Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([N:31]=[C:32]=[O:33])[CH3:30].O>ClCCl>[CH:29]([NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1)=[O:33])([CH3:30])[CH3:28]
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)Nc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To an ice-cooled solution of tert-butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino]-2-oxoethyl}carbamate (200 mg) in dichloromethane (4 ml) was added 2-propyl isocyanate (55 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by stirring, and the organic layer was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[({4′-[(isopropylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (240 mg) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](CC(O)=O)=[CH:3][CH:2]=1.[C:11]([O-:18])(=[O:17])/[CH:12]=[CH:13]/[C:14]([O-:16])=[O:15]>>[C:11]([OH:18])(=[O:17])/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15].[N:1]1([CH:2]2[CH:2]3[CH:3]([CH2:4][CH2:5][CH2:6][NH:1]3)[CH2:5][CH2:4][CH2:3]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: O=C(O)Cc1ccncc1
Product: C1CNC2C(C1)CCCC2N1CCCC1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 3 h

Procedure:
Using the procedure of Example 8, 452 mg of 4-pyridyl-acetic acid were reacted with stirring for 3 hours and the product obtained in the form of a base was converted into fumarate by the method of Example 4 to obtain 373 mg of [4aRS(4aα, 8α, 8aα)](±)-1-(4-pyridinyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinoline fumarate melting at 232° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](N1C=CN=C1)([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:12]>O1CCCC1>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCCN1CCCC1
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a flask under nitrogen, 4-Pyrrolidin-1-yl-butylamine (1.3 equiv, 10.1 g) was taken up in tetrahydrofuran (105 mL, 5 volumes). The mixture was cooled to 0° C. and 1,1′-carbonyldiimidazole (1.3 equiv, 11.6 g) was added. The mixture stirred at 0° C. for 20 minutes, then warmed to 20° C. over 10 minutes and held at 20° C. for 30 minutes.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:16][C:15]2=[O:28])[CH:11]=[N:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[O:28]=[C:15]1[CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:18][N:14]1[CH2:13][N:12]1[C:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:9][N:10]=[CH:11]1
Reactant: NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reaction time: 1 h

Procedure:
In a three necked flask, under argon, propionyl chloride (0.0134 ml) is added to a solution of 1-(5-aminomethyl-imidazol-1-ylmethyl)-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one a34 (0.050 g, 0.15 mmol) and Et3N (0.29 ml) in CH2Cl2 (3 ml) at 0° C. After 1 h, the reaction mixture is quenched with ice-water, extracted with CH2Cl2, dried over MgSO4, filtered and evaporated in vacuo. The crude reaction mixture is purified by chromatography on reverse phase silicagel to afford N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide 86(37.2 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([C@H:8]([CH3:29])[CH2:9][C@@:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:11]=NC2C=CC=C3C=2C=CC(C)=N3)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=[O:37].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([C@@H:8]([CH3:29])[CH2:9][C@:10]([OH:24])([C:25]([F:26])([F:27])[F:28])[CH:11]=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
175 mg (0.60 mmol) of (2R*,4R*-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 103 mg (0.63 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are stirred in 20 ml of toluene at 100° C. for 2 h. After the mixture is cooled, it is poured into water, with vigorous stirring to follow. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again using ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 230 mg of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol as a crude product. 