Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].Cl.Cl.[CH:10]1([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.N#N>C(Cl)Cl>[CH:10]1([C:16]2[NH:20][C:19](=[O:21])[C:18]3([CH2:22][CH2:23][N:24]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:25][CH2:26]3)[N:17]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1NC(C2CCCCC2)=NC12CCNCC2
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
2-Chloro-ethanesulfonyl chloride (440 μl, 4.21 mmol) was added to a solution of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (1.50 g, 3.24 mmol) and triethylamine (2.7 ml, 19.4 mmol) in CH2Cl2 (30 ml) at room temperature in an N2 atmosphere. The mixture was stirred at room temperature for 30 minutes, and then washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with AcOEt-hexane, and the solid was then collected by filtration and dried to give 2-cyclohexyl-8-ethenesulfonyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a colorless solid (692 mg, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (3.16 g, 20.0 mmol), 1-methyl-piperazine (2.00 g, 2.00 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DMF is heated at 100° C. for 24 h, cooled, poured into water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 2% ammonia in 10:90 ethanol:ethyl acetate as eluent) affords the title compound as an off-white solid, 4.0 g (90% yield), identified by NMR analysis.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO>[C:18]1([C:14]2[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4])[CH:17]=[CH:16][N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCn1ccnc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCn1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Add sodium hydroxide (6.0 g, 150 mmol) in water (50 mL) to a suspension of 8-(2-phenylimidazol-1-yl)octanoic acid methyl ester (7.60 g, 25 mmol) in methanol (100 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for a total of 8 hours. Remove the solvent under reduced pressure, dilute the residue with water (300 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate and triturate with hexanes to afford 8-(2-phenylimidazol-1-yl)octanoic acid (4.22 g, 52%). APCI mass spectrum m/z 285 [C17H22N2O2−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:36](Cl)=[O:37]>CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:4]3[CH:3]=[CH:8][C:7]([C:36]([C:30]4[C:29]([F:28])=[CH:34][CH:33]=[CH:32][C:31]=4[F:35])=[O:37])=[CH:6][C:5]=3[NH2:13])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4c(F)cccc4F)cc3N)n2)cc(OC)c1OC
Yield: 30 %

Procedure:
Using Method LL with 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 2,6-difluoro-phenylcarbonyl chloride (30 mg, 0.17 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (21 mg). Yield: 30%. 1H NMR (250 MHz, DMSO-d6) δ 3.65 (s, 3H, [CH3O]4), 3.85 (s, 6H, [CH3O]3+5), 7.27 (s, 2H, Harom2′+6′), 7.45-7.47 (m, 1H, Harom 3″), 7.79-7.84 (m, 2H, Harom 4″+5″), 7.86 (d, 2H, Harom 3+5, J=8.3 Hz), 8.14 (s, 1H, HPz 5), 8.15 (d, 2H, Harom 2+6, J=6.7 Hz), 8.52 (s, 1H, HPz 3), 9.56 (s, 1H, NH), 10.61 (s, 1H, NHamide). m/z 493.2 [(M+H)+ calcd for C26H22F2N4O6 492.2].
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[C:7](=[C:18]([C:22](C(Cl)(Cl)Cl)=[O:23])[NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:22]([C:18]1[NH:19][C:20]([CH3:21])=[C:6]2[C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][CH2:8][C:7]=12)=[O:23]
Reactant: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1[nH]c(C)c2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2

Procedure:
A mixture of 3.0 g (6.4 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-3-[(trichloromethyl)carbonyl]-2H,4H-pyrrolo[3,4-d][2]benzazepine, 0.5 ml (2 mmole) of a 4 M methanol solution of sodium methoxide and 100 ml of methanol was heated to 40° for 30 min. The methanol solution was concentrated at reduced pressure, and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried with anhydrous sodium sulfate and concentrated at reduced pressure to give (mp 228°-231°) tan needles. Recrystallization from methylene chloride gave fine colorless needles, mp 229°-231°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].Cl.CN[OH:27].C(N(CC)CC)C>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:27])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CNO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
A mixture of 5-amino-3-cyano 1-[2,6-dichloro-4-(trifluoromethyl) phenyl]-4-methylsulfinyl-1H-pyrazole (1g), methylhydroxylamine hydrochloride (0.26g) and triethylamine (0.4g) was stirred in methanol at ambient temperature for 2 hours, evaporated, washed (water) extracted with ethyl acetate to give 5-amino- 1-[2,6-dichloro4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.35g) as a white solid m.p. about 190° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C>CO.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH3:1][O:4][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Product: CO[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 32.8 %

