Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.[C:20]1(C)C=CC=CC=1.[NH2-].[Na+].CI>O>[O:1]=[C:2]1[C@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH3:20]
Reactant: Cc1ccccc1
Reactant: COc1cccc([C@]23CCCNC(=O)[C@@H]2CCC3)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cccc([C@@]23CCC[C@@H]2C(=O)N(C)CCC3)c1
Temperature: 25 °C

Procedure:
A solution of 5.0 g. of dl-trans-1-oxo-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine in 40 ml. of anhydrous toluene was added dropwise over thirty minutes to a stirred solution of 1.2 g. of sodium amide in 40 ml. of anhydrous toluene. The reaction mixture was heated at reflux for four hours, and then cooled to 25° C. and stirred while a solution of 4 g. of methyl iodide in 40 ml. of toluene was added in one portion. The reaction mixture was next heated to reflux and stirred for thirteen hours. After cooling the reaction mixture again to 25° C., 100 ml. of water was added dropwise over fifteen minutes. The aqueous layer was then separated, and the organic layer was washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 5.3 g. of predominantly dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[a]azepine. The product so formed was recrystallized three times from diisopropyl alcohol to afford pure dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[ c]azepine. M.P. 103°-104° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9](F)[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 1 h

Procedure:
9.1 g (0.05 mol) of 30% strength sodium methylate were added to a mixture of 10 g (0.05 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine in 100 ml of methanol at 0° C. in the course of 15 minutes while stirring. Stirring was carried out for one hour at 0° C., after which the mixture was evaporated down under reduced pressure, the residue was taken up in methylene chloride and the solution was extracted with water. Drying and evaporating down gave 10.5 g (99% of theory) of the title compound of melting point 96°-101° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]C([O-])(C)C.[K+].CI>C1COCC1>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Reaction time: 1 h
Yield: 82 %

Procedure:
Compound 13 (24 mg) was dissolved in THF (1 mL) and KOtBu (1 M in THF, 82 μL) was added. The mixture was stirred for 1 hr, followed by addition of methyl iodide (5.1 μL). The stirring was continued for additional 1 hr, then the solution was concentrated and the residue was purified by flash chromatography [silica gel, EtOAc] to afford 16 mg (82%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1 H), 8.32 (d, 1 H), 8.13 (d, 1 H), 7.75 (s, 1 H), 7.15 (dd, 1 H), 6.71 (d, 1 H), 5.0 (m, 1 H), 3.90 (s, 3 H), 3.88 (m, 1 H), 2.10 (m, 2 H), 1.70 (m, 2 H), 1.60 (m, 2 H), 1.40 (m, 2 H), 1.20 (m, 2 H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:30]1C=CC=CC=1.N>C(#N)C>[NH2:30][C:10](=[O:11])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88%) as white solid; MS (EI): m/e 225.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Reactant: C1CCNC1
Product: Clc1cc(Cl)cc(Oc2ccc(CN3CCCC3)cc2)c1

Procedure:
The title compound was prepared starting from 4-(3,5-dichloro-phenoxy)-benzaldehyde and pyrrolidine by the same method (step B) described in Example 1. 1H NMR (400 MHz, CDCI3)δ7.22 (t, J=7.8 Hz, 1 H), 7.07 (d, J=7.6 Hz,1 H), 6.96 (m, 2 H), 6.81 (m,1 H), 6.76 (m, 2 H), 3.52 (s, 2 H), 2.45 (m, 4 H), 1.70 (m, 4 H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]#[C:11][NH2:12].[Na]>C(OCC)C>[C:1]([NH:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: CCOCC
Product: N#CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Benzoylcyanamide was prepared by the addition of benzoyl chloride (6.33 g, 0.045 mol) in 100 ml of diethyl ether to a suspension of monosodium cyanamide (5.76 g, 0.090 mol) in 100 ml of ether at 4° C. The reaction was stirred overnight at room temperature and the pale yellow solid which formed was collected and dissolved in water. On acidification of the solution to pH 1, a precipitate formed which was collected and recrystallized from ethyl acetate (EtOAc)/petroleum ether (30-60° C) to give 2 (5.89 g, 89.7% yield), mp 140°-142° C. [reported mp 139°-140° C⟧ Anal. Calcd for C8H6H2O: C, 65.75; H, 4.11; N, 19.18. Found: C, 65.79; H, 4.35; N, 19.04.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:27])([F:26])[C:11]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=1)([CH3:17])[O:12][Si:13]([CH3:16])([CH3:15])[CH3:14]>C(O)C>[F:27][C:10]([F:26])([F:9])[C:11]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH2:25])=[O:2])[CH:19]=1)([CH3:17])[O:12][Si:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(O[Si](C)(C)C)(c1ccnc(C#N)c1)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(O[Si](C)(C)C)(c1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To 4 ml of ethanol were added 0.22 g of sodium bicarbonate and 0.18 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.5 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 4-[2,2,2-trifluoro-1-methyl-1-(trimethylsilyloxy)ethyl]pyridine-2-carboxamide=oxime.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36])[CH3:39]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][C:14]2[C:17]3[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=3[S:24][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[C:40]([O:41][CH3:42])=[CH:39][C:34]2[NH:35][C:36](=[O:38])[S:37][C:33]=2[CH:32]=1>>[CH2:1]([N:8]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][C:14]2[C:17]3[C:22]([NH:30][C:31]4[C:40]([O:41][CH3:42])=[CH:39][C:34]5[NH:35][C:36](=[O:38])[S:37][C:33]=5[CH:32]=4)=[N:21][CH:20]=[N:19][C:18]=3[S:24][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CN(C)CCN(Cc1ccccc1)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2sc3c(c12)CCC(C(=O)N(CCN(C)C)Cc1ccccc1)C3

