Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]3[C:15](=[S:32])[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH:10]1[C:11]2[CH:12]([C:14]3[C:15](=[S:32])[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=S)[nH]c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=S)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (v) (0.175 g) and lithium hydroxide monohydrate (0.034 g) in tetrahydrofuran (3 ml) and water (3 ml) was stirred at room temperature for 3 hours and partitioned between dichloromethane and 2 M HCl. The organic phase was dried (MgSO4) and evaporated under reduced pressure. Yield 0.095 g.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][O:12][C@@H:11]([CH2:15][OH:16])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@H:9]1[CH2:14][CH2:13][O:12][C@@H:11]([CH2:15][OH:16])[CH2:10]1
Reactant: OC[C@H]1C[C@@H](NCc2ccccc2)CCO1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCO[C@@H](CO)C1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of cis-4-(benzylamino)-(tetrahydro-2H-pyran-2-yl)methanol (1.1 g, 5.0 mol) and Pd/C (10%, 0.10 g) in methanol (20 mL) was stirred under hydrogen (1 atm) for 2 hours. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated to give cis-(4-aminotetrahydro-2H-pyran-2-yl)methanol (500 mg, 77% yield). LCMS (ESI) m/z: 132.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:5](=[O:7])[C:4]2[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1C
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(Cl)cc(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 3,5-dichlorobenzoic acid (2.6 g), (3R)-1-benzyl-3-(3,4-dimethylbenzyl)piperazine dihydrochloride (5.0 g) and triethylamine (8.54 ml) in dichloromethane (80 ml) was added 2-chloro-1-methylpyridinium iodide (3.83 g) under ice-cooling, and then the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl acetate solution was filtrated and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using hexane-ethyl acetate (10:1) as eluent to give (2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(3,4-dimethylbenzyl)piperazine (5.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].CCN(C(C)C)C(C)C.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Yield: 97.5 %

Procedure:
Dissolved (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 1.5 g (5.37 mmol) in 10 mL of THF was treated with DIEA 1.31 mL (7.51 mmol) and 0.89 mL of TMS-Cl (6.98 mmol) added drop-wise while stirring. After 2 h of stirring, 50 mL of EtOAc was added and the mix was washed with Sat. NaHCO3 (3×50 mL). The organic layer was then dried over Na2SO4, filter through silica and concentrated to afford 1.84 g (97%) of (2S,4R)-4-Trimethylsilanyloxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as a clear oil. HPLC: Rt 4.12 min. (100% area). 1H NMR (CDCl3, 400 MHz) δ: 7.37-7.28 (5H, m), 5.22-5.01 (2H, m), 4.51-4.41 (2H, m), 3.76 (2H, s), 3.70-3.66 (1H, m), 3.51-3.39.(1H, m), 2.22-2.16 (1H, m), 2.04 (3H, s), 0.11 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:7][CH:8]=2)[NH:3]1.[Cl:19][C:20]1[CH:27]=[C:24]([CH:25]=O)[C:23]([OH:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:13])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C1Cc2ccc(NC(=O)C3CCCC3)cc2N1
Reactant: O=Cc1cc(Cl)ccc1O
Product: O=C1Nc2cc(NC(=O)C3CCCC3)ccc2C1=Cc1cc(Cl)ccc1O

Procedure:
Cyclopentanecarboxylic acid (2-oxo-2,3-dihydro-1H-indol-6-yl)-amide was condensed with 5-chlorosalicylaldehyde using method B to give cyclopentanecarboxylic acid [3-(5-chloro-2-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide which was reducted using method D to give 34.4 mg (68%) cyclopentanecarboxylic acid [3-(5-chloro-2-hydroxybenzyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide as an off-white crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1>Cl.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][S:19]([NH2:22])(=[O:20])=[O:21])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2c[nH]c3ccc(/C=C/S(N)(=O)=O)cc23)CC1
Agent: [Pd]
Agent: Cl
Product: CN1CCC(c2c[nH]c3ccc(CCS(N)(=O)=O)cc23)CC1
Yield: 24.8 %

Procedure:
A mixture of the product of stage (i) (0.8 g) in ethanolic hydrogen chloride (80 ml) was hydrogenated over pre-reduced 10% palladium on carbon (50% paste with water, 0.8 g) until uptake ceased. The catalyst was filtered off, washed with hot ethanol (50 ml) and the filtrate evaporated in vacuo to give crude material (0.15 g). The catalyst residues were then warmed (70°) with 2N hydrochloric acid (200 ml), filtered and the filtrate evaporated to dryness in vacuo (azeotroped with toluene). The residue was combined with the crude product obtained above and purified by flash chromatography (silica 9385, 100 g) eluting with CH2Cl2 /EtOH/NH3 (50:8:1) to give the title compound as a solid (0.2 g) m.p. >95° (foams),
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC4C=CC=CC=4)[CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(OCc4ccccc4)c2)O3)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1

