Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].CCN(C(C)C)C(C)C.[C:29]1([C@@H:35]([NH2:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN1C(=O)CCC1>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([N+:17]([O-:19])=[O:18])=[C:2]([NH:37][C@H:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:36])[CH:10]=2)[C:6]([CH3:16])([CH3:15])[C:7]1=[O:14])([CH3:13])[CH3:12]
Reactant: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(F)cc21
Reactant: C[C@H](N)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(N[C@@H](C)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6-Fluoro-1-isopropyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one E-1.2″ (4.5 g; 16.5 mmol) is dissolved in NMP (20 ml), DIPEA (4.0 ml; 22.3 mmol) and (S)-1-Phenyl-ethylamine (2.65 ml; 20.1 mmol) is added at 20° C. The reaction mixture is stirred for 3 h at 50° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (50 μM) with eluting mixture of ethyl acetate and cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:22][C:23]1[C:27]([CH:28]=O)=[C:26]([CH3:30])[N:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:24]=1)C1C=CC=CC=1.[Cl-].[NH4+].CSC>O1CCCC1.CO.FC(F)(F)C(O)=O.O.[C].[Pd]>[CH3:30][C:26]1[N:25]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:24][C:23](=[O:22])[C:27]=1[CH2:28][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Reactant: CSc1ccc(Br)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(Cc2c(C)n(-c3ccccc3)[nH]c2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.4 %

Procedure:
To a solution of 1-bromo-4-methylthiobenzene (0.21 g) in tetrahydrofuran (10 mL) was added tert-butyllithium (1.6 mol/L pentane solution, 0.67 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole (0.20 g) in tetrahydrofuran (3 mL), and the mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added hexane, and the precipitates were collected by filtration to give a white crystals. The obtained crystals were dissolved in methanol (5 mL) and tetrahydrofuran (6 mL). To a solution was added 10% palladium-carbon powder (0.30 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=6/1-3/1) to give an oily substance. The obtained oily substance was dissolved in trifluoroacetic acid (1.9 mL) and water (0.1 mL), and to the solution was added dimethyl sulfide (0.2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.054 g).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[O:8].[CH2:13]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[N:23][C:24](Cl)=[C:25]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=4[F:45])[CH2:32][CH2:31]3)[N:26]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[N:23][C:24]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[C:25]([N:30]3[CH2:31][CH2:32][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=4[F:45])[CH2:34][CH2:35]3)[N:26]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:7]([OH:8])([C:9]([F:12])([F:11])[F:10])=[O:6]
Reactant: NC1CCC1
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of cyclobutanamine (49.9 μL, 0.584 mmol), 6-benzyl-3-chloro-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine TFA salt (116.2 mg, 0.195 mmol), sodium tert-butoxide (56.1 mg, 0.584 mmol), BINAP (18.2 mg, 0.029 mmol) and Pd2(dba)3 (26.7 mg, 0.029 mmol) in toluene (649 μL) was heated at 90° C. in a sealed tube for 16 h. The mixture was directly purified by HPLC Method A to afford 6-benzyl-N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine as its TFA salt (103.4 mg, 84%) as a yellow foam. ESI-MS m/z [M+H]+ 518.4
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:15]([NH2:17])=[O:16].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:13][C@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:15]([NH2:17])=[O:16])[CH:9]=1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: NC(=O)[C@H](N)Cc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)c(N[C@H](Cc2ccccn2)C(N)=O)cc1Br
Yield: 109.7 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (150 mg, 0.688 mmol), (R)-2-amino-3-(pyridin-2-yl)propanamide hydrochloride (170 mg, 0.714 mmol) and DIEA (0.500 mL, 2.87 mmol) in DMSO (4 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-(pyridin-2-yl)propanamide (274 mg)
Reaction SMILES: [OH:1][C@H:2]1[C@@H:14]2[C@@H:10]([C@@H:11]([O:16][CH3:17])[O:12][C@H:13]2[CH3:15])[CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.C(=O)([O-])O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:17][O:16][C@@H:11]1[C@H:10]2[CH2:9][C@@H:8]3[C@@H:3]([C:2](=[O:1])[C@H:14]2[C@H:13]([CH3:15])[O:12]1)[CH2:4][CH2:5][CH2:6][CH2:7]3
Reactant: CO[C@H]1O[C@@H](C)[C@@H]2[C@H](O)[C@H]3CCCC[C@@H]3C[C@H]12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@H]1O[C@@H](C)[C@@H]2C(=O)[C@H]3CCCC[C@@H]3C[C@H]12
Yield: 96.7 %

