Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.CCOC(C)=O>CS(C)=O>[Br:15][CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(Br)C(=O)c1ccccc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Ethyl benzoylacetate (0.27 mL, 1.6 mmol) [Fluka cat#12990] was dissolved in dimethyl sulfoxide (5.0 mL) at room temperature and the N-bromosuccinimide (0.30 g, 1.7 mmol) was added portion wise. The reaction mixture was stirred for 3 h and EtOAc was added and washed with water, water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give Ethyl 2-bromo-3-oxo-3-phenylpropanoate (0.40 g, 95%) as an oil %). LCMS calc. for C11H12BrO3 (M+H)+: m/z=271.0, 273.0. found: 271.0, 273.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Br[CH2:23][CH:24](OCC)OCC>CC(O)C>[Br:8][C:6]1[N:7]2[CH:23]=[CH:24][N:1]=[C:2]2[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3ccnc23)CC1
Yield: 23.4 %

Procedure:
A 500 mL round bottom flask was charged with tert-butyl 4-(3-amino-5-bromopyrazin-2-yl)piperazine-1-carboxylate (4.0 g, 11.2 mmol), 2-bromo-1,1-diethoxyethane (3.3 g, 16.5 mmol) and absolute propan-2-ol (200 mL). The resulting solution was refluxed under N2 for 12 h. Work-up: the resulting crystalline solid was collected by filtration, washed with EtOAc (100 mL), and dried to afford 1.0 g (23%) of the product as a yellow solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([O:3]C)=[O:2].O.O[Li].O.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (15.4 g, 36 mmol), from part E, in dioxane (150 mL) and water (100 mL) is treated with LiOH·H2O (3.31 g, 79 mmol) and stirred overnight on a water bath. The reaction is poured into saturated aqueous NaHSO4 (150 mL), extracted with methylene chloride (3×100 mL), extracts washed with saturated aqueous NaCl, dried over MgSO4 and concentrated to a volume of 100 mL. At this point crystals begin to form and 2:1 hexanes/ethyl acetate (50 mL) is added, the mixture triturated, cooled to room temperature and 17β-carboxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one collected as a fluffy white powder; yield: 9.44 g (63%); m.p. 215°-216° C. Anal. Calcd. for C24H35NO5 ·1/4H2O; C, 68.30; H, 8.48; N, 3.32. Found: C, 68.45; H, 8.41; N, 3.28.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]([N:19]([C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][CH:22]=2)[CH3:20])[N:9]=1>ClCCl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]([N:19]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH:26]([CH3:30])[C:27]([Cl:2])=[O:29])=[CH:31][CH:32]=2)[CH3:20])[N:9]=1
Reactant: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)Cl
Reaction time: 12 h

Procedure:
2-{4-[N-(1,7-Dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionyl chloride was prepared by adding phosphorus pentachloride (1.07 g) portionwise to a solution of 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid (2.0 g) in dichloromethane at room temperature and stirring the reaction mixture for a period of 12 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[OH2:12]>CC(C)=O>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][C:2]([OH:12])=[O:1])=[CH:5][CH:6]=1)#[N:9]
Reactant: O
Reactant: N#Cc1ccc(CCO)cc1
Solvent: CC(C)=O
Product: N#Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-hydroxyethyl)benzonitrile (120 mg, 0.816 mmol) in acetone (3 mL), Jone's reagent (1.5 mL, 4.005 mmol) was added. After stirring for 10 minutes at room temperature, the crude reaction mixture was poured into water (10 mL) and extracted with CHCl3 (6×10 mL). Combined organics were dried over magnesium sulfate, filtered, and concentrated to give (4-cyanophenyl)acetic acid which was used without purification.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:5]=2[N:4]=[C:3]1[S:18][CH:19]([CH3:21])[CH3:20].[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[S:11][C:5]=4[N:4]=[C:3]3[S:18][CH:19]([CH3:21])[CH3:20])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CC(C)Sc1nc2sc(-c3ccccc3)cc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: CC(C)Sc1nc2sc(-c3ccccc3)cc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-amino-2-(isopropylthio)-6-phenylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (t, J=6.7 Hz, 6H), 1.61-1.71 (m, 12H), 1.92-1.97 (m, 3H), 2.05-2.15 (m, 2H), 3.78-3.87 (m, 1H), 7.36-7.49 (m, 3H), 7.75-7.79 (m, 3H), 10.92 (s, 1H); MS (DCI/NH3) m/z 494 (M+H)+; Elemental Analysis: Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02. Found: C, 68.53; H, 5.65; N, 9.98.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: OCc1cn2c(n1)sc1cc(Cl)ccc12
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cn2c(n1)sc1cc(Cl)ccc12

