Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([CH:12]=[CH:13][C:14]2[C:15]([CH:32]([CH3:34])[CH3:33])=[N:16][N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9]C(C)(C)[O:7]1)C.[H][H]>C(OCC)(=O)C.[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:16]=[C:15]([CH:32]([CH3:34])[CH3:33])[C:14]=2[CH:13]=[CH:12][CH:10]([OH:9])[CH2:11][CH:6]([OH:7])[CH2:5][C:4]([OH:37])=[O:3])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C[C@H]1C[C@@H](C=Cc2c(C(C)C)nn(-c3ccccn3)c2-c2ccc(F)cc2)OC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1C=CC(O)CC(O)CC(=O)O
Reaction time: 96 h

Procedure:
A solution of 1.44 g (2.84 mmol) of cis-(±)-ethyl-6-[2[5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H- pyrazol-4-yl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate in 15 ml of ethyl acetate was catalytically reduced under one atmosphere of hydrogen gas in the presence of 20% Pd/C. at 25° C. for four days.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].C([Li])CCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>O1CCCC1>[OH:16][C:17]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]([OH:10])[CH3:9])[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]1
Reactant: CC(O)c1ccccc1Br
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2C(C)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)ethanol (step 1, 5.4 g, 25.1 mmol) in tetrahydrofuran (25 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (33 mL, 51.5 mmol) at −78° C. for 20 min and the mixture was stirred for 2 h at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidine-1-carboxylate (4.73 g, 27.6 mmol) in tetrahydrofuran (10 mL) at −78° C. for 15 min. This resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (2/1), then hexane/ethyl acetate (1/1) to afford 1.37 g (19%) of the title compound as a slight yellow syrup:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH:18]([CH3:20])[CH3:19].S(Cl)([Cl:24])(=O)=O.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:18]([CH3:20])[CH3:19])[Cl:24]
Reactant: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 16 h

Procedure:
(1-Oxo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (60 g., 0.189 mole) is dissolved in acetic acid (400 ml.). Sulfuryl chloride (18 ml., 0.216 mole) is added dropwise to the stirred solution. The resulting clear yellow solution is then heated at 80°-85° C. for 3/4 hour, cooled and poured slowly, with stirring, into water (3 l.). The gum that separates solidifies after 16 hours to yield 55.5 g. of (1-oxo-2-isoporpyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 158°-159° C., after recrystallization from acetic acid water (1:1).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH2:14]([C:12]1[S:13][C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:4][CH2:3]2)=[CH:10][N:11]=1)[CH3:15]
Reactant: CCc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-ethyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21]I.O>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2([CH3:21])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Nc1cccc(CC2Cc3ccccc3C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC1(Cc2cccc(N)c2)Cc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
2-[(3-Aminophenyl)methyl]indan-1-one (5.18 g, 22.0 mmol) in tetrahydrofuran (100 mL) was slowly added to a suspension of sodium hydride (2.20 g, 65.0 mmol), and tetrahydrofuran (100 mL) at room temperature and the mixture was stirred for 30 min. Methyl iodide (1.63 mL, 26.0 mmol) was added and the resulting mixture was stirred at room temperature for 5 h. Water (150 mL) was added, followed by methylene chloride (150 mL) and the resulting aqueous layer was washed with several portions of methylene chloride. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a solid: mp 95°-98° C., MS MH+252.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].C(N(CC)CC)C.CO[C:19]([C:21]1[N:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:24]2[N:34]([CH2:44][C@H:45]3[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]3)[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH2:42][F:43])=[N:36][C:23]=2[CH:22]=1)=[NH:20]>C(O)C.CCOC(C)=O>[Cl:33][C:31]1[CH:32]=[C:27]([C:25]2[C:24]3[N:34]([CH2:44][C@H:45]4[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]4)[C:35]([N:37]4[CH2:41][CH2:40][CH2:39][C@H:38]4[CH2:42][F:43])=[N:36][C:23]=3[CH:22]=[C:21]([C:19](=[NH:20])[NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[N:26]=2)[CH:28]=[N:29][CH:30]=1
Reactant: COC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tert-butyl carbazate (106 mg, 0.802 mmol) and triethylamine (418 μL, 3.006 mmol) were added to a solution of crude methyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate (Example 14.2, Step 1; 50 mg, 0.100 mmol) in ethanol (100 μL) in a vial, and the reaction was capped and stirred at ambient temperature for 72 hr. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude tert-butyl 2-((4-(5-chloropyridin-3-yl)-2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)(imino)methyl)hydrazinecarboxylate. MS ESI calc'd. for C30H40ClFN8O2 [M+H]+ 599. found 599. This material was taken on to Step 2 without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](=[O:43])[NH:34][O:35]CC3C=CC=CC=3)=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33](=[O:43])[NH:34][OH:35])=[CH:29][CH:30]=2)=[CH:20][CH:19]=1)[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)C(=O)N1CCOCC1
Yield: 80.8 %