Procedure:
To 1.23 g(5.12 mmol) of (1S,3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan and 3.26 g of sodium hydrogencarbonate in 100 ml of methylene chloride suspension were added 3.26 g(1.5 equivalents) of Dess-Martin reagent under stirring and cooling with ice, and the mixture was stirred for 1 hour at room temperature. After 6.35 g of sodium thiosulfate 5-hydrate and 50 ml of saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and stirred, two layers were separated and extraction with methylene chloride(5 ml×3) was performed from aqueous layer. The organic layers were dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain 1.18 g of (1S,3S,3aR,4aS,8aR,9aS)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan (yield 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1)=[O:7].[CH3:26][N:27]([CH3:55])[C:28](=[O:54])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>O.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][C:14]([C:42]3[CH:41]=[CH:40][C:39]([NH:38][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([C:28](=[O:54])[N:27]([CH3:26])[CH3:55])=[CH:30][CH:31]=4)=[O:37])=[CH:44][CH:43]=3)=[N:15]2)=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1ccc2c(N3CCOCC3)nc(Cl)nc2c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNC(=O)c1ccc2c(N3CCOCC3)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)N(C)C)cc4)cc3)nc2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 9.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid (2-dimethylamino-ethyl)-amide (0.08 g, 0.00022 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (0.108 g, 0.000264 mol), cesium carbonate (0.143 g, 0.00044 mol), DMF (4 mL), water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (8 mg, 0.000011 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 15-20% MeOH in chloroform) to yield the crude title compound in 50% yield, followed by preparative HPLC (0.1% TFA in water and ACN) to yield the title compound [0.013 g, 10%]. 1H NMR; (400 MHz, DMSO-d6): δ 9.65 (brs, 1H), 9.55 (s, 1H), 9.17 (s, 1H), 8.45 (brs, 1H), 8.43 (d, 2H, J=8.8 Hz), 8.16 (d, 1H, J=8.4 Hz), 7.96 (brs, 1H), 7.67 (d, 2H, J=8.0 Hz), 7.54 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 3.85-3.94 (m, 8H), 3.70 (d, 2H, J=5.2 Hz), 3.43 (brs, 2H), 2.95 (s, 6H), 2.86 (s, 6H): LC-MS (ESI): Calculated mass: 610.3; Observed mass: 611.1 [M+H]+ (RT: 0.08 min).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([O:27]C)=[O:26].[I-].[Li+]>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:24])[CH:18]([CH3:23])[CH:19]([CH3:22])[CH2:20][CH3:21])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:25]([OH:27])=[O:26]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCC(C)C(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
A mixture of methyl 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.4 g) and anhydrous lithium iodide (8.5 g) in dry pyridine (34 ml) was stirred at 100° C. for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure. Water was added to the residue to give precipitates, which were collected by filtration and washed with water. The resulting crystals were suspended in water. The suspension was adjusted to pH 1-2 with conc. hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water, and dried. The crude crystals (3.85 g) were dissolved in a mixture of chloroform and methanol under heating. The solution was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure to 40 ml and cooled in an ice bath. The resulting crystals were collected by filtration and suspended in a mixture of chloroform and methanol under heating. After the suspension was cooled to ambient temperature, the crystals were filtered and dried. There was obtained 4-oxo-10-(2,3-dimethylpentanamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (1.0 g).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[Li+:12].[OH-]>O>[Li+:12].[S:1]([O-:11])(=[O:10])([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1)=[O:2]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
Next, a sulfanilate lithium salt precursor is prepared according to step 2 in FIG. 8. Sulfanilic acid (1.35 g, 7.8 mmol) and LiOH (0.187 g, 7.8 mmol) were added in water (10 mL) with constant stirring. This step results in an available lone pair of electrons on the amino group to react with the acid chloride at the next and final step. After stirring 20 min, the clear solution was then dried in vacuum overnight to obtain a dried sulfanilate lithium salt precursor. The solid was used as the starting material in the final step.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].S(=O)(=O)(O)O.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([N+:1]([O-:4])=[O:2])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Sodium nitrate (1.7 g) was added to a concentrated sulfuric acid (7 ml) solution containing 2,3-difluorobenzoic acid (1.58 g), followed by stirring at room temperature for 0.5 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of 2,3-difluoro-5-nitrobenzoic acid (1.61 g) was thus obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH3:11][CH:12]1OC(C)OC(C)O1>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CC1OC(C)OC(C)O1
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: O
Product: CC1N=C(N)NC(N(C)C)=N1
Yield: 183.1 %

