Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=1[OH:32])([CH3:21])([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1>[C:28]([C:24]1[CH:25]=[C:26]([CH:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:27]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:23]=1[OH:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(C(c2cccc([N+](=O)[O-])c2)N2CCCCC2)cc(C(C)(C)C)c1O
Yield: 60 %

Procedure:
Using the same procedure described in Example 4, 30.2 g (0.2 mol) of 3-nitro-benzaldehyde, 37.4 g (0.44 mol) of piperidine and 39.2 g (0.19 mol) of 2,6-di-tert-butyl-phenol are allowed to react in xylene to give 48.4 g of the title compound as yellow crystals, melting at 157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]([CH3:29])[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:28])[CH:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH3:19])=[O:9])=[CH:4][CH:3]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.[O:44]1CCOC[CH2:45]1>>[N:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH:18]([CH3:19])[C:17]([O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:45]=[O:44])=[CH:31][CH:30]=2)[CH3:29])=[O:28])=[CH:26][CH:25]=1)=[C:33]=[O:35]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(N)cc1)C(=O)OCCOCCOC(=O)C(C)Oc1ccc(N)cc1
Reactant: C1COCCO1
Product: CC(Oc1ccc(N=C=O)cc1)C(=O)OCCOCCOC(=O)C(C)Oc1ccc(N=C=O)cc1
Temperature: 80 °C

Procedure:
(4-Aminophenoxy)-propionic acid 2-{2-[2-(4-aminophenoxy)-propionyloxy]-ethoxy}-ethyl ester (217 g) was dissolved in dry 1,4-dioxane (2 L) under nitrogen atmosphere. The reaction mixture was cooled down to below 10° C. A solution of triphosgene (253 g) in dry 1,4-dioxane (600 ml) was added. The mixture was heated slowly to 80° C. and maintained at that temperature for 2 hours. The condenser was then arranged for distillation and solvent removed by distillation under atmospheric pressure until the volume of the reaction mixture had been reduced to approximately one third. Fresh dry 1,4-dioxane (600 ml) was added. Solvents were distilled off under vacuum. The residue was re-evaporated two times from dry 1,4-dioxane (1200 ml). Dry toluene (600 ml) and charcoal (50 g) was added. The solution was filtered hot and toluene was distilled off under vacuum to give pure (4-isocyanato-phenoxy)-propionic acid 2-{2-[2-(4-isocyanato-phenoxy)-propionyloxy]-ethoxy}-ethyl ester (165 g) as a light yellow syrup. The product was characterized by 1H NMR (CDCl3) δ 1.65 (d, 3H, CH3), 3.65 (t, 2H, CH2), 4.30 (t, 2H, CH2), 4.75 (q, 1H, CH), 6.80 (d, 2H, Ar), 7.00 (d, 2H, Ar).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:6]1[NH:7][N:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Yield: 86 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (4.88 g, 31.1 mmol) in anhydrous methanol (50 ml) at to 0° C. was added thionyl chloride (9.61 g, 5.9 ml, 80.8 mmol) drop wise. The resulting solution was heated to reflux for 2 h. The cooled solution was evaporated to dryness to give 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (4.58 g, 86%) as a off-white solid.
Reaction SMILES: [C:1]([C:4](=[N:10][O:11][CH:12]1[CH2:14][CH2:13]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[NH2:2].F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C(N(CC)CC)C>C(Cl)Cl.C(OC(C)C)(C)C>[CH2:20]([O:3][C:1](=[NH:2])[C:4](=[N:10][O:11][CH:12]1[CH2:13][CH2:14]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:21]
Reactant: CC[O+](CC)CC
Reactant: CCOC(=O)C(=NOC1CC1)C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCOC(=N)C(=NOC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-carbamoyl-2-(cyclopropyloxyimino)acetate (syn isomer)(8.14 g) and triethyloxonium fluoroborate (11.5 g) in methylene chloride (110 ml) was stirred at ambient temperature for 16 hours. To the mixture was added triethylamine (17 ml) under ice-cooling. The mixture was washed with water, dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was dissolved in diisopropyl ether. The solution was washed with water, dried over sodium sulfate, and concentrated in vacuo to give ethyl 3-ethoxy-3-imino-2-(cyclopropyloxyimino)propionate (syn isomer(9.60 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1>>[Cl:15][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(C(F)(F)F)n1
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C(F)(F)F)n1
Temperature: 70 °C