230 mg of the crude imine in 12 ml of CH2Cl2 are admixed dropwise at −30° C. with 6 ml (6 mmol) of a 1 M boron tribromide solution. The batch is allowed to warm to room temperature and is stirred for 2 hours. It is admixed with saturated NaHCO3 solution, the phases are separated, the aqueous phase is extracted with CH2Cl2 and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 145 mg of product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[C:25]([CH3:26])=[CH:24][C:23]([NH2:27])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(C(C)C)C(C)C)C.[CH2:39]([S:41]([Cl:44])(=[O:43])=[O:42])[CH3:40].[OH-].[Na+]>ClCCl.C(O)C>[ClH:44].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]4[C:25]([CH3:26])=[CH:24][C:23]([NH:27][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[CH:22][C:21]=4[O:28][CH3:29])[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1cc(N)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(C)c(OCCCN2CCN(c3cccc4sccc34)CC2)c(OC)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A dichloromethane solution (4 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenylamine (0.2 g, 0.49 mmol) was cooled on ice. To this, N-ethyldiisopropylamine (0.15 ml, 0.87 mmol) and ethane sulfonylchloride (0.07 ml, 0.73 mmol) were added and the mixture was stirred at room temperature for one hour. Further, N-ethyldiisopropylamine (0.15 ml, 0.87 mmol) and ethane sulfonylchloride (0.07 ml, 0.73 mmol) were added and the mixture was stirred at room temperature for 19 hours. To this, an aqueous 6N-sodium hydroxide solution (0.5 ml) and ethanol (2 ml) were added and the mixture was stirred at room temperature overnight. Dichloromethane was added to the reaction solution, which was then washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure. 4N-hydrochloride/ethyl acetate solution was added to the residue. The crystal generated was filtrated and dried to obtain ethanesulfonic acid {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methyl-phenyl}amide hydrochloride (222 mg, 85% yield) as white powder.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]#[N:25])[CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][O-:29].[Na+].O>CO>[CH3:28][O:29][C:24]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)=[NH:25]
Reactant: N#CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=N)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]-piperidine-1-carbonitrile of Example 101 (20.0 g, 0.054 moles) and sodium methoxide (12.4 ml of 25% sodium methoxide in methanol 0.054 moles) in methanol (120 ml) was warmed to effect solution and then stirred at ambient temperature for 3 hours. The mixture was poured into H2O, extracted (CHCl3), dried (MgSO4), and concentrated to yield an oil. The oil was triturated with hexane which produced 19 g of a solid. The solid was recrystallized twice from toluene-hexane which yielded 14.2 g (65%) of 4-[1-[4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboximidic acid methyl ester, m.p. 113°-115° C..
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C.O.C(OCC)(=O)C>[CH2:15]([O:14][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:16]
Reactant: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1nc(C)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of the compound prepared in Example 443 (2.04 g) in ethanol (50 mL) at ambient temperature was added a 21% solution of sodium ethoxide in denatured ethanol (4.24 mL). The reaction mixture immediately turned dark purple and was stirred at ambient temperature for 2.5 hours, then diluted with water (250 mL), and the resulting mixture was stirred at ambient temperature for 3 days. The mixture was poured into a separatory funnel and diluted with water (250 mL) and ethyl acetate (500 mL). The organic layer was dried over sodium sulfate and concentrated to give about 9 g of a dark semisolid. This material was partitioned between dichloromethane (200 mL) and water (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 4/1 hexanes/ethyl acetate, to provide the title compound (0.87 g) with the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][NH:30][CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]=[C:48]=[S:49])=[C:43]([N+:50]([O-:52])=[O:51])[CH:42]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:27]3[CH2:28][CH2:29][N:30]([C:48](=[S:49])[NH:47][C:44]4[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=4[N+:50]([O-:52])=[O:51])[CH2:31][C:26]=3[S:25][C:10]=2[N:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](=[O:16])[CH:13]([OH:15])[N:14]=1
