Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([NH2:22])[C:12](=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14]>>[CH:1](=[N:22][C:11]1[CH:10]=[C:9]([CH3:8])[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: Cc1cc(N)c(C(=O)O)cc1S(C)(=O)=O
Product: Cc1cc(N=Cc2ccco2)c(C(=O)O)cc1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This product is prepared by replacing the 2,4-dichloro-5-chlorosulfonylbenzoic acid employed in Example 1, Step A, by an equimolecular proportion of 4-methyl-5-chlorosulfonylanthranilic acid and then following substantially the same procedure described in Example 1, Steps A and B, there is obtained 4-methyl-5-methylsulfonylanthranilic acid employed in the following step without purification. The compound thus obtained is combined with excess furfural and heated on a water bath at about 80° C. The water formed during the reaction is removed by azeotropic distillation with the excess furfural at about 15 mm. Hg. pressure over a one hour period. The 2-furfurylideneamino-4-methyl-5-methylsulfonylbenzoic acid formed is stirred while cooling in acetic acid while a mixture of trimethylamine-borane complex in acetic acid is added over a 10 minute period. The reaction mixture then is heated on the steam bath for 5-10 minutes, then quenched in ice water to give 2-furfurylamino-4-methyl-5-methylsulfonylbenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([CH:24]3[CH2:34][CH:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]\[CH2:18]O)(=[O:8])=[O:7])=[O:4].BrC1C=C(F)C=CC=1S(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)[C:47](OC)=[O:48])(=O)=O>>[CH3:1][O:2][C:3]([N:5]([C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([CH:24]3[CH2:34][CH:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]\[CH2:18][CH2:47][OH:48])(=[O:7])=[O:8])=[O:4]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CCO)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 64, starting from methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 65) and (Z)-4-tributylstannanylprop-3-en-1-ol (prepared according to Miura et al, Organic Letters, 2005, 7(3) 503).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.[NH2:22][C:23]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([NH:22][C:23]2[CH:35]=[C:34]([CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
1.0 mL of Methylene chloride, 0.010 mL of N,N-dimethylformamide and 0.064 mL of oxalyl chloride were added to 0.13 g of 3,4-dimethoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 1.5 mL of methylene chloride and 0.14 mL of triethylamine containing 0.15 g or tert-butyl 2-amino-4-phenethylbenzoate while ice-cooled and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and ethyl acetate and 10% critic acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed, with 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=4:1] to obtain 0.12 g of tert-butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-phenethylbenzoate as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:29][C:6]2[C:7]3[C:12]([NH:13][C@H:14]4[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]4)=[N:11][CH:10]=[N:9][C:8]=3[S:28][C:5]=2[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:30])[CH2:29][C:6]2[C:7]3[C:12]([NH:13][C@H:14]4[CH2:15][CH2:16][C@H:17]([NH:20][CH3:21])[CH2:18][CH2:19]4)=[N:11][CH:10]=[N:9][C:8]=3[S:28][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2sc3ncnc(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](Nc2ncnc3sc4c(c23)CC(C)(C)CC4)CC1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl trans-4-(6,6-dimethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexanylcarbamate (210 mg, 0.49 mmol) in 10 mL of THF was added LiAlH4 (88 mg, 2.44 mmol, 5.0 eq) carefully at 0° C. The resulting mixture was heated at reflux for 2 h and cooled down. The reaction was cooled to 0° C. and quenched with a mixture of THF/H2O. Extracted with EtOAc (3×20 mL) and the combined organics were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography in silica gel (DCM/MeOH/NH4OH=100:8:1) to give the product as white solid (140 mg, 80%). 1H NMR (400 MHz, CDCl3) δ1.01 (s, 6H), 1.18-1.30 (m, 4H), 1.58 (t, J=6.4 Hz, 2H), 1.96 (br s, 1H), 1.98-2.01 (m, 2H), 2.17-2.19 (m, 2H), 2.38-2.40 (m, 1H), 2.41 (s, 3H), 2.56 (s, 2H), 2.73-2.76 (m, 2H), 4.07-4.10 (m, 1H), 5.01 (d, J=7.2 Hz, 1H), 8.29 (s, 1H). MS: m/z 345.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(N(CC)C=O)C>[CH2:9]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1cccc(O)n1
Reactant: CCCCCCBr