Procedure:
2.15 g of 5-nitro-2-[2-(3-benzyloxyphenyl)chroman-6-yloxy]pyridine was dissolved to 600 ml of ethanol and 430 mg g of 10% palladium on charcoal was added under inert atmosphere. Starting material was hydrogenated at room temperature to give quantitative yield of 3-[6-(5-aminopyridin-2-yloxy)chroman-2-yl]phenol 1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, 1H), 7.52 (d, 1H, J 3.0 Hz), 7.17 (t, 1H, J 8.1 Hz), 7.05 (dd, 1H, J 3.0, 8.6 Hz), 6.84-6.68 (m, 7H), 5.01-4.99 (m, 3H), 2.91-2.86 (m, 1H), 2.70-2.63 (m, 1H), 2.14-2.08 (m, 1H), 1.96-1.89 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N:11]1[C:12](=[O:20])[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:23]1=[O:24]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](NC(=O)c1ccccc1N)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C1CCCCC1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 133 %

Procedure:
To a solution of (R)-(2-amino-benzoylamino)-cyclohexyl-acetic acid methyl ester (1.08 g, 3.72 mmol) in THF (30 mL) is added trichloromethyl chloroformate (550 mg, 2.78 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give the desired (R)-cyclohexyl-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (1.17 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:13]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[F:18])=[O:11])=[N:31][CH:30]=1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: [Mg].BrCCBr.[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:10])[CH3:7].Br[CH2:20][C:21]([Br:23])=[CH2:22]>C1COCC1>[CH2:6]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][C:21]([Br:23])=[CH2:20])[CH3:10])[CH3:7]
Reactant: C=C(Br)CBr
Reactant: CCOC(C)OCCCCCCBr
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(Br)CCCCCCCOC(C)OCC
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
A slurry of 5.6 g of magnesium turnings (230 mmol) in 100 ml of THF was treated with a small amount of 1,2-dibromoethane. 1-(1-Ethoxyethoxy)-6-bromohexane (38.5 g, 152 mmol) was fed slowly to the reaction mixture, maintaining the temperature at 40-50° C. At the end of the addition the reaction mixture was held 20 minutes, then transferred by cannula to solution of 33.4 9 (167 mmol) of 1,2-dibromoprop-2-ene in 25 ml of THF at 0C. The reaction mixture was stirred at 0° C. for 15 minutes, then stirred at room temperature for 15 minutes, then quenched with water. The reaction mixture was transferred into a separatory funnel. A small amount of 1 N HCl was added, the phases were separated, the ether phase was washed with water and brine, then dried over magnesium sulfate, filtered, and stripped to give 33.63 g of a yellow liquid which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C.O>[C:13]([NH:17][C:18]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: COc1ccc([C@@H](N)CO)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 5.78 g of (2R)-2-amino-2-(4-methoxyphenyl)-1-ethanol and 6.48 cm3 of tert-butyl isothiocyanate in 73 cm3 of ethanol for 17 h 30 minutes at a temperature in the region of 20° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the solid residue obtained is then ground in 45 cm3 of water, filtered and washed with twice 20 cm3 of water and twice 25 cm3 of diethyl ether. The crystals are dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 45° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)2-hydroxyethyl]-thiourea are obtained in the form of a white solid. (Rf=0.60 in ethyl acetate, on a Merck 60F254R silica plate).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.C(OCC)C.O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)=[N+:12]=[N-:13]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of 6-Bromomethylnicotinonirile (11-2) (8.0 g, 40.6 mmol) in DMF (100 ml) was added sodium azide (3.17 g, 48.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 400 ml diethylether and 100 ml water and the layers were separated. The aqueous layer was re-extracted with diethylether (2×100 ml). The combined ether extracts were washed with brine (2×100 ml) and then dried over MgSO4 and filtered to yield 6.53 g product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH3:21][S:22]CCl>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:22][CH3:21])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CSCCl
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. 1-amino-2-nitro-4-thiocyanatobenzene is treated in 20 ml. dimethylformamide under nitrogen at 20°-25° C. with 1.14 g. sodium borohydride. After 1 hour 10 ml. of methylthiomethylchloride is added and the mixture stirred overnight, diluted with water and extracted with chloroform. The dried chloroform solution is passed through a silica gel column, then evaporated to dryness leaving 1-amino-2-nitro-4-methylthiomethylthiobenzene as a red solid.
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C([O:10][C:11](=O)[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=O>FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(O)=O>[F:19][C:14]([F:20])([C:15]([F:16])([F:17])[F:18])[C:13]([F:21])([F:22])[C:12]([F:24])([F:23])[C:11]([O:1][O:2][C:11](=[O:10])[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])=[O:10]
Reactant: OO
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with nonafluorovaleric anhydride to give bis(nonafluoropentanoyl) peroxide (δ−83.2, −117.9, −124.8, −127.5) in nonafluorovaleric acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>[Na+].[I-].CO.C(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=C1CSCN1CCCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1CSCN1CCCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of 3-(4-bromobutyl)-4-thiazolidinone (4.01 g), 1-(4-fluorophenyl)piperazine (3.35 g), K2CO3 (4.64 g), NaI (150 mg) and CH3CH (150 ml) was heated at 100° C. (bath temperature) under N2 for 18 h. TLC analysis (silica gel, 8% MeOH/CHCl3) showed one major product at Rf=0.36, and the absence of starting bromide. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oil which was taken up in EtOAc. The mixture was filtered to remove the precipitate and the filtrate concentrated in vacuo to an amber oil which solidified under vacuum. The solid (5.86 g) was dissolved in CHCl3 and flash chromatographed (silica gel) and thereafter recrystallized from hexane/CH2Cl2 to yield in two crops 3.93 g of white crystals, mp 83-85° C. TLC analysis showed a trace of slower moving impurity. Recrystallization from hexane/CH2Cl2 afforded 3.1 g of white needles which were still slightly impure by TLC. The material was again flash chromatographed (silica gel) and recrystallized from hexane/CH2Cl2 to give 2.67 g of pure product, mp 84-85° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.CO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:33]([O:32][C:31]([NH:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:31]([O:32][CH3:33])=[O:37])=[CH:25][CH:24]=2)[CH2:29][CH2:28][CH2:27]1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(c1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc1)-c1cccnc1Nc1ccccc1-2
Temperature: 100 °C
Yield: 74.8 %

