Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5](=O)[CH2:6][C:7]1[C:8]([CH2:19][CH3:20])=[C:9]([C:16](=O)[CH3:17])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[CH2:19]([C:8]1[C:7]([CH2:6][CH2:5][NH:4][CH2:1][CH3:2])=[C:15]2[N:10]([C:9]=1[CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=[CH:14]2)[CH3:20]
Reactant: CCc1c(CC(=O)NC(C)=O)c2ccccn2c1C(C)=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCNCCc1c(CC)c(CC)n2ccccc12
Temperature: 25 °C

Procedure:
N-acetyl-2-(3-acetyl-2-ethylindolizin-1-yl)acetamide (330 mg, 1.3 mmol) isolated in Example 5 was stirred in anhydrous ethyl ether (120 mL) to which lithium aluminum hydride (330 mg) was added. The reaction mixture was heated in a nitrogen atmosphere under reflux overnight. After cooling to room temperature, Rochelle salt was added with stirring until everything dissolved. The phases were separated and the aqueous phase was extracted with ether one time. Evaporation of the organic phase gave a residue, which was purified by flash column chromatography on silica gel eluting with 3-10% methanol in methylene chloride containing 1% ammonium hydroxide. The product (110 mg) was dissolved in ethanol, treated with a solution of fumaric acid (110 mg) dissolved in ethanol and evaporated to give a residue which was recrystallized from methyl ethyl ketone. The title compound was obtained as a greenish-tan solid, mp: 154-158° C. Mass spectrum: [M+H]+ 245 m/z.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH:14]([S:16][C:17]3[N:18]([CH2:30][CH3:31])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=4)=[N:20][N:21]=3)[CH3:15])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH:14]([S:16][C:17]3[N:18]([CH2:30][CH3:31])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([OH:28])[CH:23]=4)=[N:20][N:21]=3)[CH3:15])[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCn1c(SC(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccnc(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1c(SC(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccnc(O)c1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
HBr (1 ml) and HOAc (1 ml) were added to 4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine (9 mg, 0.02 mmol) and the reaction was stirred at 80° C. on. Saturated NaHCO3 (aq) was added to the reaction and the mixture was extracted three times with dichloromethane. The combined organic phases were dried and concentrated to give the title compound (8.5 mg, 99%). 1H NMR (CDCl3), δ (ppm): 1.37 (t, 3 H), 1.96 (d, 3 H), 4.10 (q, 2 H), 5.23 (q, 1 H), 6.80 (m, 2 H), 7.49 (t, 2 H), 7.59 (m, 1 H), 7.99 (d, 1 H), 8.11 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[Cl:17].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:12]=[C:13]([C:6]2[CH:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH2:9])[CH:5]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Br)cc(N)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)cc(N)n1
Temperature: 80 °C

Procedure:
A mixture of 40.5 mg (0.21 mmol) 2,6-diamino-4-bromo-pyridine, 90.5 mg (0.47 mmol) 3,4-dichloro-phenyl-boronic acid, 7.8 mg (0.01 mmol) Dichloro(1,1′-bis(diphenylphosphino) ferrocene)palladium (II) dichloromethane adduct and 0.3 ml 2M Na2CO3 in 1 ml dimethoxyethane was heated to 80° C. for 17 h. The mixture was filtered over silica washed with MeOH/DCM and concentrated. The residue was taken up in 1 ml DMF and the totle compound was purified by reversed phase column chromatography eluting wit an acetonitrile/water gradient to yield 29 mg (52%), MS m/e (%): 254 M+ (100).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])[O:7][CH:8]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[O:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCc1coc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)co5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B30) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by twofold flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/1 to 0/1 (v/v) and DCM/MeOH, 1/0 to 1/1 (v/v)] as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=2)=[C:4]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:3]=1.[N:23]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]3[NH:13][N:23]=[N:14][C:9]=3[CH:8]=2)=[C:4]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:3]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2Cn2cncn2)cc1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1ccc(Oc2ccc3[nH]nnc3c2)c(Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
4-[4-Chloro-2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-1,2-phenylenediamine (3.2 g) from Example 39 was dissolved with 10% H2SO4 (30 ml) under ice cooling, followed by addition of an aqueous solution (3 ml) of sodium nitrite (1.4 g), and the temperature of the resulting solution was raised up to room temperature for stirring for 2 hours. The solution was neutralized, with an aqueous sodium hydrogen carbonate, and then extracted twice with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was washed with ether, to give the title compound (3 g; 91%). The purity of the compound was 99.1% by HPLC.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: ClCc1cnc(-c2ccccc2)o1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cnc(-c2ccccc2)o1)OCC
Yield: 59.8 %

