Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:44]([Si:47]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[O:48][CH2:49][CH2:50]O)([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[CH:14]=[C:13]([O:15][CH2:50][CH2:49][O:48][Si:47]([CH:52]([CH3:53])[CH3:54])([CH:44]([CH3:46])[CH3:45])[CH:55]([CH3:56])[CH3:57])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](OCCO)(C(C)C)C(C)C
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin.(2.0 g, 5.509 mmol) in THF (35 mL) containing triphenylphosphine (1.59 g, 6.06mmol) and 2-(triisopropylsilyloxy) ethanol (1.13 g, 6.0 mmol) at room temperature was added diethylazodicarboxylate (1.04 mL, 6.6 mmol). The mixture was stirred overnight (16 hours), the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 10% ethyl acetate/hexane to afford 2.66 g (86%)of 4-isopropyl-6-[2-(triisopropylsilyloxy)ethoxy]-2-phenylthiomethylsaccharin as an oil
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: COC[C@H](C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H](C)COC

Procedure:
A solution of (S)-1-methoxy-2-propylamine in tetrahydrofuran was allowed to undergo the reaction with ethyl chloroformate in the presence of triethylamine to obtain [(1S)-2-methoxy-1-methylethyl]carbamic acid ethyl ester.
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:17])[CH2:13][C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:18]N(C)C=O.[H-].[Na+].CI>O>[CH:1]([N:4]([C:12](=[O:17])[CH:13]([CH3:18])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A one liter reaction flask equipped with a power stirrer, condener, drying tube, thermometer and nitrogen inlet tube was charged with 48.5 g (0.19 mole) of N-isopropyl-4'-chloroacetoacetanilide and 145 ml of dry dimethylformamide. With efficient stirring in a nitrogen atmosphere, portionwise addition of 7.2 g of 57% sodium hydride in mineral oil (0.17 mole) was completed in one hour (excessive foaming). Methyl iodide (24.1 g, 0.17 mole) was added dropwise and the reaction mixture was stirred for two hours at ambient temperature. The mixture was poured into one liter of cold water and stirred. The organic material was extracted into toluene and the latter was water washed. Most of the toluene was removed on the rotary evaporator. Hexane was added which caused the mass to crystallize. There was obtained 36.4 g (80%) of white material, M.P. 77°-79°. N.M.R. (CDCl3) ∂0.9-1.4 (CH3, 9 protons), 2.0 (0=C--CH3), 2.9-3.2 (CH), 4.7-5.2 (CH, isopropyl), 6.9-7.5. (aromatic).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:4]=1[NH2:5].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1>C1COCC1>[Br:10][C:7]1[CH:6]=[C:4]2[C:3]([CH2:2][NH:1][C:16](=[O:17])[NH:5]2)=[CH:9][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc(Br)cc1N
Solvent: C1CCOC1
Product: O=C1NCc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
To a solution of compound 12 (0.90 g, 4.5 mmol) in THF (10 mL) at room temperature was added CDI (0.80 g, 4.95 mmol), and the reaction was stirred at 80° C. for 6 hr. The mixture was cooled to room temperature, and the solid formed was filtered, washed with diethyl ether to afford 0.73 g (72%) of compound 13 as off-white solid. IR (KBr) νmax. cm−1: 3308, 3158 (NH), 3022 (Ar—H), 1682 (C═O), 1514, 1411 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=5.25 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) δ=66.85 (CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52 (C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C═O). Calculated (%) for C8H7BrN2O (225.97); C, 42.32; H, 3.11; N, 12.34. found (%); C, 42.27; H, 3.16; N, 12.28.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:16]([CH3:19])[N:17]=[CH:18][C:3]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:14][C:11]1[N:10]=[CH:9][C:8]([C:6]2[N:5]=[C:4]3[N:16]([CH3:19])[N:17]=[CH:18][C:3]3=[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=3)[CH:7]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cc(Cl)c3cnn(C)c3n2)cn1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cnn(C)c3n2)cn1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To 4-chloro-6-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.32 g) and 4-(methylsulfonyl)phenol (0.40 g) in DMF (6 mL) was added potassium carbonate (0.80 g) and nitrogen was bubbled through the solution for 5 min. The reaction mixture was then heated in a microwave reactor at 150° C. for 1 h. The resulting product was purified by silica gel chromatography (0-30% EtOAc in hexane) to afford 117 (0.38 g). MS (ESI) m/z 411.1 (M+1)+
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[CH2:18][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[N:26][CH:27]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)nc1
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 53B. MS m/z 474 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
319 mg (purity 91%, 0.70 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoic acid (racemate) and 148 mg (0.77 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 263 mg (purity 88%, 56% of theory)
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:86][C@H:85]([CH2:87][F:88])[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:89][F:90])[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[F:88][CH2:87][C@H:85]1[O:86][C@@H:57]([O:56][C@@H:46]2[C@@H:45]([CH2:89][F:90])[O:44][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[C@H:58]([OH:59])[C@@H:67]([OH:68])[C@@H:76]1[OH:77]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](CF)[C@@H](O[C@@H]3O[C@H](CF)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O[C@H]1O[C@H](CF)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 2 h
Yield: 56.1 %

