Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:35])[CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Cl.[NH2:37][C:38](N)=[O:39].C([O-])(O)=O.[Na+]>O.CCO>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH:3]([OH:35])[CH2:2][NH:1][C:38]([NH2:37])=[O:39])([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CN)(c2ccc(F)cc2)OC1=O
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CNC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C

Procedure:
To a solution of (6S)-6-(3-amino-2-hydroxypropyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (300 mg, 0.62 mmol) in H2O (10 mL) was added HCl (12 N, 0.05 mL), urea (372 mg, 6.2 mmol) and EtOH (2 mL). Then the mixture was heated to reflux overnight. The reaction mixture was cooled to rt and adjusted pH to 9˜10 by saturated NaHCO3 solution. The mixture was concentrated and extracted by CH2Cl2. The combined organic layer was dried and concentrated to give the residue, which was purified by preparative HPLC followed by chiral preparative HPLC to give two isomers.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)C1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[OH:26])([O-:15])=[O:14].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DEAD (2.6 ml)was added to a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and Ph3P (4 g) in THF (50 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]ethyl}-dimethylamine. It was hydrogenated under H2 atmosphere to give {2-[4-(tert-butyl)-2-aminophenoxy]ethyl}-dimethylamine.
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][CH3:12])[C@@H:3]([CH3:10])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].N1C(C)=CC=CC=1C.[CH2:21]([Si:23](OS(C(F)(F)F)(=O)=O)([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:22]>ClCCl>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C@H:3]([CH3:10])[C@@H:2]([O:1][Si:23]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:11][CH3:12]
Reactant: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C(=O)N(C)OC
Reaction time: 5 h
Yield: 99 %

Procedure:
The above (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (7.3 g, 41.7 mmol) was dissolved in dichloromethane (150 ml), followed by addition of 2,6-lutidine (10.2 ml, 87 mmol) and trifluoromethanesulfonic acid triethylsilyl ester (14.1 ml, 62 mmol) while ice cooling, and the reaction solution was stirred for five hours. The reaction solution was diluted with dichloromethane and washed with a saturated ammonium chloride aqueous solution and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=10:1) to obtain the title compound (11.95 g) as a colorless oil.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reaction time: 8 h

Procedure:
A suspension composed of 3.0 g (12.48 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 3.18 g (18.73 mmol) of (4-acetylphenyl)boronic acid, 3.42 g (18.82 mmol) of copper(II) acetate, 3.03 ml (37.15 mmol) of pyridine and about 500 mg of 4 Å molecular sieve in 150 ml of methylene chloride is stirred overnight. The reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered. The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/acetone 99/1 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[N+:22]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[CH:1]1([CH2:7][NH:8][C:9]2[C:10]([NH2:22])=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Reaction time: 0.05 h
Yield: 99.8 %

