Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]([CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=[O:4].[OH:12]S(O)(=O)=O.N([O-])=O.[Na+]>O.CCOCC>[F:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][C@@H:2]([OH:12])[C:3]([OH:5])=[O:4]
Reactant: N[C@H](CCC(F)(F)F)C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@H](O)CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cool (0° C.), stirred solution of (2R)-2-amino-5,5,5-trifluoropentanoic acid (4.09 g, 23.90 mmol), prepared according to the process disclosed in U.S. Publication No. 2009/0111858 A1, and H2SO4 (2.8 mL, 52.5 mmol) in water (95 mL) was added a solution of sodium nitrite (9.89 g, 143 mmol) in water (30 mL) dropwise via addition funnel over 60 min. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with Et2O, the aqueous phase was separated and extracted with Et2O (3×). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure to provide Preparation 6B (4.1551 g, >99%) as an amber oil. 1H NMR (400 MHz, CDCl3) δ 4.33 (1H, dd, J=8.03, 4.27 Hz), 2.09-2.42 (3H, m), 1.88-2.02 (1H, m).
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]([C:16]1(O)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15])[CH3:11].[C:24](=[O:27])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:12][C:13](=[O:23])[CH:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]([C:24]2([OH:27])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:17]1)[CH3:15])[CH3:11]
Reactant: CCOC(=O)C(C)C1(O)CCNCC1
Reactant: O=C([O-])[O-]
Reactant: BrCCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)C1CCN(CCc2ccccc2)C(C2(O)CCNCC2)C1
Reaction time: 2 h

Procedure:
A solution of 12.0 g of phenethyl bromide in 50 cc of dimethyl formamide is added dropwise at a temperature of 60°, with stirring, to a suspension of 18.9 g of crude 2-(4-hydroxy-4-piperidyl)propionic acid ethyl ester and 11.5 g of potassium carbonate in 150 cc of dimethyl formamide. The reaction mixture is stirred at 60° for a further 11/2 hours, is then poured in a 10% potassium carbonate solution containing ice and extraction is effected with ether. The title compound, obtained after drying the ether extracts over magnesium sulphate and concentrating by evaporation, is dissolved in acetone, the calculated amount of maleic acid is added, and the resulting crude hydrogen maleate is repeatedly recrystallized from acetone. The hydrogen maleate form of the title compound has a M.P. of 138°-139°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (40 mg, 0.076 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and pyrrolidine (7 IIl, 0.084 mmol), and stirred 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide. MS (Q1) 514 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:5]2[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7](=[O:17])[C:8]3[CH:13]=[N:12][C:11]4[NH:14][N:15]=[CH:16][C:10]=4[C:9]=3[N:4]2[N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:25]([N:14]1[C:11]2[N:12]=[CH:13][C:8]3[C:7](=[O:17])[N:6]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:5]4[N:4]([N:3]=[C:2]([CH3:1])[CH:24]=4)[C:9]=3[C:10]=2[CH:16]=[N:15]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Solvent: c1ccncc1
Product: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n2n1

Procedure:
0.01 mol. of 2-methyl-4-phenyl-4H-pyrazolo[1,5-a]-pyrazolo[4'3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-2-methyl-4-phenyl-4H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is filtered off.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+]>>[CH3:1][C:2]1([CH3:21])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:26])[CH2:17][CH2:16]2)[CH2:3]1
Reactant: CC1(C)CN(CC2CCNCC2)c2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CN1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-1-piperidin-4-ylmethyl-6-nitro-2,3-dihydro-1H-indole was treated with an excess of formaldehyde and NaBH(OAc)3 and stirred overnight at RT. The reaction was quenched with MeOH and concentrated in vacuo. The residue was partitioned between EtOAc and 1N NaOH. The organic layer was removed, washed with brine, dried (Na2SO4), filtered and concentrated to provide the compound.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH2:27]([S:31]([Cl:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[ClH:34].[NH2:16][C@H:15]([C:24](=[O:26])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:14][CH2:13][CH2:12][NH:11][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, butanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:18])=O.[NH:20]1[CH2:24][CH:23]=[CH:22][CH2:21]1.[OH-].[Na+]>ClCCl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][C:11]([C:12]([N:20]3[CH2:24][CH:23]=[CH:22][CH2:21]3)=[O:14])=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Cc1cc2c(=O)[nH]cnc2cc1C(=O)O
Reactant: C1=CCNC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc2c(Cl)ncnc2cc1C(=O)N1CC=CC1

