Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:22]([C:24]4[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:30]#[N:31])[CH2:21][C:20](=[O:32])[NH:19][C:9]=3[CH:10]=2)=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccoc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-3-yl-phenyl}-carbamic acid tert.-butyl ester (Example K9) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (73 mg).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]([CH3:14])[C:3]=1[NH2:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(Cl)c1N
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline (1.00 g, 3.64 mmol), trimethylboroxin (0.66 ml, 0.59 g, 4.47 mmol), potassium carbonate (1.00 g, 7.30 mmol) and catalytic amount (10%) Pd(PPh3)4 in DMF (5 ml) was heated to 90° C. for 14 h. Water (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a colorless oil after a flash column using EtOAc:hexane (1:9) as the elute. 1H NMR (CDCl3, 500 MHz): δ 7.43 (s, 1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[NH:19]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:11])[C@@H:20]([C:33]([OH:35])=[O:34])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)Oc1ccc(C[C@@H](N)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyloxycarbonyloxysuccinimide (5.75 g) was added to a suspension of D-Tyr(tBu)-OH (5.0 g) in N,N-dimethyl formamide (40 ml). The pH of the solution was adjusted to 8 using triethylamine. The reaction mixture was stirred overnight at room temperature and then evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and diluted with ice water. The pH of the water layer was adjusted to pH 2.5 with 2 N hydrogen chloride. The organic layer was seperated and the aqueous phase was extracted with dichloromethane. The organic layers were combined and washed with water, dried over sodium sulfate and concentrated. Yield: 9.95 g. TLC: Rf=0.31, heptane/ethyl acetate 1/1.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH3:26])[C:10](=[NH:14])[O:11]CC.[O:27]1CCC[CH2:28]1>>[CH3:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[CH:9]1[O:8][C:28](=[O:27])[NH:11][C:10]1=[O:14]
Reactant: CCOC(=N)C(O)c1c(OC)ccc2ccccc12
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 12, except that 2.3 rather than 2.0 equivalents of triethylamine were used, ethyl 1-hydroxy-1-(2-methoxy-1-naphthyl)methanecarboximidate (16.5 g., 0.063 mole) in 500 ml. of tetrahydrofuran was converted to crude product. Recrystallization from ethyl acetate/toluene gave purified 5-(2-methoxy-1-naphthyl)oxazolidine-2,4-dione in two crops [7.7 g.; m.p. 199°201° C.; ir (KBr) 1820, 1740 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[C:4]([F:18])[CH:3]=1.[C:19]([CH2:24][CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:20]>O1CCCC1>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:19](=[O:20])[C:24]([CH3:25])=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:10]1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Yield: 60.2 %

Procedure:
Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 1-391). ##STR83##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][S:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CO.[OH-].[Na+:33]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][S:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)([OH:17])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2].[Na+:33]
Reactant: COC(=O)c1ccc(SCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CCN2CCC(O)(CSc3ccc(C(=O)[O-])cc3)CC2)cc1

