Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[NH:34][CH2:33][CH2:32][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C[C@@H]2CN3C(NCCN4CCCCC4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Compound 67a (100 mg, 0.240 mmol) obtained in Example 67 was dissolved in tetrahydrofuran (2 mL), and to the solution were added 2-piperidinoethylamine (61 μL, 0.480 mmol, 2.0 equivalents) and N,N-diisopropylethylamine (344 μL, 0.960 mmol, 4.0 equivalents) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform:methanol=90:10, chloroform: a 7 mol/L ammonia/methanol solution=90:10). To the product was added diisopropyl ether, and the deposited crystals were collected by filtration and dried to obtain the title compound (110 mg, 94%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][C:16]3=[N+:17]([O-])[O:18][N:19]=[C:15]3[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[S:23](Cl)Cl>>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][C:16]3=[N:17][S:23][N:19]=[C:15]3[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:22]=[CH:21][C:16]3=[N+:17]([O-:18])[S:23][N:19]=[C:15]3[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: ClSCl
Reactant: [O-][n+]1onc2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc21
Product: FC(F)(F)c1cnc(Oc2ccc3nsnc3c2)c(Cl)c1
Product: [O-][n+]1snc2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc21

Procedure:
Likewise, 5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzo-2,1,3-oxadiazole N-oxide is reduced, and the resulting dioxime is reacted with sulfur dichloride to give 5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzo-2,1,3-thiadiazole and 5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzo-2,1,3-thiadiazole N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[S:32]([O:35]C)(=[O:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:38])([F:37])[S:32]([O-:35])(=[O:34])=[O:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:14]([N:17]3[CH:21]=[CH:20][N+:19]([CH3:23])=[C:18]3[CH3:22])(=[O:15])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nccn1S(=O)(=O)N1CC=C(c2ccc(F)cc2)CC1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1n(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)cc[n+]1C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
A solution of 4-(4-fluorophenyl)-1-[(2-methyl-1h-imidazol-1-yl)sulfonyl]-1,2,3,6-tetrahydropyridine (125 mg, 389 μmol), triethylamine (54 μL, 390 μmol) and methylene chloride (5.4 mL) was stirred at 0° C. and slowly added methyl trifluoromethanesulfonate (43 μL, 390 μmol). The reaction mixture was stirred at 0° C. for 1 h. The resulting precipitate was filtered to yield the desired product (80 mg, 42%). MF=C17H19F4N3O5S2; LCMS found for C16H20FN3O2S(M+H)+: m/z=336.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH:21]3OC)=[O:15])=[CH:11][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:8][C:9]1[S:13][C:12]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:43])[N:20]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:21]3)=[O:15])=[CH:11][CH:10]=1
Reactant: COC1c2cccc(NC(=O)c3ccc(Cl)s3)c2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2)c1ccc(Cl)s1
Reaction time: 8 h

Procedure:
0.23 ml (1.4 mmol) of triethylsilane is added to a solution of 378 mg (0.704 mmol) of tert-butyl 4-[2-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1-methoxy-3-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidine carboxylate in 12 ml of dichloromethane and 0.65 ml of trifluoroacetic acid. The mixture is stirred overnight, concentrated and taken up in dichloromethane. The solution is washed with 1N sodium hydroxide solution, dried and concentrated. The residue is crystallized using diethyl ether. The resulting solid is purified further by chromatography on silica gel (gradient from dichloromethane/methanol 95:5 to dichloromethane/methanol/triethylamine 9:1:0.1). Yield: 144 mg (50.5% of theory).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:5]([NH:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=1[Cl:18])=[O:6].C(N(C(C)C)CC)(C)C>C1COCC1.C(OC(=O)C)C>[CH:19]1([CH:4]2[CH2:3][CH2:2][N:7]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=3[Cl:18])[C:5]2=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(Cl)c(CNC(=O)C(CCBr)C2CCCCC2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(CN2CCC(C3CCCCC3)C2=O)c(Cl)c1
Yield: 79.3 %

