Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][O:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N(C)CCOC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of ethyl 4-[(2-hydroxyethyl) (methyl)amino]benzoate (611 mg, 2.74 mmol) in DMF (10 ml) were added sodium hydride (60% in oil, 143 mg, 3.56 mmol) and methyl iodide (0.222 ml, 3.56 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (467 mg, 72%) as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[CH:21]1([NH:20][C:18](=[O:19])[NH:17][C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ncc2cc(NC(=O)NC3CCCCC3)ccc2c1O
Reactant: NCCC(=O)O
Product: O=C(O)CCNC(=O)c1ncc2cc(NC(=O)NC3CCCCC3)ccc2c1O

Procedure:
3-{[7-(3-Cyclohexyl-ureido)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(3-Cyclohexyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 399.1460 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:26][OH:27])[CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1>>[C:1]([O:10][CH:11]([CH2:26][O:27][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC(O)Cn1cnc2cnc3ccccc3c21
Product: O=C(OCC(Cn1cnc2cnc3ccccc3c21)OC(=O)c1ccccc1)c1ccccc1

Procedure:
Using the method of Example 115, benzoyl chloride was reacted with 1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]-quinoline (from Example 51) to provide 1-(2,3-dibenzoyloxypropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:24]([OH:33])=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[CH3:29]>>[CH3:22][C:23]1[C:24]([OH:33])=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[OH:21])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: Cc1ccc(B(O)O)c(O)c1C
Product: Cc1ccc(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c(O)c1
Yield: 54 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenylboronic acid in 54% yield using method F; δH [2H6]-DMSO 13.40,(1H, b), 8.32,(2H, d), 8.24,(2H, m), 8.14-8.00,(3H, m), 7.86,(1H, d), 6.81,(3H, m), 2.33,(3H, s), 2.30,(3H, s), 2.19,(3H, s).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)[Cl:25].[ClH:27]>O1CCOCC1>[ClH:25].[ClH:27].[ClH:25].[CH3:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:21][CH2:20]1
Reactant: CC1CCN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCN(CCN2CCC(N)CC2)CC1