Procedure:
The compound (248 mg) obtained in Example 42 was suspended in a 50% mixture of methanol and water (10 mL) and was further mixed with 2 N sodium hydroxide solution (0.3 mL), followed by heating under reflux for ten hours. The solvent was removed under reduced pressure, and the residue was crystallized from ethyl acetate. The crystals were collected by filtration, and dried to yield the titled compound (200 mg) as crystals.
Reaction SMILES: O=[C:2]1[CH:11]([CH2:12][C:13]([O:15]C)=O)[CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.N1C2CCCC(=O)C=2C=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:13](=[O:15])[CH2:12][CH:11]3[C:2]([C:3]4[CH:4]=[CH:5][CH:6]=[N:7][C:8]=4[CH2:9][CH2:10]3)=[N:36]2)=[CH:31][CH:30]=1
Reactant: COC(=O)CC1CCc2ncccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: O=C1CCCc2ncccc21
Product: O=C1CC2CCc3ncccc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoquinoline-6-acetate (prepared from 7,8-dihydroquinoline-5(6H)-one (J. Med. Chem. (1991)34, 2736) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH:14]([CH3:20])[CH2:15][CH:16]([NH2:19])[CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH:16]([CH2:15][CH:14]([CH3:20])[CH3:13])[CH2:17][CH3:18])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCC(N)CC(C)C
Product: CCC(CC(C)C)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 5-methylhexan-3-amine (example 5a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 9H); 1.38 (m, 2H); 1.47 (m, 1H); 1.65 (m, 2H); 2.24 (s, 3H); 3.86 (s, 3H); 4.16 (m, 1H); 5.65 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1H). MS (264, M+H).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Formaldehyde (37% in H2O; 15.6 μL, 0.210 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (25 mg, 0.053 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.111 g, 0.525 mmol) was then added in one portion to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure yield a white solid. The solid was suspended in DCM (2 mL) and cyclohexane (10 mL) then filtered to afford the title compound (16) (19 mg, 73%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.70-7.61 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-2.97 (m, 4H), 2.88 (d, J=10.6 Hz, 2H), 2.46-2.36 (m, 1H), 2.22 (s, 3H), 2.07-1.93 (m, 2H), 1.78-1.58 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(O)C(O)C.Cl[S:16]([C:19]1[N:27]=[C:26]2[N:21]([C:22]([O:29][CH3:30])=[N:23][CH:24]=[C:25]2[F:28])[N:20]=1)(=[O:18])=[O:17]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][S:16]([C:19]1[N:27]=[C:26]2[N:21]([C:22]([O:29][CH3:30])=[N:23][CH:24]=[C:25]2[F:28])[N:20]=1)(=[O:17])=[O:18]
Reactant: Nc1c(F)cccc1F
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Solvent: CC(O)CO
Solvent: ClCCl
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3c(F)cccc3F)nn12
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
A jacketed 250 mL (milliliter) round bottom flask equipped with a stirrer, condenser, and nitrogen inlet and outlet was loaded with 49.1 g (grams), 0.38 mol (mole) of 2,6-difluoroaniline and 25 g of 1,2-propanediol. The mixture was warmed to 35° C. by heating the jacket fluid and a solution of 30.3 g of 93 percent purity (0.10 mol) of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine in 30.2 g of dichloromethane was added portionwise with stirring under a nitrogen blanket over 3.5 hours. A solid began to form in about one hour and all of the chlorosulfonyl starting material was consumed in 5.5 hours. The resulting mixture was cooled to 20° C. and filtered, collecting the solids. The solids were washed 2×40 mL with methanol and then with 112 g of water. The white solid obtained after drying was found to be the title compound with a purity of greater than 99 percent and to amount to 34.2 g (88.9 percent of theory).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]([CH3:18])([C:14]([OH:16])=[O:15])[CH3:17])[CH:7]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
A mixture of 32.62 g of 2,4-difluoronitrobenzene, 24.2 g of 2-aminoisobutyric acid, 15.2 g of potassium carbonate, 100 ml of acetonitrile, and 100 ml of water is heated at 80° for 2 days (until TLC shows little or no starting material). The reaction is then cooled and acetonitrile is removed under reduced pressure. The pH is adjusted to 5 with 4N hydrochloric acid and the mixture is extracted with chloroform (3×300 ml). The organic layers are dried over sodium sulfate and concentrated. The material is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (6.00 g, 0.03508 mol) in CH2Cl2 (50 ml) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (5.65 g, 0.03157 mol), and N,N-diisopropylethylamine (15.1 ml, 0.0877 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 22.32 g, 0.07016 mol) is added via syringe and stirred at 60° C. After 3 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (8.70 g, 74%). Mass spectrum (m/z): 333.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=1.C(N(CC)CC)C.C[Si](C#N)(C)C>C(#N)C.O>[CH3:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[C:22](=[O:21])[CH2:27][CH2:26][CH2:25][C:24]=1[OH:28])=[O:5]
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2C)C1
Reactant: O=C1C=C(O)CCC1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)C3=C(O)CCCC3=O)c2C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.3 g (7.7 mmol) of 2-methyl-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of acetonitrile was added dropwise at 0-5° C. to a solution of 0.86 g (7.7 mmol) of 1-hydroxycyclohex-1-en-3-one and 2.13 ml (15.4 mmol) of triethylamine in 50 ml of acetonitrile. After the mixture had been stirred for three hours at room temperature, a further 0.64 ml (4.6 mmol) of triethylamine and 0.16 g (15 mmol) of trimethylsilyl cyanide were added and the mixture was stirred for twelve hours at room temperature. The reaction mixture was then stirred into 800 ml of water and washed with methylene chloride. The aqueous phase was then brought to pH 4 using 10% strength hydrochloric acid and extracted with methylene chloride. After the organic phase had been dried, the solvent was removed and the residue was taken up in diethyl ether and digested. The resulting residue was filtered off with suction. This gave 1.3 g (3.3 mmol; 43% of theory) of the title compounds.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[CH3:12][C:13](C)=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>C(Cl)Cl.CO>[C:13]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][OH:1])(=[O:14])[CH3:12]
Reactant: CC(C)=O
Reactant: OCCOc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1OCCO
Reaction time: 3 h