Procedure:
Treat a solution of 4-bromo-2-cyclohexyl-N-(2,6-dichloro-4-methoxy-benzyl)-butyramide (2.0 g, 4.6 mmol) in THF (30 mL) with diisopropyl ethyl amine (1.19 g, 9.19 mmol) at 40° C. for 12 hours and at reflux for 6 hours. Cool the reaction, dilute with ethylacetate and wash with HCl (1N) and water. After drying the organic layer over sodium sulfate, filtrate and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:4 ethyl acetate:hexane to afford 1.3 g (80%) of the title compound. MS (m/z): 356 (M+).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]=[C:28]3[CH:31]([CH3:33])[CH3:32])=[CH:23][CH:22]=2)[CH:10]=[C:11]2[C:16]=1[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]2)[CH2:5][OH:6].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH:31]([C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([CH:20]=[CH:19][C:9]3[CH:10]=[C:11]4[C:16](=[C:7]([CH:4]5[CH2:3][CH2:2][O:6][CH2:5]5)[CH:8]=3)[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12]4)[CH:30]=2)[CH2:25][CH2:26][N:27]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(C(CO)CCO)c4cc(C#N)ccc4c3)cc21
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C1=NCCc2ccc(C=Cc3cc(C4CCOC4)c4cc(C#N)ccc4c3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 7A (140 mg, 0.52 mmol) in dichloromethane (3 mL) at 0° C. was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF3.OEt2 (0.096 mL, 0.78 mmol), warmed to room temperature, stirred for 4 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19](/[CH:22]=[CH:23]/[CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:31][OH:32]>C1COCC1.O>[OH:32][NH:31][CH:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:22][S:19]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:1])([F:30])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1)(=[O:20])=[O:21]
Reactant: O=S(=O)(/C=C/C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Reactant: NO
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-pyran-4-yl)vinyl]sulfonyl}piperazine (3.13 g, 0.007 mol) was dissolved in THF (50 ml) and 50% hydroxylamine in H2O (12 ml) was added. Stirred at ambient temperature overnight, quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated to dryness to yield racemic 1-{[2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine This was separated into its enantiomers using an AD Chiralpak chiral prep HPLC column and eluting with 20% methanol/acetonitrile. The second compound off the column gave the required enantiomer, 1-{[(2S)-2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:18]([CH3:21])=[CH:19][S:20][C:10]=12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O-:23].[Na+]>CO>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11](/[C:18](/[CH3:21])=[CH:19]\[S:20][CH3:10])[C:22]1=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1csc2n1c1ccccc1[n+]2Cc1ccccc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 94.4 %

Procedure:
200 mg of 9-benzyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride (0.635 mmol) were solubilised in methanol (25 mL), then 137 mg of NaOMe (4 eq) were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was then purified by chromatography on silica gel (eluent: CH2Cl2) to afford 1-benzyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a colourless oil (186 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δH 2.18 (3H, d, J=1.1, CH3), 2.26 (3H, s, SCH3), 5.10 (3H, s, NCH2), 6.27 (1H, q, J=1.1, H5), 6.84-7.10 (4H, m, arom), 7.25-7.35 (5H, m, arom); 13C NMR (75 MHz, CDCl3) δC 16.90, 20.44, 44.79, 108.50, 109.00, 121.24, 121.48, 126.61, 127.37, 127.57 (2C), 127.65, 127.69, 128.69 (2C), 129.45, 136.22, 152.34; HRMS m/z calcd C18H19N2OS [M+H]+: 311.1212; found: 311.1211.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>O.CC(C)=O>[CH2:21]([O:20][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[O:23])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Nc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Amino-3,4-dihydrocarbostyril (60 g) is added to a solution of potassium carbonate (128 g) in water (300 ml) and acetone (300 ml), and thereto is added dropwise ethyl chlorocarbonate (46 ml) with stirring under ice-cooling. After the addition, the mixture is further reacted at the same temperature for 30 minutes. After the reaction, the reaction mixture is poured into water, and the resulting precipitate is separated by filtration, washed with water and further with diethyl ether. After drying, the crystal thus obtained is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1) and then recrystallized from ethanol to give 6-ethoxycarbonylamino-3,4-dihydrocarbostyril (68.5 g), as colorless prisms, m.p. 193°-194° C.
Reaction SMILES: [O:1]=[C:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][CH:13]([CH2:20][CH3:21])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[Cl:22]Cl>C(O)(=O)C>[O:1]=[C:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][C:13]([CH2:20][CH3:21])([Cl:22])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1
Reactant: ClCl
Reactant: CCC1Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Temperature: 100 °C