Procedure:
2-Amino-6-(trifluoromethyl)pyrimidin-4-ol (200 mg, 1.1 mmol) is dissolved in POCl3 (3 eq., 0.3 mL, 3.3 mmol) and dimethylaniline (0.28 mL, 2 eq.) is added. The reaction mixture is heated at 70° C. for 4 h. The resulting mixture is poured into a mixture of ice-water, and the resulting precipitate is collected to yield the desired compound 24 in 59%. ESI-MS m/z 198 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>COCCOC>[CH2:23]([O:22][C:20]([C:19]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:12])=[CH:4][N:3]2[CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2cc(B(O)O)ccc2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2.5 g of 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 50 mL of 1,2-dimethoxyethane are added 2.14 mL of ethyl 3-bromo-2-oxopropionate. The reaction mixture is stirred for 3.5 hours at 25° C., 50 mL of ethanol are then added and the resulting mixture is refluxed for 16 hours. The reaction mixture is cooled and concentrated to dryness. The residue is suspended in 100 mL of water at 0° C. and treated, while stirring vigorously, with solid sodium carbonate until a pH of 8-9 is obtained. The precipitate is filtered off by suction and washed with 100 mL of water at 0° C. and then dissolved in 150 mL of methanol. The solution is dried over magnesium sulfate, filtered, concentrated and dried under vacuum to give 2.36 g of 2-ethoxycarbonylimidazo[1,2-a]pyridine-6-boronic acid in the form of a cream-coloured solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:10]=[C:11]([CH2:15][N:16]([CH3:25])[C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:12]=[N:13][CH:14]=3)=[CH:7][CH:8]=2)[S:26]1
Reactant: CN(Cc1cncc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Product: CN(Cc1cncc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 58.2 %

Procedure:
In a manner similar to that of Example 1(d), starting with 0.8 g (2.4 mmol) of N-[5-(4-formylphenyl)pyrid-3-ylmethyl]-N-methylbenzamide and 0.35 g (2.9 mmol) of 2,4-thiazolidinedione, 0.6 g (60%) of N-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]pyrid-3-ylmethyl}-N-methylbenzamide is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](SC)[CH:15]=2)[CH:10]=[C:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:21][S:22]([O-:24])=O.[K+].[CH3:26]O.O>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:22]([CH3:26])(=[O:24])=[O:21])[CH:15]=2)[CH:10]=[C:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc(C)n(C(=O)OC(C)(C)C)c2c1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc2ccc(S(C)(=O)=O)cc2n1C(=O)OC(C)(C)C

Procedure:
The product of step 1 (20.3 g) was treated with 135 g OXONE™ in 300 mL 1:1 MeOH/water for 2 h. The mixture was partitioned between methylene chloride and water, the organic layer was separated, washed, dried, and evaporated to dryness to yield 6-methanesulfonyl-2-methyl-indole-1-carboxylic acid tert-butyl ester (16 g) as a solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:26][N:27]([CH3:29])[CH2:28][C:8]=23)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>C(Cl)(Cl)Cl.O.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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:7]([C:5]3[S:6][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:3][CH:4]=3)[C:8]3[C:9](=[N:26][N:27]([CH3:29])[CH:28]=3)[N:10]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1Cc2c(nc(-c3ccc(F)cc3)c(-c3ccncc3)c2-c2ccc(Br)s2)N1
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: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: Cn1cc2c(-c3ccc(-c4cccnc4)s3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 80 °C
Yield: 37.8 %

