Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:4][O:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)c2)O1
Temperature: 40 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution of (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate (8.5 g, 32 mmol) in THF (80 ml) was added a solution of LiOH (2.3 g, 96 mmol) in water (20 ml). The mixture was stirred for 15 hours at 40° C. The mixture was concentrated and diluted with saturated solution of Na2CO3 (50 ml), washed with ethyl acetate (50 ml×2), The aqueous layer was adjusted to pH=4 by addition of aqueous 3N HCl. The precipitate was collected by filtration and the filtered cake was dried in vacuo to obtain (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid as a white solid, (5.8 g, 72% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)([O-])O.[Na+]>ClCCl>[S:16]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:7][CH:8]=1)(=[O:18])(=[O:17])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Reaction time: 8 h

Procedure:
4-Pyrrolidinophenethyl alcohol (16.41 g, 85.9 mmol) was dissolved in dichloromethane (150 ml). Dissopropylethylamine (19.0 ml, 108 ml) and methanesulfonyl chloride (8.40 ml, 108 mmol) were added to the obtained solution at 0° C., and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 4-pyrrolidinophenethyl mesylate in the form of a white solid (21.14 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]([OH:31])[CH2:24][P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([NH:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:12]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([NH:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)=[O:12])[C:23]([CH2:24][P:25](=[O:30])([O:28][CH3:29])[O:26][CH3:27])=[O:31]
Reactant: COc1cc(C(O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CP(=O)(OC)OC)ccc1OCC(=O)Nc1nc2ccccc2s1
Yield: 41 %

Procedure:
To a solution of dimethyl {2-[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)phenyl]-2-hydroxyethyl}phosphonate (19.0 g) in chloroform (300 ml) is added active manganese dioxide (17.7 g), and the mixture is refluxed for three hours. To the mixture is additionally added active manganese dioxide (18 g), and the mixture is refluxed for three hours. To the mixture is further added active manganese dioxide (20 g), and the mixture is refluxed for three hours. The manganese dioxide is collected by filtration, and washed with chloroform. The filtrate and the washings are combined and concentrated under reduced pressure to remove the chloroform. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=200:1→50:1) to give dimethyl {[3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methyl}phosphonate (7.76 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.BrC1C=CC([C@@H](N2CC[C@](C3C=CC(F)=CC=3)(C)OC2=O)C)=CC=1.CC1C=C(B(O)O)C=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@@](C)(c4ccc(F)cc4)OC3=O)cc2)ccn1
Agent: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](C)(c2ccc(F)cc2)OC1=O
Agent: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CCC(C)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
Isomer 1 of the title compound, (S)-6-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one, was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-methyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.28, m/z=405 (M+1); 1H NMR (CDCl3) 8.84 (d, 1H, J=6.1 Hz), 7.81 (d, 1H, J=5.9 Hz), 7.75 (s, 1H), 7.70 (d, 2H, J=8.2 Hz), 7.52 (d, 2H, J=8.20 Hz), 7.34-7.31 (m, 2H), 7.09 (t, 2H, J=8.6 Hz), 5.81 (q, 1H, J=7.2 Hz), 2.89 (s, 3H), 2.84-2.72 (m, 2H), 2.31 (dt, 1H, J=13.9, 3.7 Hz), 2.11-2.03 (m, 1H), 1.64 (s, 3H), 1:38 (d, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:25]([OH:34])([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCCCC(=O)CCCCCCCC
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (5.00 g, 20 mmol) in dry diethylether (170 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 12.5 mL, 20 mmol) in dry diethylether (170 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Heptadecan-9-one (6.22 g, 24 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 85 mL) and water (85 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by gradient column chromatography (eluent hexane/EtOAc 95:5) to afford the title compound (IIe) as a yellow oil (6.3 g, 75%). 1H-NMR (CDCl3): δ=7.34 (dd, J=5.1 Hz, J=1.3 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 7.07 (dd, J=3.5 Hz, J=1.2 Hz, 1H), 6.99 (dd, J=5.1, J=3.5 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 2.36 (t, J=7.7 Hz, 4H), 1.39-1.07 (m, 20H), 0.91-0.81 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[I:11][C:12]1[CH:13]=[C:14]([C:6]2[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Ic1cccc(I)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2cccc(I)c2)o1
