Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[OH:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(CCCCOc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CO)CCCCOc1ccccc1

Procedure:
A solution of 129 g of 2-methyl-6-phenoxy-hexanoic acid in 200 ml of absolute ether and 100 ml of absolute THF was added dropwise, under exclusion of humidity, to 32 g (0.84 mol) of LiAlH4 in 1.2 l of absolute ether. After reflux and stirring for 5 hours the LiAlH4 in excess was destroyed with acetic acid and then destroyed by dropwise addition of water and a 10% sulfuric acid. The organic layer was washed with saturated NaHCO3 -solution, dried and evaporated. The crude product was immediately further reacted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1-c1cccc(Cl)c1
Yield: 89.5 %

Procedure:
To a mixture of 2-(3-chlorophenyl)-4-nitroanisole (0.5 g, 1.9 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added platinum(IV)oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chlorophenyl)-4-methoxyaniline as a light yellow oil (405 mg, 1.7 mmol).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9].C[N:15](C=O)C>>[CH:1]1[CH:6]=[C:5]([NH2:15])[C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9]
Reactant: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Reactant: CN(C)C=O
Product: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C

Procedure:
About 1 mg of Vitamin D binding protein, DBP, is buffer exchanged three times with 100 mM PBS at pH 8.2. The final volume was 200 uL. Succinyl-amino-buty-ethyl-isoluminol NHS ester (4.6 mg) is dissolved in DMF. The isoluminol (17 uL) is added to the DBP and the mixture is maintained at room temperature for about 1 hour with occasional shaking. The unreacted label is removed by size exclusion chromatography using SEPHADEX-G25 (23×1 cm) and 100 mM PBS, pH 6.0 as the mobile phase.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[N:21][CH:22]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
A flask was charged with 3-Bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-32, 3.3 g, 10 mmol), 2-fluoro-pyridine-5-boronic acid (1.4 g, 10 mmol), toluene (40 mL), 2M aq. Na2CO3 (10 mL, 20 mmol), ethanol (10 mL) and Pd(PPh3)4 (577 mg, 0.5 mmol). The reaction mixture was bubbled with nitrogen gas for 5 minutes. Then the yellow reaction mixture was stirred at 80° C. After overnight stirring the reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted in EtOAc (20 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with hexane/EtOAc (9:1) to produce 3.23 g (93% yield) of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 3.73 (s, 3H), 3.98 (s, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.11 (dd, J=8.4, 2.8 Hz, 1H), 7.25-7.51 (m, 5H), 7.82 (td, J=8.2, 2.4 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:27][NH2:28])=[O:18])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{26} (7.25 g, 19.4 mmol, 1 equiv.), anhydrous hydrazine (1.8 mL, 58.3 mmol, 3 equiv.), ethanol (39.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{26} (6.54 g, 94%) as a yellow oil. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.35-7.32 (m, 4H), 7.27-7.22 (m, 4H) 7.19-7.16 (m, 1H), 4.20 (s, 1H), 3.84 (br s, 2H), 3.06 (s, 2H), 2.52 (br s, 4H), 2.38 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 141.7, 140.9, 132.5, 129.0, 128.5, 128.5, 127.6, 127.1, 75.1, 60.4, 53.7, 51.6.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15].[OH-].[Na+]>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)(=[O:16])=[O:15])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide was prepared as described in Example 34B from 3,4-dimethyl-5-amino isoxazole (0.122 g, 1.0 mmol), furan-2-sulfonyl chloride (0.50 g, 3.0 mmol) and NaOH (64 mg). Flash chromatography (50% ethyl acetate/hexanes) yielded 70 mg of a yellow solid. Recrystallization from CHCl3 /hexanes produced an off-white solid (46 mg, 29% yield), m.p 107°-110° C.
Reaction SMILES: C[N:2]([CH3:15])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)=O.N[C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=C[NH:19][N:18]=1>C(O)(=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:19]3[N:18]=[CH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CCc1ccc(C(=O)C=CN(C)C)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(CC)cc3)ccnc12

Procedure:
A mixture of 4.07 g. of 3-dimethylamino-4'-ethylacrylophenone and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours. The compound is recovered from the reaction in the previously described fashion to yield crystals, m.p. 101°-103° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:21]3=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:45][C:34]([F:33])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: O=C(c1ccc(OCCCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(OCCCCCN2CCC(NC(=O)C(F)(F)F)CC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil.
Reaction SMILES: F[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[NH4+:15].[OH-]>>[NH2:15][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: [NH4+]
Reactant: Cc1cc(-c2ccccc2)nnc1F
Agent: [OH-]
Product: Cc1cc(-c2ccccc2)nnc1N

