Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([B])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[NH2:23][C:24]1[CH:29]=[C:28]([C:18]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)=[CH:16][C:17]=2[O:20][CH2:21][CH3:22])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Reactant: [B]c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(N)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrakis-triphenylphosphine-palladium (555 mg; 0.48 mmol) is suspended in dimethoxyethane (7 ml) while gassing with argon, and 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (4.14 g; 10 mmol) in dimethoxyethane (60 ml) is added. After stirring for 15 minutes at room temperature, 3-amino-phenylboron acid monnohydrate (2.37 g; 15 mmol) in ethanol (17 ml) is added, the mixture is stirred at room temperature for a further 10 minutes, aqueous 2 M sodium carbonate solution (44 ml) is added and the mixture is then boiled under reflux for 4 hours. The reaction mixture is concentrated and the residue is stirred with water and filtered off with suction. The filter cake is stirred with MeOH (230 ml) and filtered off with suction. The filtrate is concentrated and the residue is chromatographed over silica gel (225 g) with methylene chloride/methanol/ammonia (19/1/0.05, later 90/10/1). The pure fractions are combined and concentrated and the residue is dried under a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: COc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 40.9 %

Procedure:
Using the procedure of example 1, p-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 5 (35 mg, 41%). 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 8.27 (m, 2H), 8.07 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.06 (d, J=5.6 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 3.86 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.C(N(CC)CC)C.[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)CCC>[NH2:12][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: NCC1CCCCC1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1nc2c(c(NCC3CCCCC3)n1)CCCC2

Procedure:
A mixture of 4-chloro-5,6,7,8-tetrahydroquinazoline-2-ylamine (107 mg, 0.58 mmol), triethylamine (221 mg, 2.18 mmol), cyclohexylmethylamine (132 mg, 1.17 mmol) and n-butanol (3 ml) was reacted for 4 hours at 80-90° C. According to the post-treatment of Example 1, the object compound was obtained (102 mg, 67.9%).
Reaction SMILES: [OH-].[Na+].C([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(=O)C.[Cl-].[Na+]>O>[NH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:11][CH2:12]1
Reactant: CC(=O)NC1CCC(N2CCNC2=O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC1CCC(N2CCNC2=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 3271 g of sodium hydroxide in 33,000 ml of water is added 3271 g of 1-(4-acetamidocyclohexyl)-2-imidazolidinone. The mixture is stirred and refluxed for 4 hours. The reaction mixture is cooled to room temperature and 3271 g of sodium chloride is added with stirring. The reaction mixture is extracted a total of 10 times using a total volume of 93,000 ml of dichloromethane. The dichloromethane solution containing the product is concentrated in vacuo to a volume of about 5 liters. To this solution is added 300 g of magnesium sulfate, anhydrous. The mixture is stirred at room temperature for about 3 hours, filtered and the filtrate concentrated in vacuo to dryness. The resulting residue is dried in high vacuum to constant weight to give 1-(4-aminocyclohexyl)-2-imidazolidinone, as a mixture of isomers which crystallizes on standing at room temperature.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 5-bromo-2-furoic acid (1.14 g) and 3-aminophenylacetic acid ethyl ester (1.06 g) in anhydrous DMF (15 ml) was added diisopropylamine (2.1 ml) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.25 g). The solution was stirred at room temperature for 16 hours then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with 1M hydrochloric acid, water, aqueous sodium carbonate solution, brine, dried over sodium sulphate and evaporated in vacuo. Compound 11 (1.8 g) was obtained following silica gel column chromatography of the residue in 2:1 ethyl acetate:petroleum ether.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1)=O.[C:17]([NH2:20])(=[O:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([C:3]3[N:20]=[C:17]([CH3:18])[O:19][CH:2]=3)=[CH:6][C:7](=[O:16])[O:8]2)=[CH:13][CH:12]=1
