Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([NH:19][C:18]([NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)=[O:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 8 h

Procedure:
ε-N-2ClZ-L-lysyl-L-aspartyl-β-benzyl ester-L-valyl-L-tyrosyl-O-benzyl ether-benzyl ester-3-thioamide (2 mmol) was dissolved in dry DMF (0.5 ml) at 0° C. under N2 and α-N-Boc-N-tosyl-L-arginine (2 mmol) was added to the solution with stirring. HOBt (2 mmol) and DCC (2 mmol) were added slowly at 0° C. and stirring was allowed to continue overnight. The mixture was diluted with 8 volumes of ethyl acetate and the N,N'-dicyclohexylurea so formed was filtered away from the solution. The filtrate was transferred to a separating funnel and washed successively with 5% aqueous sodium bicarbonate, 5% aqueous citric acid, and saturated brine. The organic phase was collected and dried over MgSO4, filtered, and concentrated in vacuo. The residue was purification by flash chromotography using 9:1 chloroform-methanol as an eluant to afford the α-N-Boc-N-tosyl-L-arginyl-ε-N-2ClZ-L-lysyl-L-aspartyl-β-benzyl ester-L-valyl-L-tyrosyl-O-benzyl ether-benzyl ester-4-thioamide in good yield (78%). The following physical characteristics were recorded for the compound: Melting point 105°-107° C.; IR (CHCl3) 1756, 1%90 cm-1UV (CHCl3) lambdamax 271. Elemental composition (C71H84Cl3N9O14S2): Theoretical: C, 58.13; H, 5.65; N, 8.34; S, 4.79. Found: C, 58.54; H, 5.81; N, 8.65; S, 4.40.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 89 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 120, step 2 and 2-fluoro-5-methylaniline (0.043 g, 0.34 mmol), the title compound (0.108 g, 90%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH:25]([NH2:28])[CH2:26][CH3:27].ClCCl>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:28][CH:25]([CH2:24][O:23][CH3:22])[CH2:26][CH3:27])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCC(N)COC
Reactant: Clc1cc(Nc2nccc(-c3ccnc(Cl)c3)n2)ccn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCC(COC)Nc1cc(-c2ccnc(Nc3ccnc(Cl)c3)n2)ccn1
Yield: 199 %

Procedure:
300 mg of N,4-bis(2-chloropyridin-4-yl)pyrimidin-2-amine (0.94 mmol), 486 mg of 1-methoxybutan-2-amine (4.71 mmol), were heated at 240° C. for 90 minutes under micro-waves irradiation in 0.6 ml of 1-Methyl-2-pyrrolidinone. After cooling, the reaction mixture was poured into 10 ml of dichloromethane, washed twice with 5 ml of water. After drying over magnesium sulfate, filtration and concentration in vacuo, the crude product was chromatographed on silica (ethyl acetate/heptane) to yield 0.72 g of N-(2-chloropyridin-4-yl)-4-(2-{[1-(methoxymethyl)propyl]amino}pyridin-4-yl)pyrimidin-2-amine (yield=19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@:5]1([CH2:11][N:12]=[C:13]=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.C1(C)C=CC=CC=1.[CH3:23][OH:24]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@:5]1([CH2:11][NH:12][C:13]([O:24][CH3:23])=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: COC(=O)C[C@]1(CN=C=O)CC[C@@H](C)C1
Reactant: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@]1(CNC(=O)OC)CC[C@@H](C)C1
Temperature: 25 °C
Yield: 77 %

