Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1C)C(O)=O)(=[O:4])=[O:3].[C:15](=[O:18])([O-:17])[O-].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[CH:27]([OH:29])=[O:28]>O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:18])[CH:11]=[CH:12][C:13]=1[C:27]([OH:29])=[O:28])(=[O:4])=[O:3]
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: O=CO
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)ccc1C(=O)O

Procedure:
To a solution of 44 g of 3-(aminosulfonyl)-4-methyl benzoic acid (Example 1) in 500 ml H2O was added 11.0 g of sodium carbonate and 72 g of potassium permanganate in 8 g portions at 50°-60° over 5.5 hours. Then, 1 ml formic acid was added to decompose excess oxidant and the solution was filtered hot (60°) through Celite. The filter pad was washed with hot water. The combined filtrate was concentrated, in vacuo to approximately 300 ml and brought to pH 6 with concentrated HCl. A small amount of solid was filtered off. The filtrate was brought to pH 3.5 with concentrated HCl. The resulting solid was collected, washed with water and dried to give 33 g of solid; m.p. 259-290 (known m.p. 312-314). This material was used, without further purification, in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[CH2:11]O.[Li+].[Cl-].S(Cl)([Cl:17])=O.O>CN(C)C=O>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([S:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(SC)cc1CO
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SC)cc1CCl
Reaction time: 0.25 h

Procedure:
To a solution of Example 170B (1.23 g, 6.69 mmol) in 15 mL of N,N-dimethylformamide was added LiCl (567 mg, 13.4 mmol), then 2 mL (27 mmol) of thionyl chloride. The solution warmed spontaneously on addition of the thionyl chloride. After 15 min, 50 mL of water was added, then the aqueous suspension was extracted with diethyl ether (3×15 mL). The combined organic layers were back extracted with water (1×15 mL), saturated NaHCO3(aq.) (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to 1.24 g (92%) of an oil. This was used in the next step on the same day and without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[NH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: c1cncc(C2CCNC2)c1
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2cccnc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-pyrrolidin-3-ylpyridine (8.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.0 mg). Calcd for C19H16ClN3O2: 353.0931, found 353.0932.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:15][C:16](=[O:41])[CH:17]([N:21]([C:23](=[O:40])[C@H:24]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:25]C(OC(C)(C)C)=O)[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:15][C:16](=[O:41])[CH:17]([N:21]([CH3:22])[C:23](=[O:40])[C@H:24]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH2:25])[CH:18]([CH3:20])[CH3:19])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-2-[N-(N-Boc-phenylalanyl)-N-methylamino]-3-methylbutanamide (333 mg) was dissolved in methylene chloride (4 ml) and, after adding TFA (2 ml), the solution was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and washed with saturated aqueous NaHCO3. The resulting organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 75:1:0.1) to yield N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl-2-(N-methyl-N-phenylalanylamino)butanamide in the amount of 164 mg (60%).
Reaction SMILES: C[N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7]2.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH3:2].[C:14]([O:13][C:11]([N:5]1[CH2:6][CH2:7][CH:8]2[NH:2][CH:3]([CH2:10][CH2:9]2)[CH2:4]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN1C2CCC1CN(C(=O)OC(C)(C)C)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2CCC(C1)N2
Product: N

Procedure:
9-Methyl-3-tert-butoxycarbonyl-3,9-diazabicyclo-[4.2.1]-nonane (3.4 g, 14.1 mmol), Diethylazodicarboxylate (12.3 g, 70.7 mmol) and toluene (35 ml) was stirred at reflux for 1.5 h. Sodiumhydroxide (50 ml, 1 M) was added. The aqueous phase was extracted twice with ethyl acetate (50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 1.13 g, 35%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[F:37][C:38]1([F:50])[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:47]1[CH2:48][CH2:49][CH:44]([N:41]2[CH2:40][CH2:39][C:38]([F:50])([F:37])[CH2:43][CH2:42]2)[CH2:45][CH2:46]1)=[O:15])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: FC1(F)CCN(C2CCNCC2)CC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(F)(F)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 200 mg (0.98 mmol) 4,4-difluoro-[1,4′]bipiperidinyl.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[OH-:12].[Na+]>O>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1O
Temperature: 20 °C