Procedure:
5-Chloromethyl-2-phenyl oxazole (870 mgs, 4.50 mmol) and triethylphosphite (1.17 ml, 6.75 mmol) were heated at reflux for 3 h, cooled, the excess triethylphosphite removed under reduced pressure and the residue column chormatographed (0 to 5% MeOH/CH2Cl2, 10 g silica) to give the title compound (794 mgs, 2.69 mmol, 60%); δH (CDCl3) 1.30 (6H, t, J 7 Hz, OCH2CH3), 3.30 (2H, d, JP-H 22 Hz, CH2 --P) 4.10 (4H, m, OCHH2CH3), 7.00 (1H, d, JP-H 3 Hz, CH-4), 7.40 (3H, m, Ph), 8.00 (2H, m, Ph).
Reaction SMILES: [CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][O:48]C(=O)C)[O:43]C(=O)C)[O:38]C(=O)C)[O:33]C(=O)C)[O:28]C(=O)C)=[O:26])[C@@H:16]([O:17]C(=O)C)[C@H:11]([O:12]C(=O)C)[C@H:10]1[NH:52][C:53](=[O:114])[C:54]1[CH:113]=[CH:112][C:57]([C:58]([NH:60][C@@H:61]2[C@@H:67]([O:68]C(=O)C)[C@H:66]([O:72]C(=O)C)[C@@H:65]([CH2:76][NH:77][C:78]([C@@H:80]([C@H:85]([C@@H:90]([C@@H:95]([CH2:100][O:101]C(=O)C)[O:96]C(=O)C)[O:91]C(=O)C)[O:86]C(=O)C)[O:81]C(=O)C)=[O:79])[O:64][C@:62]2([CH2:105][C:106]2[CH:111]=[CH:110][CH:109]=[CH:108][CH:107]=2)[OH:63])=[O:59])=[CH:56][CH:55]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1>[CH2:1]([C@@:8]1([O:22][C@H:21]([CH2:23][NH:24][C:25]([C@@H:27]([C@H:32]([C@@H:37]([C@@H:42]([CH2:47][OH:48])[OH:43])[OH:38])[OH:33])[OH:28])=[O:26])[C@@H:16]([OH:17])[C@H:11]([OH:12])[C@H:10]1[NH:52][C:53](=[O:114])[C:54]1[CH:113]=[CH:112][C:57]([C:58]([NH:60][C@@H:61]2[C@@H:67]([OH:68])[C@H:66]([OH:72])[C@@H:65]([CH2:76][NH:77][C:78]([C@@H:80]([C@H:85]([C@@H:90]([C@@H:95]([CH2:100][OH:101])[OH:96])[OH:91])[OH:86])[OH:81])=[O:79])[O:64][C@:62]2([CH2:105][C:106]2[CH:107]=[CH:108][CH:109]=[CH:110][CH:111]=2)[OH:63])=[O:59])=[CH:56][CH:55]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)c2ccc(C(=O)N[C@@H]3[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CNC(=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O[C@@]3(O)Cc3ccccc3)cc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)O[C@@]1(O)Cc1ccccc1)c1ccc(C(=O)N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)O[C@@]2(O)Cc2ccccc2)cc1

Procedure:
A solution of terephthalic acid bis-[[benzyl 3,4-di-O-acetyl-2,6-didesoxy-6-(2,3 ,4,5,6-penta-O-acetyl-D-gluconoylamino)-α-D-glucopyranosid-2-yl]-amide] in methanol/dioxan 2:1 was deacetylated as described in Ex. 11.F. and gave terephthalic acid bis-[(benzyl 2,6-didesoxy-6-D-gluconoylamino-α-D-glucopyranosid-2-yl)-amide], MS: m/z 1023.3 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[I-].[Na+]>CC(C)=O.CCOCC>[CH:12]1([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: C#Cc1cccc(O)c1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C#Cc1cccc(OCC2CC2)c1
Yield: 84.2 %