Reactant: CC(N)=O
Reactant: Cc1ccc2c(C(=O)CBr)cc(=O)oc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(-c3coc(C)n3)cc(=O)oc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromoacetyl)-7-methyl-2H-chromen-2-one (750 mg, 2.67 mmol) in N,N-dimethylformamide (2.5 mL), acetamide (158 mg, 2.67 mmol) was added. The reaction was then stirred overnight at 100° C. After cooling, the reaction mixture was dissolved with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was pre-adsorbed on silica gel and purified by column chromatography (EtOAc/hexanes, 30:70 to 80:20) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.52 (s, 1H), 8.21 (d, 1H), 7.23 (s, 1H), 7.21 (d, 1H), 6.52 (s, 1H), 2.57 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[CH2:9]([N:12]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][C:15]1C=CC=C2[C:16]=1[CH:17]=[CH:18]N2)[CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH2:24]([N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][C:15]1[C:4]2[C:3]([CH:18]=[CH:17][CH:16]=1)=[N:2][C:6](=[O:7])[CH:5]=2)[CH2:25][CH3:26]
Reactant: CCCN(CCC)CCc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCc1cccc2c1=CC(=O)N=2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
N-chlorosuccinimide (2.52 g, 18.9 mmol) was added to a solution of 4-[2-(dipropylamino)ethyl]indole (IV) (3 g, 12.28 mmol) in toluene (10 mL) and was stirred at room temperature for 1 h. The resultant mixture was washed with an aqueous solution of NaOH 5% and then an aqueous solution of HCl 1N (30 mL) was added to the organic layer and was heated at reflux temperature for 1 h. When the mixture reached room temperature, the organic layer was separated and the aqueous layer was basified with an aqueous solution of NaOH and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 2.1 g (66%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I), which was purified and converted into its hydrochloride salt.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]2[C:8]([C:9](=[O:25])[C:10]([CH3:24])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12]2)=[CH:7][CH:6]=1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)#[N:27]>C(O)C.O>[CH3:24][C:10]1[C:9](=[O:25])[C:8]2[C:13](=[C:14]([C:15](=[O:17])[CH:16]=[CH:32][C:31]3[CH:34]=[CH:35][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[O:12][C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-methoxy -8-acetyl-3methylflavone (2.31 g, 0.0075 mol) and 4-cyanobenzaldehyde (0.98 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 2.1 g of product m.p. 223-224C, 1H-NMR (CDCl3)δ:2.18 (s, 3H), 3.96 (s, 3H), 7.04-8.36 (m, 13H).
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15]>CCCCCC>[CH2:1]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:27]([NH:26][C:18]1[C:17]([CH:14]([CH3:15])[CH3:16])=[CH:22][CH:21]=[CH:20][C:19]=1[CH:23]([CH3:25])[CH3:24])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCc1ccccc1N
Solvent: CCCCCC
Product: CCCCCCc1ccccc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a 5 ml n-hexane solution of 0.42 g (2.35 mmol) of 2-hexylaniline was added 5 ml (2.35 mmol) of a hexane solution of 0.47M 2,6-diisopropylphenyl isocyanate at room temperature and the whole was stirred for 16 hours. The precipitated crystals were collected by filtration to give 0.55 g (61% yield) of 1-(2-hexylphenyl)-3-(2,6-diisopropylphenyl)urea, the physical properties of which being shown in the following Table 3. The compound No. 25 listed in Table 3 was similarly prepared as above.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=5)[CH:25]=4)(=[O:31])=[O:30])[CH2:37][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cn1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Nc1ncc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cn1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-amino-5-pyrimidyl)benzoic acid and 1-[(6-chloronaphthalen-2-yl]sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].O=[C:7]1[CH:18]([C:19](OC)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:4][C:3]1[N:5]=[C:19]([OH:20])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:7]=2[N:2]=1
Reactant: COC(=O)C1CCCCC2(CCCCC2)C1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1(CCCCC1)CCCC2
Temperature: 120 °C