Procedure:
(2-Chlorophenyl)acetic acid (3.4 g, 0.02M), crushed sodium hydroxide pellets (4.8 g, 0.12M) and `SOLVESSO` 200 (30 g) were stirred for 0.5 hours. Cupric sulphate pentahydrate (0.2 g, 0.0008M) was added and the mixture heated at 190°-196° C. for about 4 hours. The reaction mass was cooled to 20° C. and treated with water (50 g), transferred to a separator with a further amount of water (50 g) and filtered. The separated aqueous filtrates were acidified to about pH4 using 36% hydrochloric acid and the product was extracted into ethyl acetate (180 g). (2-Hydroxyphenyl)acetic acid (2.62 g) was isolated as a solid by distillation of the ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([OH:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc(Br)c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Product: C[C@@H](O)c1cc(Br)cc(Br)c1

Procedure:
1-(3,5-dibromo-phenyl)-ethanone and (S)-(−)-2-methyl-CBS-oxazaborolidine were reacted as described in Example 35, Step 1 to provide (R)-1-(3,5-dibromo-phenyl)-ethanol.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[C:23]([O:27][C:28](=[O:34])[NH:29][C:30](=[O:33])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[C:23]([O:27][C:28](=[O:34])[N:29]([C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)[C:30](=[O:33])[CH2:31][CH3:32])([CH3:25])([CH3:24])[CH3:26]
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reaction time: 1 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (1.00 g, 2.92 mmol), propionyl-carbamic acid tert-butyl ester (Intermediate W) (0.55 g, 3.21 mmol) and triphenylphosphine (0.115 g, 0.44 mmol) are placed under an inert atmosphere of Argon. THF (10 ml) is added followed by tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.15 mmol). The reaction mixture is stirred at 50° for 1 hour. The solvent is removed in vacuo and purification by chromatography on silica eluting with EtOAc/hexane (1:4) affords the title product. 1H nmr (CDCl3, 400 MHz); 8.70 (s, 1H), 6.15 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.60 (m, 1H), 3.15 (m, 1H), 2.75 (q, 2H), 2.10 (m, 1H), 1.55 (s, 9H), 1.15 (t, 3H), MS (ES+) m/e 426 (MH+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][NH:74][C@H:75]([CH3:82])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:24]([N:74]([CH3:73])[C@@H:75]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[CH3:82])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN[C@H](C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: C[C@H](c1ccccc1)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol), DiPEA (7.1 mL; 40 mmol) and acetonitrile:CH2Cl2 (1:1; 100 mL) followed by (R)-(+)-N,α-dimethylbenzylamine (2.0 mL; 13 mmol), then stirred overnight. After work up the crude product was purified by chromatography on silica gel with EtOAc to provide 6.0 g (91%) of the sub-title compound.
Reaction SMILES: I[C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1I.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][N:11]3[C:5]2=[N:4][C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:8]=2)=[C:2]3[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3I)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3-c2ccccc2)CC1
Temperature: 105 °C

Procedure:
To a solution of 1,2-diiodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 219A) (212 mg, 0.386 mmole) in THF (3 mL) are added benzeneboronic acid (120 mg, 1 mmole), water (3 mL), Ba(OH)2 (460 mg, 2 mmoles) and PdCl2(dppf)2 (40 mg). The flask is evacuated and filled with argon. The reaction mixture is heated at 105° C. for 48 hours. AcOEt is added and the organic phase is washed with water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-1,2-diphenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 90° C.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>CN(C=O)C>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)OCCN3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 680 mg, 2.2 mmol) was dissolved in DMF (20 mL). DIPEA (0.76 mL, 4.4 mmol) and 4-(4-methoxyphenyl)piperazine (422 mg, 2.2 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 500:8:1 mixture of DCM:EtOH:NH3, followed by a 50:8:1 mixture of DCM:EtOH:NH3). The residue was recrystallised from EtOAc to give 2-(4-methyl-piperazin-1-yl)ethyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (137 mg, 17%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH:17]1([NH2:23])CCC[CH2:19][CH2:18]1.C(#N)C=C>C1(C)C=CC=CC=1.C(O)(=O)C.COC1C=CC(O)=CC=1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([CH2:19][CH2:18][C:17]#[N:23])[C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: NC1CCCCC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: COc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C=CC#N
Product: CN(C)C1(c2ccccc2)CCC(=O)C(CCC#N)C1
Temperature: 90 °C
Yield: 813.7 %

