Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[C:6]([OH:24])[CH:5]=1.BrC1C=CC=CC=1O.F[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1[N+]([O-])=O.FC1C=C(C=CC=1[N+]([O-])=O)C#N>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)[C:39]3[C:38]([O:24][C:6]=2[CH:5]=1)=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][CH:40]=3)=[O:25]
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c(O)c1
Agent: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Oc1ccccc1Br
Product: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CCN(Cc2ccccc2)CC1

Procedure:
Using an adaptation of the method described in Procedure 1, substituting 4-(1-benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic acid methyl ester, 1d for 2-bromophenol, and 1-fluoro-3-methoxy-2-nitrobenzene for 3-fluoro-4-nitrobenzonitrile, the title compound 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid methyl ester, 2d was obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[F:15][C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27][CH2:28][C:29]3([C:37](Cl)=[O:38])[CH2:35][CH:34]4[O:36][CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.Cl>ClCCl>[OH:3][NH:2][C:37]([C:29]1([CH2:28][S:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:40]=[CH:41][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:35][CH:34]2[O:36][CH:31]([CH2:32][CH2:33]2)[CH2:30]1)=[O:38]
Reactant: NO
Reactant: O=C(Cl)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NO)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and is stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). The organic phase is then concentrated to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1N.C(=O)(O)[O-]>>[NH:18]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:17]1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1N
Reactant: N#Cc1ccc2nccc(-c3ccncc3)c2c1
Agent: O=C([O-])O
Product: c1ccc2[nH]c(-c3ccc4nccc(-c5ccncc5)c4c3)nc2c1
Temperature: 250 °C

Procedure:
A mixture of 4-(4-pyridinyl)-6-quinolinecarbonitrile, (231 mg, 1 mmol) 1,2-diaminobenzene (108 mg, 1 mmol) and polyphosphoric acid (1.4 g) was heated in the microwave at 250° C. for 1.5 hours. The reaction was poured onto water which was neutralized with bicarbonate. The product was filtered, washed with water, and dried. The product was further purified by dissolving in hot methanol, filtering and cooling to obtain crystals. The yield was 47.7 mg, 30%. MS (ES)+ m/e 323 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>O.N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10](/[CH:11]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
A mixture of 3-phenoxybenzaldehyde (214 g), malonic acid (300 g) and pyridine (450 cm3) was heated at 50° C. until all the malonic acid had dissolved, after which piperidine (20 cm3) was added and the mixture heated at 100° C. for 3 hours. The mixture was poured into iced water (3.0 l) and acidified with concentrated hydrochloric acid (600 cm3). The precipitated solid was collected by filtration, washed with water and then dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate, after which the solvent was removed by evaporation under reduced pressure to give a solid residue which was recrystallised from a chloroform-hexane mixture to give E-3-(3-phenoxyphenyl)propenoic acid (219 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 2,5-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (commercially available, for example from J&W Pharmlab, 7.57 g, 32.7 mmol) in dichloromethane (200 mL) was added triethylamine (4.79 mL, 34.4 mmol), 4-dimethylaminopyridine (0.20 g, 1.64 mmol) and p-toluenesulfonyl chloride (6.55 g, 34.4 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (200 mL) and the solution washed with water (200 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (3 column volumes), a gradient from 30-50% (over 6 column volumes) then 50% EtOAc (3 column volumes)) to yield the title compound as a colourless gum (2.28 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1.O.[NH2:21][NH2:22]>CO>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1ccc(C(=O)NCc2ccnn2C)s1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1nccc1CNC(=O)c1ccc(C(=O)NN)s1
Yield: 49 %

Procedure:
Methyl 5-(1-methyl-1H-pyrazol-5-ylmethylcarbamoyl)thiophene-2-carboxylate (0.25 g, 0.90 mmol) in methanol (2.5 mL) was stirred with hydrazine monohydrate (0.17 mL, 3.6 mmol) at 70° C. for 3.5 hours. The precipitated solid was recovered by filtration, washed with chloroform and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (1-methyl-1H-pyrazol-5-ylmethyl)amide (yield 49%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A solution of 5-bromofuran-2-carboxylic acid (381 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4 (aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 209 mg of 5-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.13.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1.C[O-].[Na+].O>C(#N)C>[CH2:37]([C:36]1[CH:35]=[C:34]([C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=2)[N:26]=[C:24]([NH:23][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:11]([O:10][CH3:9])[CH:12]=2)[N:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCC#CC(=O)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: CCCCc1cc(-c2ccc(Cl)cc2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 16.3 %

