvent, 0.1 g of the title product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]3[N:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH3:20])=[O:9])=[C:4]([F:21])[CH:3]=1.[CH:22]1[CH:27]=[C:26]2[C:28]([N:30]([CH2:33]C(O)=O)[C:31](=[O:32])[C:25]2=[CH:24][CH:23]=1)=[O:29].FC(F)(F)C(O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+].C(#N)C>[Cl:19][C:16]1[CH:17]=[C:18]([CH2:33][N:30]2[C:31](=[O:32])[C:25]3[C:26](=[CH:27][CH:22]=[CH:23][CH:24]=3)[C:28]2=[O:29])[C:13]2[N:14]([C:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:21])=[C:11]([CH3:20])[N:12]=2)[N:15]=1
Reactant: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc2c(CN3C(=O)c4ccccc4C3=O)cc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
Combine (4-chloro-2-fluorophenyl)(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)methanone (5.6 g, 17.3 mmol), N-phthaloylglycine (6.0 g, 1.7 equiv.), acetonitrile (60 mL), water (15 mL), trifluoroacetic acid (0.26 mL, 0.2 equiv.), and silver nitrate (294 mg, 0.1 equiv.) in a round bottom flask with attached addition funnel and place under nitrogen. Heat to 70° C. and maintain at this temperature for 15 min. Dissolve ammonium persulfate (7.1 g, 1.8 equiv.) in water (15 mL) and charge to an addition funnel Add drop-wise to the reaction flask over approximately 20 min. Heat reaction at 70° C. for 1 h. A precipitate forms during this time; filter via Buchner funnel to isolate the title compound crude (7.3 g, 87%) as an off-white solid. LCMS (4 min)=483.0, 485.0, M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH:22][C:35]4[N:36]=[CH:37][C:32]5[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)[C:33]=5[N:34]=4)=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCCN(C(=O)OC(C)(C)C)C5)OC4=O)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.084 g, 0.287 mmol, 1.0 eq) and gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester which was used directly in the following BOC deprotection.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].C(#N)C.[CH2:11]([N:13]1[C:22]2[CH:21]=[CH:20][C:19]([CH:23]([CH3:25])[CH3:24])=[CH:18][C:17]=2[C:16](=[O:26])[C:15]2[C:27](O)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[C:33]([C:14]1=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:12].S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH2:11]([N:13]1[C:22]2[CH:21]=[CH:20][C:19]([CH:23]([CH3:25])[CH3:24])=[CH:18][C:17]=2[C:16](=[O:26])[C:15]2[CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[C:33]([C:14]1=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:12]
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(O)(c1ccccc1)c1ccccc1-2
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: ClCCCl
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(c1ccccc1)c1ccccc1-2
Temperature: 25 °C

Procedure:
To a mixture of trimethylsilyl chloride (0.19 mL, 1.5 mmol), sodium iodide (224 mg, 1.5 mmol) and acetonitrile (61 mg, 1.5 mmol) was added dropwise a solution of 5-ethyl-8-isopropyl-11-hydroxy-11-phenyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10-one in 1,2-dichloroethane with stirring at room temperature. The mixture was stirred at 50° C. overnight followed by allowing to cool to room temperature. The reaction mixture was treated diluted aqueous solution of sodium sulfite. The separated organic layer was washed with water four times and then with saturated sodium chloride solution followed by drying with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform) followed by crystallization from diethyl ether to give the title compound. 1H-NMR(CDCl3) δ 1.30(6H,d,CH(CH3)2), 1.79(3H,t,NCH2CH3), 3.05(1H,septet,CH), 4.81(2H,q,NCH2), 5.18(1H,s,H-11), 7.16-7.64(10H,m,Ar-H), 7.96(1H,d,H-6), 8.37(1H,d,H-9)
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5](=[N+:15]=[N-:16])[C:6]([C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])C.ClC1N=CC=CC=1C(Cl)=O.[N+](=CC(OCC)=O)=[N-]>>[O:7]=[C:6]1[C:5]([C:4]([OH:3])=[O:17])=[N:15][NH:16][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]1=2
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccnc1Cl
Agent: CCOC(=O)C=[N+]=[N-]
Agent: O=C(Cl)c1cccnc1Cl
Product: O=C(O)c1n[nH]c2ncccc2c1=O
Reaction time: 18 h
Yield: 204.1 %

Procedure:
3-(2-Chloropyridin-3-yl)-2-diazo-3-oxopropionic acid ethyl ester—2-Chloronicotinoyl chloride (10 g) and ethyl diazoacetate (19.4 g) were heated together at 55° C. for 3 hours then left at ambient temperature for 18 hours. The mixture was concentrated in vacuo and the residue chromatographed on silica gel, eluting with 30-50% ethyl acetate in hexane. This gave the title compound (9.08 g, 63%). NMR (CDCl3) δ1.15 (3H, t), 4.15 (2H, q), 7.25 (1H, t), 7.58 (1H, dd), 8.48 (1H, dd).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[C:14]([CH3:38])=[C:15]([N:19]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:20][CH2:21][CH3:22])[C:14]=2[CH3:38])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(OC)cc2)c1C

Procedure:
Prepared from 4-methoxyphenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).