Procedure:
Palladium on BaSO4 (5%, 0.5 g) was added to a degassed solution of the benzyl hydroxamate 15 (1.6 g) in MeOH (50 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 16 (1.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): 10.35 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.13-7.17 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.52 (m, 1H), 3.21-3.49 (m, 8H), 2.69-2.83 (m, 4H), 2.20 (t, J=8.0 Hz, 2H), 1.28 (s, 9H).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BH4-].[Na+]>>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCC(O)/C=C/I

Procedure:
Treatment of 63 g. (0.25 mole) of 1-iodo-trans-1-octen-3-one (Example 724) with sodium borohydride in the manner described in Example 726 gave 58 g. of yellow oil. The oil is purified by adsorption chromatography on a magnesia silica gel column using benzene as eluent to give a light yellow oil.
Reaction SMILES: [CH:1]12[NH:17][CH:5]([CH:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][CH:13]=3)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:18](Cl)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH:33]1[C:34]2[CH:22]([CH2:21][O:20][C:18]([N:17]3[CH:5]4[CH:6]([C:8]5[CH:13]=[N:12][C:11]([N:14]([CH3:15])[CH3:16])=[CH:10][CH:9]=5)[CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4]4)=[O:19])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)c1ccc(C2CC3CCCC2N3)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(C2CC3CCCC2N3C(=O)OCC2c3ccccc3-c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
219 mg (0.95 mmol, 1 eq) of (−)-[5-(8-aza-bicyclo[3.2.1]oct-6-yl)-pyridine-2-yl]-dimethylamine (VII-1) are dissolved in 1.8 ml of dioxane and 2.75 ml of 10% sodium carbonate solution. 257 mg (1 mmol, 1.05 eq) of Fmoc-Cl in portions is added and it is stirred for 1 h at RT. After this time it is diluted with EE and washed with water. The aqueous phase is re-extracted for three times with EE. The combined organic phases are dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (EE:hex=1:2). 422 mg (0.93 mmol, 98%) of a colorless foam/solid is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C)c1
Yield: 22.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (893 mg) described in Preparation Example 65 and (R)-4-methyloxazolidin-2-one (231 mg) described in Preparation Example 25, the title compound (215 mg) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].[CH2:12]=[CH:13][C:14](=[CH2:16])[CH3:15]>C1C=CC=CC=1>[CH3:16][C:14]1[CH2:15][C:9]([CH3:11])([CH3:10])[CH:8]([C:6](=[O:5])[CH3:7])[CH2:12][CH:13]=1
Reactant: C=CC(=C)C
Reactant: CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)C1CC=C(C)CC1(C)C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A flask is charged with 63 g of aluminium chloride and 2160 ml of anhydrous benzene. The apparatus is filled with nitrogen and 441 g of mesityl oxide are added, whilst stirring and maintaining the temperature of the mixture at +15°. The mixture is then left for 30 minutes at this temperature, whilst stirring. 1224 g of isoprene dissolved in 1800 ml of anhydrous benzene are then added in the course of 1 hour at +15°. Reaction is then effected for 20 hours at 16° followed by 6 hours at +25°, with stirring. The contents of the flask are then transferred to a separating funnel and the product is washed twice with 500 ml of 10% hydrochloric acid, once with 500 ml of water, once with 500 ml of a 9% solution of sodium bicarbonate and twice with 500 ml of water. The benzene is distilled off on a water bath, finally, under a pressure of 30 mm of mercury. 1070 g of crude product are obtained, which are purified in a Vigreux flask under a pressure of 1 mm of mercury. 560 g of 1,5,5-trimethyl-4-acetyl-cyclohex-1-ene (76.3%) are obtained, having the following physical properties:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+]>C(O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(O)cn2)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc(OCCCC)cn2)cc1
Yield: 49.3 %