Procedure:
The tert-butyl ester 9 (2 g, 6.14 mmol) is suspended in 10 ml of dioxane. DCM is then added until the solid dissolved. To this mixture, 4M−HCl in dioxane (12.3 ml, 49.2 mmol) is added. After stirring over night the solvents are evaporated to leave a white solid product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[CH2:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:9]2[CH2:10][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=Cc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CC1c1ncc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
A mixture of 0.485 g of 3,5-dichloro-2-vinylpyridine (0.0014 mol) and 0.15 ml of ethyl diazoacetate (0.00127 mol) are added dropwise to 5 ml of refluxing xylene. The reaction mixture is refluxed for thirty minutes and left at room temperature overnight. After concentration to dryness and purification on silica, 250 mg of essentially pure ethyl 2-(3,5-dichloropyridin-2-yl)cyclopropanecarboxylate (75%) are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:24][C@@:25]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([S:33]([CH2:32][C@@:25]3([CH3:24])[NH:26][C:27](=[O:31])[NH:28][C:29]3=[O:30])(=[O:34])=[O:35])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]1(CS(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)NC(=O)NC1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
4-(4-Fluorophenyl)piperidine hydrochloride (63 mg, 0.29 mmol) was taken up in 3 mL of dry THF, neutralized with diisopropylethylamine (50 μL, 0.29 mmol) and cooled on an ice-water bath. [(4S)-4-metyl-2,5-dioxo-imidazolodin-4-yl]methanesulfonyl chloride (80 mg, 0.35 mmol) was added and after stirring for 10 min, diisopropylethylamine (50 μL, 0.29 mmol) was added and the reaction mixture was stirred at ambient temperature until LC-MS (APCD) indicated consumption of the amine. The reaction mixture was evaporated and the residue taken up in EtOH and heated to 50° C. and allowed to cool before water was added. The precipitated product was collected and washed with EtOH/water and dried in vacuum to yield 87 mg.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:12]1>C(Cl)(Cl)Cl>[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2[NH:25][CH:24]=[CH:23][N:22]=2)=[CH:12]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(=O)NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Acetic anhydride (0.20 g) was added dropwise to a stirred solution of 1-(2-aminoethyl)-3-(1-imidazolylmethyl)indole (0.48 g) in dry chloroform (10 ml) at room temperature. The solution was stirred for 10 minutes and then evaporated. The residue was stirred with aqueous sodium bicarbonate solution and the solid product was filtered off, washed with water, dried and crystallised from ethyl acetate/petrol (b.p. 60°-80° C.) to give 1-(2-acetylaminoethyl)-3-(1-imidazolylmethyl)indole (0.26 g), m.p. 126°-128° C. Found: C, 68.08; H, 6.43; N, 20.17. C16H18N4O requires: C, 68.06; H, 6.43; N, 19.85%.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](=[O:20])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Mg]Cl>CCCCCCC.C1COCC1>[F:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([OH:20])([CH3:27])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2(C)O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-oxoindane-5-carboxylate (45.9 mg, 0.129 mmol) in heptane (1 mL) and THF (1 mL) at −20° C. under N2, was added dropwise 3N MeMgCl in THF (86 uL, 0.258 mmol). The reaction mixture was stirred at −20° C. for 2 h. The mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-hydroxy-3-methylindane-5-carboxylate. LCMS calc.=395.2; found=394.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H); 7.20 (s, 1H); 7.09 (d, J=8.6 Hz, 1H); 6.62 (d, J=12.1 Hz, 1H); 3.72 (s, 3H); 3.70 (s, 3H); 3.28-3.20 (m, 1H); 3.15-3.09 (m, 1H); 2.96-2.90 (m, 1H); 2.36-2.24 (m, 2H); 1.91 (br s, 1H); 1.66 (s, 3H); 1.30 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CN1CCN2C(Cc3cc(OC)c(OC)cc3C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8,9-Dimethoxy-6-phenyl- 1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added potassium carbonate (0.8 g) and methyl bromoacetate (0.5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent; chloroform ethyl acetate=9:1) to give 8,9-dimethoxy-2-methoxycarbonylmethyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (940 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH:27](/B(O)O)=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH:27]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:9]=2)=[CH:6][CH:7]=1)=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(C=Cc3ccccc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.46 g, 3.2 mmol), trans-beta-Styreneboronic acid (0.7 g, 4.9 mmol), Na2CO3 (2M, 7 mL), and Pd(PPh3)2Cl2 (300 mg, 0.26 mmol) in toluene/ethanol (1:1, 20 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 6-(4-Styryl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as yellow solid in 68% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:10]([C:14](=[O:16])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:25][C:26]=2[NH2:31])=[N:11][NH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-1H-pyrazole-3-carboxylic acid (10.0 g, 44.1 mmol), 4-morpholin-4-ylmethyl-benzene-1,2-diamine (10.0 g, 48.5 mmol), EDC (10.14 g, 52.9 mmol) and HOBt (7.15 g, 52.9 mmol) in DMF (150 mL) was stirred at ambient temperature for 20 h and then the majority of the solvent removed in vacuo. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL), the layers separated and the organic portion washed with brine, dried over MgSO4 and reduced in vacuo to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (17.6 g, 96%) as a brown solid. LC/MS analysis indicates product contains ˜15% of the di-amide. This shows at approx. 5% level in 1H NMR. Di-amide is cleaved in subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:24])=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
100 g (348 mmol) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 600 ml of N,N-dimethylformamide and treated with 64.1 g (395 mmol) of 1,1'-carbonyldiimidazole. After stirring at 50° for 30 minutes 80 ml of 25% ammonia were added dropwise at 13° to 20° and the mixture was stirred for 30 minutes and poured into 21 of water. By suction filtration of the resulting suspension and drying the crystals there were obtained 52.7 g (76%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 223°-224°.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[CH2:29][C:30]([CH3:33])([NH2:32])[CH3:31].Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[CH2:29][C:30]([NH:32][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7])([CH3:31])[CH3:33]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Reactant: CC(C)(N)CC1Cc2ccccc2C1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (342 mg, 1.30 mmol) described in WO 2004/106280, 1-(2,3-dihydro-1H-inden-2-yl)-2-methylpropan-2-amine (234 mg, 1.24 mmol) described in WO 01/53254, and lithium perchlorate (79 mg, 0.74 mmol) in toluene (12 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and washed with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oily substance (206 mg, yield 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.Cl.O.[Cl:24][CH2:25]Cl>>[Cl:24][CH2:25][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:17])([F:18])[F:16]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1OC
Reactant: ClCCl
Agent: C=O
Agent: Cl
Solvent: O
Product: COc1cc(CCl)c(CCNC(=O)C(F)(F)F)cc1OC
Reaction time: 3 h
Yield: 77 %