Procedure:
A mixture of 3-fluoro-4-methyl-6-phenylpyridazine (1.0 g) and 50 mL of 28% aqueous NH4OH is heated in a pressure bottle to 95°-100° C. The reaction mixture is cooled and thereafter extracted with CH2Cl2. The organic materials are then extracted with 10% aqueous HCl. The acid phase is washed with CH2Cl2, cooled and basified with caustic. The resulting mixture is extracted several times with CH2Cl2. The organic extracts are then combined and dried with MgSO4 and the remaining liquid is concentrated to give 550 mg (56%) crude product as a yellow solid. Recrystallization from EtOH gives an analytically pure material melting at 132°-134° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:12]1([CH2:18][CH2:19][CH2:20][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCc1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CCCn2cncn2)cc1
Reaction time: 12 h

Procedure:
A mixture of 14 parts by weight of 1,2,4-triazole, 200 parts by weight of acetonitrile, 32 parts by weight of potassium carbonate and 40 parts by weight of 3-phenylpropyl bromide is stirred for 12 hours. The mixture is then filtered and the filtrate is concentrated. Distillation gives 25 parts by weight of pure 1-(3-phenylpropyl)-1,2,4-triazole; b.p. (0.013 mbar): 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine and pyridine-2-carboxylic acid as starting materials, MS (LC/MS): 408.0 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[C:18]1([CH3:28])[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[NH2:1][C@H:2]([C:7]([O:9][CH2:28][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8])[CH2:3][C:4]([O:6][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
One embodiment of the invention, in a method for the preparation of PALA compounds, comprises the steps of reacting L-aspartic acid with benzyl alcohol and p-toluenesulfonic acid to obtain L-aspartic acid, dibenzyl ester p-toluenesulfonate, reacting the L-aspartic acid, dibenzyl ester p-toluenesulfonate with triethylamine, adding phosphonoacetyl chloride to produce PALA dibenzyl ester; and separating the PALA dibenzyl ester from unreacted phosphonoacetyl chloride. The PALA dibenzyl ester is separated in any suitable way. Since it is insoluble in water, the PALA dibenzyl ester and unreacted phosphonoacetyl chloride preferably are separated by washing the reaction mixture with water to remove the phosphonoacetyl chloride.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([C@@H:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=[O:12])[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[Cl:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:13][C:10](=[CH2:14])[CH:9]([N:8]1[C:19](=[O:20])[CH:6]([N:5]2[C:4](=[O:21])[C:3]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]3[C:1]2=[O:26])[CH:7]1[S:11]([Cl:27])=[O:12])[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)C1N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2S(=O)C1(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl
Yield: 95 %

Procedure:
A solution of 18.8 g. (50 mmol) of methyl 6β-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 6.7 g. (50 mmol) of N-chlorosuccinimide in 1000 ml. of dry carbon tetrachloride was refluxed for 70 minutes. The mixture was cooled and then was washed with water and brine. After drying over MgSO4, the solvent was evaporated, and 19.5 g. (95%) of the title compound as a colorless solid was obtained. The nmr spectrum (CDCl3) indicates that the product is the sulfinyl chloride.
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].CC(C)([O-])C.[K+].[CH:37]([C:39]1[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=1)=O.O>CN(C)C=O>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]=[CH:37][C:39]2[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=2)[N:10]=1)(=[O:4])[CH3:3]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)s2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
To a solution of {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphonium chloride (3.771 g, 8.325 mmol) in anhydrous N,N-dimethylformamide (35 ml) was added potassium tert-butoxide (2.515 g, 22.41 mmol) at 0° C., and the mixture was stirred for 15 min. 5-Formylthiophene-2-carboxylic acid (1.000 g, 6.404 mmol) was added by small portions, and the mixture was stirred at 0° C. for 30 min. The mixture was warmed to room temperature, stirred for 2 hr, and poured into iced water (300 ml). After stirring for 30 min, the mixture was washed twice with ethyl acetate. The aqueous layer was cooled to 0° C., and adjusted to pH 3 by dropwise addition of 6M hydrochloric acid. After stirring at 0-5° C. for 2 hr, the precipitated crystals were collected by filtration, washed 3 times with water, and twice with diisopropyl ether and dried under reduced pressure to give 5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophene-2-carboxylic acid (1.104 g, 3.751 mmol, yield 58.6%) as a yellow ocher solid.
Reaction SMILES: C([N:4]1[CH2:17][C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:9]2[CH2:8][N:7]3[CH2:6][CH2:5]1)(=O)C.[OH-].[K+].O>CO>[CH:12]1[CH:13]=[CH:14][C:15]2[CH2:17][NH:4][CH2:5][CH2:6][N:7]3[C:16]=2[C:11]=1[CH:10]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:9]1[CH2:8]3
Reactant: CC(=O)N1CCN2CC3CCCCCC3c3cccc(c32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1cc2c3c(c1)C1CCCCCC1CN3CCNC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
The compound from example 7 (0.5 g, 1.67 mmol) was dissolved in methanol (5 mL). To the mixture was added KOH (0.99 g and 16.7 mmol) and water (5 mL). The reaction mixture was heated to 100° C. and held for 4 hours. Methanol was then added (10 mL) and the mixture was held for an additional 20 hours (16 mL). At 24 hours, KOH (0.47 g, 8.3 mmol) and methanol (16 mL) were added. After 48 hours, the reaction mixture was cooled to room temperature. The methanol was removed, and the reaction mixture was transferred to separatory funnel with methylene chloride and water. The reaction mixture was extracted with methylene chloride (3×). The combined extracts were dried with magnesium sulfate, filtered and concentrated to dryness to give 430 mg of yellow oil. Further purification (20% ammonia(2M solution in ethanol)/ethyl acetate) yielded 0.273 g of desired product (63%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO.OS(O)(=O)=O.[C:22]([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:22])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc2c(O)ncnc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2c(O)ncnc12
Temperature: 50 °C