Procedure:
Prepared analogously to Example 2b or 2c from 6-methyl-4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid, thionyl chloride, 2,5-dihydropyrrole, sodium hydroxide solution and dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:34])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][C:25]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=O)=[CH:24][CH:23]=2)=[CH:4][C:3]=1[Cl:35].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1.CCOCC>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][C:25]([CH2:27][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:24][CH:23]=2)[OH:34])=[CH:4][C:3]=1[Cl:35]
Reactant: CCN(CC)C(=O)c1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCN(CC)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]-N,N-diethyl-2-furancarboxamide (0.83 g) in benzene (6 ml) was added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (175 mg) in dry ether (15 ml) under nitrogen. The mixture was stirred under nitrogen at 22° for 24 h, then quenched sequentially with water (1 ml), 2N sodium hydroxide solution (1 ml) and water (2 ml). The mixture was filtered through hyflo and the solids washed with toluene-ether (1:1, 10 ml). The combined filtrate and washings were dried and evaporated in vacuo to an oil. Purification by FCC eluting with System C (93:5:2) afforded the title compound as a pale yellow oil (0.59 g), t.l.c. (System A 39:10:1) Rf 0.5.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]([O:26]CC)=[O:25])=[CH:14]3)=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]([OH:26])=[O:25])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(COC)nc3)cc(OC(C)C)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.5 %

Procedure:
A mixture of ethyl 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylate (1.65 g), 1M aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 h. Water and 1M hydrochloric acid (10 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (1.43 g, 93%) as a brown amorphous solid. MS 357 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:23][N:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:29]2[CH2:28][CH2:27][N:26]([C:24]3[S:23][N:22]=[C:21]([C:17]4[S:16][CH:20]=[CH:19][CH:18]=4)[N:25]=3)[CH2:31][CH2:30]2)=[O:15])=[CH:5][CH:6]=1
Reactant: c1csc(-c2nsc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3cccs3)ns2)CC1
Yield: 18.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (235 mg, 0.872 mmol), 1-[3-(2-thienyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.793 mmol) and diisopropylethylamine (0.152 ml, 0.872 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3.5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, followed by methanol:ethyl acetate=1:9) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 54.9 mg (18.6%) of the desired product as a solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=O.[CH3:18][OH:19]>C(Cl)Cl>[CH3:18][O:19][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:7]#[CH:1])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Potassium carbonate (316 mg, 2.28 mmol) was added to a stirred solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl (400 mg, 2.08 mmol) and 4-formyl-benzoic acid (341 mg, 2.08 mmol) in MeOH (20 mL) and continued stirring at room temperature overnight. The reaction mixture was filtered and concentrated to get the residue. The residue obtained was diluted with DCM and organic phase was washed with 5% sodium bicarbonate and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 310 mg (79.4% yield) 4-ethynyl-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH2:11]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CS(C)=O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:25][CH2:24]1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Reactant: COC(CCCCBr)OC
Solvent: CS(C)=O
Solvent: CO
Product: COC(CCCCN1CCC(CNCc2ccccc2)CC1)OC
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 5-bromopentanal dimethyl acetal and 4-[(benzylamino)methyl]piperidine using a similar method to that described for Example 8 (step 2). δ (250 MHz, d6 -DMSO) 1.26-2.14 (13H, m), 2.49 (2H, t, J=7.0 Hz), 2.63 (2H, d, J=6.6 Hz), 3.04-3.14 (2H, m), 3.49 (6H, s), 3.95 (2H, s), 4.61 (1H, t, J=5.7 Hz), 7.44-7.62 (5H, m), m/e (ES) 335 (M+1+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1)(=O)=O.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.[I-].[K+]>CN(C=O)C>[CH3:20][C:9]1([CH2:8][CH2:7][CH2:6][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methane-sulfonate (2 g, 6.6 mmol), tert-butyl piperazine-1-carboxylate (1.4 g, 7.5 mmol), triethylamine (1.3 g, 12.85 mmol), potassium iodide (1.8 g, 10.8 mmol) and DMF (15 ml) was stirred at 60° C. overnight. The reaction mixture was allowed to return to room temperature and then added water, and the resulting solution was extracted with ethyl acetate three times. The organic phases were combined, washed with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl]piperazine-1-carboxylate (1.9 g, yield 73%) as a white powder.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][C@H:16]([OH:21])[C@:15]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2.C(N([CH2:28][CH3:29])CC)C.[CH2:30]([Si:32]([CH2:36][CH3:37])([CH2:34][CH3:35])Cl)[CH3:31].O>N1C=CC=CC=1>[CH2:30]([Si:32]([CH2:28][CH3:29])([CH2:34][CH3:35])[O:21][C@@H:16]1[C@@:15]2([CH3:22])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19][C@@H:18]([O:20][Si:32]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:30][CH3:31])[CH2:17]1)[CH3:31]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCN(CC)CC
Reactant: C[C@]12C(=CC[C@@H]3[C@@H]1CC[C@]1(C)C(=O)CC[C@@H]31)C[C@@H](O)C[C@@H]2O
Solvent: O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@@H]1CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](CC)(CC)CC)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 600 ml of pyridine, 9.13 g of 1α-hydroxydehydroepiandrosterone was suspended. Under an argon stream, 100 ml of triethylamine and 39.0 g of triethyl chlorosilane were added to the suspension, and the mixture was stirred for 24 hours at room temperature. After adding 500 ml of water, the solvent was distilled off under vacuum. The residue was subjected to extraction with benzene. The benzene layer was successively washed with an aqueous solution of 0.5N HCl, water, saturated sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The residue obtained by distilling off the solvent under vacuum was subjected to silica gel column chromatography and eluted with chloroform, whereby 9.64 g of 1α,3β-bis(triethylsilyloxy)-5-androsten-17-one was obtained as a pale yellow crystal. Part of the compound was recrystallized from methanol to give colorless needles having a melting point of 99°-100° C.
Reaction SMILES: [Cl-].[NH2:2][NH2:3].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])C>CCO>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NN
Agent: [Cl-]
Solvent: CCO
Product: FC(F)(F)c1cc[nH]n1
Yield: 86 %