Procedure:
To a solution of cyclohexylmethyl-(2-nitro-4-phenoxy-phenyl)-amine (0.55 g, 1.69 mmol) in THF (50 mL) was added palladium, 10% on activated carbon (0.55 g). The reaction flask was equipped with a septum and was placed under vacuum for 3 min. This flask was placed under hydrogen atmosphere (balloon inflated with hydrogen) and the reaction mixture was stirred for 18 h. The palladium was filtered off through a plug of diatomaceous earth and washed with EtOAc. The solvent was removed via rotary evaporation providing N1-cyclohexylmethyl-4-phenoxy-benzene-1,2-diamine (0.50 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[Br:15][C:16]1[CH:20]=[N:19][N:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]([CH3:36])([N+:33]([O-])=O)[CH3:32])[NH2:25].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:33][C:31]([CH3:36])([CH3:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[CH:23][C:22]=1[C:17]1[N:18]([CH3:21])[N:19]=[CH:20][C:16]=1[Br:15]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(OC(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-Trifluoromethoxybenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (21 mg, 81%) as a TFA-salt. LCMS m/z (%)=529.3 (M+H 81Br 76.1%), 527.5 (M+H 79Br 64.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3 H), 1.18 (s, 3 H), 3.67 (s, 3 H), 3.84 (d, J=9.85 Hz, 1 H), 4.00 (d, J=9.85 Hz, 1H), 7.30 (d, J=9.09 Hz, 1 H), 7.60-7.65 (m, 1 H), 7.67 (s, 1 H), 7.68-7.73 (m, 2 H), 7.85-7.93 (m, 4 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 8.01 (d, J=7.83 Hz, 1 H), 10.48 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:22]=[CH:23][CH:24]([OH:34])[CH2:25][C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH:19]([CH3:21])[CH3:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:22]=[CH:23][CH:24]([OH:34])[CH2:25][CH:26]([OH:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH:19]([CH3:21])[CH3:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of 5.5 g of the title product of Step 4, above, in 100 ml of THF was added 12 ml of a 1.0 m solution of triethylborane in THF. After stirring at R.T. for 3 hours, the mixture was cooled to -78°, then 450 mg of sodium borohydride was added. The mixture was stirred at -78° for 24 hours. The reaction was then quenched with saturated aq. ammonium chloride solution, and extracted twice with MTBE. The extracts were combined and solvent was removed under reduced pressure to obtain a residue. The residue dissolved in 100 ml of methanol. After stirring at R.T. for 24 hours, the solvent was removed under reduced pressure and the resulting residue was flash chromatographed using 1% methanol/methylene chloride to elute the product, yielding 2.4 g of the title product of this example. (HPLC indicated an erythro:threo mixture of 82.3:17.7). Recrystallization of the product from cyclohexane increased the ratio to 88.3:11.7; m.p.=123°-125° .
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]([F:16])([CH2:14][OH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[F:7][C:8]([F:16])([CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(F)(F)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dihydropyrane (2 ml, 22 mmol) was added to a solution of ethyl 2,2-difluoro-3-hydroxypropionate (3.1 g, 20 mmol) and pyridinium p-toluenesulfonate (0.25 g, 1 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred overnight at room temperature and the desired compound ethyl 2,2-difluoro-3-tetrahydropyranyloxypropionate was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (4 g, 80%).
Reaction SMILES: ClC1C=CC(C2C3CCC(C(OC)=O)CCCC=3ON=2)=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:34]3[CH2:35][CH2:36][CH2:37][CH:38]([C:41]([O:43]C)=[O:42])[CH2:39][CH2:40][C:33]=3[O:32][N:31]=2)=[CH:26][CH:25]=1.[OH-].[K+].O>CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:34]3[CH2:35][CH2:36][CH2:37][CH:38]([C:41]([OH:43])=[O:42])[CH2:39][CH2:40][C:33]=3[O:32][N:31]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)noc2CC1
Agent: COC(=O)C1CCCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2CC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
3 g (0.0094 mol) of a mixture of methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-6-carboxylate and methyl 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-7-carboxylate were dissolved in 75 ml of methanol. 1.5 g of potassium hydroxide and 7 ml of water were added and the mixture was stirred at 20° C. for 18 hours. The methanol was removed by evaporation and an excess of water was added. The mixture was extracted twice with ethyl acetate and the aqueous phase was acidified with 2N hydrochloric acid. The aqueous-acidic layer was extracted three times with ethyl acetate and the combined ethyl acetate extracts were washed with sodium chloride solution and dried over magnesium sulfate. After evaporation and several crystallizations of the residue from ethyl acetate/hexane, there was obtained 0.78 g of 3-(4-chlorophenyl)-4,5,6,7,8,9-hexahydrocyclooct[d]isoxazole-7-carboxylic acid of melting point 147°-150° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: [N-]=[N+]=NCc1nc2c(c(=O)[nH]1)COCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.9 %

Procedure:
To a solution of 2-(azidomethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (19 g, 92 mmol) in THF (945 mL) at 35° C. was added triphenylphosphine (26.5 g, 101 mmol). Gas evolution was noted immediately and after approximately 40 minutes a fine precipitate formed. The reaction was allowed to stir for 1.5 h then 18.17 mL water was added. After an addition 2 h the reaction mixture was cooled to room temperature, filtered twice, concentrated to approximately ⅓ of the original volume and filtered once more. The solid material was washed with THF to yield a total of 15.82 g of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 2.66 (t, J=5.56 Hz, 2H) 3.76 (s, 2H) 3.94 (t, J=5.56 Hz, 2H) 4.49 (s, 2H)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=3)[N:16]=[C:15]([CH3:30])[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][C:15]1[CH:14]=[C:13]([N:10]2[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=2)[N:16]=1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)c2cc(Oc3ccccc3)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCC(N)C2)c2cc(Oc3ccccc3)ccc2n1

Procedure:
The product from step (i) above was treated with trifluoroacetic acid in dichloromethane (1:1) to give, after evaporation, the title compound as an orange oil, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8](=[O:21])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[N+]([O-])=O.C(OCC)(=O)C>CN1C(=O)CCC1>[C:1]([O:5][C:6]([C:7]1[C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][C:37]=2[O:21][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)cc1I
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(C)(C)c2oc3cc(C#N)ccc3c2C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
4-(4-Ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester (1.00 g, 2.40 mmol) was dissolved in NMP (4 ml), added with cesium carbonate (1.56 g, 4.80 mmol, 2.0 eq.), and the mixture was stirred for 5 min. The NMP solution (2 ml) of 4-chloro-3-nitro-benzonitrile (542 mg, 2.88 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at 50° C. for 64 hrs under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (20 ml) was added and the organic layer was washed with saturated aqueous solution of ammonium chloride (20 ml). The organic layer was further washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white amorphous, 320 mg, 26%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.[NH3:14]>CC(O)C>[NH2:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12
Reactant: N
Reactant: O=[N+]([O-])c1cnc2sccc2c1Cl
Solvent: CC(C)O
Product: Nc1c([N+](=O)[O-])cnc2sccc12
Yield: 87 %