Procedure:
A mixture of 1002.6 g of metformin hydrochloride, 359.1 g of paraldehyde and 51.6 g of toluene-4-sulfonic acid monohydrate in 2405.9 g of isobutanol is heated under reflux for 6 hours. Some of the solvent is removed by distillation. The mixture is cooled to 12°, and the white precipitate is separated off, giving 953.8 g (81.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL) were added 2-iodopropane (4.9 g, 28.75 mmol) and K2CO3 (4 g, 28.75 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) extracted with EtOAc (3×25 mL), the combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by prep TLC to give 5-bromo-1-isopropylpyridin-2(1H)-one (380 mg, 31%). 1H NMR (CDCl3): 1.35 (d, 6H), 5.65-5.75 (m, 1H), 6.48 (d, 1H), 7.30 (m, 1H), 7.41 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SCC1CC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SCC2CC2)c(Cl)c1
Yield: 97.2 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (41 mg, 0.19 mmol) obtained in Step C of Preparation Example 18 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (50 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (72 mg, 90%).
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:41](O[C@@H]1[C@@H](CO)O[C@@H](N2C3N=C(NC(=O)C(C)C)NC(=O)C=3N=C2)C1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>>[Si:41]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
This compound was prepared from 5'-O-(4,4'-dimethoxytrityl)-thymidine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N2 -isobutyryl-2'-deoxyguanosine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-methyl-pyrimidine (example E.77) (0.37 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.24 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.27 g, 70%). MS (ISP) 387.2 [(M+H)+]; mp 158° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5](=[N:32]O)[C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[N:28]O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.N.[H][H]>[Ni].C(O)C>[CH3:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:30]=[CH:31][C:6]([CH:5]([NH2:32])[C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([CH3:1])[CH:3]=3)=[CH:7][CH:8]=2)=[CH:19][CH:18]=1)[NH2:28]
Reactant: Cc1cccc(C(=NO)c2ccc(OCCOc3ccc(C(=NO)c4cccc(C)c4)cc3)cc2)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Cc1cccc(C(N)c2ccc(OCCOc3ccc(C(N)c4cccc(C)c4)cc3)cc2)c1
Reaction time: 7 h
Yield: 42.2 %

Procedure:
A reaction mixture is prepared from 1,2-bis[4-(3-methylbenzoyl)phenoxy]ethane dioxime (10.6 g, 0.022 mole), 400 ml absolute ethyl alcohol saturated with ammonia gas and Raney nickel catalyst W-6 (2 g). This mixture is subjected to 500 psi hydrogen pressure, heated to 90° and stirred for seven hours. The Raney nickel is removed by filtration and the alcohol and ammonia by distillation. The residual crude material is crystallized from ethanol to yield 4.2 g (42%) of material mp 113°-115°.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:8]=2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: Fc1ccc(-c2cc(N3CCNCC3)nc3c2CCCCCC3)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CCCN1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)CCCCCC3)CC1
Yield: 38.1 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.4 g), n-propyl bromide (0.56 g), potassium carbonate (0.68 g), potassium iodide (0.1 g) and methanol (50 ml) is refluxed for 15 hours. The reaction mixture is concentrated under reduced pressure and thereto is added water. The mixture is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. To the residue is added a solution of maleic acid in ethanol, and the resulting maleate product is recrystallized from ethanol to give the dimaleate of the desired compound (0.6 g), m.p. 149°-152° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:23])[C:11]([Cl:22])=[C:12]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:8]1=[O:24])(=[O:3])[CH3:2].N12CCCC1=CCCN2.[CH:34]([C:36]([CH3:38])=[O:37])=[CH2:35].C(O)(=O)C>O1CCCC1.N12CCCC1=CCCN2.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1([CH2:35][CH2:34][C:36](=[O:37])[CH3:38])[CH2:15][C:14]2[C:9](=[C:10]([Cl:23])[C:11]([Cl:22])=[C:12]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:8]1=[O:24])(=[O:3])[CH3:2]
Reactant: C=CC(C)=O
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Agent: C1=C2CCCN2NCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)(CCC(C)=O)C2
Temperature: 40 °C
Reaction time: 2.33 h

Procedure:
Methyl {[2-(2-acetoxyethyl)-6,7-dichloro-2,3-dihydro-1-oxo-1H-inden-5-yl]oxy}acetate (3.2 gm, 0.00853 mole) was dissolved in tetrahydrofuran (30 ml), stirred and heated to 40° C. Then diazabicyclo[4.3.0]non-5-ene (50 microliters) was added followed by methyl vinyl ketone (1.2 gm, 0.0170 mole). The mixture was stirred and heated at 50°-52° C. for 100 minutes, then more diazabicyclo[4.3.0]non-5-ene (2 drops) and methyl vinyl ketone (0.6 ml) were added and stirring and heating continued for another 140 minutes. The mixture was cooled, diluted with ethyl acetate, poured into ice water (250 ml) containing acetic acid (1 ml). The layers were separated and the aqueous layer extracted first with methylene chloride then with ether. The combined organic extracts were washed with water and dried over MgSO4. Evaporation of the solvents in vacuo gave the product (3.6 gm.).