Procedure:
The compound (122.6 mg, 0.10 mmol) synthesized in Example 5 (5e) was dissolved in methanol (10 mL) containing 1% aqueous hydrochloric acid solution and 20% palladium hydroxide-carbon (100 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.5 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and the aqueous solution (100 mL) was subjected to ion exchange resin (Dowex 50w×8) column, it was eluted with 1% ammonia water (100 mL). The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (25.9 mg, 56%) as a colorless solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@@H:6]([OH:8])[C@H:5]1[CH2:4][NH:3][CH2:2]2.[CH:9]([C:11]1[C:12]([F:23])=[CH:13][N:14]=[C:15]2[C:20]=1[N:19]=[C:18]([O:21][CH3:22])[CH:17]=[CH:16]2)=[CH2:10]>CCO>[F:23][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[CH2:9][CH2:10][N:3]1[CH2:4][C@H:5]3[C@H:1]([CH2:7][C@H:6]3[OH:8])[CH2:2]1)=[N:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Reactant: O[C@@H]1C[C@@H]2CNC[C@@H]21
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@@H](O)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 23.4 %

Procedure:
A solution of (±)-(1S,5R,6R)-3-azabicyclo[3.2.0]heptan-6-ol (700 mg, 6.2 mmol) and 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (1.3 g, 6.2 mmol) in EtOH (4 mL) were heated at 85° C. After 12 h, the solution was concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (460 mg, 23%) as a yellow oil: LC/MS (ES) m/e 318 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[O:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COC2(CCN(c3ccc(O)cc3)CC2)CN1Cc1ccccc1
Reactant: BrCCCN1CCCC1
Agent: Br
Product: O=C1COC2(CCN(c3ccc(OCCCN4CCCC4)cc3)CC2)CN1Cc1ccccc1

Procedure:
The entitled compound was obtained as a yellow solid, according to the same method as in Example 4-(c) or according to a method similar to it but using 4-benzyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecan-3-one produced in Example 4-19-(b) and 1-(3-bromopropyl)pyrrolidine hydrobromide produced according to a method described in a patent (U.S. Pat. No. 4,751,302).
Reaction SMILES: [F:1][C:2]1[N:3]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=[C:5](/[CH:7]=[CH:8]/[C:9](=O)[CH3:10])[N:6]=1.Cl.[CH3:32][O:33][NH2:34].N1C=CC=CC=1>CCO>[F:1][C:2]1[N:3]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:4]=[C:5]([CH:7]=[CH:8][C:9](=[N:34][O:33][CH3:32])[CH3:10])[N:6]=1
Reactant: CON
Reactant: CC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)C=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Examples 55 and 56: E-2-Fluoro-4-(3-oxobut-1-enyl)-1-triphenylmethylimidazole in EtOH was treated with O-methylhydroxylamine hydrochloride and pyridine for 18 hours. Solvent was evaporated and 2-fluoro-4-(3-methoxyiminobut-1-enyl)-1-triphenylmethylimidazole isolated by crystallisation as a 3:1 mixture of isomers. The major Z, E-isomer had the following n.m.r. in CDCl3 : 1.96 (s, 3H); 3.9 (s, 3H); 6.48 (d, 1H); 6.6 (s, 1H); 7.04-7.4 (m, 16H).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH:3]([OH:16])[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[Cl:18][C:2]([Cl:1])([Cl:17])[CH:3]([O:16][C:19](=[O:21])[CH3:20])[CH:4]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:5](=[O:10])[C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Yield: 43 %

Procedure:
314.6 g (1 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one were heated at 95° C. in 1,000 ml of acetic anhydride for 30 hours. The excess anhydride was then distilled off in vacuo, the residue was taken up in 750 ml of methylene chloride and the methylene chloride mixture was washed with 10% strength sodium bicarbonate solution until neutral. The organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue was stirred with 150 ml of diisopropyl ether. 153.8 g (43% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one were obtained as the pure diastereomer of the A* form of melting point 129°-131° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([C:34](=[O:36])[CH3:35])[CH3:37])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Yield: 55.6 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(N-methylacetamido)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (72 mg, 112 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-{1-[3-(acetyl-methyl-amino)-propyl]-5-difluoromethoxy-1H-indazol-3-yl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (32 mg, 56%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.39 (s, 1H), 8.22 (br. s., 1H), 7.84-7.98 (m, 2H), 7.40 (d, J=9.8 Hz, 1H), 6.93-7.47 (m, 1H), 4.48-4.60 (m, 1H), 3.36-3.42 (m, 2H), 2.95 (s, 3H), 2.79 (s, 3H), 1.93 (d, J=7.5 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:27])[N:16]([CH2:17][CH2:18][C:19](=[S:21])[NH2:20])[C:15](=[O:22])[C:14]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:13]12>>[C:15]1(=[O:22])[N:16]([CH2:17][CH2:18][C:19]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:20]=2)[C:12](=[O:27])[C:13]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:14]12
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 3-phthalimidopropanethioamide
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(O)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 65 %