Agent: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCOc1cccc(C)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 12.0 g (0.11 mol) of 6-hydroxy-2-methylpyridine (commercially available) and 18.2 g (0.11 mol) of n-hexyl bromide dissolved in 100 ml of N,N-diethylformamide was added 15.2 g (0.11 mol) of potassium carbonate, and the mixture was stirred at 80° to 90° C. for 8 hours. Into the resultant mixture was poured 300 ml of ice-water, the mixture was extracted with ethyl acetate, and the oily extract obtained was separated by silica gel column chromatography (ethyl acetate:hexane=1:9) to give 12.1 g of an oily substance (yield 57.0%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O.O.[OH-].[Na+]>C1COCC1>[N:14]1[CH:15]=[CH:16][C:11]([CH2:9][OH:8])=[CH:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1ccnc(-c2ccccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccccn2)c1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
A cooled (−10° C.) suspension of LiAlH4 (40 mg; 1.05 mmol) in anh. THF (3 ml) was treated with a solution of methyl[2,2′-bipyridine]-4-carboxylate (205 mg; 0.95 mmol) in anh. THF (2 ml). The mixture was further stirred at −10° C. for 5 min., and then at rt for 20 min. Water (40 μl), 15% aq. NaOH (40 μl), and water (0.12 ml) were then successively added, and the resulting mixture was further stirred at rt for 1 h. Filtration, concentration to dryness under reduced pressure, and additional drying under HV afforded [2,2′-bipyridin]-4-ylmethanol as a colorless solid. LC-MS (conditions A): tR=0.25 min.; [M+H]+: 187.14 g/mol.
Reaction SMILES: COC([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:16]CC3C=CC=CC=3)[C:12]([O:14][CH3:15])=[CH:13][C:7]=2[C:6]=1[Cl:24])=O.[OH-].[Na+]>CO>[Cl:24][C:6]1[C:7]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[S:9][CH:5]=1
Reactant: COC(=O)c1sc2cc(OCc3ccccc3)c(OC)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Cl)csc2cc1O
Temperature: 21 °C

Procedure:
3-Chloro-6-benzyloxy-5-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (1.33 g), methanol (27 ml) and 5M sodium hydroxide (27 ml) were refluxed for 2.5 hours. Methanol was evaporated and the resultant solid was filtered. The solid was dissolved in water and acidified with concentrated hydrochloric acid. The mixture was stirred in an ice-water bath, filtered and dried in vacuum. The resultant solid, copper (0.17 g) and quinoline (10.6 ml) were heated at 21° C. for one hour. To the cooled mixture was added 10% hydrochloric acid (26 ml) and dissolved in ethyl acetate. The solution was washed with 10% sodium carbonate and 1M hydrochloric acid and then it was evaporated to dryness. The residue, acetic acid (24 ml) and concentrate hydrochloric acid (3.2 ml) were refluxed 5 hours. The solution was evaporated to dryness. The residue was dissolved in diethyl ether and then extracted with 1M sodium hydroxide. The water phase was acidified with 6M hydrochloric acid and extracted into ethyl acetate. The solution was dried, evaporated to dryness and then triturated with diethyl ether and filtered.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[O:12][C:13]([CH:16]3[CH2:18][CH2:17]3)=[N:14][N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>CO.[NH4+].[Cl-]>[C:1]1([S:7]([CH:10]([C:11]2[O:12][C:13]([CH:16]3[CH2:17][CH2:18]3)=[N:14][N:15]=2)[CH:22]2[CH2:23][CH2:24][CH2:25][C:20](=[O:26])[CH2:21]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cc1nnc(C2CC2)o1)c1ccccc1
Reactant: O=C1C=CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: O=C1CCCC(C(c2nnc(C3CC3)o2)S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 44.2 %

Procedure:
To 2.47 g (9.3 mmol) of 2-benzenesulfonylmethyl-5-cyclopropyl-[1,3,4]oxadiazole in 25 mL of MeOH at 0° C., 170 μL (0.93 mmol, 0.1 eq) of a solution of sodium methoxyde (5.4 M in MeOH) were added. After 15 min, 895 mg (9.3 mmol, 1 eq) of cyclohex-2-enone were added. The reaction mixture was stirred from 0° C. to RT over 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1 gave 1.48 g (44%) of 3-[benzenesulfonyl-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclohexanone as a racemic mixture of diastereomers, white solid, MS: 361 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Cl:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)([Cl:15])=[S:14].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:13]([O:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[S:14]
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(OC(=S)Cl)ccc1Cl
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Into 50 ml of chloroform were dissolved 9.2 g of 3-tert-butyl-4-chlorophenol and 6.3 g of thiophosgene, and 60 ml of 1N-sodium hydroxide solution were added dropwise thereto with stirring at room temperature. After completion of this dropwise addition, the mixture was subjected to stirring over a period of 3 hours. From the reaction mixture was separated chloroform layer, which was thereafter dried over anhydrous calcium chloride. Then, chloroform was distilled off and the residue was distilled under reduced pressure to give 9.5 g of O-3-tert-butyl-4-chlorophenyl chlorothioformate having boiling point of 103°-106° C./0.5 mmHg, of which properties are as follows.
