Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]3([C:18]4[C:27](=[CH:26][C:21]5[O:22][CH2:23][CH2:24][O:25][C:20]=5[CH:19]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2c(F)cccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 196-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.26 (m, 10H), 7.19 (ddd, J=8.2, 8.2, 6.1 Hz, 1H), 6.89 (s, 1H), 6.83 (dd, J=8.9, 8.9 Hz, 1H), 6.50 (s, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.83 (q, J=9.6 Hz, 2H), 4.14 (dd, J=5.3, 3.2 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 157.9 (d, 1JC-F=247 Hz), 144.3, 143.8 (d, 3JC-F=8.4 Hz), 137.2 (d, 3JC-F=13.6 Hz), 130.5 (d, 3JC-F=8.6 Hz), 128.1, 127.8 (d, 3JC-F=9.0 Hz), 119.2, 117.3 (d, 2JC-F=19.0 Hz), 110.4, 110.0 (d, 2JC-F=19.7 Hz), 107.8 (d, 4JC-F=2.8 Hz), 98.7, 77.5, 64.1, 63.5, 58.6, 55.8 (d, 4JC-F=2.8 Hz); MS (ES+) m/z 480.0 (M+1),
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH2:11](I)[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CC(C)CI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Temperature: 50 °C
Yield: 51.6 %

Procedure:
A mixture of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (3 g, 18.8 mmol), isobutyl iodide (5 mL, 43.5 mmol) and potassium carbonate (5.3 g, 38.4 mmol) in anhydrous DMF (200 mL) is heated at 50° C. for 8 hours. Additional isobutyl iodide (4.3 mL, 37.5 mmol) is added, and the reaction mixture heated at 50° C. for 24 hours. After hot filtration, the filtrate is evaporated to dryness under reduced pressure. The obtained oil is further purified by silica-gel flash chromatography to give 2.1 g of pure product (Yield: 52%).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:45]([C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[NH2:46]>O.CN(C)C=O>[CH2:51]([O:50][C:48](=[O:49])[C:47]([NH:45][NH:46][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])=[O:53])[CH3:52]
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.50 g), 1H-1,2,3-benzotriazol-1-ol (0.24 g) and N,N-dimethylformamide (10 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.30 g) at room temperature, and the mixture was stirred for 10 min. Ethyl hydrazino(oxo)acetate (0.33 g) was added, and the reaction mixture was stirred at room temperature for 2 hr. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.43 g, yield 63%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 133-134° C.
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].[CH2:10]([NH:17][CH2:18][C:19]1[CH:20]=[C:21]([CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:30])=[C:24]2[OH:40])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH2:10]([N:17]1[CH2:18][C:19]2=[C:28]3[C:23](=[CH:22][C:21]([CH2:41][N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)=[CH:20]2)[C:24](=[O:40])[C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[O:30])=[CH:26][N:27]3[CH2:2][C:3]1=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Reactant: O=C(CBr)OC(=O)CBr
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)CN(Cc1ccccc1)C(=O)C2
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Bromoacetic anhydride (40 mg) is added to a stirred solution of 8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 29, 53 mg) in NMP (0.3 mL). After 30 min, triethylamine (50 mg) is added. The solution is diluted with water and the resulting precipitate is filtered and dried under vacuum to give 44 mg of the title compound. Physical characteristics: HRMS m/z 571.2104 (C32H31ClN4O4).
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][CH:16]=[C:15]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13]>CO>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][CH:16]=[C:15]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:7][C:6]=1[Cl:5])(=[O:1])[NH2:13]
Reactant: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C#N)c(Cl)c2)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
An 8 ml vial was loaded with a mixture of 30% H2O2 (50 uL), 3N NaOH (0.15 ml) and MeOH (0.125 ml). To this mixture 3-[1-(3-chloro-4-cyanophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid (40 mg, 0.105 mmol) was added at room temperature. The reaction mixture was stirred at rt for 45 minutes, TLC showed the starting material to be consumed. The reaction mixture was diluted with water, acidified to pH=2, stirred for 10 minutes, and filtered off. The solid was washed with water and dried to give 30 mg of 3-(1-(4-carbamoyl-3-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid, 73% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15](/[CH:17]=[N:7]/[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1)[CH3:16]
Reactant: Cc1ccc(C(N)=O)cc1I
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)/N=C/N(C)C)cc1I
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A suspension of 3-iodo-4-methylbenzamide (preparation 48a, 2.00 g, 7.7 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (4.0 mL, 30.1 mmol) was heated in a sealed tube at 90° C. with stirring. After 2 hours, the mixture was cooled and concentrated in vacuo. The residue was triturated with diethyl ether and hexanes, and the solid that formed was filtered and dried to give the title compound (1.90 g, 78%) as a yellow solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[N:18]=[C:19]([N:22]=[C:23]([NH2:25])[NH2:24])[S:20][CH:21]=2)[N:16]=1)=O)(C)(C)C>C(O)C>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[N:18]=[C:19]([N:22]=[C:23]([NH2:25])[NH2:24])[S:20][CH:21]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: CCO
Product: NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Hydrogen chloride gas was babbled to a solution of 4-[2-(2-t-butoxycarbonylaminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole (3.0 g) in ethanol (30 ml) for 10 minutes at room temperature. The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-[2-(2-aminoethyl)thiazol-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride (2.3 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:16][CH2:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:21]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a stirred solution of ethyl acrylate (141 g, 1.41 mole) and N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (Compound D17 of EP 0363085, 435 g, containing approximately 75% of D17, 1.4 moles) in dichloromethane (2.5L) at -5° C. was added trifluoroacetic acid (16.1 g, 0.14 mole) in dichloromethane (100 ml) ensuring that the temperature did not rise above 0° C. This mixture was then transferred by cannula to stirred, refluxing dichloromethane (50 ml) over 40 minutes at such a rate as to maintain gentle reflux. The reaction mixture was then refluxed for a further 1h before cooling to room temperature. It was then washed with saturated aqueous potassium carbonate, dried (Na2SO4), and concentrated in vacuo to a gum which was distilled to afford the title compound (D1) as a clear oil (286 g, 88%) b.p. 120°-150° C. at 4 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)=[O:19])[C:4](=[O:9])[N:3]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Nc1nc(O)ncc1F
Solvent: C1CCOC1
Product: Nc1nc(=O)n(C(=O)Nc2cccc(Cl)c2)cc1F
Yield: 82.1 %