Procedure:
((1S,3R)-1-Isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester (5.19 g, 24.5 mmol) was refluxed in methanol (30 mL) and toluene (80 mL) for 17 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, heptane-ethyl acetate 9:1) to give 4.62 g (77%) of [(1S,3R)-1-(methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[NH:5][CH:6]1[CH:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[CH:13]=2)[O:8][CH2:7]1)[CH3:2].[ClH:35]>C(Cl)Cl.C(O)(C)C>[ClH:35].[NH2:26][CH2:25][CH2:24][O:23][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([NH:5][C:4](=[O:34])[O:3][CH2:1][CH3:2])[CH:15]2[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)NC1COc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)NC1COc2ccc(OCCN)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
487 mg (1.04 mmol) of [4-benzyl-6-(2-tert-butoxycarbonylamino-ethoxy)-chroman-3-yl]-carbamic acid ethyl ester were dissolved in 10 ml methylene dichloride and 2 ml of a solution of hydrogen chloride in isopropanol (5-6 N) were added and the mixture was stirred over night at room temperature. The reaction mixture was warmed to 40° C., stirred for additional 45 min, and concentrated. The residue was dissolved in water and washed with ether. The aqueous phase was concentrated and the residue co-distilled with toluene to give 463 mg (1.14 mmol, quant.) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([CH:3]=1)[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cnc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cnc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromo-2,3-dimethoxy-pyridine (43 g) in THF (500 ml) at −78° C. was added n-butyllithium (191 mmol). After stirring for 30 minutes at −78° C. DMF (28.8 g) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with NH4Cl (saturated in water, 500 ml). The aqueous layer was extracted with ethyl acetate, the organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica eluting with heptane with increasing amounts of ethyl acetate.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:16]CC)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1>>[CH2:1]([C:8]1[C:21]2[CH2:20][O:19][CH2:23][C:22]=2[C:10]([OH:16])=[C:11]([CH:13]([CH3:14])[CH3:15])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: CCOc1oc(Cc2ccccc2)nc1C(C)C
Product: CC(C)c1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
36.8 g of 2-benzyl-4-isopropyl-5-ethoxyoxazole (150 millimoles) and 210 g (3 moles) of 2,5-dihydrofuran are heated in an autoclave at 190° C. for 5 hours. Unconverted 2,5-dihydrofuran is distilled off. The residue is taken up in methylene chloride and the solution is extracted with 10% strength sodium hydroxide solution. On neutralizing the alkaline solution, crude 4-benzyl-6-isopropyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol is obtained and is extracted with methylene chloride (20.4 g). The product is converted to the hydrochloride by means of dilute hydrochloric acid and the hydrochloride is recrystallized from ethanol; melting point 232°-233° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[C@@H:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=4)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]3[C:34](=[O:43])[C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCCl.ClCCl.O=[Mn]=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[C@@H:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[C:24]([C:30]([F:32])([F:33])[F:31])[CH:23]=4)=[O:20])[CH2:17][CH2:16][CH2:15][N:14]3[C:34](=[O:43])[C:35]3[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Agent: O=[Mn]=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of cis-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-(hydroxymethyl)-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (130 mg, 0.22 mmol) in 1,2-dichloroethane (2 mL) was added MnO2 (380 mg, 4.4 mmol) at room temperature. The reaction mixture was stirred for 3 h and was then diluted with dichloromethane, filtered through a plug of SiO2, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to get the desired compound (as a mixture of cis enantiomers) in 31% yield (40 mg). 1H NMR (400 MHz, CDCl3) δ 10.2 (bs, 1H), 8.12-6.88 (m, 10H), 3.82-3.04 (m, 4H), 2.88-1.40 (m, 18H). MS: (ES) m/z 596 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:6]=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:22])[N:13]([CH3:21])[CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:6]=2)=[C:2]([F:1])[CH:26]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reaction time: 3 h
Yield: 77.8 %

Procedure:
3-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (243 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (6 ml), and then 10% palladium carbon (128 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the reaction system and stirring for 3 hrs. After replacing with nitrogen inside the system, the catalyst was filtered and washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) and concentrated under a reduced pressure to provide the titled compound (175 mg, 78.0%) as pale yellow powder.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:36]CCl>C(O)C>[ClH:36].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCCN2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.4 g, 0.92 mmol) was dissolved in ethanol (10 ml) and a 4 N sodium hydroxide solution (0.70 ml) was added. The mixture was stirred at room temperature for 4 h. A 4 N hydrochloric acid solution was added until pH 1. Dichloromethane (300 ml) was added and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in a mixture of ethyl acetate and acetone and left for crystallization. This afforded 0.13 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.C([O-])(O)=O.[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=[N:27][OH:28])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=NO
Reaction time: 1 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.100 g, 0.363 mmol) (Example 9a) in ethanol (3 mL) is added to NaHCO3 (0.246 g, 2.901 mmol) and hydroxylamine hydrochloride (0.208 g, 2.901 mmol) in water (1 mL). After 1 hr, water is added and the mixture is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gives a residue, which is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 49:1), resulting in the separation of the two isomers. Each isomer is obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:14]=1)=[O:12].[CH2:33](I)[CH3:34]>CN(C=O)C>[CH2:33]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:11]([N:7]5[CH2:8][CH2:9][CH2:10][C@@H:6]5[CH2:5][O:4][CH3:3])=[O:12])[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[C:27]1[CH3:32])[CH3:34]
Reactant: CCI
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@@H]5COC)sc34)ccc21
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
NaH (16 mg, 0.4 mmol) was added to a solution of (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone (85 mg, 0.2 mmol) in DMF (5 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and EtI (57 mg, 0.40 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (46 mg, 51%). MS: 450 (MH+); HPLC Rf: 6.83 min; HPLC purity: 95%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Br:32])[CH2:9][F:10])[N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OC(CF)c1cccc(Br)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCC(Br)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)-2-fluoroethanol (0.525 g, 2.39 mmol) and triphenylphosphine (1.252 g, 4.77 mmol) were taken up in DCM (25 mL). A solution of carbon tetrabromide (1.582 g, 4.77 mmol) in DCM (10 mL) was added and the resulting mixture stirred at room temperature overnight. The precipitate was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a colorless oil.
Reaction SMILES: CC(C)=[O:3].Br[CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O>[OH:3][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)=O
Reactant: O=c1ccc2ccc(CBr)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1ccc2ccc(CO)cc2o1