Procedure:
In a three-necked flask, mix N-[2-(3,4-dimethoxyphenyl)ethyl]-2,2,2-trifluoroacetamide (35 g, 126 mmoles) and 37% aqueous formaldehyde (776 mL, 1.014 mole) in 120 mL of dichloromethane at 0° C. To the resulting two-phase mixture slowly add, at 0° C., 345 mL of 37% aqueous hydrochloric acid solution and heat at 40° C. After being in contact for 3 hours, hydrolyse the mixture using 250 mL of water and wash the aqueous phase with dichloromethane (2×100 mL). Combine the organic phases, dry them over MgSO4 and carry out drying in vacuo to obtain a beige meringue (38.2 g). The product obtained is recrystallised from toluene to obtain 31.5 g of a white powder corresponding to the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[N+:16]([O-])=O.C(O)(=O)C>C(O)C.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[C:2]=1[NH2:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c2c1OCCO2
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(N)c2c1OCCO2
Yield: 89.2 %

Procedure:
A stirred suspension of methyl 8-amino-7-nitro-1,4-benzodioxan-5-carboxylate (300 mg, 0.0012 mole) in ethanol (30 ml) together with glacial acetic acid (5 ml) was hydrogenareal over 10% Pd-C (100 mg) at atmospheric pressure and temperature for 5 h. The catalyst was filtered off and the filtrate concentrated in vacuo. The residue was basified with concentrated potassium carbonate solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford methyl 7,8-diamino-1,4-benzodioxan-5-carboxylate as a beige solid (240 mg, 92%). 1H NMR (CDCl3) δ:6.91(s,1 H), 4.21(s,4 H), 3.96(br s.2 H), 3.74(s,3 H), 3.0(br s,2 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:11].[I:12](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:11][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([I:12])=[CH:10][C:2]=1[F:1]
Reactant: O=I(=O)Cl
Reactant: Nc1c(F)ccc2c1OCO2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Nc1c(F)cc(I)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
5-Fluoro-1,3-benzodioxol-4-amine (1.1 g, 7.10 mmol), benzyltrimethylammonium dichloroiodate (2.7 g, 7.76 mmol) and calcium carbonate (0.92 g, 9.2 mmol) in a mixture of dichloromethane (10 ml) and methanol (5 ml) were stirred at room temperature for 3 hr. The mixture was filtered through Celite and then evaporated to a dark brown solid. The residue was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 4-amino-5-fluoro-7-iodo-1,3-benzodioxole (1.14 g, 57%) as a pale brown solid; NMR Spectrum: (CDCl3) 3.61 (s, 2H), 6.00 (s, 2H), 6.81 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:16]#[C:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](/[CH:16]=[CH:17]\[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C#CC2CCCCC2)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C\C2CCCCC2)nc1
Yield: 30 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-cyclohexylethynyl-pyridine (0.7 g, 2.21 mmol) and Lindlar's Catalyst (0.1 g) to EtOAc (20 mL). Bubble hydrogen (via balloon) through the mixture for 2 h and stir under static atmosphere of hydrogen overnight. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (0.21 g, 30%) and starting material (0.42 g, 60%). Repeat the reaction on the recovered starting material to obtain the desired intermediate (242 mg, 57%; 452 mg total, 64% overall). MS (APCI+) m/z: 217 (M-Boc+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21](=[O:29])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]#[N:19])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[NH2:30][OH:31]>C(O)C>[NH2:19][C:18](=[N:30][OH:31])[CH:15]1[CH2:14][CH2:13][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[NH:20][C:21](=[O:29])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)[CH2:17][CH2:16]1
Reactant: N#CC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Reactant: NO
Solvent: CCO
Product: NC(=NO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Temperature: 25 °C

Procedure:
N-[6-Chloro-2-(4-cyano-1-piperidinyl)-5-quinolinyl]-cyclohexaneacetamide (Example 113) (0.2 g), hydroxylamine (50% w/v in H2O) (0.23 mL) and ethanol (2.5 mL) were heated within a microwave in a sealed 10 mL vial at 90° C. for 100 minutes. The reaction was cooled to room temperature and the resulting precipitate was filtered and washed with ethanol to afford the subtitle compound as a solid (0.18 g).
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:20](O)C>>[CH3:20][N:13]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12]1
Reactant: CCO
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire batch of methyl 1-5-benzoylpyrrole-3-carboxylate from Example 84 was combined with 200 ml. of ethanol and 100 ml. of 1 N sodium hydroxide and refluxed for 2 hours. The ethanol was boiled away, the aqueous residue was cooled to room temperature, extracted with 25 ml. of ether and acidified with conc. hydrochloric acid to yield crystalline product (4 g., m.p. 210°-212° C.). A portion (1.5 g.) was recrystallized from acetone to yield purified 1-methyl-5-benzoylpyrrole-3-carboxylic acid (925 mg., m.p. 215°-216.5° C., m/e 229).