Procedure:
146 mg (340 μmol) (RS)—N-benzyl-4-chloro-N-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 92a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.4 mg (4%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][S:20]([N:23]([CH3:47])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:18][O:17][C:3]1[C:4]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:36]1[N:35]=[CH:34][C:33]2=[CH:32][CH:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]([CH3:47])[S:20]([CH3:19])(=[O:22])=[O:21])[N:38]2[N:37]=1
Reactant: COc1c(N)cccc1C(=O)N1CCN(C)CC1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)cccc1C(=O)N1CCN(C)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (3-Amino-2-methoxy-phenyl)-(4-methyl-piperazin-1-yl)-methanone (107 mg, 0.430 mmol), Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-(2-{2-[2-Methoxy-3-(4-methyl-piperazine-1-carbonyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide a yellow solid (42 mg, 32%). LCMS (E/I+) 550.16 (M+H). NMR 1H (DMSO-d6)-9.79 (bs, 1H), 9.02 (s, 1H), 8.13 (bs, 1H), 8.06 (s, 1H), 7.90-7.96 (m, 1H), 7.45-7.65 (m, 3H), 7.09 (t, 1H, J=7.80 Hz), 7.05 (d, 1H, J=4.63 Hz), 7.00 (d, 1H, J=4.63 Hz), 6.92 (bs, 1H), 2.70-4.50 (m, 20H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].C[O:16][B:17]([O:20]C)[O:18]C.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:16][B:17]([OH:20])[OH:18]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reaction time: 0.33 h

Procedure:
Into a Solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (121.3 g) in tetrahydrofuran (730 mL), n-butyllithium (2.64M hexane solution; 182 mL) was dropped at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added a solution of trimethoxyborane (61.7 mL) intetrahydrofuran (20 mL) at −78° C. The temperature was raised until the inner temperature of the reaction mixture reached −10° C., a saturated ammonium chloride aqueous solution (730 mL) was added, and the mixture was further stirred for 15 minutes. To the resulting reaction mixture was added ethyl acetate, extraction with ethyl acetate was performed, and the resulting organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate (2:3), 90.4 g of a title compound was obtained as white solid.
Reaction SMILES: C(S[C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)=[N:10][C:8]=2[N:9]=1)C.ClC1C=C(C=CC=1)C(OO)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.O1CCOCC1>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[N:10][C:8]=3[N:9]=2)[CH2:42][CH2:41]1
Reactant: CN1CCNCC1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde (5-4a) (1.0 g, 2.69 mmol) in CH2Cl2 (30 mL) was added m-chloroperoxy benzoic acid (0.660 g, 3.0 mmol). The solution was stirred for 1 hr then quenched with sat. NaHCO3 and 10% Na2S2O3 and stirred for 30 min. The reaction mixture was diluted with CH2Cl2, extracted, dried with MgSO4, and filtered. A portion of the resulting sulfoxide (0.700 g, 1.81 mmol) was dissolved in dioxane (7 mL) with methyl piperazine (181 mg, 1.81 mmol) and heated to 100° C. for 20 min. in a microwave reactor. The mixture was concentrated under reduced pressure and the residue was purified by HPLC (Phenomenx Synergi column; 20-85% acetonitrile/water+0.1% TFA) to give the title compound (5-5a). 1H-NMR (500 MHz, d4-CD3OD) δ 10 (s, 1H), 9.48 (s, 1H), 8.65 (s, 1H), 7.88 (d, 2H), 7.64 (d, 2H), 7.46 (m, 6H), 7.33 (m, 3H), 7.26 (m, 3H), 3.6-3.4 (m, 8H), 3.00 (s, 3H) LRMS m/z (M+1) Calcd: 410.5, found 410.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10](Cl)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([CH3:28])[CH3:27]>CS(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:26]([CH3:28])[CH3:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2ccccc2F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1ccccc1F