Procedure:
A solution of 71 g potassium hydroxide in 300 ml water is dripped under reflux, into a mixture of 215 g 4-hydroxy-4'-nitrobiphenyl (see Example 3) and 4000 ml ethanol. Then, 217 g 6-bromohexanol is added, subsequently, the mixture is heated under reflux for 15 h. After cooling, the solvent is removed in a vacuum and the residue is slurried up with water dried. The raw product is filtered off, washed neutral with water and recrystallized from ethanol (melting point: 119° C.); yield: 65%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc(C)c(C)nc3OC)CC2)c1
Yield: 85 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[N:10]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH2:9])[CH:5]=[C:6]([N:13]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:15][CH2:14]2)[N:7]=1
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: Cc1nc(N)cc(Cl)n1
Product: Cc1nc(N)cc(N2CCN(CCN3CCOCC3)CC2)n1

Procedure:
210 mg (1.47 mmol) of 2-methyl-4-chloro-6-aminopyrimidine 20-1 and 294 mg (1.47 mmol) of 4-(2-piperazin-1-ylethyl)morpholine 7-3 were used to obtain the desired product 20-2 as a yellow oil/solid. MS M+1=307. H1 NMR (CDCl3): 2.37(s, 3H), 2.53(br m, 4H), 2.57(br m, 4H), 3.57(m, 4H), 3.73(m, 4H), 4.52(br s, 2H), 5.41(s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(#N)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:14]([F:13])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
18.7 g of 2-chlorobenzoylisocyanate were added to 150 ml of a solution of 17.7 g of 4-trifluoromethylaniline in dry acetonitrile. After stirring at room temperature for a few hours, the crystalline precipitate was sucked off, washed with successively acetonitrile, ethanol and petroleum ether and dried in air. The desired product was obtained in a yield of 29.0 g; melting point 214° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([N+]([O-])=O)[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N+:9]=1[O-:10].[OH:21][CH2:22][CH2:23][OH:24]>>[OH:21][CH2:22][CH2:23][O:24][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[N+:9]([O-:10])=[C:4]([CH3:3])[CH:5]=1
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-c2cc(OCCO)cc(C)[n+]2[O-])n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Sodium hydride (2.07 g, 51.8 mmoles) was added to 1,2-dihydroxyethane (100 ml). After 15 minutes 6,6'-dimethyl-4-nitro-2,2'-bipyridine-N-oxide (17) (6.35 g, 25.9 mmoles) was added and the mixture was stirred at 60° C. for 4 hours. Excess of 1,2-dihydroxyethane was removed by evaporation in high vacuum and the product was purified by flash chromatography.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrC[CH2:7][C:8]1([CH3:34])[CH:12]([C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])[N:11]2[C:21](=[O:33])[CH:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:10]2[S:9]1>O.CC(C)=O>[S:1]([CH2:7][C:8]1([CH3:34])[CH:12]([C:13]([O:15][CH2:16][C:17]([Cl:18])([Cl:19])[Cl:20])=[O:14])[N:11]2[C:21](=[O:33])[CH:22]([NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:10]2[S:9]1)[C:2]#[N:3]
Reactant: CC1(CCBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(CSC#N)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 80.4 %

Procedure:
Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenyl-acetamido)penam-3-carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with ether and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][N:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC(OCC)OCC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a suspension of NaH (1.44 g, 60.2 mmol) in N,N-dimethylformamide (DMF)(30 mL) was slowly added 121a (5.80 g, 30.1 mmol) at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, followed by the addition of 2-bromo-1,1-diethoxyethane (11.9 g, 60.2 mmol). The reaction was heated at 70° C. for 30 h and quenched with water (100 mL). The mixture was then extracted with ethyl acetate (3×100 mL). The combined organic phase was concentrated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to afford 121b (4.7 g, 51%). MS-ESI: [M-ethanol+H]+ 264. 1H NMR (500 MHz, DMSO-d6) δ 6.65 (s, 1H), 4.59 (t, J=5.0 Hz, 1H), 4.17-4.16 (m, 4H), 3.59-3.57 (m, 2H), 3.27-3.26 (m, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.51 (t, J=6.0 Hz, 2H), 1.73-1.71 (m, 2H), 1.63-1.61 (m, 2H), 1.25 (t, J=7.0 Hz, 3H), 1.02 (t, J=7.0 Hz, 6H).