Procedure:
To a stirred solution of hydrazine monochloride (6.62 g, 1.6 eq.) in EtOH (300 mL) was added dropwise compound 84 (10.16 g, 1 eq.) in EtOH (200 mL). The reaction mixture was refluxed for 6 hrs and evaporated to dryness. Water and EtOAc were added to the residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 86a as a brown solid in 86% yield.
Reaction SMILES: [OH:1][N:2]1[C:6]([I:7])=[C:5]([I:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[I:8][C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[I:7]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ncc(I)c1I
Product: CN(C(=O)On1ncc(I)c1I)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4,5-diiodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (76%, crystals).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]2)=[CH:37][C:36]=1[O:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][CH:44]([N:47]([CH3:48])[CH3:49])[CH2:43][CH2:42]4)=[CH:37][C:36]=3[O:50][CH3:51])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 77.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (140 mg, 0.30 mmol), 1-[4-amino-3-(methyloxy)phenyl]-N,N-dimethyl-4-piperidinamine (67 mg, 0.27 mmol) and p-toluenesulfonic acid (140 mg, 0.71 mmol) in iPrOH was heated in the microwave at 180° C. for 13.5 min. The mixture was dissolved in DCM and concentrated onto silica gel. The crude material was purified by flash column chromatography to give the title compound (142 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.48-7.36 (m, 3H), 7.20 (t, J=8.2 Hz, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.67 (m, 1H), 6.49-6.45 (m, 2H), 3.79 (s, 3H), 3.70 (d, J=12.4 Hz, 2H), 2.68-2.63 (m, 2H), 2.18 (s, 7H), 1.84-1.81 (m, 2H), 1.52-1.44 (m, 2H). MS (ESI) m/z=675 [M+H]+.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N:22]3[C:18]([S:19][CH:20]=[CH:21]3)=[CH:17][N:16]=2)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N:16]([CH3:2])[CH:17]=[C:18]3[N+:22]=2[CH:21]=[CH:20][S:19]3)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3n(C)cc4scc[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.3 %

Procedure:
Iodomethane (0.71 g) is added to 57.2 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-5-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 3 days. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane methanol=1:1) to give 66.6 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(6-methylimidazo[5,1-b]thiazolium-5-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[OH:18][C@H:10]1[C@H:9]2[CH2:17][C@H:12]([C@@H:13]([C:14]([O:16][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])[N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 5-6 (1.0 g) in dichloromethane (8 mL), were added benzyl alcohol (504 mg), dicyclohexylcarbodiimide (962 mg) and 4-(dimethylamino)pyridine (12 mg). The mixture was stirred at room temperature for 20 hrs.