Procedure:
2.8 g of the resulting 2-(p-pentylphenyl)-5-hydroxypyridine, 2 g of 1-bromobutane and 0.8 g of potassium hydroxide placed in 60 ml of ethanol were heated under reflux for 4 hours. The potassium bromide precipitated during the reaction was removed by filtration. The ethanol was removed by distillation. The residue was extracted with diethylether and the ether layer was washed with water several times and then the ether was removed by distillation. The residue was distilled under reduced pressure. The collected fraction having a boiling point of 185° to 187° C./2 mmHg was recrystallized from methanol to yield 1.7 g of 2-(p-pentylphenyl)-5-butyloxypyridine.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl>[N:12]1([NH:11][C:10](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nn1cccc1
Temperature: 85 °C
Reaction time: 21 h
Yield: 49.9 %

Procedure:
Under an atmosphere of nitrogen, a solution of 2,5-dimethoxytetrahydrofuran (400 g, 3.03 mol) and tert-butyl carbazate (364 g, 2.75 mol) in 1,4-dioxane (2.5 L) were combined in a flask. Then, aqueous hydrochloric acid solution (2N, 35.8 mL, 71.5 mmol) was added dropwise and the reaction mixture was stirred for 21 hours at 85° C. The reaction mixture was treated with saturated sodium carbonate aqueous solution (120 mL) at room temperature. The quenched mixture was filtered to give a precipitate which was dried to give the title compound as a gray solid (250 g). The organic phase of the filtrate was concentrated and the resultant precipitate was washed with diisopropyl ether (200 mL) and filtered to give the title compound as a gray solid (60 g). The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→3:1→2:1) to obtain the title compound (47 g). A total of 357 g of the title compound having the following physical data was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4ccccc4C3)c(F)cc2c1=O
Yield: 35.6 %

Procedure:
133 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 83 mg of isoindoline, 152 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 65 mg of the target compound.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[N:14]3[C:15]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=4[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:18][CH2:19][C:13]3=[N:12][N:11]=2)=CC=1.Br.[OH-].[Na+]>C(O)(=O)C>[C:20]1([C:17]2[C:16]3[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=3[N:14]3[C:10]([CH2:9][OH:8])=[N:11][N:12]=[C:13]3[CH2:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(COCc2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2)=NC3)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.33 h

