Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([N:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2)[CH3:6])(=O)[CH3:3]>O1CCCC1>[ClH:1].[ClH:1].[CH2:2]([N:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:12]2)[CH3:6])[CH3:3]
Reactant: CCCNC1CCc2c(cccc2N(C)C(C)=O)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCNC1CCc2c(cccc2N(C)CC)C1

Procedure:
Starting from 0.56 g (1.89 mmol) of 5-(N-acetyl-N-methyl-amino)-2-n-propylamino-tetraline-hydrochloride (Example 4.7.8) which is converted into the base, the title compound is obtained as a base by reduction in 20 ml of absolute tetrahydrofuran analogously to Example 4.5.1 c), but using 1.90 ml of 2-molar diboran solution in tetrahydrofuran (THF) as reducing agent. The base is purified by column chromatography (50 g of silica gel, methylene chloride/methanol/conc. ammonia 90:10:0.5) and crystallised as the dihydrochloride analogously to Example 4.1.1, in a yield of 0.33 g (54.6% of theory) and with a melting point of 200° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCBr)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 33 g of 11β-fluoro-7α-(5-hydroxypentyl)oestr-4-ene-3,17-dione in 330 ml of dichloromethane is treated with 28.9 g of triphenylphosphine and 36.7 g of carbon tetrabromide at −5° C. and stirred for 0.5 hours. Dichloromethane is then added and the mixture is washed with water, saturated sodium hydrogencarbonate solution and sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated in vacuo. The crude product is then chromatographed on silica gel using a hexane-ethyl acetate gradient. 28.5 g of 7α-(5-bromopentyl)-11β-fluorooestr-4-ene-3,17-dione of melting point 75-76° C. are obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)(C)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)N1CCNCC1

Procedure:
348.5 g of 1-benzyl-4-tert-butyl piperazine are dissolved in 1200 cc of 99% ethanol and 10 g of a 5% palladium/charcoal catalyst are added to the resulting solution. The solution is subsequently shaken in a hydrogenation apparatus, in a hydrogen atmosphere (1 atmosphere) and at room temperature, until the take up of hydrogen is complete. Filtration is subsequently effected, the filtrate is concentrated by evaporation in a vacuum and the residue is distilled in a vacuum. 1-tert-butyl piperazine is obtained in the form of a colourless oil, having a B.P. of 66°-70° at 12 mm of Hg, which crystallizes upon standing. The crystals have a M.P. of 35°-40°.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@H](OCOCCOC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To the resultant compound from Example 4 (2.51 g, 8.84 mmol) in methylene chloride (20 ml) was added diisopropylethylamine (4.60 ml, 26.4 mmol) and methoxyethoxychloromethane (3.00 ml, 26.3 mmol). After stirring at room temperature for 24 h the mixture was concentrated, diluted with ethyl acetate, washed with 0.5M H3PO4, saturated NaHCO3 solution, then brine, dried over Na2SO4, and evaporated. Chromatography on silica gel with ethyl acetate/hexane mixtures afforded 2.63 g (80%) of the desired product as an oil. EI-MS: M+ =371.
Reaction SMILES: C([O:4][CH:5]1[S:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.CNN.C(O)(=O)C.Cl>CN(C)C=O>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[S:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1SC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CNN
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 1,2,3,4,6-penta-O-acetyl-5-thio-D-glucopyranose (34.0 g, 0.0837 mol) in N,N-dimethylformamide (300 mL), a mixture of methylhydrazine (6.70 mL, 0.120 mmol), acetic acid (15 mL, 0.120 mmol) and N,N-dimethylformamide (10 mL) was added in ice. After stirring at room temperature for 2.5 hours, 0.5M HCl (300 mL) was added to the reaction mixture in ice, which was then extracted twice with ethyl acetate (250 mL). The combined organic phases were washed sequentially with water (200 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL) and saturated aqueous sodium chloride (100 mL), followed by addition of MgSO4 and activated charcoal (1 g). After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure. The resulting residue was crystallized from isopropyl ether (70 mL) to give 2,3,4,6-tetra-O-acetyl-5-thio-glucopyranose (26.9 g, 88%) as a colorless crystal.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[C:15]([I:16])=[C:14]([NH:17][C:25]([CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:26])[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]=1[I:19])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Allylcarbamoyl-5-amino-2,4,6-triiodo-benzoyl chloride (6) (5 g, 8.11 mmol) was dissolved in dry DMA (5 mL) and acetoxyacetylchloride (1.73 mL, 16.2 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ice-water (5×20 mL). The organics were collected, dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The residue was washed with acetonitrile, filtered and dried under vacuum to give acetic acid (3-allylcarbamoyl-5-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-methyl ester as a white solid. (4.47 g, 77%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS.
Reaction SMILES: S(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[C-:16]#[N:17].[Na+]>O.CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]([C:16]#[N:17])[OH:11])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(O)c1ccc(F)c(Br)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of sodium bisulfite (28.3 g, 271 mmol) in water at 50° C. is treated with 3-bromo-4-fluorobenzaldehyde (45.8 g, 225 mmol), stirred at 50° C. for 2 h, cooled with an ice bath, diluted with ether, treated dropwise with an aqueous solution of sodium cyanide (12.2 g, 248 mmol) over a period of 30 min and stirred at room temperature overnight. The reaction mixture is separated, and the aqueous phase is extracted with ether. The extracts are combined with the organic phase, washed with brine, dried over magnesium sulfate and concentrated to dryness to afford the title compound as a clear oil, 47.6 g (92% yield), identified by NMR analysis. 1H NMR (300 MHz, CDCl3) δ 7.75 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 5.54 (m, 1H), 3.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:24][CH2:23][CH2:22][NH2:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NCCN
Product: NCCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
20 mg (0.063 mmol) of N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are stirred for 26 h at 110° with 1 ml of ethylenediamine. Concentration and chromatography (methylene chloride:methanol:conc. ammonia solution=80:20: 1) give N-(3-chloro-phenyl)-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine; Rf =0.15 (methylene chloride:methanol:conc. ammonia solution=80:20:1), FAB-MS: 341 (M+ +1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8].[Cl:18][C:19]1[CH:20]=[C:21]([C@H:26]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[NH:58]S(C)(=O)=O)[CH2:48][CH2:47]2)[CH2:27][N:28]([CH3:43])[C:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([C:41]#[N:42])[CH:32]=2)=[O:30])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8].[Cl:18][C:19]1[CH:20]=[C:21]([C@H:26]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[NH:58][C:1](=[O:3])[CH3:2])[CH2:48][CH2:47]2)[CH2:27][N:28]([CH3:43])[C:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([C:41]#[N:42])[CH:32]=2)=[O:30])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CN(C[C@@H](CCN1CCC(c2ccccc2NS(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reactant: CC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C1CCN(CC[C@H](CN(C)C(=O)c2cc(C#N)cc3ccccc23)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 104.4 %