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Reactant: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=S)N2CCc3c(sc4c3C(c3ccccc3Cl)=NC(O)C(=O)N4CCc3ccccc3)C2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido[4′,3′:4,5]thieno[2,3-e]-1,4-diazepine-2-one (0.167 g, 0.29 mmol) is dissolved in dichloromethane (2 ml). Triethylamine (0.06 ml, 0.44 mmol) then 4-methoxy 2-nitrophenylisothiocyanate (0.062 g, 0.29 mmol) are added. After agitation at 23° C. for 2 hours, the solvent is evaporated off. After purification by chromatography on a silica column (eluent: dichloromehane-methanol: 98-2), the fractions contining only the product are evaporated. The solid is taken up in ether and a drop of dichloromethame and a drop of acetone are added. After filtration on flit and washing the solid with ether, the desired product is obtained in the form of a yellow powder (0.08 g, 41%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([N:32]=[C:33]=[O:34])[CH:12]=[C:13]([Cl:31])[C:14]=1[O:15][C:16]([F:30])([F:29])[CH:17]([O:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[F:18].[CH3:35][N:36]1[C:43](=[O:44])[CH2:42][C:40](=[O:41])[N:39]([CH3:45])[C:37]1=[O:38].C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:45][N:39]1[C:40](=[O:41])[CH:42]([C:33](=[O:34])[NH:32][C:11]2[CH:10]=[C:9]([Cl:8])[C:14]([O:15][C:16]([F:29])([F:30])[CH:17]([O:19][C:20]([F:28])([F:27])[C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[F:18])=[C:13]([Cl:31])[CH:12]=2)[C:43](=[O:44])[N:36]([CH3:35])[C:37]1=[O:38]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C=Nc1cc(Cl)c(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)F)c(Cl)c2)C(=O)N(C)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.04 g (10.3 mmol) of triethylamine and then 9.25 g (20.5 mmol) of 3,5-dichloro-(4-(2-(1,1,2,2,3,3-hexafluoropropoxy)-1,1,2-trifluoroethoxy))-phenyl isocyanate were added to 3.20 g (20.5 mmol) of 1,3-dimethylbarbituric acid in 40 ml of toluene at room temperature. The mixture was subsequently stirred at 40° C. for 2 hours, 200 ml of methylene chloride were added and the mixture was washed with 100 ml of 2N aqueous hydrochloric acid and several times with water. After drying over magnesium sulfate, the mixture was concentrated.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)=[CH:44][CH:43]=1>C(Cl)Cl.C1COCC1>[F:41][C:42]1[CH:43]=[CH:44][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50]([O:34][C@@H:35]3[CH2:39][CH2:38][NH:37][C:36]3=[O:40])=[CH:49][CH:48]=2)=[CH:54][CH:55]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)nc1
Reactant: O=C1NCC[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccc(F)cc2)nc1

Procedure:
A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1.8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (SiO2; DCM/MeOH 15:1) to provide the title compound. MS ESI+: m/z=289 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].O[N:18]=[C:19]([NH2:35])[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=2[O:26][C:25]1=[O:34].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([O:1]/[N:18]=[C:19](\[NH2:35])/[CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[O:26][C:25]3=[O:34])=[O:3])[C@H:16]2[NH:15]1
Reactant: Cc1ccc2oc(=O)n(CCCCC(N)=NO)c2c1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2oc(=O)n(CCCC/C(N)=N/OC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
To a suspension of biotin 7 (23 mg, 0.092 mmol) and compound 13 (22 mg, 0.083 mmol) in anhydrous DMF (0.5 ml) was added EDCl (16 mg, 0.10 mmol) and DIPEA (13 mg, 0.10 mmol) and stirred under a nitrogen atmosphere at ambient temperature for 12 h. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml) and brine (25 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 19:1 dichloromethane/methanol to give a yellow oil (21 mg, 51%).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3].[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[O:10])=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3]