Procedure:
2-(2-Hydroxyethoxy)phenol (308 g; 2 mol) was taken up in a 5 L Erlnmeyer flask fitted with mechanical stirrer. Anhydrous acetone (4 L, dried over K2CO3), and potassium carbonate powder (290 g; 2.1 mol) were added, and the mixture was stirred vigourously. Acetic anhydride (207 ml; 2.2 mol) was added from an additional funnel slowly over a period of 1 hour. Stiiring was continued for 3 hours. TLC (CH2Cl2/MeOH:9:1, v/v) showed disapperence of starting material. The reaction mixture was filtered, solid washed thoroughly with acetone (1 L). The combined fractions was concentrated and purified by chromatography eluting with hexane and ethyl acetate (0% to 35% EtOAc; v/v). The product was obtained as a colorless viscous oil. Yield 258-264 gms (70-72%)
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2sccc12

Procedure:
4-hydroxythieno[2,3-d]pyrimidine (300 mg, 2.0 mmol) in phosphorous oxychloride (1.5 ml) was heated to reflux for 1 hour. 4-chlorothieno[2,3-d]pyrimidine obtained by distilling off the solvent under reduced pressure. Without further purification of 4-chlorothieno[2,3-d]pyrimidine the resultant mixture was heated to reflux with 2-aminoindan (1.1 g, 8.0 mmol) in dry ethanol (6 ml) under an argon atmosphere for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel chromatography (hexane:ethyl acetate=5:2) to obtain the title compound (150 mg, 0.56 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14](Cl)=[C:9]2[NH:8][C:7]=1[CH3:16])=[O:5])[CH3:2].[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:16])[NH:8][C:9]=23)[CH2:18][CH2:19]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ccnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl-7-chloro-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example A3) and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c5) the title compound is obtained as off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].CS([C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:19]2[NH:20][CH:21]=[CH:22][C:23]=2[N+:24]([O-:26])=[O:25])[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNc2[nH]ccc2[N+](=O)[O-])c1
Yield: 15 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (0.325 g) and 2-methylsulphinyl-3-nitropyrrole (0.25 g) was refluxed in ethanol (12 ml) over 6 days. The solution was evaporated to dryness and the residue was chromatographed on silica gel eluted with 10% methanol/chloroform to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-3-nitropyrrole (0.072 g) as a yellow solid m.p. 90°-95° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[C:23]1([N:29]2[C:33]([N:34]3[CH2:37][C:36]4([CH2:40][NH:39][CH2:38]4)[CH2:35]3)=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:39]3[CH2:40][C:36]4([CH2:37][N:34]([C:33]5[N:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[N:30]=[N:31][N:32]=5)[CH2:35]4)[CH2:38]3)=[O:21])[C:4]=12
Reactant: c1ccc(-n2nnnc2N2CC3(CNC3)C2)cc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CC4(C3)CN(c3nnnn3-c3ccccc3)C4)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.050 g), 2-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (0.044 g), BOP reagent (0.080 g) and Hunig's base (0.2 mL) were mixed in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with methanol (10 mL) and volatiles were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography using MeOH/CHCl3 (1:9) as an eluent to afford 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(6-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1,2-dione (30 mg). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.47-2.49 (s, 3H), 3.93 (s, 4H), 4.08-4.13 (m, 2H), 4.20-4.36 (d, 2H), 7.54-7.62 (m, 5H), 7.84 (s, 1H), 8.30-8.32 (s, 1H), 9.22 (s, 1H), 12.26 (bs, 1H). LCMS MS (M+H)+ Calcd.: 526, Observ.: 526.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([NH:20][OH:21])([CH3:19])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:20]([CH:17]([CH3:19])[CH3:18])[OH:21])[N:3]=1)[CH2:14][CH3:15]
Reactant: CC(C)NO
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(O)C(C)C)n1
Yield: 61 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and N-isopropyl-hydroxylamine hydrochloride were reacted as described in Example 13 to yield N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV) (61% yield). ESI-MS (m/z): 269 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Temperature: 150 °C

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.10 mmol, Aldrich) in 1,4-dioxane (10 mL) in a sealed tube was treated with 2-bromopyridine (0.40 g, 2.50 mmol, Aldrich) and heated at 150° C. for 12 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.48(m, 9H), 1.86–1.94(m, 2H), 3.30–3.58(m, 4H), 4.52(brs, 0.5H), 4.67(brs, 0.5H), 4.80(brs, 0.5H), 4.92(brs, 0.5H), 6.32(d, J=9.0 Hz, 1H), 6.57(t, J=6.0 Hz, 1H), 7.38–7.55(m, 1H), 8.12(d, J=6.0 Hz, 1H). MS (DCI/NH3) m/z 276 (M+H)+.