Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13](C2C=CC=CC=2CN)=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[C:26]1(S(Cl)(=O)=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2[CH2:59][NH:60][S:61]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)(=[O:63])=[O:62])=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:14][CH:15]=[CH:16][C:17]=1[CH2:59][NH:60][S:61]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)(=[O:62])=[O:63])=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1ccccc1
Product: O=C(NCCc1ccccn1)c1c(CNS(=O)(=O)c2ccccc2)cccc1-c1ccccc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and phenylsulfonyl chloride, according to the general working procedure 117 mg of 2′-(phenylsulfonylaminomethyl)-biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained;
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].O1[C:9]2([CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:25]=[C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][C:35]([F:38])([F:37])[F:36])[NH:23][N:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[O:8]CC1>CO.O>[F:38][C:35]([F:36])([F:37])[O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][C:24]1[NH:23][N:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:12]3[CH2:13][CH2:14][C:9](=[O:8])[CH2:10][CH2:11]3)=[N:16][CH:17]=2)[CH:25]=1
Reactant: FC(F)(F)Oc1ccccc1COc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CO
Product: O=C1CCC(c2ccc(-c3cc(OCc4ccccc4OC(F)(F)F)[nH]n3)cn2)CC1

Procedure:
Indium chloride (0.11 g, 0.536 mmol) was added to a solution of Example 93E (0.255 g, 0.536 mmol) in methanol (3 ml) and water (3 mL). The resulting solution was heated (85° C.) for 5 hours before the methanol was evaporated. The residue was partitioned with ethyl acetate and water, and the organic phase was washed with brine, dried (magnesium sulfate), filtered, and concentrated. The crude product was used in the following step without further purification.
Reaction SMILES: [N:1](C1C2C(=CC=CC=2)C=CC=1O)=[O:2].[OH-:14].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.Cl.N[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1O>O>[N:1]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[OH:14])=[O:2]
Reactant: Nc1c(O)ccc2ccccc12
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc2ccccc2c1O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
48 g of 1-nitroso-2-naphthol are suspended in a mixture of 300 ml of water and 60 ml of 5n NaOH, then another 240 ml of 5n NaOh are added. While stirring well hot water vapor is passed through the solution until the temperature reaches 35° C. Subsequently 120 g of freshly prepared sodium dithionite is added with the temperature rapidly rising to 60° C. The solution assumes an amber-colored tint. After 15 minutes, the solution is rapidly cooled to under 20° C. by adding 200 g of ice and 100 ml of concentrated hydrochloric acid. The white, flaky precipitation is filtered by vacuum and suspended in a mixture of 500 ml of water and 50 ml concentrated hydrochloric acid. Overheated water vapor is passed into this mixture with such a volume flow that the temperature reaches 90° C. within 10 min. At this temperature is stirred another hour while reducing the vapor flow. The still hot solution is filtered with the aubergine-colored precipitation remaining. Upon cooling the filtrate, a light, flaky precipitation falls out which is sucked away, scavenged with diluted hydrochloric acid and then with ether and dried. Yielded were 45 g of 1-amino-2-naphthol-hydrochloride. The amino-hydroxy aromatic compounds were employed in all the transformations into this acidic form, because the free bases with the exception of 5-amino-6-quinoline proved to be very unstable.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH2:5]([CH:7]1[O:9][CH2:8]1)Cl.[OH-].[Na+].C(=O)=[O:13]>O>[CH2:2]([O:13][CH2:5][CH:7]1[O:9][CH2:8]1)[CH:1]1[O:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: O=C=O
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C(OCC1CO1)C1CO1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A one liter flask was charged with: 75 g (grams) of the flaked reaction product of Example 6; 200 g of isopropyl alcohol; and 52.5 g of water to form a reaction mixture. The reaction mixture was heated to 55° C. After 10 minutes there was add 388.5 g of epichlorohydrin. The reaction mixture was reheated to 55° C. and then 30 g of a 20% solution of sodium hydroxide in water was added while maintaining a temperature of 55° C. The 55° C. temperature was held for another 30 minutes. Then there was added 90 g of 20% solution of sodium hydroxide in water. The reaction mixture was held at 55° C. for another hour, heated to 65° C. and held for 30 minutes and then transferred to a separatory funnel. The upper clear brown organic layer (145.6 g) was stirred with 150 g water and 50 g of dry ice. The aqueous layer was discarded and the organic layer washed a second time and then vacuum distilled to recover excess epichlorohydrin and 105 g of dark resin of the epoxidized product of Example 6. This epoxy resin has a weight per epoxy equivalent of 203.1 and 225.8. This compares with a weight per epoxy equivalent of 210 for EPON 1031. Viscosities and weight per epoxy equivalent (WPE) of the epoxy resin of this Example 8 as well as comparisons with other epoxy resins prepared from polyphenols are shown below in tables wherein this example may be referred to as EX8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O1CCCC1>[Cl:17][CH2:18][CH2:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:21]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCl)N1CCc2ccccc21
Temperature: 10 °C