Procedure:
2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-chloroimidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 16.8 mmol) in methylene chloride/MeOH (300 mL: 50 mL) and active MnO2 (20 g, excess), 2.2 g (55% yield) of the aldehyde derivative was isolated as brown solid. (M+H) 236.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])(=O)=O.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:14][C:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1sccc1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1C#C[Si](C)(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2.07 g of 2-methoxycarbonyl-3-thienyl trifluoromethane sulfonate, 2.02 ml of trimethylsilylacetylene, 1.57 g of tetrakis (triphenylphosphine)palladium(0), 272 mg of cuprous iodide, 2.98 ml of triethylamine and 30 ml of N,N-dimethylformamide was stirred at 65° C. for 3 hours in a nitrogen atmosphere. Silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to silica gel column chromatography using 6% ethyl acetate/hexane, to give 1.78 g of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][C:16]=1[CH3:17])C.O[Li].O>>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:13][C:12]=1[CH2:11][CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH:5]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(CC#CCCCc1nc(-c2ccccc2)oc1C)c1cccs1
Agent: [Li]O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCCC#CCC(C(=O)O)c1cccs1
Yield: 47 %

Procedure:
The ester 1-12 was then hydrolyzed in a manner similar to the preparation of 1-11 with LiOH.H2O to provide 90 mg of acid 1-13 (47% yield). NMR CDCl3 (δ): 7.97 (2H, m); 7.43 (3H, m); 7.21 (1H, d, J=5.1 Hz); 7.06 (1H, d, J=3.1 Hz); 6.96 (1H, m); 4.21 (1H, dd, J=5.3, 10.7 Hz); 2.89 (2H, m); 2.62 (2H, m); 2.34 (3H, s); 2.23 (2H, m); 1.82 (2H, m). M+1=363.2. Biological Data: EC50=303 nM in AD3T3-L1 reporter assay. Maximal response of 97% rosiglitazone.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C-:12]#[N:13].[Na+]>[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([C:12]#[N:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)c([N+](=O)[O-])c1

Procedure:
11.75 g (77.2 mmol) of 4-methyl-2-nitroaniline underwent a Sandmeyer reaction in a conventional process by diazotization and substitution with NaCN and CuSO4 to give 9.6 g of crude 4-methyl-2-nitrobenzonitrile. 1H-NMR (DMSO-d6, δ in ppm): 8.25 (1H), 8.05 (1H), 7.80 (1H), 2.50 (3H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1B1OC(C)(C)C(C)(C)O1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.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>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: Oc1ccccc1Br
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)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: [K+]
Solvent: ClCCCl
Product: Cn1cccc1-c1ccccc1O
Temperature: 80 °C
Yield: 33.7 %

Procedure:
1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole (5.0 g, 24 mmol), tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.2 mmol), 2-bromophenol (4.2 g, 24 mmol), and potassium carbonate (24 mL of 2.0 M, 48 mmol) were combined in 1,2-dichloroethane (291 mL). The mixture was heated at 80° C. for 16 h. The mixture was cooled to 25° C. before it was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 2-(1-methylpyrrol-2-yl)phenol (1.4 g, 34%). ESI-MS m/z calc. 173.2, found 174.2 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: N.O1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4(OCC[O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36].Cl>CC(C)=O>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([O:35][CH3:36])[CH:11]=3)=[CH:16][N:17]([CH:25]3[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COc1cc(-c2cn(C3CCC4(CC3)OCCO4)c3ncnc(N)c23)ccc1N
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate (5.7 g, 0.011 mol), conc. ammonia solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at 120° C. The solvent was evaporated and the residue reconstituted in EtOAc/water (250 mL/100 mL). The organic layer was separated , dried (sodium sulphate), filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1 mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was dissolved in acetone (200 mL) and HCl (SN, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred at room temperature overnight and the solvent was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling) and extracted with EtOAc (3×150 mL). The combined organics were washed with water (2×100 mL). During the extraction process a solid precipitated. This solid was filtered and triturated in hot EtOAc/MeOH. The insolubles were filtered, the filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulphate), filtered and evaporated. The resulting solid was triturated with diethyl ether/ethyl acetate (5:1) and filtered to give 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a yellow solid. (2.3 g, combined yield=78%). 1H NMR (d6 DMSO, 400 MHz): 8.17(1H, s), 7.32(1H, s), 6.88(1H, s), 6.77(1H, m), 6.73(1H, m), 6.71(1H, m), 6.07(2H, bs), 5.14(1H, m), 3.81 (3H, s), 2.72(2H, m), 2.35(4H, m), 2.18 (2H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=11.24 min, 95%
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[F:16][C:17]([F:47])([F:46])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@H:32](OS(C)(=O)=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:46])([F:47])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@@H:32]([N:9]2[CH2:10][CH2:11][CH:6]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:8]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=1
Reactant: OCCCN(CC1CC1)C1CCNCC1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](OS(C)(=O)=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](c1ccccc1)N1CCC(N(CCCO)CC2CC2)CC1
Yield: 46.2 %