Reactant: NCC(F)(F)F
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-azido-3-iodobenzoic acid (5.00 g, 17.3 mmol) obtained in Example 379a) in DMF (80 ml) were added sequentially 2,2,2-trifluoroethylamine (2.5 g), triethylamine (3.6 ml), HOBt (1.3 g) and WSC (5.0 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/20 to 1/1) to give the title compound as a pale-yellow solid (2.93 g, 46%).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:2]([CH3:4])[CH3:3])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 22 h
Yield: 98.6 %

Procedure:
2-Bromopropane (4.51 mL, 5.90 g, 48 mmol) was added to a mixture of 4-benzyloxy-2-nitrophenol (J.Biol.Chem., 1985, 260, 3440, 2.94 g, 12 mmol) and potassium carbonate (9.95 g, 72 mmol) in dimethylformamide (20 mL) and the mixture was stirred at 50° C. for 22 h. The mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (3.40 g, 99%). 1H NMR (360 MHz, CDCl3) δ 7.41-7.33 (6H, m), 7.12 (1H, dd, J 9.1, 3.1 Hz), 7.02 (1H, d, J 9.1 Hz), 5.05 (2H, s), 4.52 (1H, hept, J 6.1 Hz), and 1.35 (6H, d, J 6.1 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccc(F)cc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)cc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2,4-difluoro-phenylhydrazine according to the method described for example 43. MS: M=429.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][C@H:5]2[CH3:24].[CH3:25][O:26][CH2:27][C@@:28]12[C@@H:45]3[C@H:36]([C@H:37]4[C@@:41]([CH2:43][CH2:44]3)([CH3:42])[C@@H:40]([OH:46])[CH2:39][CH2:38]4)[CH2:35][C@H:34]([CH3:47])[C:33]1=[CH:32][C@@H:31]([OH:48])[CH2:30][CH2:29]2.C[O:50][CH2:51][C@@:52]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC1=C[C@@H](O)CC2>>[C:27]([O:23][C@H:7]1[CH2:6][C@@H:5]([CH3:24])[C@@:4]2([CH2:3][O:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:22][C:51](=[O:50])[CH3:52])=[CH:8]1)(=[O:26])[CH3:28].[C:3]([O:48][C@H:31]1[CH2:30][CH2:29][C@@:28]2([CH2:27][O:26][CH3:25])[C:33]([C@@H:34]([CH3:47])[CH2:35][C@@H:36]3[C@@H:45]2[CH2:44][CH2:43][C@@:41]2([CH3:42])[C@H:37]3[CH2:38][CH2:39][C@@H:40]2[O:46][C:51](=[O:50])[CH3:52])=[CH:32]1)(=[O:2])[CH3:4]
Reactant: COC[C@@]12C(=C[C@@H](O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: COC[C@]12CC[C@H](O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: COC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: COC[C@@]12C(=C[C@@H](OC(C)=O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(C)=O)[C@@]3(C)CC[C@@H]12
Product: COC[C@]12CC[C@H](OC(C)=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
Substituting 19-methoxy-1β-methyl-4-androstene-3β,17β-diol and 19-methoxy-6α-methyl-4-androstene-3β,17β-diol in lieu of the 19-methoxyandrost-4-ene-3β,17β-diol above results in the preparation of 19-methoxy-1β-methyl-4-androstene-3β,17β-diol diacetate and 19-methoxy-6α-methyl-4-androstene-3β,17β-diol diacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:14]2C=CN=CC=2)[NH2:13])[CH:5]=[C:6](OC)[CH:7]=1.C[O:21][CH2:22]Cl.[OH-].[Na+].[C:26](O)(=O)[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:21][CH3:22])[CH2:14][N:12]([NH:13][C:27]1[CH:26]=[CH:14][N:12]=[CH:11][CH:10]=1)[CH2:11][CH2:10]2
Reactant: COCCl
Reactant: CC(=O)O
Reactant: COc1cc(F)cc(CCN(N)c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1F)CCN(Nc1ccncc1)C2
Temperature: 0 °C
Yield: 23 %

Procedure:
Lithium aluminum hydride (4.5 g) was added portionwise to a suspension of the N-[2-(3-fluoro-5-methoxyphenyl)ethylidine]-N'-4-hydrazine hydrochloride (16.8 g) in tetrahydrofuran (300 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hr, and sodium sulfate decahydrate was added. The mixture was filtered and was concentrated to provide 15.1 g of N-[2-(3-fluoro-5-methoxyphenyl)ethyl]-N-pyridin-4-yl hydrazine. A solution of N-[2-(3-fluoro-5-methoxyphenyl)ethyl]-N-pyridin-4-yl hydrazine (15.1 g) and chloromethyl methyl ether (5.3 g) in acetic acid (240 ml) was heated under reflux for 2 hrs and then cooled to 0° C. 50% Sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was recrystallized from methanol to provide 3.5 g (23%) of product, mp 216-218° C.