Procedure:
A 1 L round bottom flask was charged with 4-hydroxyquinazoline-8-carboxylic acid (A), MeOH (300 mL), and H2SO4 (10 mL). The reaction was heated to 50° C. for 2 days. Upon cooling to room temperature, the reaction mixture was neutralized with NaHCO3 and diluted with water. The methanol was removed in vacuo, and the precipitate was collected, washed with water and heptanes, then dried to give methyl 4-hydroxyquinazoline-8-carboxylate (18.3 g, 65%, over 2 steps combining both isomers from A and B).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:28])[CH3:27].C(OC(=O)C)(=O)C>O>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1

Procedure:
The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed on a steam bath with glacial acetic acid (5 ml) and acetic anhydride (10 ml) for 1 hour. The mixture was poured into water (200 ml), stirred well and the collected precipitate washed with water and dried. After recrystallisation from methanol the product weighed 2.45 g and melted at 196°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([C:9]#[N:10])=[CH:5][CH:6]([CH3:8])[CH3:7].[N+]([CH3:15])([O-])=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:9]#[N:10])[CH2:15][CH:5]1[CH:6]([CH3:8])[CH3:7])=[O:11]
Reactant: COC(=O)C(C#N)=CC(C)C
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)C1(C#N)CC1C(C)C
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid methyl ester (10.5 g, 68.3 mmol) in dry acetonitrile (60 mL) was added nitromethane (5.5 mL, 103 mmol) and a portionwise addition of alumina-supported potassium flouride (40% wt, 22 g). The reaction mixture was stirred under reflux for 2 hours and cooled to room temperature. The solid was removed by filtration through a short pad of celite and washed with acetonitrile. Excess of solvent was removed in vacuo and the residue was re-dissolved in ether. The ether layer was washed with water, brine, dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes/EtOAc (8:2) as an eluent to afford 1-cyano-2-isopropyl-cyclopropanecarboxylic acid methyl ester (7.7 g, 68%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.13 (t, J=7.2 Hz, 6H), 1.39–1.45 (m, 2H), 1.65–1.74 (m, 1H), 1.81 (dd, J=4.4, 8.9 Hz, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 19.6, 21.8, 21.9, 25.3, 31.2, 39.3, 53.7, 117.6, 168.7.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1.I([O-])(=O)(=O)=[O:20].[Na+].O>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:20])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1
Reactant: CSc1ccc(-c2cnn3c(O)ncnc23)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(-c2cnn3c(O)ncnc23)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.7 %

Procedure:
To a suspension of 4-hydroxy-8-(4-methylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazine (258 mg) and sodium metaperiodate (430 mg) in methanol (20 ml) is added water (0.5 ml), and the mixture is stirred at room temperature for 40 hours. The insoluble material is separated by filtration, washed with water and dried to give the title compound (180 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH3:43][S:44]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2 and charged with PS-DIEA (150.00 mg, 0.46 mmol). Methanesulfonyl chloride (10 μL, 0.47 equiv) was added in one portion. After 10 min., another 5 μL of methanesulfonyl chloride (0.24 equiv) was added. After another 10 min., another 2.1 L of methanesulfonyl chloride (0.1 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with CH2Cl2. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2, dry loaded with silica, and eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=0.85), 8.29 (1H, d, J=8.86), 8.20 (2H, dd, J=1.51, J=1.12), 7.97 (2H, m), 7.86 (1H, dd, J=1.72, J=1.72), 7.53 (4H, m), 7.24 (1H, d, J=5.26), 7.08 (1H, d, J=6.75), 3.85 (2H, d, J=11.88), 2.98 (2H, d, J=7.08), 2.68 (2H, t), 2.20 (1H, m), 1.94 (2H, d, J=10.92), 1.50 (2H, m); MS (ES+): m/z 513.02/514.03 (80/70) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CNc1nc(Cl)ncc1N
Temperature: 60 °C
Yield: 69.4 %

Procedure:
To a stirred solution of 2-chloro-N-methyl-5-nitropyrimidin-4-amine (1.9 g, 10 mmol) in acetic acid (30 mL) was added iron powder (4 g, 71 mmol), and the suspension mixture was heated to 60° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was diluted by brine and ethyl acetate. The solid was filtered off, and the filtrate was extracted with ethyl acetate (50 mL*12). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated to give the title compound (1.1 g, 69%). MS (ES+) C5H7ClN4 requires: 159, 161. found: 160, 162 [M+H]+.