Procedure:
4.7 g of 4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidine are stirred together with 9.6 g of (R)—N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared from D-(−)-mandelic acid) and 3.4 ml of triethylamine in 200 ml of acetone for four hours at 65° C. The mixture is concentrated by evaporation in vacuo, combined with 100 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic fractions are dried over sodium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed with methylene chloride/methanol 1:1 over silica gel. The fractions found to be uniform by TLC are collected and the solvents are eliminated in vacuo. 5.5 g of (S)—N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide are obtained as a brownish-yellow oil, [α]D20=+35.1°
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Br[CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(=O)OCC>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH2:27][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:8]4[CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:25])[NH:6][N:7]=4)[CH:24]=[CH:23][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: COC(CBr)OC
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(OC)OC)cc3)oc2c1

Procedure:
100 mg (298 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 38.5 μL (316 μmol) 2-bromo-1,1-dimethoxy-ethane, 125 mg (904 μmol) potassium carbonate and 3 ml DMF are stirred for 6 h at 150° C. and then at RT over the weekend. Then the mixture is diluted with EA, and extracted with 10% sodium carbonate solution and then with sat. saline solution. The solv. of the org. phase is eliminated i.V. The residue is purified on silica gel (eluant: DCM/methanol) the solv. of the corresponding fractions is eliminated i.V. and the residue is recrystallised with EA/cyclohexane.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[NH:24][C:25](=O)[O:26]CC>CN(C)C=O>[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[N:24]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:25]1=[O:26]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
1.28 g of ethyl 3-amino-4,4,4-trifluorocrotonate was added to a 10 ml dimethylformamide solution of 0.33 g of sodium hydride (purity: 55%) under ice cooling and stirred at room temperature for 15 minutes, followed by addition of 1.31 g of ethyl 2,3,4-trifluorophenylcarbamate and was stirred at 90° C. for 4 hours. Then dimethylformamide was distilled away under reduced pressure and the residue was dissolved in 100 ml of water. This aqueous solution was washed with diethyl ether, then added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with water and dried, and then the solvent was distilled away under reduced pressure to obtain 0.3 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:42])=[O:41])[C:5]([C@@:7]1(C)[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2(OC(C)=O)[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:19](=[O:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[CH:4]([O:39][C:40]([CH3:42])=[O:41])[C:5]([C@@H:7]1[CH:8]([OH:37])[CH2:9][CH:10]3[C@@H:11]([CH2:31][O:32]3)[C@H:12]1[C@@H:13]2[O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)OC1C(=O)[C@@H]2C(O)CC3OC[C@H]3[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)CC(=O)C(C)=C1C2(C)C

Procedure:
Baccatin III (150 g, 0.25 mol) was dissolved in acetone (1.43 L). Commercially available manganese dioxide (450 g) was added in three portions under strong stirring. After the starting product disappeared (4 h) the suspension was filtered and the solvent evaporated off. The crude was suspended in AcOEt (100 ml) and refluxed for 1 h, then c-Hexane (100 ml) was added. The title compound was obtained from mother liquors, after evaporation of the solvent, as a white solid (140 g, 95%).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[NH2:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28]>C1(C)C=CC=CC=1>[Cl:45][C:44]1[CH:43]=[CH:42][C:26]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:25][C:24]=1[NH:23][C:12](=[O:13])[CH:6]([N:5]1[C:1](=[O:22])[C:2]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:3]2[C:4]1=[O:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(C(=O)OCC)N2C(=O)c3ccccc3C2=O)c1

Procedure:
Diethyl 2-phthalimidomalonate (15.26 g, 50.0 mmol) and n-dodecyl 3-amino-4-chlorobenzoate (16.99 g, 50.0 mmol) were added to toluene (300 ml) and refluxed under Dean and Stark conditions for 5 days, occasionally removing a small amount of distillate and replenishing the solvent as necessary. The reaction was followed by TLC (1:2 ethyl acetate:60-80° C. petroleum ether), the Rf of the product being between that of the two starting materials. The toluene was removed on the rotary evaporator and on standing the viscous oil solidified. Crystallization from 60-80° C. petroleum ether gave a white solid, 13.92 g, 47%
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=3[F:32])[C:13]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:12]2[C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][NH:8]3)=[C:26]([F:32])[CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (420 mg, 0.83 mmol) in DCM (5 ml) was added TFA (1.2 mL, 16.2 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (232 mg, 80%). LCMS (Method B): RT=3.22 min, [M+H]+=350/352.