Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[O:12][C:13]1[CH:20]=[C:19]([CH:21]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].[OH-].[K+].C=O.C(O)(=O)C>C(#N)C.CO>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[O:12][C:13]1[CH:20]=[C:19]([C:21]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH2:3][OH:4])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1Oc1cccc(Cl)c1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: Cl
Product: N#Cc1ccc(C(CO)(c2ccc(Cl)cc2)n2ccnc2)cc1Oc1cccc(Cl)c1
Reaction time: 18 h

Procedure:
To a solution of 2-(3-chloro-phenoxy)-4-[(4-chloro-phenyl)-imidazol-1-yl-methyl]-benzonitrile trifluoroacetate (0.065 g, 0.122 mmol) in acetonitrile (5 mL) was added 1M KOH (0.5 mL) (pH=9-10) and 37% aqueous formaldehyde (0.14 mL) After stirring for 18 hr the mixture was adjusted to pH=3 with acetic acid, diluted with CH3OH (3 mL) and purified on prep HPLC. The TFA salt was converted to the HCl salt to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]2[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][C:31]=2[F:32])[NH:28][N:27]=[CH:26]3)=[O:21])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:33]([S:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]2[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][C:31]=2[F:32])[NH:28][N:27]=[CH:26]3)=[O:21])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])(=[O:37])=[O:36])[CH3:34]
Reactant: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)c(N)c2)CC(=O)N1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2cc3cn[nH]c3cc2F)ccc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Example 78, beginning with the product from Example 80 and using ethanesulfonyl chloride in place of methanesulfonyl chloride. MS (ES+) m/e 414 [M+H]+.
Reaction SMILES: C(OCC)(OCC)O[CH2:3][CH3:4].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)C>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:3](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:4])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: N#CCC#N
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: COc1ccc(NC(C)=C(C#N)C#N)cc1

Procedure:
A mixture of triethyl orthoformate (29.6 g., 0.20 mole), 4-methoxyaniline (24.6 g., 0.20 mole) and malononitrile (13.2 g., 0.20 mole) in 250 ml. of ethanol are heated under reflux for 3 hours. The desired crystalline product separates on cooling. It is isolated by filtration and washed with ethanol. Recrystallization from equal parts of ethanol and acetone gives 28.5 g. of product having a melting point of 254°-255°C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][CH:34]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)=[O:14])=[O:8])(=[O:3])[CH3:2].C(OCC)C.[ClH:47].C(O)(=O)C>>[ClH:47].[C:1]([S:4][CH2:5][CH:6]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][CH:34]=1)[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCc2ccc(CN)cc2)c1

Procedure:
4-(t-Butyloxycarbonylaminomethyl)benzyl 3-[(2-acetylthiomethyl 3-phenylpropionyl)amino]benzoate (compound of Example 121) (0.73 g) is dissolved in 1M hydrochloric acid-acetic acid solution (20 ml), and the mixture is reacted at room temperature for 45 minutes. The reaction mixture is added slowly to diethyl ether (100 ml) with stirring under ice cooling. The precipitates are separated by filtration and washed with diethyl ether to give the title compound (0.61 g). m.p.: 111°-113° C. (amorphous) IR (KBr; cm-1): 1710, 1685, 1650
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:30])(=[O:29])[NH2:28])=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([CH:10]([CH3:11])[CH3:12])[C:7]2=[O:13])=[CH:16][CH:17]=1)(=[O:29])=[O:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: c1ccncc1
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 52.7 mg (0.123 mmole) of 5-n-butyl-2,4-dihydro-2-isopropyl-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step I) in 1 ml of dry pyridine stirred at room temperature under argon was added 143 μL (173 mg; 1.23 mmole) of benzoyl chloride. After 12 hours at room temperature, the mixture was treated with saturated NaH2PO4 solution and extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 4% MeOH and 0.2% ammonium hydroxide in CH2Cl2) gave 42.3 mg (69%) of the title compound as a white solid; satisfactory purity by TLC in 94:6:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 533 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:31])[CH3:30])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:33])([CH3:32])[C:5]1=[O:34].C(N([CH2:40][CH3:41])CC)C.[C:42](Cl)(=[O:44])C>C1COCC1>[CH3:33][C:6]1([CH3:32])[C:7]2[C:12](=[CH:11][C:10]([C:13]([N:15]([CH:29]([CH3:30])[CH3:31])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]3)=[O:14])=[CH:9][CH:8]=2)[N:4]([CH2:3][CH2:2][NH:1][C:42](=[O:44])[CH2:40][CH3:41])[C:5]1=[O:34]
Reactant: CC(=O)Cl
Reactant: CC(C)N(C(=O)c1ccc2c(c1)N(CCN)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NCCN1C(=O)C(C)(C)c2ccc(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added triethylamine (0.14 ml), THF (3 ml) and acetyl chloride (0.07 ml) under ice-cooling, and the mixture was stirred at room temperature for one hour. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (190 mg) as colorless amorphous.