Procedure:
To a stirred suspension of 3.35 g of 4-chloro-5-nitrothieno[2,3-b]pyridine 7 in 160 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 45°-50° C. during 4 hours. After removal of the solvent, the residue is suspended in water. The solid is washed with water and cold ether, affording 2.65 g (87%) of Compound 8 as crystals. Recrystallization from methanol-ether gives a pure sample melting at 227°-228.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])(=[O:25])=[O:24].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:30]([C:29]4[CH:28]=[C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Reactant: Clc1ccc2nc(N3CCNCC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1cccc(NS(=O)(=O)c2ccccn2)c1)N1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Compound 10 is prepared using synthesis method 2: intermediate 3b (0.16 g, 0.67 mmol) is placed in 21 mL of acetonitrile in the presence of 0.18 g (0.67 mmol) of intermediate 5a and 103 μL of Et3N. 0.21 g (0.67 mmol) of TBTU is then added and the mixture is then stirred for 5 h at ambient temperature. After evaporation under reduced pressure the residue is taken up by water and extracted using AcOEt. After the organic phases are dried and after reduction to dryness the residue obtained is purified by flash chromatography (CH2Cl2-MeOH, gradient 99-1 to 95-5 over 65 min). 0.23 g of solid is obtained (yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2nc(CCl)cs2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN3CCN(C)CC3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.1 %

Procedure:
In 10 ml of dimethylformamide were dissolved 860 mg of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole and 320 mg of N-methylpiperazine. Thereto was added 130 mg of sodium hydride. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. The residue was extracted with chloroform. The extract was water-washed, dried and subjected to distillation to remove the solvent. The residue was dissolved in ethanol. To the solution was added ethanol saturated with hydrogen chloride gas, and the mixture was allowed to stand. The resulting crystals were collected by filtration, washed with a small amount of ethanol, dried and recrystallized from ethanol to obtain 820 mg of 2-(3,4-dimethoxyphenyl)-4-(4-methylpiperazinylmethyl)thiazole.
Reaction SMILES: [N:1]([C:4]1[C:9]([Br:10])=[CH:8][N:7]=[C:6]2[N:11]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:5]=12)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:10][C:9]1[C:4]([NH2:1])=[C:5]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[CH:12][N:11]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]2=[N:7][CH:8]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N=[N+]=[N-])c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(N)c12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
4-Azido-5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (115 mg, 0.24 mmol), triphenylphosphine (64 mg, 0.24 mmol), and water (44 μL, 2.4 mmol) were dissolved in tetrahydrofuran (1 mL). The reaction was stirred at 23° C. for 1 h. Water (100 μL, 5.5 mmol) was added and the mixture was stirred an additional 14 h. The reaction mixture was directly loaded onto silica gel and purified using flash silica gel chromatography using a gradient of (ethyl acetate and methanol 9:1) in hexanes to afford 5-Bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamine (MS: m/z 448.1/450.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]([CH2:16][NH2:17])[OH:15]>C(O)C>[OH:15][CH2:14][CH2:16][NH:17][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: CCO
Product: O=C(O)c1cccc([N+](=O)[O-])c1NCCO
Temperature: 100 °C

Procedure:
2-Chloro-3-nitrobenzoic acid (5.0 g, 24.8 mmol) was suspended in ethanol (90 mL) and ethanolamine (4.5 mL, 74.8 mmol) was added. The resulting clear solution was heated at 100° C. for two days. The volatiles were removed under reduced pressure. The residue was treated with water (40 mL) and the mixture was acidified with 1M hydrochloric acid to pH 2. A yellow precipitate formed was collected by filtration and washed with water to yield 2-(2-hydroxyethylamino)-3-nitrobenzoic acid, 5.14 g (92%). MS (ESI) m/z 225 [M−H]. 1H NMR (400 MHz, CD3OD) δ ppm 3.04 (t, J=5.31 Hz, 2H), 3.69 (t, J=5.31 Hz, 2H), 6.71 (t, J=7.96 Hz, 1H), 7.93 (dd, J=8.21, 1.64 Hz, 1H), 8.13 (dd, J=7.71, 1.64 Hz, 1H).