Procedure:
To a solution of 3-ethynylphenol (1.18 g, 10.0 mmol) in acetone (30 mL) is added (bromomethyl)cyclopropane (1.02 mL, 10.0 mmol), sodium iodide (0.75 g, 5.0 mmol) and CS2CO3 (6.52 g, 20.0 mmol) at room temperature. After refluxing over night, the reaction mixture is cooled, diluted with Et2O (300 mL) and pass through a thin layer of silica gel. The solution is concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:1/99) to give the title compound (1.45 g, 84%) as an oil. MS (+) APPI: 173 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28].N1CCOCC1.Cl>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Reactant: FC(F)(F)CCCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: Cn1c(=O)c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
A solution of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.048 g, 0.2 mmol) in THF (1 ml) was treated with caesium carbonate (0.78 g, 0.24 mmol) and 4-bromo-1,1,1-trifluorobutane (0.044 g, 0.25 mmol). The mixture was stirred at ambient temperature for 1 hour then heated at 50° C. for 4 hours and then cooled. The mixture was degassed by alternately applying vacuum and nitrogen pressure to the mixture and then treated with morpholine (0.17 ml, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol). After 2 hours the mixture was treated cautiously with 2M aqueous hydrochloric acid (2 ml) and the product extracted with chloroform (2×4 ml). The combined organics were evaporated and the product purified by reverse-phase mass directed HPLC to afford the title compound 6.2 mg (10%); NMR; δH (400 MHz, d6-DMSO); 1.84-1.92 (m, 2H), 2.28-2.35 (m, 2H), 3.22 (s, 3H), 3.99-4.03 (m, 2H) 14.31 (br.s, 1H); m/z 311.2[MH+].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:25]=[CH:26][CH:27]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([NH:19][C:20](OCC)=O)[N:14]=1)[CH3:3]>O1CCCC1>[CH3:18][N:17]1[C:13]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:25]=[CH:26][CH:27]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=2)=[N:14][C:15]([NH:19][CH3:20])=[N:16]1
Reactant: CCOC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Solvent: C1CCOC1
Product: CNc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Yield: 33.8 %

Procedure:
A mixture of 5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-1H-1,2,4-triazole-3-carbamic acid, ethyl ester (0.35 g) lithium aluminum hydride (0.13 g) and tetrahydrofuran (10 ml) was heated under reflux for 48 h. The mixture was quenched with water (0.5 ml), filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica with methanol as the eluant to give the title compound as a pale yellow oil (0.1 g). TLC silica; methanol/0.88 ammonia 80:1, Rf 0.43. NMR (CDCl3) 2.78 t (1H); 3.0-3.3 m (3H); 5.47 t (1H); 5.95 t+brs (3H); 6.50 q (2H); 6.6 s (5H); 7.17 t (3H); 7.78 s (6H); 7.93 m (2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][C@@H:11]([CH3:15])[C:10]1=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:27](=[O:28])[NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C@@H:11]([CH3:15])[C:10]1=[O:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCC(=O)OC(C)(C)C)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCC(=O)OC(C)(C)C)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 0.75 g (3.10 mmol) of 3-((S)-3-methyl-2-oxo-piperazin-1-yl)-propionic acid tert-butyl ester with 0.1HCl in 16 ml of dichloromethane was treated at 0° C. with 0.70 g (3.70 mmol) of 3,4-dichlorophenyl isocyanate and 0.52 ml (3.70 mmol) of triethylamine. After 30 min the reaction was warmed to room temperature and extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after purification by flash silica gel column (EtOAc/n-heptane 1:2 to 3:1) 0.91 g (68%) of the titled compound as white foam. MS: 374.1 (MH+, 2Cl).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:13]([C:11]#[N:12])[C:14]([NH:16][NH2:17])=[O:15]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)NN
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)NN
Yield: 50.2 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.55 g (5.5 mmol) cyanoacethydrazide in 40 ml ethanol was added 2 drops piperidine. After 21/2 hours of reflux, the reaction mixture was cooled, filtered and washed with cold ethanol to give 0.55 g (50% yield) of product, an orange solid, m.p. 220° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[C:19]5[N:33](C6CCCCO6)[N:32]=[CH:31][C:20]=5[C:21](=[O:30])[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:23]=4[CH:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.CN1CCCN(C2C(C3C=CC4C5NN(C6CCCCO6)CC=5C(=O)N(CC(F)(F)F)C=4C=3)=CC=CN=2)CC1.[ClH:79]>O>[ClH:79].[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[C:19]5[NH:33][N:32]=[CH:31][C:20]=5[C:21](=[O:30])[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[C:23]=4[CH:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCN(c2ncccc2-c2ccc3c4c(cnn4C4CCCCO4)c(=O)n(CC(F)(F)F)c3c2)CC1
Agent: CN1CCCN(c2ncccc2-c2ccc3c4c(c(=O)n(CC(F)(F)F)c3c2)CN(C2CCCCO2)N4)CC1
Agent: Cl
Solvent: O
Product: CN1CCCN(c2ncccc2-c2ccc3c4[nH]ncc4c(=O)n(CC(F)(F)F)c3c2)CC1
Yield: 28 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(4-methyl-1,4-diazepan-1-yl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(4-methyl-1,4-diazepan-1-yl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (2 hydrochloride, 5.5 H2O; yield: 28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[OH:6].[CH3:16]I.[H-].[Na+]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[O:6][CH3:16]
Reactant: COC(=O)CC(O)c1cccc(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(OC)c1cccc(OC)c1