Procedure:
A mixture of 2,3-dihydro-1H-indole (50 g), triethylamine (132 g) and tetrahydrofuran (1000 mL) was cooled down to 10° C. followed by the addition (over a period of 60 min) of a solution of 3-chloropropanoyl chloride (55 g) in tetrahydrofuran (400 mL). The mixture was filtered, and the remaining solution was evaporated in vacuo to dryness. The residue was purified by flash chromatography (eluent: ethyl acetate/heptane 1:3) giving the title compound as a crystalline white material (31 g).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([C:19]3[N:20]=[CH:21][S:22][CH:23]=3)=[CH:17][CH:18]=2)[N:4]=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[S:22]1[CH:23]=[C:19]([C:16]2[N:15]=[CH:14][C:13]([CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[S:38])[C:3]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:4]3)=[CH:18][CH:17]=2)[N:20]=[CH:21]1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3cscn3)nc2)c2ccccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-c3cscn3)nc2)c2ccccc2c1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1-{[6-(1,3-thiazol-4-yl)pyridin-3-yl]methyl}-1,4-dihydrocinnoline-3-carboxylate (750 mg, 2.00 mmol) was dissolved in toluene (9 mL), sparged under nitrogen and treated with Lawesson's Reagent (486 mg, 1.20 mmol, 0.6 equiv). The mixture was placed into an oil bath preheated to 105° C. for 1 hour, cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 60:40; hexanes:ethyl acetate) to provide the titled compound as a dark green solid.
Reaction SMILES: CO.[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27]#[N:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:32][OH:33]>C(N(CC)CC)C>[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27](=[N:32][OH:33])[NH2:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: NO
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Yield: 52.2 %

Procedure:
To a 30 ml methanol solution of 1.5 g of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile were added 1.1 ml of triethylamine and 540 mg of hydroxylamine hydrochloride, followed by heating under reflux for 27 hours. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 850 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br.BrC[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: BrCc1cccnc1
Agent: Br
Product: Cl
Product: Clc1ccc2c(c1SCc1cccnc1)CCNCC2

Procedure:
Use a method similar to the Example 347, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-(bromomethyl)pyridine hydrobromide to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:24]=2)[CH:19]=[CH:18]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3ccc4cc[nH]c4c3)ccc2n1)C1CC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (473 mg, 1.44 mmol), 1H-indole-6-ol (250 mg, 1.87 mmol), potassium carbonate (597 mg, 4.32 mmol) and N,N-dimethylformamide (4.0 mL) was stirred at 110° C. for 2 days. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→85/15), and precipitated from ethyl acetate/hexane to give the title compound (48 mg, 10%) as a white powder.
Reaction SMILES: C=CC1C=CC=CC=1.CCCCCCCCCCC.C(=O)=O.C1(CCC=O)C=CC=CC=1.[C:33]1([C@@H:39]([CH3:42])[CH:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH:39]([CH3:42])[CH:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@@H](C=O)c1ccccc1
Agent: O=C=O
Agent: O=CCCc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: CCCCCCCCCCC
Product: CC(C=O)c1ccccc1
Temperature: -60 °C