Yield: 25.9 %

Procedure:
5-Formyl-2-furanboronic acid (280 mg, 2 mmol) and 1,3-diiodobenzene (660 mg, 2 mmol) were dissolved in 1,2-dimethoxyethane (15 mL), tetrakis(triphenylphosphine)palladium (114 mg, 0.1 mmol) was added thereto, 2 mol/L sodium carbonate (4.6 mL) was then added thereto, and the mixture was heated to reflux for 3 hours while stirring. After the reaction was completed water (20 mL) was added, and extraction with ethyl acetate (20 mL×2) was carried out. The organic layer was washed with saturated brine, water was removed using anhydrous sodium sulfate, the solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give 5-(3-iodophenyl)furan-2-carbaldehyde in a yield of 155 mg (yield 25.9%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[CH:19][C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]2[NH:17][C:18]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[N:25]=3)=[C:19]([I:1])[C:20]=2[C:21]([NH2:23])=[O:22])[CH:15]=1
Reactant: CNc1nccc(-c2cc(C(N)=O)c(-c3cc(Cl)ccc3C)[nH]2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nccc(-c2[nH]c(-c3cc(Cl)ccc3C)c(C(N)=O)c2I)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
N-iodosuccinimide (301 mg, 1.34 mmol) was added to a solution of 2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide (433 mg, 1.27 mmol) in dry DMF (5 mL). The reaction mixture was stirred at room temperature for 5 h and poured into iced water (50 mL). The solid was then filtered with suction, washed thoroughly with water, dried in an oven under vacuum at 50° C. and purified by flash chromatography over silica gel (DCM/MeOH/7 N NH3 in MeOH 95/5/0.5) to afford the title compound (344 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:35]([OH:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:38][CH:35]([CH3:37])[CH3:36])[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: CC(C)O
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1Cl
Product: CC(C)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 399 instead of the compound prepared in Example 215 and isopropanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].[CH2:23]1[C@H:30]([N:31]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:33])[C:28](=[O:29])[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]([C@@H:15]([NH:19][C:25](=[O:26])[CH2:24][CH2:23][C@H:30]([N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:33])[C:28]([OH:29])=[O:27])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) and N-phthaloyl-L-glutamic anhydride (259 mg, 1 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol). The solution was stirred at room temperature for 2 h. The reaction was quenched with 1N HCl (10 mL) and the pH was adjusted to 2.0-3.0. The mixtures were extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo and the residue was purified by preparative HPLC (350 mg, 60%) to yield Compound C-2, which is identical to the S-R stereoisomer of the Compound C racemate in Examples 5 and 5a. 1H-NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 1.52 (s, 3H), 1.55 (s, 3H), 1.60 (s, 3H), 1.86-1.98 (m, 8H), 2.33-2.43 (m, 2H), 2.54-2.57 (m, 2H), 2.78 (dd, J=5.0, 15.0 Hz, 1H), 2.91 (dd, J=5.0, 15.0 Hz, 1H), 3.06 (dd, J=5.0, 10.0 Hz, 1H), 3.14 (dd, J=5.0, 10.0 Hz, 1H), 4.65 (dd, J=5.0, 10.0 Hz, 1H), 4.96 (t, J=5.0 Hz, 1H), 5.00 (m, 2H), 5.11 (t, J=5.0 Hz, 1H), 6.79 (d, J=10.0 Hz, 1H), 7.63-7.65 (m, 2H), 7.74-7.76 (m, 2H), 8.00 (broad, 2H). 13C-NMR (125 MHz, CDCl3): δ 16.06, 16.18, 17.76, 25.19, 25.78, 26.47, 26.73, 29.77, 32.59, 32.79, 39.65, 39.72, 51.10, 51.85, 119.37, 123.76, 123.80, 124.36, 131.39, 131.62, 134.40, 135.36, 140.24, 167.75, 172.78, 173.05, 174.51; ES-MS: mass calcd for Chemical Formula: C31H40N2O7S 584.72. Found (M+) m/z 585.3, (M+Na) m/z 607.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[K+].I[CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:19]([N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCI
Reactant: Clc1ccc(CNc2cncnc2)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(Cl)cc1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 g of N-[(4-chlorophenyl)methyl]-(5-pyrimidyl)amine dissolved in 50 ml of tetrahydrofuran was added 2 g of a 24.6% suspension of potassium hydride in oil. The reaction was allowed to stir at room temperature for approximately 1 hour at which time 2 g of iodobutane was added to the reaction mixture. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in diethyl ether and the organic phase was washed with water, separated and dried over anhydrous magnesium sulfate. Following concentration of the solution under reduced pressure the residue was chromatographed over silica gel. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford N-butyl-N-[(4-chlorophenyl)methyl]-(5-pyrimidyl)amine as a solid. mp=67°-68° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:3]=1N.[C:13]([O-])([O-])=[O:14].[K+].[K+]>CC(C)=O>[CH3:13][O:14][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C)cc([N+](=O)[O-])cc1C

Procedure:
2,6-Dimethyl-4-nitroaniline (15 g) Me2SO4 (22 g) and K2CO3 (23 g) were dissolved in 150 mL acetone and refluxed for 3 hours. The reaction mixture was filtered and concentrated. The organic residue was dissolved in warm hexane and let to crystallize out in the fridge. After filtration, 2-methoxy-1,3-dimethyl-5-nitrobenzene was collected as white solid (12 g). 1H-NMR (300 MHz, CDCl3): δ=7.95 (s, 2H), 3.80 (s, 3H), 2.38 (s, 6H) ppm. MS: m/z 182 (100, M+H)+
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C([C:10]([OH:19])([CH:15]([CH3:18])[CH:16]=[CH2:17])[C:11]([CH3:14])([CH3:13])C)(C)(C)C.C(=O)C1C=CC=CC=1.C(OCC)C>CCCCC.C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:18][CH:15]([CH:16]=[CH2:17])[CH:10]([C:11]1[CH:13]=[CH:3][CH:2]=[CH:1][CH:14]=1)[OH:19]
Reactant: [Li]CCCC
Reactant: C=CC(C)C(O)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCCCC
Solvent: O=Cc1ccccc1
Product: C=CC(C)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.58 ml of a 1.6-molar solution of n-butyllithium (2.52 mmol) in pentane were added dropwise at −78° C. under argon for 5 minutes to a stirred solution of 500 mg (2.52 mmol) 3-tert-butyl-2,2,4-trimethylhex-5-en-3-ol in 4 ml THF. The solution obtained was stirred for 15 minutes, then 256 μl (2.52 mmol) benzaldehyde and subsequently for 3 minutes a solution of 343 mg (2.52 mmol) ZnCl2 in 2 ml THF were added. The reaction mixture was stirred for 1 hour at −78° C. and then heated to room temperature. Subsequently it was processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 10% diethyl ether/light gasoline. There was obtained the alcohol as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1([Mg]Br)C=CC=CC=1.O>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone (168 mg, 0.5 mmol) was dissolved in 10 mL of anhydrous THF. Phenyl magnesium bromide (1.5 mL, 1.5 mmol) was added dropwise at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 1 h. Water (3 mL) was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.40-7.20 (m, 7H), 7.10 (d, 1H), 7.95 (m, 2H), 7.85 (m, 1H), 6.75 (m, 1H), 4.80 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.62 (m, 2H), 3.0 (s, 3H), 2.80-2.60 (m, 3H), 2.40 (s, 3H).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8]1[NH:9][CH2:10][CH2:11][N:12]=1.[OH:13][CH2:14][CH2:15][NH:16][NH2:17]>C(O)C>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[OH:13][CH2:14][CH2:15][N:16]([C:8]1[NH:9][CH2:10][CH2:11][N:12]=1)[NH2:17]
Reactant: NNCCO
Reactant: CSC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NN(CCO)C1=NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methylthio-2-imidazoline sulfate (2:1) (1.98 g) and 2-hydroxyethylhydrazine (2.12 g) are heated in ethanol (3 ml) at reflux for 1 hr., then stirred at 25° C. for 3 hr. The solution was diluted with ethanol (20 ml) and kept at 4° C. for 18 hours. The crystals which separated were filtered out and washed with ethanol. Weight 811 mg, mp 190-4° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.Cl.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][NH2:42].C([O-])(=O)C.[K+]>C(O)C.O>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]1[C:11]2[CH:10]=[C:9]3[CH2:8][CH2:7][C@H:6]4[C@H:15]([C@:14]3([CH3:16])[CH2:13][C:12]=2[CH:17]=[N:42]1)[C@H:2]([OH:1])[CH2:3][C@@:4]1([CH3:31])[C@@:22]2([CH2:21][CH2:20][C@H:5]41)[C:26]1([CH2:30][O:29][CH2:28][O:27]1)[O:25][CH2:24][O:23]2