Procedure:
To a solution of 3 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 30 ml of methanol is added 1.7 g of zinc acetate, and the mixture is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, followed by addition of ethyl acetate. The resulting insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.912 g of (3S,4R)-4-methoxy-3-tritylamino-2-oxoazetidine.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[C:24]([C:29]([NH2:31])=[O:30])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[O:18])[CH:14]=[CH:15][CH:16]=1)=[O:10]>CN(C)C=O>[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[C:24]([C:29]([NH2:31])=[O:30])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)(=[O:1])=[O:18])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)(=O)c4cccc(C(=O)N(C)C)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Oxone (0.22 g) was added portionwise to a stirred solution of Example 575 (0.035 g) in N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature under nitrogen for 24 h, a further portion of oxone (0.17 g) was added, and the mixture stirred for a further 5 h. The reaction was quenched with a solution of sodium sulphite (1.2 g) in water (15 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a buff solid (0.035 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>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.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To an oven-dried flask under N2 was added N-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (5.6 g, 20 mmol), anhydrous degassed THF (200 mL), dichlorobis(triphenylphosphine)palladium(II) (1.7 g, 2.5 mmol), copper(I) iodide (0.28 g, 1.5 mmol), and trimethylsilylacetylene (7.0 mL, 50 mmol). Next, TEA (27 mL, 197 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography to afford the desired product (5.3 g, 89%) as an off white solid. ES-LC/MS m/z=302 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([NH:17][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 81.2 %

Procedure:
Tertiarybutyloxycarbonyl-L-valine (25 g) in dichloromethane (200 ml) was treated with 1-hydroxybenzotriazole (15.5 g) hexylamine (11.6 g) and DCC (26 g) at room temperature for 2 days. The solution was filtered and the organic phase washed with aqueous sodium hydrogen carbonate, aqueous citric acid (1M) and water, dried over sodium sulphate and concentrated in vacuo to afford tertiary butyloxy-carbonyl-L-valine N-hexylamide (28 g) which crystallised from methanol-water as needles; m.p. 74°-76° C.; (Found: C,63.8; H,10.6; N,9.4. C16H32N2O3 requires C,64.0; H,10.7; N,9.32%); νmax (Nujol): 3280 and 1630 cm-1 ; δ(CDCl3) 0.8-1 (9H,m, 3xCH3); 1.3 (8H,m,(CH2)4); 1.45 (9H,s, (CH3)3C); 2.1 (1H, m,CH(CH3)2); 3.3 (2H,m, NHCH 2); 3.9 (1H,dd, J=8 Hz and 5 Hz., α--CH); 5.2 (1H,d, J=8 Hz, CONH) and 6.26 (1H,m,NH).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][CH:18]([CH3:21])[CH2:19][NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][O:17][CH:18]([CH3:21])[CH2:19][NH:20][CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CC(CN)OCc1ccccc1
Product: CC(CNCC(O)c1ccccc1)OCc1ccccc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
A mixture of styrene oxide (1.96 g, 0.010 mol) and 2-benzyloxypropylamine (2.48 g, 0.15 mol) was heated at 140° C. for 6 hours and then allowed to cool to ambient temperature and stand for 12 hours. The solidified reaction mixture was triturated with isooctane and filtered to obtain an impure solid that was recrystallized from isooctane to obtain 2.40 g of a white solid (84% yield); mp 90°-100° C. (undefined).
Reaction SMILES: C(=O)(O)[O-].[Na+].[N+](C1C=CC(C[O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:20]3[S:19][C@:18]2([CH2:37][O:38][C:39](=[O:44])[NH:40][C:41](=[O:43])[CH3:42])[CH3:36])=[O:16])=CC=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[C:41]([NH:40][C:39]([O:38][CH2:37][C@@:18]1([CH3:36])[C@H:17]([C:15]([OH:16])=[O:14])[N:21]2[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:20]2[S:19]1)=[O:44])(=[O:43])[CH3:42]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 87 %