Procedure:
To a 300 mL stainless steel autoclave equipped with two sapphire windows containing Rh(acac)(CO)2 (10.4 mg, 4×10-2 mmol) and (R,S)-BINAPHOS (60 mg, 8×10-2 mmol) were added styrene (2.08 g, 2.0 mmol) and n-undecane (156 mg, 1.0 mmol) (the internal standard for GC analysis). The air was replaced by CO through pressurization (2-3 atm) and release for 2-3 times, and CO (7 atm) was introduced followed by H2 (14 atm). The reaction vessel was cooled to -60° C. and CO2 (78 atm) was introduced. The mixture was allowed to stir at 65° C. and 100 atm overnight. The autoclave was cooled to 0° C. and all the gasses were carefully released. The GC analysis showed that the conversion of the reaction was 91% and the ratio of 3-phenylpropanal to (R)-2-phenylpropanal was 1:12.5. The enantiomeric purity of 2-phenylpropanal thus formed was determined to be 85% enantiomeric excess by converting it to (R)-2-phenylpropanol followed by esterification with (S)-methoxy(trifluoromethyl)phenylacetyl chloride in the presence of triethylamine in CH2Cl2, and subjecting the resulting chiral ester to the 1H NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.CN1CC[O:28][CH2:27]C1.CCN=C=NCCCN(C)C.Cl.[CH:43]1[CH:44]=[CH:45][C:46]2[N:51](O)[N:50]=[N:49][C:47]=2[CH:48]=1>CN(C=O)C.O>[Cl:23][C:21]1[CH:20]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:22]=1)[CH2:5][O:6][C:7](=[O:19])[NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:27]([C:43]1[CH:44]=[CH:45][C:46]3[NH:51][N:50]=[N:49][C:47]=3[CH:48]=1)=[O:28])[CH2:13][CH2:12]2
Reactant: O=C(Nc1ccc2c(c1)CCNC2)OCc1cc(Cl)cc(Cl)c1
Reactant: On1nnc2ccccc21
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
Starting material 47 (46 mg, 0.1 mmol), 1H-1,2,3-benzothiazole-5-carboxyllic acid (22 mg, 0.1 mmol) and 4-methyl morpholin (40 μL, 0.4 mmol) were dissolved in 2 ml DMF. Then EDCl (38 mg, 0.2 mmol) and HOBt (26 mg, 0.2 mmol) were added and the mixture was stirred over night at ambient temperature. The reaction mixture was mixed with water and the resulting precipitate was filtered and dried in vacuo at 45° C. The desired product 48 could thereby be isolated as light brown solid (34 mg, 0.07 mmol, 52%).
Reaction SMILES: OC1C(C)=CC(N)=CC=1C.[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[N:32][NH:31][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:26][CH:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1cc(N)cc(C)c1O
Agent: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Product: Cc1cc2c(c(C)c1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 4-hydroxy-3,5-dimethylaniline according to Procedure A. The title compound was prepared from 5-hydroxy-4,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 2.18 (s, 3H), 2.47 (s, 3H), 6.50 (s, 1H), 7.22 (s, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 10.78(s, 1H), 12.98 (s, 1H); APCI−MS: m/z 359 (M−H)−. Anal. Calcd for C16H16N4O4S.0.25 H2O: C, 52.67; H, 4.56; N, 15.35; S, 8.79. Found: C, 52.69; H, 4.47; N, 15.33; S, 8.87.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH:36]6[CH2:38][CH2:37]6)[CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: c1cc2c3cnc(Nc4ccc(N5CCN(C6CC6)CC5)cn4)nc3n(C3CCCC3)c2cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in THF (5 mL) were added water (0.05 mL), (1-ethoxy-1-cyclopropyloxy)-trimethylsilane (1174 mg, 1.0 mmol), acetic acid (0.55 mL) and sodium cyanoborohydride (1 mL, 1 M in THF, 1.0 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was concentrated and the residue was disolved in ethyl acetate and washed with saturated NaHCO3 and brine then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with CH2Cl2:methanol:NH4OH (400:10:1) to give compound 187 as a yellow solid (60 mg, 26% yield). 1H NMR (500 MHz, CDCl3) δ 9.08 (1H, s), 8.90 (1H, s), 8.51 (1H, d, J=5 Hz), 8.39 (1H, d, J=10 Hz), 8.18 (1H, bs), 8.07 (1H, d, J=2 Hz), 7.84 (1H, d, J=5 Hz), 7.39 (1H, dd, J=10 Hz, J=2 Hz), 5.38 (1H, p, J=10 Hz), 3.17 (4H, q, J=5 Hz), 2.83 (2H, t, J=5 Hz), 2.42 (2H, m), 2.21-2.14 (4H, m), 1.88 (2H, m), 1.71 (1H, m), 0.53-0.46 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 454.2, Calculated 454.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH:15]=O)[CH:7]=[N:6]2.CO.ClCCCl.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+]>>[CH:23]1([NH:29][CH2:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2ncc(C=O)nc2cc1OC
Reactant: NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cc2ncc(CNC3CCCCC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.067M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in 2:1 MeOH/1,2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine (0.11 mL, 0.9 mmol). The reaction is allowed to stir at room temperature overnight, then NaBH4 (0.038 g, 1 mmol) is added and the reaction mixture is stirred overnight. The mixture is then concentrated and chromatographed (50% EtOAc/hexanes—approximately 5% MeOH in 50% EtOAc/hexanes). The oil is dissolved in EtOAc/hexanes and treated with HCl in EtOH. The resulting solution is concentrated and the solids are triturated with isopropanol to provide a white solid after drying in vacuo at 60° C. (m.p. 185-190° C., dec.). Anal. Calcd. for C,7H23N302 *HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07.
Reaction SMILES: [OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]([O:19]CC)=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].O>C1COCC1>[OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Yield: 90.6 %