Procedure:
Methylβ-(m-methoxyphenyl)-β-hydroxy-propionate was reacted with methyl iodide/sodium hydride to give methyl-β-(m-methoxyphenyl)-β-methoxy-propionate, which was then reduced with LiAlH4 in dry ether to give 3-(m-methoxyphenyl)-3-methoxy-propanol. This latter product was converted into 3-(m-methoxyphenyl)-3-methoxy-propanal by oxidation with pyridinium chlorochromate in dry dichloromethane.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:27])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])=[O:9])[CH3:4]>CS(C)=O.C(OCC)(=O)C>[CH2:3]([O:5][C:6]([C:7]1[C:8]([OH:9])=[N:10][C:11]2[C:12]([C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:27])[CH3:4]
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(O)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a suspension of sodium hydride (60%; 32 mg, 0.8 mmol) in DMSO (3 ml) was added a solution of N-[4-chloro-2-(2-chloro-phenylethynyl)-phenyl]-malonamic acid ethyl ester (200 mg, 0.532 mmol) in DMSO (2 ml) under nitrogen at 25° C., and the reaction mixture was stirred for 2 h at 80° C. The reaction mixture was diluted with ethyl acetate (15 ml), and the organic layer was washed with brine (3×10 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (20% EtOAc in hexane) to afford 6-chloro-4-(2-chloro-benzyl)-2-hydroxy-quinoline-3-carboxylic acid ethyl ester (63 mg, 32%) as an off white solid. LC-MS (ESI): 376 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH2:9][CH2:10][N:11]=[C:12]3[C:13]([Cl:18])=[C:14]([NH2:17])[C:15](=[O:16])[C:3]1=[C:4]23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH:9]=[CH:10][N:11]=[C:12]3[C:13]([Cl:18])=[C:14]([NH2:17])[C:15](=[O:16])[C:3]1=[C:4]23
Reactant: CSc1c2c3c(n1C)C(=O)C(N)=C(Cl)C3=NCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CSc1c2ccnc3c2c(n1C)C(=O)C(N)=C3Cl
Yield: 60.4 %

Procedure:
A solution of 10 mg of isobatzelline A in 5 ml of dioxane was stirred with 10 mg of DDQ at room temperature overnight. The resulting product was purified by HPLC (LiChrosorb NH2, 3% MeOH-CHCl3) to give 6 mg of isobatzelline D.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][N:6]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: Cc1ncc(CNCCCN)s1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: Cc1ncc(CN2CCCNC2=C[N+](=O)[O-])s1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
N-(2-Methyl-5-thiazolylmethyl)trimethylenediamine (18.5 g) was dissolved in 100 ml of acetonitrile, and 1-nitro-2,2-bis(methylthio)ethylene (16.5 g) was added. With stirring, the mixture was refluxed for 6 hours. After the reaction, the reaction mixture was cooled to room temperature. The resulting crystals were collected by filtration and washed with methanol to give 10.2 g of the desired 1-(2-methyl-5-thiazolylmethyl)2-(nitromethylene)tetrahydropyrimidine.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:23]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[I:23][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Nc1ccc(I)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(I)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A 500 ml., 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with the compound of Example I, C. (24.8 g., 0.114 mole), 4-iodoaniline (25 g., 0.114 mole) and ethanol (300 ml.). The mixture was stirred and heated overnight. The mixture was concentrated to dryness by rotary evaporator and the residue was collected and dried at 100°C to yield 49 g. (97.7%) brown crystals, m.p. 296°-305°C. Recrystallization from ethanol gave m.p. 313°-315°C.
Reaction SMILES: C(OC(=O)C)(=O)C.C(OC(=O)CC)(=O)CC.[C:17]([NH:21][C@H:22]([CH2:33][O:34][CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:20])[CH2:18]C>>[CH3:18][C:17]([NH:21][C@@H:22]([C:23]([NH:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[CH2:33][O:34][CH3:35])=[O:20]
Reactant: CCC(=O)N[C@H](COC)C(=O)NCc1ccccc1
Agent: CCC(=O)OC(=O)CC
Solvent: CC(=O)OC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1

Procedure:
The present inventors also observed that commercially available acetic anhydride contained some percentage of propanoic anhydride. As a result, during the last acetylation step (figure I), (2R)-2-propanoylamino-N-benzyl-3-methoxypropionamide of Formula III (hereinafter referred as “Impurity-B”) is obtained as an impurity along with lacosamide.