Procedure:
tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (100 mg, 0.179 mmol), triethylamine (0.5 mL), bis(triphenylphosphine)dichloropalladium(II) (38 mg, 0.054 mmol) were dissolved in DMF (3 mL) and MeOH (3 mL). Atmosphere of the mixture was exchanged to CO gas, then heated to 100° C. for 88 hours. The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:2×3) to afford the desired product (36 mg, 37%) as a colorless oil. 1HNMR (CDCl3) 400 MHz δ: 8.13 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.33 (td, J=7.4 Hz and 1.7 Hz, 2H), 7.30-7.24 (m, 4H), 7.14 (td, J=7.4 Hz and 1.1 Hz, 1H), 6.95 (d, J=7.4 Hz, 1H), 6.82-6.78 (m, 1H), 6.59 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.24 (s, 1H), 5.11 (br s, 1H), 3.88 (s, 3H), 2.57-2.42 (m, 4H), 2.17-2.08 (m, 1H), 1.91-1.83 (m, 1H), 1.39 (br s, 9H). LCMS: 538 [M+H].
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1>C1COCC1>[CH2:1]([CH:9]1[CH2:10][CH2:11][CH2:12][C:7](=[O:13])[CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CCCC1
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC1CCCC(=O)C1
Temperature: -78 °C
Yield: 94 %

Procedure:
A THF (5 mL) suspension of CuBr.Me2S (26.3 mg, 0.128 mmol) was treated with 1.0 equiv of n-BuLi at -78° C. under an argon atmosphere. The mixture was allowed to warm up slightly with the formation of a bright yellow solid. The mixture was again cooled to -78° C. and treated with Li(CHIRAMT) formed from compound 4 (85.8 mg, 0.261 mmol) and n-BuLi (1.0 equiv). The yellow slurry was stirred with gradual warming until a homogeneous burgundy solution was obtained. In the case of R--Me, a homogeneous mixture was not obtained even after prolonged stirring at room temperature, and it was evident that unreacted (CuMe)n was still present. The solution was cooled to -78° C. and THF (8 mL each) solutions of n-BuMgCl (25.0 equiv) and cyclohexenone (0.3068 g, 3.19 mmol) were added dropwise and simultaneously over a 5 min period. The resulting reaction mixture was stirred for an additional 10 min at -78° C., quenched with saturated aqueous NH4Cl solution (7 mL), and worked up as described in the previous section. Pure 3-butylcyclohexanone (0.4617 g, 94%) was obtained as checked by glc.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:34])(=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Na+]>CC(C)=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:34][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCC(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 77.5 %

Procedure:
In 150 ml of 50% aqueous acetone are dissolved 5.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 2.5 g of sodium n-hexanoate and the solution is refluxed for 6 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 300 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 750 ml of diisopropyl ether-n-hexane (9:1), elution is carried out with 1000 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 4.2 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](C)(C)[O:19][SiH2]C(C)(C)C)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A mixture of 1-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (630 mg, 1.4 mmol) and lithiumhydroxide-hydrate (119 mg, 2.8 mmol) in 20 mL MeOH and 10 mL water was stirred at RT for 32 h. The mixture was evaporated in vacuo and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4 and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 12.3 (bs, 1H), 8.36 (s, 1H), 7.81 (s, 1H), 7.23-7.31 (s, 4H), 5.34 (s, 2H), 5.18 (t, 1H), 4.47 (s, 2H).