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol) was added to a solution of cyclohexylamine (109 mg, 1 mmol), glacial acetic acid (26 mg, 0.43 mmol) and 4-methoxyphenol (26 mg, 0.21 mmol) in 10 ml of toluol. The mixture was heated to 90° C. (bath temperature) and mixed with acrylonitrile (4 ml, 60.8 mmol) within 2 h. The batch was then heated to 120° C. After 3 h the heating was removed and the batch mixed with 1N NaOH (20 ml) after RT was reached. The mixture obtained was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with water and then dried over MgSO4. The residue (2.2 g) obtained after removal of the solvent solidified upon standing and was mainly composed of the initial ketone and a more non-polar product compared to this. One of the two possible diastereoisomers of the ketone was obtained with a yield of 400 mg (14%) in the form of an oil by means of chromatographic purification [silica gel 60 G (10 g); cyclohexane/ethyl acetate 1:10 (120 ml)].
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][NH:7][CH2:6][C@H:5]1[NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[N:14][CH:13]=[C:12]([CH2:18][CH3:19])[N:11]=1)[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([C:15]1[C:10]([NH:9][C@H:5]2[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:8][N:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]2)=[N:11][C:12]([CH2:18][CH3:19])=[CH:13][N:14]=1)[CH3:17]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)cnc1CC
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine (4.50 g, 17 mmole) in CH2Cl2 (0.1 M, 170 mL) under N2 at 0° C. was added triethyl amine (7.09 mL, 3.0 eq.). Methyl chloroformate (1.44 mL, 1.1 eq.) was added drop-wise over 15 min. After 1 hour, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with CH2Cl2 (1×200 ml), dried with MgSO4, filtered and concentrated. Purification with Biotage MPLC (40 g, 10-50% ethyl acetate in heptane gradient) provided 5.35g (98%) of methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2972, 2937, 2877, 2338, 1937, 1708, 1581, 1546, 1499, 1453, 1392, 1189, 1174, 1135, 1103 (s) cm−1 HRMS (ESI) calcd for C16H26N4O3+H1 323.2083. found 323.2089. Anal. Calcd for C16 H26 N4O3: C, 59.61; H, 8.13; N, 17.38. Found: C, 59.23; H, 8.35; N, 17.33.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1>C(C1C=CC([Mg]Br)=CC=1)(C)C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:26]3[CH:30]=[CH:10][C:9]([CH:14]([CH3:15])[CH3:13])=[CH:28][CH:27]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: CC(C)c1ccc([Mg]Br)cc1
Product: CC(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-iso-propylphenylmagnesium bromide. Yield: 52 mg of a white solid. LC-MSD, m/z for C25H21N2O2 [M+H]+=461.0, 463.0; HPLC retention time: 2.7 min.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:2].[H][H]>CO.[Pd]>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][NH2:2])[N:8]=1
Reactant: Cc1ccnc(C#N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccnc(CN)n1
Yield: 91.9 %