Procedure:
A suspension of 4-(5-bromothien-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.2 mmol, obtained in example 188), 3-pyridylboronic acid (0.04 g, 0.3 mmol), K2CO3 (0.06 g, 0.4 mmol), Pd(PPh3)4 (0.017 g, 0.01 mmol), 1,2-dimethoxyethane (1.31 mL) and water (0.04 mL) was heated at 80° C. under argon atmosphere overnight. It was allowed to cool and diluted with CHCl3 and water. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 35 mg of the desired compound (yield: 50%).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([O-:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])(C)(C)C.[OH-].[Na+]>O.C(O)C>[C:6]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])([OH:41])=[O:5]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)[O-])CCCC2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)O)CCCC2)CCc2ccccc21
Reaction time: 15 h

Procedure:
6.43 g ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate (for preparation see Example 5) was dissolved in 140 ml of a 1:1 (v/v) mixture of water and ethanol, and 4.28 g solid NaOH was added thereto with stirring. After 15 h, the solvent was evaporated at reduced pressure, the residue was taken up in 100 ml EA and washed once with 50 ml aqueous KHSO4 solution. The aqueous phase was extracted twice with 30 ml EA each time. The combined organic phases were washed twice with 30 ml aqueous common salt solution each time and dried over sodium sulfate. Evaporation of the solvent yielded 5.41 g of the title compound.
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2Hpyran-2-yl)oxy)butyrate (10C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1L) at such a rate to maintain a gentle reflux. After the addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:29])=[C:18]([NH:22]C(=O)OCC=C)[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:29])=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (15 g, 34.7 mmol) in DCM (500 mL), HOAc (5 g, 83.3 mmol), Pd(PPh3)2Cl2 (0.5 g, 0.69 mmol) were added. Then tri-n-butyl tin hydride (15 g, 52 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound. (10.5 g, 87.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, J=5.2 Hz, 1H), 7.01-6.96 (m, 2H), 6.89-6.85 (m, 1H), 6.63-6.59 (m, 1H), 5.29 (br. s., 2H), 3.38-3.30 (m, 1H), 1.37 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-:10].[NH2:11][CH2:12][CH2:13][CH2:14][OH:15].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.C(Cl)Cl>[OH:15][CH2:14][CH2:13][CH2:12][NH:11][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-:10]
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Reactant: NCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(NCCCO)c1
Yield: 76.1 %