Procedure:
A solution of 5-(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (2.0 g.) in acetic acid (300 ml.) is warmed to 65° C. on a steam bath and treated during a 10-minute period with a solution of chlorine (700 mg.) in acetic acid (25 ml.). The reaction mixture is heated one hour at 100° C. and the solvent is distilled at reduced pressure to a volume of 50 ml. which on treatment with water affords 0.8 g. (36%) of 5-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxymethyl)tetrazole which melts at 128° C. after recrystallization from ethylacetate and hexane.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[O:43]=[C:38]1[NH:39][C:40](=[O:42])[CH2:41][N:37]1[S:34]([C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CC(=O)NC4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
Acetic acid (0.15 mL, 2.6 mmol) was added dropwise into a mixture N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (320 mg, 1.3 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-2,4-imidazolidinedione (440 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (331 mg, 1.56 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce a white solid (496 mg, 67% yield): mp 200-202° C.; c 1.35-1.42 (m, 2H), 1.81-1.97 (m, 2H), 2.83-2.97 (m, 6H), 3.95-3.97 (m, 2H), 4.22 (s, 2H), 4.57-4.6 (m, 1H), 7.1 (M, 3H), 7.2 (m, 1H), 7.75 (m, 2H), 8.4 (brs, 2H); MS m/e 566 (M−H)+; Analysis for: C23H29N5O8S2 Calc'd: C, 48.67; H, 5.11; N, 12.34 Found: C, 47.64; H, 5.2; N, 11.26.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[N:5][CH:4]=1.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1.O>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[CH3:12][N:2]([CH3:1])[C:3]1[N:8]=[C:7]([C:9]([NH:13][C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[O:11])[CH:6]=[N:5][CH:4]=1
Reactant: CN(C)c1cncc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 0.58 g of 6-(dimethylamino)pyrazine-2-carboxylic acid in 10 ml of tetrahydrofuran, 0.53 ml of triethylamine and 0.47 ml of pivaloyl chloride were added dropwise successively at 0 ° C. under stirring. After stirring for 1 hour at 0 ° C., 0.33 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 6 hours. After cooling, 70 ml of water was added to the reaction mixture. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.36 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31]1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:34][CH2:35]2)=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)O)N1
Reactant: NC1CCN(CCCOc2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: O=C1COc2c(cc(Cl)cc2C(=O)NC2CCN(CCCOc3ccccc3)CC2)N1

Procedure:
A solution of 2.3 g of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 100 ml of tetrahydrofuran is cooled to below 0° C. and 2 ml of triethylamine is added under stirring thereto. Further, 1.1 g of ethyl chlorocarbonate is added and the mixture is stirred for 3 hours. To the resultant mixture is added 2.5 g of 4-amino-1-(3-phenoxypropyl)piperidine and the mixture stirred for 8 hours followed by collecting by filtration and washing with tetrahydrofuran and water. To a suspension of thus obtained crystals in 100 ml of methanol are added 10 ml of 10% hydrochloric acid and 30 ml of water and then the suspension is stirred. The collection of the crystals by filtration gives 6-chloro-3,4-dihydro-3-oxo-N-[1-(3-phenoxypropyl)-4-piperidyl]-2H-1,4 -benzoxazine-8-carboxamide hydrochloride, melting at 290°-300° C. with decomposition.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.O[C:14]1C=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]CC=O.[C-]#N.[K+].C(C1CCC2C(=CC=CC=2)O1)#[N:28].CN1CCOCC1>CN(C=O)C.N1C=CC=CC=1>[N:28]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:20][NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4]2)[CH:14]=1
Reactant: N#CC1CCc2ccccc2O1
Reactant: NCC1CCc2ccccc2O1
Reactant: O=CCCc1ccccc1O
Agent: [C-]#N
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1cncc(CNCC2CCc3ccccc3O2)c1