Procedure:
To a nitrogen flushed solution of the title compound from Step A (1 g, 8.39 mmol) in methanol (40 ml) was added 10% palladium on carbon (100 mg) and the resulting mixture stirred under a balloon of hydrogen for 3 h. The mixture was filtered through celite and evaporated to give 950 mg (91%) of the title compound (i-6) as an orange oil. 1H NMR (CDCl3): 2.54 (s, 3H), 4.16 (s, 2H), 7.03 (d, J 5.0 Hz, 1H), 8.56 (d, J 5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:15][CH3:16])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.Cl[C:18]([S:20]Cl)=[O:19].[C:22](#N)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:10]2[N:15]([CH3:16])[C:18](=[O:19])[S:20][C:11]=2[N+:12]([O-:14])=[O:13])[CH3:22])=[CH:4][N:3]=1
Reactant: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC#N
Reactant: O=C(Cl)SCl
Product: CN(Cc1ccc(Cl)nc1)c1c([N+](=O)[O-])sc(=O)n1C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-chloro-5-pyridylmethylamino)-1-methylamino-2-nitroethylene (3.0 g) and acetonitrile (30 ml) was added slowly and dropwise chlorocarbonylsulfenyl chloride (1.8 g) at 10° to 20° C. After an overnight stirring, the solvent was distilled off from the reaction liquid under reduced pressure and the thus obtained residue was refined with column chromatography (eluant: ethanol/chloroform=1/10) to obtain the desired 4-[N-(2-chloro-5-pyridylmethyl)-N-methylamino]-3-methyl-5-nitro-2-thiazolone (1.0 g) having a melting point in the range from 147° to 148° C.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: [K]
Product: N#Cc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-cyanophenoxy)hexyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,6-dibromohexane.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:24]=1[OH:25]
Reactant: Oc1cccc2ccccc12
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2cccc3ccccc23)C(O)=C1O
Yield: 26.2 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 1-naphthol with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 75 mg (26% yield) of 3,4-dihydroxy-5-[2-(1-naphthoxy)ethyl]-2(5H)-furanone as colorless cubes: mp 163-164° C. (ether/hexanes) 1H NMR (acetone-d6) δ 8.38-8.25 (m, 1H), 7.92-7.79 (m, 1H), 7.60-7.34 (m, 4H), 7.05-6.93 (m, 1H), 5.11 (dd, J=5.3, 8.7 Hz, 1H), 4.39 (dd, J=2.6, 4.7 Hz, 2H), 2.75-2.52 (m, 1H), 2.25-2.05 (m, 1H). 13C NMR (acetone-d6) δ 169.62, 154.92, 153.61, 135.13, 127.83, 126.78, 126.50, 125.92, 125.05, 122,41, 120.66, 118.53, 105.28, 72.85, 63.93, 32.58. Anal Calcd for C16H14O5: C, 67.11; H, 4.89. Found: C, 66.70; H, 4.88.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH3:10].[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12]>O.[OH-].[Na+]>[NH2:10][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([O:12][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[OH:14])[N:4]=1
Reactant: Oc1ccccc1O
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)nc(Oc2ccccc2O)n1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
A suspension of 36.9 parts of cyanuric chloride in 250 parts of water at 0°-5° C was prepared. To the stirred suspension at this temperature were added separately over about 30 minutes a solution of ammonia (3.4 parts) in water (80 parts) concurrently with a solution of sodium hydroxide (8.0 parts) in water (80 parts). Stirring was continued at 0°-5° C for about 90 minutes after completion of the addition. The temperature of the mixture was then increased to 35° C and solutions of catechol (22 parts) in water (180 parts) and sodium hydroxide (8 parts) in water (70 parts) were added with stirring at this temperature over about 40 minutes. Stirring was continued for about 1 hour at 35° C when the reaction reached neutrality. The reaction mixture was cooled to 10° C and the product isolated by filtration, washed with water and dried. 2-amino-4-chloro-6 -(2'-hydroxyphenoxy)-s-triazine was thereby obtained as an off-white powder of indefinite melting point due to decomposition, analysing for carbon 43.2%, hydrogen 2.6%, nitrogen 23.2% and chlorine 14.3%. (C9H7ClN4O2 requires carbon 45.3%, hydrogen 2.9%, nitrogen 23.5% and chlorine 14.9%).