Procedure:
The title compound was prepared from (2-chloro-2′-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example D3) (9.568 g, ca. 26 mmol) and Me2NH (60% in H2O, 12 mL) in DMSO (87 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (4.54 g).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CO>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: COc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Solvent: CO
Product: COc1cc(C2=NNC(=O)CC2)ccc1OCC(O)CNC(C)(C)C
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[4-(2,3-epoxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (1.2g, 0.0043 mole), methanol (24 ml), and t-butylamine (2.76 ml, 0.026 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a glassy residue (1.44g, 95%). The crude hemisulphate of 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 266°-268.5° C) was recrystallised from methanol-ether to give the pure hemisulphate m.p. 270°-272° C decomposition.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[C:25]([F:31])[C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[C:25]([F:31])[C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of rac-(2′S,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.12 g, 0.2 mmol) prepared in Example 175 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.34 g, 3 mmol), then aqueous solution (1N) of NaOH (1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a light yellow solid (Yield 0.11 g, 93%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][CH:31]1[C:39](Cl)=[O:40]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:39]([CH:31]3[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:30]3)=[O:40])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: O=C(Cl)C1Cc2ccccc2O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnnc1C(=NOCc1cccc(NC(=O)C2Cc3ccccc3O2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (100 mg, 0.32 mmol) in dry dichloromethane (4 mL) under argon was added pyridine (39 μL, 0.48 mmol) at room temperature, followed after fifteen minutes by 2,3-dihydro-1-benzofuran-2-carbonyl chloride (88 mg, 0.48 mmol). The reaction mixture was stirred overnight at room temperature and quenched by filtration on bi-layer cartridge filled with 1.4 g of basic alumina and 1 g of silica. The cartridge was rinsed twice by 10 mL of dichloromethane. The combined filtrated solutions were evaporated in vacuo to yield a colorless oil. Purification on silica gel afforded of N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-2,3-dihydro-1-benzofuran-2-carboxamide as a colorless oil [150 mg, yield 96%; HPLC/MS: nm/z=456 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: N.C1O[CH:5]([C:6]2[C:7]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:8][N:9](C(OC)=O)[CH:10]=2)[O:4]C1.Cl>O1CCOCC1.O>[N+:20]([C:17]1[O:16][C:15]([C:7]2[C:6]([CH:5]=[O:4])=[CH:10][NH:9][N:8]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Agent: Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 0.2 h

Procedure:
Add 54 ml of concentrated ammonia solution dropwise to a suspension of 95.5 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal in 750 ml of dioxan. Stir the resulting admixture for 12 minutes. Then add thereto 160 ml of 2N hydrochloric acid to adjust its pH to 1. Stir the thus-acidified product for 30 minutes before diluting it with 2000 ml of water. Allow the resulting precipitate to stand overnight in a cooling cupboard to obtain a quantitative yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde with a melting point of 184° to 186° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][CH2:14]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of Example 213a (7.00 g, 19.91 mmol) and triethylamine (3.61 mL, 25.9 mmol) in tetrahydrofuran (150 mL) was added BOC2O (5.08 mL, 21.90 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc and washed with brine and saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 150 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 5.42 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H](C(N[C@@H](C(NCC(O)=O)=O)CCSC)=O)CC1C=CC(O)=CC=1>>[NH:1]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[C@@H:2]([C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])[CH2:7][CH2:6][C:14](=[O:15])[NH2:16]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C

Procedure:
Using BOC-(D)-Gln-ONP(0.96 g) and H-Gly-Phe-NHNH-COCH3 (0.72 g), the desired compound (0.95 g) is obtained in a similar manner to (III) of Example 45. m.p. 198°-199° C., [α]D23 -0.8° (C=0.50, DMF), Rf1 =0.19.