Procedure:
A suspension of N-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (153 mg, 0.41 mmol), 1-(4-chloro-phenyl)-hept-2-yn-1-one (100 mg, 0.45 mmol, CAS 105363-17-5) and sodium methanolat (120 mg, 1.24 mmol) in acetonitrile (2.0 mL) was heated two times to 120° C. for 30 minutes in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (9:1 v/v) as eluent to yield the title compound as a yellow solid (30 mg, 16%). MS ISP (m/e): 448.3/450.1 (100/37) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.04 (d, 2H), 7.98 (s, 1H), 7.64 (s, 1H), 7.46 (d, 2H), 7.29 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.89 (s, 1H), 3.89 (s, 3H), 2.74 (t, 2H), 2.31 (, 3H), 1.79 (m, 2H), 1.43 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([O:40][C:41]1([C:47]#[CH:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH:38]=[CH2:39].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:48]=[C:47]([C:41]5([O:40][CH2:37][CH:38]=[CH2:39])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#CC1(OCC=C)CCCCC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CO
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(C5(OCC=C)CCCCC5)nn4)nn23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.06 g, 0.120 mmol), 1-(allyloxy)-1-ethynylcyclohexane (0.039 g, 0.240 mmol), Cu(II)SO4.5H2O (3.00 mg, 0.012 mmol) and (+)-sodium L-ascorbate (0.024 g, 0.120 mmol) in MeOH (2 mL) was stirred for 16 h at rt. Then, purified by prep-HPLC to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(1-(allyloxy)cyclohexyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0287 g, 0.043 mmol, 36.0% yield) as pale yellow paste. 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 6.41 (s, 1H), 5.99-6.08 (m, 1H), 5.90 (br. s., 1H), 5.82 (tdd, J=5.3, 10.5, 17.2 Hz, 1H), 5.73 (s, 2H), 5.47 (d, J=16.4 Hz, 1H), 5.17-5.23 (m, 2H), 5.01-5.06 (m, 1H), 4.12-4.28 (m, 2H), 4.00-4.03 (m, 2H), 3.74 (td, J=1.5, 5.4 Hz, 2H), 2.61 (s, 3H), 1.90-2.06 (m, 6H), 1.67-1.75 (m, 4H), 1.54-1.61 (m, 1H), 1.44-1.52 (m, 2H), 1.35 (s, 3H), 1.23-1.25 (m, 12H). LCMS (M+H)=664.7.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:17]I.Cl>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH3:17])[N:3]=1
Reactant: CI
Reactant: Cc1cc2c(I)n[nH]c2cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(I)nn(C)c2cc1[N+](=O)[O-]
Yield: 36.2 %

Procedure:
The compound (16.1 g, 53.1 mmol) of step A was dissolved in N,N-dimethylformamide (200 ml), 60% sodium hydride (2.41 g, 60.3 mmol) was added under ice-cooling with stirring, and the mixture was stirred at 0° C. for 45 min. Then, methyl iodide (5.0 ml, 80.3 mmol) was added, and the mixture was stirred at the same temperature for 100 min. To the reaction mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated. The obtained solid was purified by silica gel column chromatography (hexane:dichloromethane:ethyl acetate-10:1:1) to give the title compound (6.09 g, yield 36%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7]([O:9]C(C)(C)C)=O.[CH3:26][CH:27](C)[CH2:28][C:29](O)=O.[CH3:33][C:34]1[CH:35]=[C:36]([C:43]([N:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][CH3:48])=[O:44])[CH:37]=[C:38]([CH:42]=1)[C:39]([OH:41])=O>>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][C@H:2]([NH:1][C:39](=[O:41])[C:38]1[CH:42]=[C:34]([CH3:33])[CH:35]=[C:36]([C:43]([N:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][CH3:48])=[O:44])[CH:37]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7](=[O:9])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CC(C)CC(=O)O
Reactant: CCN(C[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Product: CCCCC(=O)NN(CC)C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)c1cc(C)cc(C(=O)N(CCC)CCC)c1

Procedure:
Synthesized as described above from tert-butyl 2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate, 3-methylbutanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid. MS (ESI+) for C32H46F2N4O4 m/z 589.3 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:33]=[CH:34][C:35]=1[NH:36]C(=O)OC(C)(C)C.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-]>ClCCl>[NH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:31][C:30]=1[NH:29][C:8]([C:7]1[CH:11]=[CH:12][C:4]([NH:1][C:2]([N:26]2[CH2:27][CH2:28][C:22]3([CH2:23][CH2:24][N:20]([CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21]3)[CH2:25]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: O=C=Nc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(NC(=O)N2CCC3(CCN(Cc4ccccc4)C3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL of dichloromethane was added 2-benzyl-2,7-diazaspiro[4,4]nonane (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+546.3, obs'd 546.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1.Br[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[CH2:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=2)[CH2:20][CH3:21])[C:14](=[O:16])[CH:13]([CH3:17])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CC(C)C(=O)N1
Reactant: CCC(Br)c1ccc(OC(F)(F)F)cc1
Product: CCC(c1ccc(OC(F)(F)F)cc1)N1C(=O)C(C)CC1c1c(OC)cccc1OC