Procedure:
To a 1:1 mixture of acetone and water (560 ml) was added 7-bromomethy1coumarin (7.0 g, 29.3 mmol). The resulting suspension was refluxed for 48 hrs at which time the reaction mixture became a clear solution. The solution was then cooled and neutralized with sodium bicarbonate (2.4 g, 29.3 mmol) and concentrated in vacuo to about 65 ml. A thick mass of crystals resulted. The crystals were collected by filtration to yield 5.27 g of product after drying in vacuo (100% of theory). The melting point was 116°-117° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:32])[C:15]([CH3:31])=[C:16]([CH:30]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C)C=O>[Si:37]([O:32][C:14]1[C:15]([CH3:31])=[C:16]([CH:30]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:13]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39]
Reactant: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a suspension of 1.0 g of p-nitrobenzyl 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoate in 30 ml of dimethylformamide were added 0.71 g of tert-butyldimethylchlorosilane and 0.48 g of triethylamine, and the mixture was stirred at 20° C. for 24 hours. The solvent was evaporated in vacuo, and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using methylene chloride as eluent to yield 0.90 g of p-nitrobenzyl 3-(tert-butyldimethylsilyloxy)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl )-2-methylbenzoate as white solid, m.p. 125°-127° C.
Reaction SMILES: [N:1]1[C:2]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[Br:24]N1C(=O)CCC1=O>C1COCC1>[Br:24][C:3]1[N:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[N:15][C:6]=3[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]2=[N:1][C:2]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)Cc1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 2-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.14 g, 1 eq.) in THF (10 mL) was added N-bromosuccinimide (0.077 g, 1 eq.). The reaction was stirred at room temperature for 30 minutes, poured onto water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude product was purified by column chromatography (2-5% methanol in dichloromethane). The methyl 2-(3-bromo-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.162 g, 98%) was obtained. 1H NMR (DMSO-d6) 400 MHz δ 8.23 (dd, JA=4.4 Hz, JB=1.6 Hz, 1H), 7.96 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.77 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 7.38-7.33 (m, 1H), 7.19 (dd, JA=8.0 Hz, JB=4.8 Hz, 1H), 7.14-7.05 (m, 2H), 3.75 (s, 2H), 3.74 (s, 3H); LCMS: 385, 387 [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C1C=CC=CC=1>[Cl:23][C:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:22]
Reactant: COCCOCCOCCOCCO
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 12.9 g. (62 mmoles) of tetraethylene glycol monomethyl ether and 4.9 g. (62 mmoles) of pyridine is added dropwise to 77 ml. (124 mmoles) of a 17.2% solution of phosgene in benzene stirred in an ice bath with protection from moisture. The pyridine hydrochloride precipitates during the 35 to 40 minute addition and stirring is continued in the ice bath for an additional 2 hours. The reaction mixture is allowed to warm to room temperature and stirred overnight. The benzene solution is decanted from the pyridine hydrochloride which is washed with additional benzene. A stream of nitrogen is passed through the solution to remove excess phosgene as well as most of the benzene. The residual oil is dissolved in benzene-hexane and filtered to remove additional pyridine hydrochloride. The filtrate is evaporated to dryness in vacuo affording 17.1 g. of a residual oil, the infrared analysis of which reveals a strong carbonyl absorption and minimal hydroxyl absorption. The oil is used as is in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:7]=1.Cl.[NH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)/[C:16](=[N:30]/[OH:31])/[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(S(=O)(=O)c3ccc4c(c3)CCC4=O)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(S(=O)(=O)c3ccc4c(c3)CC/C4=N\O)c2)CCOCC1
Yield: 49 %

Procedure:
Using an analogous procedure to that described in Example 50, 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylsulphonyl]indan-1-one oxime in 49% yield, m.p. 225°-226° C.;
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:17][C@@H:18]1[CH2:32][C@H:31]2[C@@H:21]([CH2:22][C:23]3[C:33]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]2=4)[NH:25][CH:24]=3)[N:20]([CH3:34])[CH2:19]1)(=O)=O>O>[CH3:34][N:20]1[C@H:21]2[C@@H:31]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:33]=3[C:23]([CH2:22]2)=[CH:24][NH:25]4)[CH2:32][C@@H:18]([CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH2:19]1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C[C@H](Cn2cncn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
0.4 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of 1,2,4-triazole and 20 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. After allowing the mixture to cool, water was added to the reaction mixture, and the precipitated crystals were separated by filtration, washed with water and purified by alumina column chromatography (eluted with dichloromethane). The product was recrystallized from methanol to obtain 0.8 g of the titled compound as colorless needles having a melting point of 245°-253° C.