Procedure:
A suspension of 10% palladium on charcoal (400 mg) in ethyl acetate (40 ml) and aqueous 0.5% sodium bicarbonate was prehydrogenated and charged with (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (400 mg 0.68 mmol). The whole was shaken at 50 psi hydrogen pressure for 30 minutes and polish filtered. The aqueous was washed with ethyl acetate (20 ml), combined with a back extract of H2O (20 ml), overlayed with ethyl acetate (25 ml) and adjusted to pH 2.9 with 35% sulfuric acid. The layers were separated and the rich organic phase was washed with water (20 ml), combined with a back extract (EtOAc, 20 ml), dried (4A sieves), polish filtered and concentrated in vacuo to a colorless foam (270 mg) in 87% yield; nmr 100 MHz (CDCl3 --D2O) ppm 7.32 (2, m, m-phenyl H's) 6.96 (3, m, o,p-phenyl H's), 5.59 (2, br s, mag. equiv. C5,C6 --H's), 4.79 (1, s, C3 --H), 4.59 (HOD and ##STR65## 4.08 (m, AB of C2 --CH2O), 2.25 (3, s, ##STR66## and 1.58 (3, s, C3 --Me) with small ethyl acetate impurity.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])=[CH:7][CH:8]=1)=[O:41]
Reactant: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonyl(methyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E205-2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[N:27](COCC[Si](C)(C)C)[CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[NH:27][CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c(N)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (35 mg, 0.062 mmol) in DCM (6 ml) was added TFA (3.0 mL) and the reaction mixture was stirred for 3 hours at RT. The solvent was removed and the crude material was purified via reverse phase HPLC and neutralized to give N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (9.0 mg, 0.021 mmol, 33% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70 (s, 1H), 7.20-7.42 (m, 2H), 6.58 (d, 1H), 6.49 (d, 1H), 4.62 (s, 2H). LC-MS (ES+) m/z 438.13, [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
A mixture of 1-(4-Nitro-phenyl)-piperidin-4-one (84 mg, 0.38 mmol) and 1-methylpiperazine (0.085 mL, 0.76 mmol) in MeOH (2 mL) is stirred at room temperature for 5 hours. Then to the reaction mixture is added 0.2 mL of HOAc, followed by NaCNBH3 (72 mg, 1.14 mmol). The mixture is stirred at room temperature for 0.5 hour, then concentrated. The residue is taken up in EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, 2N NH3 in MeOH:CH2Cl2=1:99 to 10:90) to give 46 mg of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH:12]([F:14])[F:13])[CH:3]=1.[CH2:15](O)[CH:16]([OH:19])[CH2:17][CH3:18]>>[F:14][CH:12]([F:13])[O:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH3:9])[O:19][CH:16]([CH2:17][CH3:18])[CH2:15][O:10]1
Reactant: CC(=O)c1ccc(Cl)cc1OC(F)F
Reactant: CCC(O)CO
Product: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
12.8 parts of 1-(4-chloro-2-difluoromethoxyphenyl)ethan-1-one and 10.4 parts of 1,2-butanediol are heated under reflux for 12 hours in 100 ml of abs. toluene in the presence of 0.2 part of p-toluenesulfonic acid as catalyst, while removing the water of reaction with a water separator. The reaction mixture is cooled to room temperature and then washed with 2×100 ml of water, dried over sodium sulfate and filtered. The solvent is removed by evaporation and the residual oil is purified by high-vacuum distillation; b.p. 78°-80° C./0.04 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH2:7]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Fc1cccc(C=CCCl)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(F)c1)CC2
Yield: 44 %

Procedure:
Prepared from 3-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 44% of theory, Melting point: 128°-132° C. (ether).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:29][O:30][CH:31](OC)[O:32][CH3:33]>CO>[CH3:29][O:30][CH:31]([O:32][CH3:33])[C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(OC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
A flask equipped with a magnetic stir bar and vigreux column was charged with 4-nitro-benzaldehyde (5.0 g, 33.1 mmol), pyridinium p-toluenesulfonate (1.66 g, 6.62 mmol), trimethoxymethane (3.51 g, 33.1 mmol) and methanol (100 mL). The mixture was heated at 50° C. for 12 h and was concentrated in vacuo. The residue was redissolved in EtOAc and washed with aq. NaOH (1M), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a clear, light yellow oily product (6.36 g, 97%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:12]=1)(O)=[O:9]>ClCCl>[ClH:4].[Cl:7][C:8]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:12]=1)=[O:9]
Reactant: O=C(O)c1cn(-c2cccc3cccnc23)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1cn(-c2cccc3cccnc23)c2ccccc12
Temperature: 22 °C
Reaction time: 15 h
Yield: 115 %

Procedure:
0.6 cm3 (6.88 mmol) of oxalyl chloride is added to a suspension, cooled to a temperature in the region of 5° C., of 0.74 g (2.28 mmol) of 3-carboxy-1-(quinol-8-yl)-1H-indole hydrochloride in 15 cm3 of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.9 g of 3-chlorocarbonyl-1-(quinol-8-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.