Reaction SMILES: [OH:1][C@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(OCC)(=O)C.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][N:29]([CH3:30])[CH2:31][CH2:32][N:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@@H:3]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:2]([OH:1])[C:8]1=[O:9]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A 5-L three-necked flask equipped with a heating mantle, a mechanical stirrer and a condenser was charged with 162 g (0.54 mol) of (+)-(2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one and then 1 L of ethyl acetate. After stirring to dissolve the solution, 100 g (0.694 mol) of dimethylaminoethyl chloride.HC1 was added in one portion followed by 300 g (2.16 mol) of finely ground K2CO3 and 5 mL of H2O. (The 5 ml. of water was essential to cause a reaction between the phases, while addition of much more water would have resulted in gummy mixture that was difficult to filter.) This heterogeneous mixture was rapidly stirred at reflux for 5 hours. By thin layer chromatography (8:1, CH2C12 -MeOH, short wave UV), reaction was complete and therefore the mixture was allowed to cool to room temperature, filtered through a sintered glass funnel and washed with 100 mL 1:1 hexanes-ethyl acetate. The solvent was evaporated and on standing the oil crystallized. Recrystallization from ether gave 140 g (70%) of colorless crystalline (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, m.p. 79-81° C., [α]D20=+ 156.4°(C=1.0; CHC13).
Reaction SMILES: CS(Cl)(=O)=O.C(OC(=O)[NH:12][C:13]([C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH2:35]O)=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:37])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])(C)(C)C.C(N(C(C)C)CC)(C)C.C[N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(Cl)Cl>[CH3:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[C:29]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20]([C:18]2[CH:19]=[C:15]([C:13]([NH2:12])=[NH:14])[S:16][C:17]=2[S:38][CH3:39])(=[O:21])=[O:22])[CH:24]=1
Reactant: CN1CCOCC1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (100 μL) was added over 1 min to a 0° C. solution of {[4-(6′-hydroxymethyl-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 5: step c) (30 mg)) and diisopropylethylamine (0.25 mL) in DCM (10 mL). The solution was stirred for 1 h at 0° C. and warmed to rt. 4-Methylmorpholine (0.5 mL) was added and the solution was stirred for 3 h at rt. The volatile components were removed in vacuo and the residue was treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in vacuo and the residue was purified by preparative HPLC (C18-column, 10–70% CH3CN over 30 min) which yielded the title compound as a opaque glass (6.8 mg). 1H-NMR (CD3OD): δ 8.40 (s, 1H), 8.13 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.97 (t, 1H, J=1.6 Hz), 7.82 (t, 1H, J=7.9 Hz), 7.61 (m, 2H), 7.49 (m, 2H), 4.15 (d, 1H, J=13.5 Hz), 4.07 (d, 1H, J=13.5 Hz), 3.82 (br s, 4H), 2.75 (s, 3H), 2.18 (s, 2H), 2.03 (s, 3H), 1.31 (s, 2H). ESI-MS (m/z): Calcd. for C24H27N3O3S3 (M+H): 502.1; found: 502.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[C:9]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:10]=3[CH2:11][C:5]2=[N:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:28][C:3]1[N:4]=[C:5]2[CH2:11][C:10]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:9]=3[C:8]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:7][N:6]2[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)nc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
900 mg of 8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 10 ml of dimethylformamide with 441 mg of N-bromosuccinimide and stirred for 1.5 hours at room temperature. After dilution with 40 ml of water, the precipitated product is suctioned off, and 900 mg of 9-bromo-8-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.ClCCCC[CH:23]1[C:27]2([CH2:32][C:31](=[O:33])[NH:30][C:29](=[O:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:43][C:44](=O)[CH2:45][CH3:46]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([CH2:43][CH2:44][CH2:45][CH2:46][N:30]2[C:29](=[O:34])[CH2:28][C:27]3([CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:32][C:31]2=[O:33])[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C1CC2(CCCC2CCCCCl)CC(=O)N1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Product: COc1ccc2[nH]cc(C3CCN(CCCCN4C(=O)CC5(CCCC5)CC4=O)CC3)c2c1