Procedure:
Ethyl N-[(2-hydroxy-10-H-pyrimido[5,4-b][1,4]benzothiazin-1-yl)acetyl]-N-(2-Boc-aminoethyl)glycinate (201 mg, 0.4 mmol) was dissolved in THF (10 mL) and LiOH (2M, aqueous, 1.0 mL) was added. After 15 minutes at room temperature water (10 mL) was added, the THF was evaporated in vacuo and HCl (2M, aqueous, 1.0 mL) was added with vigorous stirring. The solid yellow material was filtered off and dried in vacuo to give 173 mg (91%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O.Cl[C:37]1[N:41]2[N:42]=[C:43]([O:46][CH3:47])[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1>O.C(O)C>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]2[N:41]([C:37]([S:21][C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9]([NH:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[O:10])[S:13][C:14]=4[CH:20]=3)=[N:38][N:39]=2)[N:42]=1
Reactant: O=C(NCCN1CCCC1)Nc1nc2ccc(S)cc2s1
Reactant: COc1ccc2nnc(Cl)n2n1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCCC5)sc4c3)n2n1
Yield: 23.7 %

Procedure:
The 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea was prepared according to the method described in Example 17a, but using 547 mg of 1-[2-(pyrrolidin-1-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 25 cm3 of degassed ethanol, 8 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 787 mg of DL-dithiothreitol and 313 mg of 3-chloro-6-methoxy[1,2,4]-triazolo[4,3-b]pyridazine. 189 mg of 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2>C1(C)C=CC=CC=1>[C:10]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:15])=[O:8])([OH:9])=[O:11].[C:7]([C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:10]([C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH3:15])=[O:11])([OH:9])=[O:8]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ccccc2c1C(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Product: Cc1[nH]c2ccccc2c1C(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 19,3 g 3-nitrophthalic anhydride, 13,1 g 2-methylindole and 60 ml toluene is heated for 3 hours at 100° C and cooled to 25° C. The precipitate thus obtained is filtered off, washed with toluene and methanol and dried in vacuo 80° C to yield 25,9 g (80% of theory) of the two isomers 3-(2'-carboxy-3'-nitro-benzoyl)-2-methyl indole and 3-(2'-carboxy-6'-nitro-benzoyl)-2-methyl indole, having a melting point of 199° - 202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:5].[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:5][C:23](=[O:24])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:6]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
2.5 g (7.5 mmol) of 2-chloro-6-fluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide are heated to reflux temperature (internal temperature 80° C.) for 16 hours in 35 ml of a 20% solution of phosgene (67 mmol) in toluene. Excess phosgene and toluene are then distilled off, and the residue is dissolved in 30 ml of methylene chloride and heated to reflux temperature for 30 minutes with the addition of 6.7 ml (48 mmol) of triethylamine. The mixture is subsequently washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After chromatographic purification of the crude product with toluene/n-hexane (1:1) as the eluent and recrystallization from methylene chloride/n-hexane there is obtained pure 5-(2-chloro-6-fluorophenyl)-3-(α,α,α-trifluoro-o-tolyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 109°-109.5° C.; IR spectrum: 1792 cm-1 ; mass spectrum: 358(14), 314(23), 159(100).