Reactant: NNc1ccc(F)cc1F
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@]12Cc3cnn(-c4ccc(F)cc4F)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2
Temperature: 90 °C
Yield: 59.7 %

Procedure:
(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde (Steroids 2003, (68), 177-191) (400 mg, 0.92 mmol) was dissolved in ethanol (10 ml) and water (1 ml). (2,4-difluorophenyl)hydrazine hydrochloride (167 mg, 0.92 mmol) and potassium acetate (160 mg, 1.63 mmol)) were added and the mixture was heated under microwave irradiation at 90° C. for 20 minutes. The mixture was partitioned between EtOAc (10 ml) and water (10 ml). The organic phase was washed with water (2 times 10 ml) and brine (5 ml) and was dried over Mg2SO4. Filtration followed by evaporation of the solvent gave 297 mg of the crude compound which was used as such without further purification. APCI-MS m/z: 541 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:16][C:17](=[O:19])[CH3:18])([CH2:11][C:12](=O)[CH2:13]Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:16][C:17](=[O:19])[CH3:18])([CH2:11][C:12]1[CH:13]=[N:28][C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:27]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)CBr)(NC(C)=O)C(=O)OCC
Reactant: Nc1ccccc1N
Product: CCOC(=O)C(Cc1cnc2ccccc2n1)(NC(C)=O)C(=O)OCC

Procedure:
Condensation of 2-acetamido-2-(3-bromo-2-oxopropyl) malonic acid diethyl ester with 1,2-phenylendiamine yielding 2-acetamido-2-(2-quinoxalinylmethyl) malonic acid diethyl ester 151 g (1.39 mol) of 1.2-phenylenediamine were suspended under stirring in 4 l of ethanol in a 20 l round flask. A solution of 516 g (1.45 mol) 2-acetamido-2-(3-bromo-2-oxopropyl)-malonic acid diethyl ester in 7 l ethanol was slowly added by dropping over 48 hours. At the same time, a solution of 180 ml (1.3 mol) triethylamine in 1 l ethanol was added by dropping from a separate tap funnel so that the pH value of the reaction solution did not fall below pH 4. The reaction batch was kept agitated for 3 days after completing the addition of α-bromomethyl ketone. The yellowish brown solution was then liberated from the solvent in a vacuum. The residue was immediately taken up under slight heating in 2.5 l ethyl acetate and allowed to cool down. The triethyl ammonium hydrobromide precipitate that developed after some time was sucked off and washed with ethyl acetate. The filtrate was heated with 25 g of activated carbon to about 50° C. and stirred for 15 minutes, then the solution was filtered off using a frit filled with silica gel and washed. The filtrate was reduced by evaporation to about 900 ml in which process a portion of the product precipitated as yellow crystal needles. 250 ml hexane were added to the batch and allowed to stand for some hours at 4° C. The precipitated product was sucked off and recrystallized from an ethyl acetate-hexane mixture. The parent lye was purified by chromatography. The overall yield of 2-acetamido-2-(2-quinoxalinylmethyl)-malonic acid diethyl ester was 70% of the theoretical yield.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC.[CH:25]1([N:28]([CH3:47])[C:29]2[C:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[S:42][C:33]=3[N:32]=[C:31]([CH2:43][C:44]([OH:46])=O)[N:30]=2)[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([N:28]([CH3:47])[C:29]2[C:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[S:42][C:33]=3[N:32]=[C:31]([CH2:43][C:44]([N:3]([CH3:4])[CH3:2])=[O:46])[N:30]=2)[CH2:27][CH2:26]1
Reactant: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCCC3)C1CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
The EDCI (0.477 g, 0.00241 mol), HOBt (0.22 g, 0.00144 mol) and N,N-dimethyl amine in THF (2 M, 1.2 ml, 0.00241 mol) were added to a solution of [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diazabenz[a]azulen-2-yl]-acetic acid (0.4 g, 0.0012 mol) in 10 ml of THF. The mixture was stirred for 3 h at room temperature then concentrated under vacuum. The crude was purified by chromatography on silica gel using 2% MeOH-DCM to give 2-[4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-N,N-dimethyl-acetamide (0.25 g, 58%) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 2H), 3.06 (s, 3H), 2.92-3.02 (m, 8H), 2.84-2.88 (m, 2H), 2.72-2.83 (m, 1H), 1.82-1.90 (m, 2H), 1.67-1.78 (m, 2H), 1.50-1.60 (m, 2H), 0.62-0.72 (m, 2H), 0.40-0.48 (m, 2H); LC-MS: [M+H]=359.4 m/z.