Reaction time: 20 h

Procedure:
A mixture of 2.3 g of 5-methoxy-3-(4-piperidinyl)-1H-indole, 2.58 g of 8-[4-chlorobutyl-8-azaspiro[4,5]decane-7,9-dione, 2.12 g of sodium carbonate, 150 mg of sodium iodide and 50 ml of butanone was refluxed under an inert atmosphere with stirring for 20 hours and after another 1.29 g of the dione were added. Reflux was continued for 6 hours. The mixture was filtered and washed with acetone and the filtrate was evaporated to dryness. The residue was crystallized from 60% ethanol to obtain 3.4 g of 8-[4-{4-(5-methoxy-1H-indol-3-yl)-1-piperidinyl}-butyl]-8-azaspiro[4,5]decane-7,9-dione melting at ≈150° C.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([Cl:16])=[CH:11][C:10]=1[Cl:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.[CH:25]([O:28][B:29](OC(C)C)[O:30][CH:31](C)C)(C)C.C([Li])[CH2:39][CH2:40][CH3:41]>O1CCCC1.C1(C)C=CC=CC=1>[Si:5]([O:8][C:9]1[C:10]([Cl:17])=[CH:11][C:12]([Cl:16])=[C:13]([B:29]2[O:30][CH2:31][C:40]([CH3:39])([CH3:41])[CH2:25][O:28]2)[CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(I)c(Cl)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]CCCC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)COB(c2cc(O[Si](C)(C)C(C)(C)C)c(Cl)cc2Cl)OC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl(2,4-dichloro-5-iodophenoxy)dimethylsilane (857 mg) obtained in Step 1 above in tetrahydrofuran (1 ml) and toluene (4 ml) was prepared under nitrogen atmosphere. The solution was cooled to −78° C. (dry ice/acetone). After triisopropylborate (0.6 ml) was added, n-butyllithium (1.6N; n-hexane solution, 1.62 ml) was added dropwise thereto over 5 minutes. The mixture was stirred at the same temperature for 30 minutes, and then warmed by removing the cold bath. When the inner temperature reached 0° C., 2,2-dimethylpropane-1,3-diol (0.27 g) was added to the solution and then warmed to room temperature. After stirring at room temperature for 8 hours, water (20 ml) was added to the solution and extracted with ethyl acetate (20 ml). The ethyl acetate solution was sequentially washed with a half-saturated aqueous ammonium chloride solution (15 ml), water (15 ml), and a saturated aqueous sodium chloride solution (10 ml). Then, the organic solution was pre-dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=20:1 to 9:1) to yield pale yellow oily 2-[5-(tert-butyldimethylsilanyloxy)-2,4-dichlorophenyl]-5,5-dimethyl[1,3,2]dioxaborinane (547 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:9](O)[CH2:8][CH2:7][O:6][P:5]1(=[O:18])[N:11]([CH2:15][CH2:16][Cl:17])[CH2:12][CH2:13][Cl:14].[CH:19]1([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[SH:26][CH2:27][CH2:28][S:29]([O-:32])(=[O:31])=[O:30].ClC(Cl)(Cl)C(O)=O>CN(C)C=O>[CH:19]1([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl:1][CH2:2][CH2:3][N:4]1[CH:9]([S:26][CH2:27][CH2:28][S:29]([O-:32])(=[O:31])=[O:30])[CH2:8][CH2:7][O:6][P:5]1([N:11]([CH2:15][CH2:16][Cl:17])[CH2:12][CH2:13][Cl:14])=[O:18]
Reactant: O=P1(N(CCCl)CCCl)OCCC(O)N1CCCl
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CN(C)C=O
Product: O=P1(N(CCCl)CCCl)OCCC(SCCS(=O)(=O)[O-])N1CCCl
Reaction time: 48 h

Procedure:
340 mg (1 mmol) of 3-(2-chloroethyl)-2-(bis-(2-chloroethyl)-amino)-4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol) cyclohexylammonium-2-mercaptoethanesulphonate in 2 ml of dimethylformamide were mixed with a trace of trichloroacetic acid and were stored for 2 days at -25° C. The reaction mixture was then precipitated with 20 times the quantity of ether. The residue was washed and dried.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C=O)C>O>[Si:14]([O:8][C:5]1[CH:4]=[C:3]([F:9])[C:2]([Cl:1])=[N:7][CH:6]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cnc(Cl)c(F)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1cnc(Cl)c(F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-5-fluoropyridin-3-ol (13.1 g), tert-butyl (chloro)diphenylsilane (27.7 mL), 1H-imidazole (7.25 g) and DMF (100 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (29.5 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH2:20])[CH2:3]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH:20][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Product: CN(C)C(=O)NNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 68.7 %

Procedure:
The process is carried out as in Example 4 with the difference that 0.6 g (0.00213 moles) of 6-methyl-8β-hydrazinomethyl-ergoline and 0.25 g (0.00234 moles) of dimethylcarbamoyl chloride are used as the starting substances. 0.5 g (69%) of 6-methyl-8β-([N'-dimethylcarbamoyl-hydrazino]-methyl)-ergoline are obtained; m.p.: 205°-206° C., [α]D20 =-36.2° (c=1, in 96% ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[CH:15]=[C:14]3[O:16][CH2:17][O:18][C:13]3=[CH:12][C:11]=2[CH:19]([CH3:24])[C:20](OC)=[O:21])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:28][NH2:29]>COCCO>[CH2:17]1[O:16][C:14]2=[CH:15][C:10]3[C:8]([C:7]4[CH:25]=[CH:26][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:29][NH:28][C:20](=[O:21])[CH:19]([CH3:24])[C:11]=3[CH:12]=[C:13]2[O:18]1
Reactant: NN
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Solvent: COCCO
Solvent: O
Product: CC1C(=O)NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of methyl 2-(2-(4-nitrobenzoyl)-4,5-methylenedioxyphenyl)propionate (211 mg, 0.59 mmol), hydrazine hydrate (0.15 mL, 2.4 mmol), and 2-methoxyethanol (6 mL) was heated to reflux for 72 h. The solvent was removed in vacuo and the crude product was purified by chromatography to yield 7,8-methylenedioxy-5-methyl-1-(4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one which was treated with excess amount of hydrazine and Raney Ni for 1 h. The reaction was then allowed to settled and liquid phase was decanted. The solvent was then removed and residue obtained was purified by chromatography (10% acetone in CH2Cl2) to yield the product (5 mg). 1H NMR (CDCl3) 8.44 (s, 1H), 7.43 (d, J=8.7, 2H), 6.86 (s, 1H), 6.68 (d, J=8.7, 2H), 6.65 (s, 1H), 6.04 (s, 1H), 6.00 (s, 1H), 4.83 (b, 2H), 3.29 (q, J=6.8, 1H), 1.59 (d, J=6.8, 3H).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([CH3:39])[C:17]2[C:22]([C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=[C:19]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:18]=2)=[O:13])C1C=CC=CC=1.[OH-].[K+]>CCO>[CH2:25]([O:24][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:20][CH:21]=2)[C:16]([CH3:39])=[N:15][C:14]=1[C:12]([NH:11][CH2:10][C:9]([OH:40])=[O:8])=[O:13])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(=O)NCC(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A mixture of [(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester (160 mg, 0.3 mmol; Example D-81d), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 18 h before the solvent was evaporated in vacuo. To the residue was added water (5 ml) and the mixture was washed with Et2O (2×20 ml). Then the solution was acidified by addition of aqueous 6N HCl and extracted with EtOAc (2×20 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan gum (93 mg); MS-(+)-ion: M+1=443.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:25]1([CH2:31][CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:35](=[O:36])[C:34]([S:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:38]([OH:39])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethyl acetophenone (1.75 g, 11.82 mmol), lithium diisopropylamide (1.89 g, 17.73 mmol), chlorotrimethylsilane (2.25 mL, 17.73 mmol), THF (120 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 155-157° C.; 1H NMR (400 MHz, DMSO-d6) δ2.34 (s, 6 H), 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.21 (m, 6 H), 7.41 (s, 2 H), 8.74 (d, 2 H).