Procedure:
A mixture of 2-chloro-4-methylpyridine-N-oxide hydrochloride (7.16 g, 39 mmole), 3-aminopropanol (6.01 g, 80 mmole), and NaHCO3 (16.8 g, 200 mmole) in tert-amyl alcohol (50 mL) was heated at reflux for 19 hr. The reaction mixture was diluted with CH2Cl2 (200 mL) and filtered, and the filtrate was concentrated on the rotavap. Recrystallization from CH2Cl2/Et2O gave the title compound (5.41 g, 75%) as a yellow solid: TLC (15% MeOH/CH2Cl2) Rf 0.44; 1H NMR (400, CDCl3) δ7.92 (d, J=6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J=6.6, 2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47 (q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82-1.88 (m, 2 H); MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:21](Br)[C:22]([CH2:27]Br)([CH2:25]Br)[CH2:23]Br.[C:30](=[O:33])([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([CH2:27][O:33][C:30]3[CH:18]=[CH:19][C:14]([C:11]4[N:12]=[CH:13][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][N:10]=4)=[CH:15][CH:16]=3)([CH2:25][O:20][C:17]3[CH:16]=[CH:15][C:14]([C:11]4[N:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:13][N:12]=4)=[CH:19][CH:18]=3)[CH2:23][O:20][C:17]3[CH:16]=[CH:15][C:14]([C:11]4[N:10]=[CH:9][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:13][N:12]=4)=[CH:19][CH:18]=3)=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: BrCC(CBr)(CBr)CBr
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCc1cnc(-c2ccc(OCC(COc3ccc(-c4ncc(CCCCCCC)cn4)cc3)(COc3ccc(-c4ncc(CCCCCCC)cn4)cc3)COc3ccc(-c4ncc(CCCCCCC)cn4)cc3)cc2)nc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
) 5.0 g of the known compound 4-(5-heptyl-2-pyrimidyl)phenol are dissolved in 70 ml of dimethyl sulfoxide together with 1.35 g of pentaerythrityl tetrabromide. 15 g of finely powdered potassium carbonate are added, and the mixture is stirred at 80° C. for 16 h. Conventional work-up gives 2.1 g of tetrakis[4-(5-heptyl-2-pyrimidyl)phenyloxymethyl]methane, m.p. 179°.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([OH:31])=O)=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:8][CH:7]=1.[NH2:35][NH2:36]>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:20]3[C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29]([NH:35][NH2:36])=[O:31])=[N:18][CH:17]=[N:16][C:15]=3[S:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=C(O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Thionyl chloride (13 mg, 0.11 mmol) was added to a solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic acid (43 mg, 0.10 mmol) in tetrahydrofuran (2.0 mL) with stirring at 70° C. Stirring continued for one hour at 70° C. and then the mixture was cooled to 25° C. and added to a solution of hydrazine (32 mg, 1.0 mmol) in tetrahydrofuran (2.0 mL). The reaction was stirred at room temperature for one hour and the solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with of aqueous sodium bicarbonate solution (20 mL), concentrated, and purified by column chromatography over silica gel using 2% methanol in ethyl acetate as eluant to give 22 mg (50%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzohydrazide as a white solid. MS [M+H] 439.2, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.50-7.35 (m, 2H), 7.32-7.21 (m, 3H), 7.18 (s, 1H), 7.10-6.97 (m, 2H), 6.94 (d, J=2.7 Hz, 1H), 4.59 (t, J=6.9 Hz, 2H), 4.11 (s, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.09 (m, 2H).
Reaction SMILES: ClC1C=C(C=CC=1Cl)C[O:6][C:7](=[O:26])[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)[OH:9].[OH-].[Li+].Cl.CCOC(C)=O>C1COCC1.CO>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([OH:9])[C:7]([OH:26])=[O:6])=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-acetic acid 3,4-dichloro-benzyl ester (9.4 g) was dissolved in 120 mL of THF-methanol (4:1) and 2N lithium hydroxide solution (39 mL) added. The resulting reaction mixture was stirred at room temperature 16 h. The mixture was poured onto 1N HCl and EtOAc and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residual oil was taken up in minimal DCM and hexanes added to give a solid. The solid was filtered and washed with hexanes to afford the desired product [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid in pure form (6.1 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.41 (m, 1H), 7.31 (m, 2H), 6.96 (m, 2H), 5.10 (s, 2H), 4.94 (s, 1H).
Reaction SMILES: ClC1C2NC(=O)C(C)(C)N=C(C3C=CC=CC=3F)C=2C=C([N+]([O-])=O)C=1.Cl[C:27]1[C:37]2[NH:36][C:35](=[O:38])[C:34]([CH3:40])([CH3:39])[N:33]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:31]=2[CH:30]=[C:29]([N+:48]([O-:50])=[O:49])[CH:28]=1>CCOCC.CCCCCC>[Cl:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:32]1[C:31]2[CH:30]=[C:29]([N+:48]([O-:50])=[O:49])[CH:28]=[CH:27][C:37]=2[NH:36][C:35](=[O:38])[C:34]([CH3:40])([CH3:39])[N:33]=1
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Agent: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 10 g (0.029 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (a) of Example 13, 9-chloro-5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 105° (ether/n-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:25](=[O:41])([O:27][CH2:28][CH:29]([NH2:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:25](=[O:41])([O:27][CH2:28][CH:29]([NH:40][C:21](=[O:22])[CH2:20][N:10]1[C:11](=[O:19])[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=1)[NH2:26]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reactant: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 77A, 100 mg (0.29 mmol) were introduced in 3 ml of DMF and admixed with 98.3 mg (0.35 mmol) of the compound from Example 60A, 66.1 mg (0.35 mmol) of EDC, 49 mg (0.35 mmol) of HOBt and 75 μl (0.43 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 30 min and then admixed with 1 ml of 1N hydrochloric acid and purified by preparative HPLC (Method 10). This gave 140 mg (84% of theory) of the title compound.