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one with 1-(1-bromopropyl)-4-(trifluoromethoxy)-benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 438.28 g/mol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:12]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1.[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: COC(=O)c1nccnc1N
Reactant: ClCl
Solvent: CC(=O)O
Product: COC(=O)c1nc(Cl)cnc1N
Product: Nc1cnc(Cl)cn1

Procedure:
One of the intermediates, 2-amino-5-chloropyrazine is prepared following the general procedure of Palamidessi and Bernardi, J. Org. Chem. 29, 2491 (1964), wherein methyl 2-amino-3-pyrazinylcarboxylate is allowed to react with chlorine in acetic acid to yield methyl 2-amino-5-chloro-3-pyrazinylcarboxylate. This ester is hydrolyzed with aqueous sodium hydroxide to yield 2-amino-3-carboxy-5-chloropyrazine, which is then heated in tetrahydronaphthalene and decarboxylated to yield the desired 2-amino-5-chloropyrazine.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[C:17]2[C:12](=[C:13]([O:21][CH3:22])[C:14]3[O:20][CH2:19][O:18][C:15]=3[CH:16]=2)[CH2:11][N:10]([CH3:23])[CH2:9]1.C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1>C1C=CC=CC=1>[CH3:22][O:21][C:13]1[C:14]2[O:20][CH2:19][O:18][C:15]=2[CH:16]=[C:17]2[C:12]=1[CH2:11][N:10]([CH3:23])[CH2:9][C:8]2=[O:7]
Reactant: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Agent: CC(C)(C)[O-]
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Agent: [K+]
Solvent: c1ccccc1
Product: COc1c2c(cc3c1OCO3)C(=O)CN(C)C2
Temperature: 0 °C
Yield: 8.2 %

Procedure:
673 mg (6 mmol) of potassium-t-butoxide was added to a solution (20 ml) of 593 mg (2.5 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) and 2.25 g (12.5 mmol) of fluorenone in anhydrous benzene under a nitrogen atmosphere and refluxed under heating for 10 minutes. Then 15 ml of ice-cold water was added to the solution to stop the reaction. The solution was extracted with ethyl ether and then the organic layer was extracted with a 5% hydrochloric acid solution. The aqueous layer was made basic, then extracted with ether, dried, filtered and concentrated. The resulted residue was purified by silica gel column chromatography (eluent: 4% methanol/chloroform) to obtain 48.1 mg of 2,3-dihydro-8-methoxy-2-methyl-6,7-methylenedioxy-4(1H)-isoquinolone (12) (yield: 8%). Melting point: 116°-119° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:27]([CH2:29]O)[CH:28]=1.O>C(#N)C>[Br:20][CH2:29][C:27]1[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=1[S:31]([CH3:34])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(Cl)cc1CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (1.19 g) was suspended in acetonitrile (50 ml), bromine (0.24 ml) was added, and the mixture was stirred at room temperature for 30 min. A solution of [5-chloro-2-(methylsulfonyl)phenyl]methanol obtained in Step 2 (1 g) in acetonitrile (10 ml) was added to the reaction mixture. The mixture was stirred at 70° C. for 3 hr, treated with water, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:3) to give 2-(bromomethyl)-4-chloro-1-(methylsulfonyl)benzene (0.46 g).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:22]2[CH2:23][O:24][CH:25]=CC=2)[CH2:12][CH2:13][CH:14](CO)CCCCC)(=O)=O)=CC=1.[CH2:29]1[O:37][CH:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)C(O)CCCCC>CN(P(N(C)C)(N(C)C)=O)C>[C:31]1([CH:30]2[CH2:25][O:24][CH:23]([CH2:22][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:29][O:37]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCCCC(CO)CCC(OS(=O)(=O)c1ccc(C)cc1)C1=CC=COC1
Reactant: c1ccc(C2CO2)cc1
Agent: CCCCCC(O)CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC1COC(c2ccccc2)CO1

Procedure:
A solution of 4.06 g. 4-hydroxymethyl-3-oxa-1-phenyl-nonan-1-ol 1-mono-p-toluene sulphonate (obtainable by reaction of styrene oxide with heptane-1,2-diol and partial tosylation of the 4-hydroxymethyl-3-oxa-1-phenylnonan-1-ols obtained) in 100 ml. phosphoric acid hexamethyltriamide is heated for 24 hours to 80°. One evaporates, works up as usual and obtains 2-phenyl-5-pentyl-1,4-dioxane as an oily isomer mixture. Isomerization of 1 g. of the mixture by 2 hours heating with 0.05 g. K tert.-butylate in 10 ml. dimethyl sulphoxide to 80° leads to trans-2-phenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([S:17](Cl)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([S:17]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:19])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Cn1cccc1CCNS(=O)(=O)Cc1ccccc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and benzylsulphonyl chloride analogously to Example A.