Procedure:
Acetyl chloride (0.060 g) was added to a solution of 4-(2-aminophenyl)-N-Boc-piperidine (0.070 g) (Example 21 sub-part (b)) and triethylamine (0.090 g) in DCM (2 mL) and stirred overnight. The reaction was diluted with Et2O and extracted sequentially with aqueous sodium bicarbonate and 1N HCl. The organic extract was dried and evaporated to give the title compound (0.070 g) as a colorless oil. MS m/z 341 (M+Na). 1H NMR (CDCl3) δ 7.26 (m, 4H), 7.69 (br, 1H), 4.15 (m, 2H), 2.67 (m, 3H), 2.23 (s, 3H), 1.75 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=S(=O)(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 78.4 g (0.4 mol) of benzophenone hydrazone, 64.6 g (0.64 mol) of triethylamine and 1 liter of ether, and 105.6 g (0.6 mol) of benzenesulfonic acid chloride was dropwise added thereto in one hour while stirring at room temperature and then heated under reflux for 72 hours. The reaction liquid was cooled down to 20° C. and then washed (separated) twice with 500 ml of deionized water. The ether layer was dried over anhydrous magnesium sulfate and filtered off, and then the mother liquid was concentrated by means of a rotary evaporator to obtain reddish yellow crystal. This crude crystal was added to 1 liter of diethyl ether and heated under reflux for 30 minutes, and then the crystal was filtered off at 30° C. This was dried under reduced pressure to thereby obtain white crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:7]=1)=[O:19]
Reactant: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(NC(=O)c3c(Cl)cc(Cl)cc3Cl)n2)CC1
Yield: 38.3 %

Procedure:
Using a method similar to Example 104 using N-(6-amino-pyridin-2-yl)-2,4,6-trichloro-benzamide (Preparation 55, 375 mg, 1.18 mmol), 1-methyl-4-piperidone (270 mg, 0.29 mL, 2.37 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4 Å (1 g), glacial acetic acid (0.21 g, 0.20 mL, 3.54 mmol), sodium triacetoxyborohydride (625 mg, 2.95 mmol) gives the title compound (187 mg, 45% yield): dihydrochloride salt: mass spectrum (ion spray): m/z=412.0 (M+1), 1H NMR δ (CDCl3) 7.78 (s, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.36 (s, 2H), 6.18 (d, 1H), 4.26 (d, 1H), 3.55 (m, 1H), 2.73 (d, 2H), 2.28 (s, 3H), 2.11 (m, 4H), 1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][C:39]#[CH:40].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:40]#[C:39][CH2:38][N:37]([CH3:41])[CH3:36])[C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[CH:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OS(=O)(=O)C(F)(F)F)cccc2-c2ccc(Cl)cc2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a mixture of EXAMPLE 196C (380 mg), N,N-dimethylprop-2-yn-1-amine (0.227 ml), tetrakis(triphenylphosphine)palladium(0) (123 mg) and triethylamine (0.492) in N,N-dimethylformamide (1.5 ml) was added copper(I) iodide (27.1 mg) and tBuNI (394 mg). The reaction mixture was heated at 100° C. for 4 hours, cooled and diluted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with a mixture of methanol, dichloromethane and triethyl amine to provide the title compound.
Reaction SMILES: [CH3:1][C:2](CC)=O.C(=O)([O-])[O-].[K+].[K+].C(I)C.[OH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH2:20][C:19]2=[O:30]>>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:28])([CH3:29])[CH2:20][C:19]2=[O:30])[CH3:2]
Reactant: COc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1cc2c(cc1OC)OC(C)(C)CC2=O
Yield: 95 %