Procedure:
A mixture of guanidine hydrochloride (430 mg, 4.5 mmol), the product from Example 16B (430 mg, 1.8 mmol), and potassium carbonate (623 mg, 4.5 mmol) in DMF (8 mL) was heated at 100° C. for 16 hours. Then, the temperature was raised to 120° C. for 2 hours. The mixture was cooled to ambient temperature and filtered through a layer of diatomaceous earth, then the filter pad was washed with a small amount of DMF. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel (10:45:45 MeOH/CH2Cl2/EtOAc, eluant) to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) ppm 10.62 (s, 1 H), 6.04 (s, 2 H), 2.57-2.64 (m, 2 H), 1.93-2.05 (m, 2 H), 1.60-1.71 (m, 4 H), 1.35-1.57 (m, 9 H), 1.15-1.28 (m, 1 H). MS (DCI+) m/z 248 (M+H).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].[Cl-].[Na+].C(O)(=[O:17])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:17])[CH2:6][CH2:5]1)=[O:2]
Reactant: O=CNC1CCCc2sccc21
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=CNC1CCC(=O)c2sccc21

Procedure:
A solution of N-formyl-4,5,6,7tetrahydrobenzo[b]thiophen-4-amine (60 g) in 50% aqueous acetic acid (1,112 ml) is stirred and ceric ammonium nitrate (727 g) is added over 20-25 minutes at 25° to 30° C. The mixture is stirred at room temperature for 15 minutes, saturated with sodium chloride and extracted with methylene chloride (2 × 770 and 1 × 400 ml). The combined methylene chloride extracts are washed with brine (380 ml) and then with water (155 ml). The water wash is extracted with methylene chloride (155 ml) and this extract is combined with the main methylene chloride extract. The methylene chloride is evaporated and the residue is triturated with ether (250 ml), collected and washed with ether to afford the title formamide, m.p. 104° to 110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:32][C:30](=[O:31])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[CH:6][CH:7]=1
Reactant: CCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (1.4 mmoles) of 5,5-bis(4-fluorophenyl)-4-(1-ethyl-1H-tetrazol-5-yl)2,4-pentadienal in tetrahydrofuran at -50° C., was added 1.75 mL of 0.8M (1.4 mmoles) of a freshly prepared solution of ethyl acetoacetate dianion [described in Example 10]. The solution was stirred for 30 minutes at -50° C. and then allowed to warm to -10° C. during the next 30 minutes. The solution was quenched with 1N HCl and extracted with methylene chloride. The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with chloroform to give 0.4 g of the title compound as an oil. MS (CI): m/e=497 for (M+H)+.
Reaction SMILES: O[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1
Reactant: Cn1nc(O)c2scc(-c3ccncc3)c2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1nc(Cl)c2scc(-c3ccncc3)c2c1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
The mixture of 7-hydroxy-5-methyl-3-(pyridin-4-yl)thieno[2,3-d]pyridazin-4(5H)-one and 4-hydroxy-6-methyl-3-(pyridin-4-yl)thieno[2,3-d]pyridazin-7(5H)-one (2.0 g, 7.71 mmol) was dissolved in POCl3 (15 mL) and stirred at 120° C. for about 18 h. Following this, most of the solvent was removed under reduced pressure. Water was added in caution until the POCl3 was consumed. MeOH was added, basified with K2CO3. The suspension was filtered through a Büchner funnel. The filtrate was concentrated to dryness under reduced pressure. The resulting brown oil was purified by preparative HPLC to give the title compound as white solid. Preparative HPLC was performed using a 2767 PHW003 HPLC-system (Waters) equipped with a C18 preparative column (10 um 21*250 mm, Boston). Mobile Phase: A: water (10 mM NH4HCO3), B: CH3CN; Gradient: 30-43% B in 8 min, stop at 14 min; Flow Rate: 30 mL/min; Detective Wavelength: 214\254 nm; Rt: 5.77 mM. LC-MS (Method B): m/z 278 (M+H)+, Rt: 1.79 min. 1H NMR (400 MHz, CDCl3): δ=8.69-7.68 (m, 2H), 7.67 (s, 1H), 7.49-7.48 (m, 2H), 3.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 80 °C

Procedure:
A mixture of 10 g. (0.065 mol) of 2-amino-4-nitrophenol, 125 ml. of dry toluene and 25 ml. of glacial acetic acid is heated to affect solution. Acetic anhydride (7.57 g., 0.074 mol) is added dropwise over a period of twenty minutes and the resulting mixture is heated at about 80° C. for two hours. The reaction mixture is filtered and the solid is washed with toluene, then recrystallized from methanol to give 2-acetamido-4-nitrophenol, m.p. 283°-284° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer A) and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]2[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=2[CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-chlorophenyl)ethynyl]benzaldehyde (intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a yellow powder (62%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.41 (m, 4H), 7.38-7.28 (m, 4H), 7.16 (d, J=2.7 Hz, 1H), 6.87-6.76 (m, 2H), 4.34 (s, 2H), 1.68 (s, 6H). M− (ESI): 416.1. HPLC, Rt: 5.45 min (Purity: 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][C@H:25]([CH3:29])[C@H](O)C)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:23])(=[N:17]C(OCC)=O)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30]C[O-].[Na+].[Na+].[Cl-]>C(O)C>[Br:1][C:2]1[C:3]([O:24][CH2:25][CH3:29])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:23][CH3:30])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(Br)c(O[C@H](C)[C@@H](C)O)n2)cc1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Nc2ccc(S(=N)(=O)CC)cc2)ncc1Br

Procedure:
28 mg (0.056 mmol) of (RS)—S-[4-({5-bromo-4-[(1R,2R)-2-hydroxy-1-methylpropoxy]pyrimidin-2-yl}amino)phenyl]-N-(ethoxycarbonyl)-S-methyl sulfoximide in 0.11 ml of ethanol is mixed with 0.32 ml (0.113 mmol) of a 0.35 molar solution of NaOEt in ethanol and stirred under reflux for 6 hours. The batch is stirred overnight at room temperature, and then added to a saturated NaCl solution. It is extracted with ethyl acetate, and the combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 85:15). 9 mg (0.023 mmol, corresponding to 42% of theory) of the product is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>C1(C)C=CC=CC=1>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: C=C(C)c1cccc(C(=C)C)c1
Reactant: Oc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A 500-ml three-neck reactor was charged with amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and toluene (30 ml). The contents were heated up to 80° C. in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and toluene (30 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid matography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,2-diisopropylbenzene, 28.8 g, yield 88%), the intended product, and the o,p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 2.79 g, yield 8.5%), were obtained. After completion of the same aftertreatment and purification operations as those in Example 3, bisphenol M was isolated (17.7 g., isolation yield 54%, purity 99.6%).
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].O.[H][H]>C(O)(=O)C>[CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([CH:7]2[NH:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21

Procedure:
A solution of 1.2 g 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H), 5-dione in 75 ml acetic acid and 10 ml water containing 100 mg 5% palladium on carbon is shaken in an atmosphere of hydrogen at a pressure of 10 psi and room temperature. One equivalent of hydrogen is absorbed in 75 minutes. The mixture is filtered, and the filtrate concentrated under reduced pressure. To the residue is added toluene which is then removed in vacuo. This is repeated. To the gummy residue is added a small volume of acetonitrile to give the desired 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione as a crystalline solid identical to that prepared in Example 1.