Reaction SMILES: C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH:36]1[C:37]([CH2:54][C@H:55]([NH2:59])[C:56]([O-:58])=[O:57])=[CH:38][C:39]([I:53])=[C:40]([O:43][C:44]2[CH:45]=[C:46]([I:52])[C:47]([OH:51])=[C:48]([I:50])[CH:49]=2)[C:41]=1[I:42].O.[Na+].C(OCCC)(=O)C1C=C(O)C(O)=C(O)C=1>O>[CH:38]1[C:37]([CH2:54][C@H:55]([NH2:59])[C:56]([OH:58])=[O:57])=[CH:36][C:41]([I:42])=[C:40]([O:43][C:44]2[CH:49]=[C:48]([I:50])[C:47]([OH:51])=[C:46]([I:52])[CH:45]=2)[C:39]=1[I:53]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: CCCOC(=O)c1cc(O)c(O)c(O)c1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
The microcrystalline cellulose, mannitol, and sucrose were screened or milled and then blended with levothyroxine sodium for about 6 minutes. Acacia, dissolved in water, and propyl gallate, dissolved in alcohol, were added over about 10 minutes to granulate the mixture. The wet granulation was dried at a temperature below 60° C. until the moisture content was less than about 4%. The dried granulation was sized by passing it through a mill, and then blended with the additional ingredients listed in the table below using conventional mixing equipment.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([CH3:12])([C:9](O)=[O:10])[CH2:5][CH2:4]1.[AlH4-].[Li+].[OH-].[Na+]>O1CCCC1.O.C(OCC)C>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([CH2:9][OH:10])([CH3:12])[CH2:5][CH2:4]1
Reactant: CN1CCC(C)(C(=O)O)CC1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCC(C)(CO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
To a stirred suspension of 1,4-dimethylpiperidine-4-carboxylic acid hydrogen chloride (1.00 g, 5.17 mmol) in tetrahydrofuran (18.9 mL) was added lithium tetrahydroaluminate (1.0N solution in tetrahydrofuran, 20.7 mL, 20.7 mmol) dropwise over 5 minutes. The reaction mixture was stirred at ambient temperature for 12 hours and then diluted with water (20 mL), basified to pH ˜12 by addition of sodium hydroxide pellets, and then diluted with diethyl ether (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a colorless oil (543 mg, 73%). 1H NMR (400 MHz, d6-DMSO) δ 4.44 (m, 1H), 3.12 (d, J=5.4, 2H), 2.50 (m, 2H), 2.39-2.31 (m, 2H), 2.13 (s, 3H), 2.12-2.09 (m, 1H), 1.42 (m, 2H), 1.16 (m, 2H), 0.82 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39]([C:41]1[C:42]2[CH:43]=[CH:44][NH:45][C:46]=2[CH:47]=[CH:48][CH:49]=1)=[NH:40]>CN(C=O)C.CCOC(C)=O>[NH:45]1[C:46]2[C:42](=[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)[CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: N=C(NO)c1cccc2[nH]ccc12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (500 mg, 2.44 mmol) in DMF (15 ml) was added EDAC (514 mg, 2.67 mmol) and HOBt (367 mg, 2.67 mmol) and the solution left standing for 30 minutes. Added N-hydroxy-1H-indole-4-carboximidamide (D9) (427 mg, 2.44 mmol) and left standing for 1 hour. To the solution were added EDAC (117 mg, 0.61 mmol) and HOBt (84 mg, 0.61 mmol) and left standing for 2 hours. To the solution were added EDAC (234.9 mg, 1.22 mmol) and HOBt (167.7 mg, 1.22 mmol) and left standing overnight. Heated at 80° C. overnight, cooled and added EtOAc (30 ml). Washed with water (30 ml), sat. sodium hydrogen carbonate (30 ml) and water (30 ml). Dried over MgSO4 and evaporated off the solvent. The residue was triturated with diethyl ether to give 353 mg of the title compound as a pale brown solid. δH (400 MHz, d6-DMSO) 1.39 (6H, d), 4.94-5.03 (1H, m), 7.09-7.10 (1H, m), 7.30 (1H, t), 7.56-7.59 (2H, m), 7.67 (1H, d), 7.92 (1H, dd), 8.45 (1H, dd), 8.55 (1H, d), 11.52 (1H, broad s). MS (ES) C20H16N4O2 requires 344; found 345 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:24])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:22][N:21]([CH3:23])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C:3]2=[O:24])=[CH:16][CH:17]=1
Reactant: CN(C)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccc(N(C)C)cc3)C2=O)cc1
Temperature: 150 °C
Yield: 12.9 %

Procedure:
3-Chloro-1-[4-(dimethylamino)benzyl]-4-phenyl-1H-pyrrole-2,5-dione (0.20 mmol, 68 mg) and 4-methoxyaniline (0.48 mmol, 59 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 11 mg (13%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 2H), 7.15 (bs, 1H), 7.13-7.04 (m, 3H), 6.97 (m, 2H), 6.70 (d, 2H), 6.60-6.51 (m, 4H), 4.67 (s, 2H), 3.69 (s, 3H), 2.93 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=2[CH2:8][NH:7][C:6]1=[O:17]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=2[CH:8]=[N:7][C:6]1=[O:17]
Reactant: Cc1cc(C)c2c(n1)N(CCN(C)C)C(=O)NC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2cnc(=O)n(CCN(C)C)c2n1
Yield: 48.7 %

Procedure:
A solution of 1-(2-dimethylaminoethyl)-5,7-dimethyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-2-one (5.0 g, 20 mmol) in chloroform (150 ml) containing activated manganese dioxide (15 g) is refluxed for 15 hours. The reaction mixture is filtered hot and the collected manganese dioxide re-extracted with hot chloroform. The combined organic extracts are evaporated and the residue crystallized from cyclohexane to yield 2.4 g of pure title product; m.p.: 137°-139° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[N:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:41]3[CH:42]=[CH:37][N:38]=[C:39]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:40]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1ccnc(N2CCOCC2)n1
Product: C[C@@H](c1ccc(-c2ccnc(N3CCOCC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 4-(4-bromopyrimidin-2-yl)morpholine following a procedure analogous to that described in Example 35. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=517 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.25 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.30 (m, 1H), 2.50 (m, 2H), 3.15 (m, 1H), 3.29 (m, 4H), 3.84 (m, 4H), 5.59 (q, 1H), 7.05 (d, 1H), 7.12 (d, 2H), 7.25-7.40 (5H), 7.94 (d, 2H), 8.17 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:4]=[N:3][C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Cl)nn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCOCC2)nn1
Temperature: 116 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A mixture of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (150 mg, 0.5 mmol) and morpholine (0.17 mL, 2 mmol) was stirred at 116° C. for 4 h. After extraction with ethyl acetate/water the organic phase was concentrated and chromatographed (SiO2, heptane/ethyl acetate=100:0 to 70:30) to afford the title compound as a white solid (40 mg, 23%). MS: m/e=353.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[O:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][C:13]3=[O:23])[CH2:4][CH2:3]1.[ClH:24]>>[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[O:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]3=[O:23])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2cccc(N3CCN(C)CC3)c2o1
Agent: Cl
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)O)oc23)CC1

Procedure:
Ethyl 8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylate as prepared in Reference Example 1d (1.01 g. 3.19 mmol) was suspended in 6 M HCl (60 ml) and to reflux for 1.5 h (after 20 min a clear solution was obtained). The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (×3) and the solution was again concentrated in vacuo to give 8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride as a yellow powder (1.02 g, quantitative yield). LC/MS (M+1) m/z 289.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(Cl)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)cc(Cl)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
To a solution of Example 86 (0.100 g, 0.184 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 1 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale green solid (0.032 g, 33% yield). MP: 122-124° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.19 (s, 1H), 8.06 (s, 1H), 8.04 (dd, J=7.9, 1.5 Hz, 1H), 7.86 (m, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.53 (t, J=7.1 Hz, 1H), 7.28 (br s, 1H), 7.06-6.87 (m, 6H), 6.03 (q, J=6.9 Hz, 1H), 1.88 (d, J=7.1 Hz, 1H). Mass: 528.11 (M++1).