Procedure:
In 100 ml of methyl-ethyl-ketone 4.45g (20 millimoles) of 6-hydroxy-7-methoxy-2,2-dimethy-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.7 g (2.4 ml, 30 millimoles) of ethyl iodide are added and the reaction mixture is refluxed for 5 hours. The precipitated inorganic salt is filtered off, washed twice with 20 ml of acetone each and the solvent is removed. The residue is crystallized from 90% ethanol. Thus 4.75 g of the desired compound are obtained, yield 95%. Mp.: 86°-87° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:14])([P:10]([OH:13])(=[O:12])[OH:11])[P:6]([OH:9])(=[O:8])[OH:7].[OH-].[Na+].[CH:17](=O)[CH2:18][CH:19]([CH3:21])[CH3:20]>[Pd]>[OH:14][C:5]([P:6]([OH:9])(=[O:7])[OH:8])([P:10]([OH:13])(=[O:11])[OH:12])[CH2:4][CH2:3][CH2:2][NH:1][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: CC(C)CC=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCNCCCC(O)(P(=O)(O)O)P(=O)(O)O
Yield: 20 %

Procedure:
4 g. 4-Amino-1-hydroxybutane-1,1-diphosphonic acid are dissolved in 64 ml. 1N aqueous sodium hydroxide solution, mixed with 3.8 ml. isovaleraldehyde and, after the addition of 2.5 g. of 10% palladium-charcoal, hydrogenated at a pressure of 5 bar. The course of the reaction is monitored electrophoretically until the starting material has disappeared. The reaction mixture is filtered, acidified with Amberlite R 120 (H+ form) and evaporated until crystallisation commences, 1.3 g. of crystals thus being obtained in a yield of 20% of theory; m.p. 225°-227° C. (decomp.); Mrel =0.39. 1-Hydroxy-4-(N-3-methylbutylamino)-butane-1,1-diphosphonic acid remaining in the mother liquor, which is formed as an intermediate, can be used again for the reductive alkylation.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>CO>[C:1]1([NH:7][C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccccc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Methyl 6-(3-phenylureido)nicotinate (200 mg, 0.43 mmol) was dissolved in methanol (2 mL) at room temperature. Lithium hydroxide (100 mg, 4.17 mmol) was added, followed by water (10.5 mL). The mixture was heated to 50° C. and stirred overnight. The mixture was brought to pH 4-5 by addition of concentrated hydrochloric acid. The solid that had formed was then filtered and dried under vacuum to give the title compound (69 mg). MS (ESI) m/z 258.1[M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CCO>[NH2:34][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 120 °C
Yield: 79.9 %

Procedure:
To a 330-mL pressure vessel was added 2-(2-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (6.50 g, 13.3 mmol), EtOH (80 mL), and ammonium hydroxide (30%, 80.0 mL, 616 mmol, J. T. Baker, Philipsburg, N.J.). The tube was sealed and heated at 120° C. for 10 h and then the solvent was removed in vacuo. The residue was partitioned between water (100 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (2×100 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (330 g of silica, 1 to 5% 2 M NH3 in MeOH in DCM) to afford 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (5.0 g) as a mixture of four isomers.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O>>[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: C=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: O=C(O)[C@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
D-Phenylalanine (50 g, 0.3 mol) concentrated hydrochloric acid (386 ml), and formalin (37% wt, 113.7 ml) were heated at 95° C. with vigorous stirring for 4 h. The reaction mixture was cooled to room temperature and stirred for a further 2 h. The reaction mixture was filtered and the precipitate washed with cold water to give (3R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as a white solid (25 g, 42%). Benzyl alcohol (64 g) and p-toluene sulphonic acid (26.9 g) were added and the reaction mixture was refluxed in benzene (400 ml) under Dean Stark conditions. The solvent was removed in vacuo, the crude residue was triturated with diethyl ether to give a solid which was then recrystallised from water and methanol to give the title compound as a white solid (28 g, 35%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22].N1CCCC1>C(O)C>[C:3]1([CH:1]=[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][C:14]2=[O:22])[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2cccccc1-2
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1ccc2cccccc1-2
Yield: 101.7 %

Procedure:
1-Formylazulene (2 mmol) was dissolved in 40 mL ethanol. 266 mg oxindole (2 mmol) and 200 mL ethanol were then added. Next, a 4 mL solution containing 1M pyrrolidine and ethanol was added to react at room temperature for three days. After removal of solvent, the resulting solution was extracted by 150 mL acetyl acetate and 50 mL water. The resulting solution was extracted again by 50 mL citric acid aqueous solution and ethyl acetate. The ethyl acetate layer was collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was then purified by column chromatography (Silica Gel 60, dichloromethane) and dried to give Compound 001 (552 mg, 95%).