Procedure:
A solution of 2.8 g 2-aminomethyl-chromane [obtainable by reacting 3-(2-hydroxy-phenyl)-propanal with KCN and subsequent catalytic reduction of the 2-cyano-chromane] and 2.2 g 3-chloromethyl)-pyridine in 250 ml of DMF are stirred together with 1 g N-methyl-morpholine for 12 hours at 20° and worked up in a conventional manner to give N-(3-pyridylmethyl)-N-(2-chromanyl-methyl)-amine. Stirring with 0.5 equivalents of maleic acid in 100 ml ethanol gives the maleate, m.p 163°-164°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([NH:24][C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.C(O)(=O)C.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=[CH:21][C:22]([NH:24][C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[OH:9]
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=CC=CC(=O)Nc2ccccc2C(=O)O)cc(OC)c1O
Yield: 541.7 %

Procedure:
To a solution of 56 mg (0.12 mmol) of the amide compound prepared above in 1 ml of dioxane was added 4 ml of 80% acetic acid. The mixture was heated under reflux for 2 hours. Water was added to the reaction solution, and crystals then formed were isolated by filtration and recrystallized from methanol. There was obtained 24 mg (0.65 mmol) of N-{5-(3,5-dimethoxy-4-hydroxyphenyl)-2,4-pentadienoyl}anthranilic acid. Spectrophotometric data of the product support the structure shown below. ##STR69##
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][C@@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:30])[NH:22]1>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[C:27]([F:30])[CH:26]=[CH:25][CH:24]=3)[CH2:29][C@H:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Reactant: C[C@@H]1Cc2c(F)cccc2N1
Agent: [Na+]
Product: C[C@@H]1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Yield: 33.8 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 220 mg of sodium (5-chloro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and 110 mg of (R)-2-methyl-4-fluoro-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)). After silica column purification: eluent 99/01 then 98/02 then 97/03 dichloromethane/methanol, 100 mg of 5-chloro-2-[2-((R)-2-methyl-4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[S:11][C:5]2[S:6][C:7](Br)=[C:8]([CH3:9])[C:4]=2[C:3]=1[CH3:12].B([O-])[O-].[CH2:16]([C:22]1[CH:23]=[CH:24][S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].[Na+].[Na]>COCCOC.C(OCC)C>[CH2:16]([C:22]1[CH:23]=[C:24]([C:2]2[S:11][C:5]3[S:6][C:7]([C:24]4[S:25][CH:26]=[C:22]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=4)=[C:8]([CH3:9])[C:4]=3[C:3]=2[CH3:12])[S:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1c(Br)sc2sc(Br)c(C)c12
Reactant: CCCCCCc1ccsc1
Agent: [Na+]
Agent: [Na]
Agent: [O-]B[O-]
Solvent: COCCOC
Solvent: CCOCC
Product: CCCCCCc1csc(-c2sc3sc(-c4cc(CCCCCC)cs4)c(C)c3c2C)c1

Procedure:
To a solution of 2,5-dibromo-3,4-dimethylthieno[2,3-b]thiophene (3.02 g, 9.28 mmol) and sodium 4-hexylthiophene boronate (5.14 g, 20.4 mmol) in degassed DME (200 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (0.5 g, 5 mol %). The solution was heated to reflux and a saturated solution of sodium hyodrogen carbonate (4.2 g, 49 mmol) was added slowly. The reaction was refluxed for 16 h, cooled and diluted with diethyl ether. The layers were separated and the organics washed with 5% HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over silica (eluent: petrol) to afford the product after recrystallisation from petroi (1.03 g, 22%). :M/Z 500 (M+). Found C, 66.9.1, H, 6.9, S, 25.3. Calc. for C28H36S4 C, 67.2; H 7.2, S, 25.6. NMR gave the expected signals.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].[H-].[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:3]1[CH2:4][N:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:19][CH:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A solution of Carbobenzyloxyglycine methyl ester (10 g, 44.8 mmol) and Methyl acrylate (4.03 mL, 44.8 mmol) in Toluene (100 mL) at 0° C. was added 60% NaH in mineral oil (1.971 g, 49.3 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 20 minutes. The reaction mixture was heated to 50° C. for 3 hrs. The reaction mixture was quenched with 10% citric acid solution until pH about 3, and then it was extracted with 100 mL×3 of EtOAc. The combined organic phases were washed with 100 mL of brine and dried over Na2SO4. Filtration and concentration to yield the product (12 g, 96% yield). MS (ES+) m/z: 278.2 (M+H); HPLC retention time: 2.44 min (analytical HPLC Method H).