Procedure:
To a solution of 3,0 g 1-[(p-methoxybenzyloxy)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 30 ml of glacial acetic acid is added at 25° 24 ml 48% aqueous hydrobromic acid. The reaction mixture is stirred for 20 minutes, neutralised with 30% sodium hydroxide solution and extracted with methylenechloride. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated to dryness. The crystallisation of the residue from acetate-ether-petrol ether yields 6-phenyl-8-chloro-4-H-s-triazolo[4,3-a][1,4]benzodiazepine-1-methanol, M.P. 209°-211°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
4-Nitrobenzoic acid (1.00 g, 6.00 mmol), tert-butyl 1-piperazinecarboxylate (1.10 g, 6.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.70 g, 9.00 mmol) and N-methylmorpholine (1.30 ml, 12.00 mmol) were dissolved in dichloromethane (10 ml) and the reaction mixture stirred at 20° C. for 5 h. The reaction was then washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-50% EtOAc in hexane gradient to afford tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.88 g, 5.60 mmol, 94%) as a white solid. LCMS (1) Rt: 2.01 min; m/z (ES+) No M+H+, but 280 (-tBu) and 236 (-Boc).
Reaction SMILES: [Sb:1]([Cl:6])([Cl:5])([Cl:4])([Cl:3])[Cl:2].[CH2:7]([O:11][P:12]([O:19]CCCC)([O:14]CCCC)=[O:13])[CH2:8][CH2:9][CH3:10]>C(Cl)Cl>[Sb:1]([Cl:6])([Cl:5])([Cl:4])([Cl:3])[Cl:2].[P:12]([O-:19])([O-:14])([O:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:13]
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCOP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask under a nitrogen atmosphere, 8.01 g (0.0268 M) of antimony pentachloride was dissolved in 100 ml of methylene chloride. To this yellow solution was added dropwise with stirring a solution of 7.13 g (0.0268 M) of tributylphosphate in 20 ml of methylene chloride. The addition was accomplished at a rate such that the exotherm did not become excessive, the temperature being kept below the reflux temperature of methylene chloride (cooling should not be required). By the end of the addition, the initial yellow color had changed to a light brown. The reaction mixture was stirred at ambient temperature for one hour, after which time the solvent was removed by evaporation at reduced pressure. The dark brown liquid was thoroughly dried in vacuo (0.1 mm Hg). NMR (CDCl3, TMS) δ4.45(9H,q,J=6.0 Hz), 1.85(6H,m), 1.50(6H,m), 1.00(6H,t,J=6.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[OH-].[Na+].Cl>C(O)(=O)C>[CH3:1][C:2]1[N:3]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:7])=[O:8])[N:15]=[N:14][N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2ccccc2c(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccccc1C(=O)O
Temperature: 27.5 °C

Procedure:
The crude 2-methyl-4-oxo-3,1-benzoxazine was dissolved in acetic acid (1.9 L). Sodium azide (130.0g) was added to the solution in portions with stirring. The reaction mixture was cooled in an ice bath to maintain the reaction temperature at 25 to 30° C. during the addition. The reaction mixture was allowed to stir at ambient temperature over the weekend. The acetic acid was removed under vacuum to provide a white solid. The solid was combined with 10% sodium hydroxide (1.4 L) then heated on a steam bath for 1 hour. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for an additional hour then allowed to cool to ambient temperature overnight. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for 2 hours then allowed to cool. The reaction mixture was poured with rapid stirring into a mixture of concentrated hydrochloric acid (1.0 L) and ice (3 L). The resulting mixture was stirred at ambient temperature overnight. A precipitate was isolated by filtration, rinsed with water then slurried with water (4 L). The solid was isolated by filtration, rinsed with water then oven dried at 50° C. to provide 278.0 g of crude 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid as a tan solid, m.p. 157-160° C. The crude material was dissolved in 10% sodium hydroxide (2.5 L). The resulting solution was heated (95-99° C.) for 2.5 hours, cooled, then poured with vigorous stirring into a mixture of concentrated hydrochloric acid (500 mL) and ice (5 L). The resulting mixture was allowed to stir for 2 hours. The precipitate was isolated by filtration, rinsed with water, then slurried with water (3 L). The solid was isolated by filtration, rinsed with water then dried overnight at ambient temperature to provide 228 g of 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid, m.p. 164-166° C.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].Cl.[CH3:12][CH2:13]O>[Pd]>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:12][CH3:13])=[O:9])[N:3]=[CH:4]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)CCc1c[nH]cn1

Procedure:
The title compound was prepared from urocanic acid (Aldrich) in 2 steps using standard chemical procedures (esterification using HCl in EtOH followed by hydrogenation with 10% Pd-C in EtOH). 1H NMR (CDCl3): δ 1.23 (3H, t), 2.65 (2H, t), 2.94 (2H, t), 4.15 (2H, q), 6.81 (1H, S), 7.56 (1H, s).