Procedure:
Using the procedure of Example 5 but using tetrahydrofuran (THF) instead of DMF as solvent, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.94 mmol) and 3-chlorophenyl isocyanate (0.260 mL, 2.13 mmol) were reacted to yield 4-amino-N-(3-chlorophenyl)-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.45 g, 82%) as a white solid: mp 250-252° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.65 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 7.29-7.20 (m, 2H), 7.06 (d, J=7.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H); ESIMS m/z 280.9 ([M−H]−).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([Cl:9])[CH:7]=[CH2:8]>C1CCCCC1>[Br:1][CH2:2][CH2:3][CH2:4][Cl:5].[Br:1][CH:7]([CH3:8])[CH2:6][Cl:9]
Reactant: C=CCCl
Agent: ClCCCBr
Solvent: C1CCCCC1
Product: CC(Br)CCl
Yield: 3 %

Procedure:
The same process as in example 2 was carried out, but the cyclohexane was replaced by 3-bromo-1-chloropropane. The reaction developed in the same way. After 30 minutes of irradiation at 22° C, 90% of allyl chloride had been converted. The reaction product was degassed and the unreacted allyl chloride was distilled. The remaining product was formed by 3-bromo-1-chloropropane (solvent + formed product) and about 3% of 2-bromo-1-chloropropane. This operation has the advantage of making the solvent distillation unnecessary.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4](Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>C(O)(=O)C>[C:14]([O:17][C:4]12[CH2:3][C:2]3([CH3:1])[CH2:12][CH:6]([CH2:7][C:8]([CH3:11])([CH2:9]3)[CH2:10]1)[CH2:5]2)(=[O:16])[CH3:15]
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC12CC3CC(C)(CC(C)(C3)C1)C2
Temperature: 0 °C

Procedure:
2.486 (10.2 mmoles) of 3,5-dimethyl-1-bromoadamantane is refluxed for 16 hours with 2.034 g (20.7 mmoles) of potassium acetate in 10 mL of acetic acid. The solution is poured over 100 grams of ice, allowed to melt, and extracted with 3×10 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, then dried over sodium sulfate. The solvent is removed under vacuum, yielding 1.521 (67%) of the desired product, a colorless oil. TLC: Rf=0.68 (silica plate: eluant hexane 90%, ethyl acetate 10%). 1HNMR (CDCl3, 500 Mhz): 0.858 (s, 6H), 1.115 (d, 2H, J=12.4 Hz), 1.177 (d, 2H, J=12.4 Hz), 1.260 (d, 2H, J=12.3 Hz), 1.367 (d, 2H, J=12.3 Hz), 1.714 (d, 2H, J=11.6 Hz), 1.766 (d, 2H, J=11.6 Hz), 1.939 (s, 2H), 1.976 (s, 3H), 2.191 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:45][CH:44]([O:46][CH3:47])[CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:48])[N:30]([CH3:49])[N:29]=3)[C:18]=1[CH2:19][O:20]C(=O)C)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]5[CH2:45][CH:44]([O:46][CH3:47])[CH2:43]5)=[CH:37][N:36]=4)[C:31](=[O:48])[N:30]([CH3:49])[N:29]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4COC(C)=O)nn(C)c3=O)nc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CN(Cc2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
Acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{5-[5-(3-methoxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzyl ester (175 mg, 0.26 mmol, Eq: 1.0) was dissolved in 2.6 ml of THF. Sodium hydroxide (1.3 ml of a 1.0M solution in water, 1.3 mmol, Eq: 5.0) was added dropwise. The reaction was stirred at room temperature overnight. Starting material was still present the next morning. The reaction was heated at 50° C. for two hours at which point no starting material remained. The reaction was diluted with ethyl acetate and water and the layers were separated. The organic layer was dried and concentrated. The residue was triturated with isopropyl acetate, filtered, washed with ether, and dried in a vacuum oven to give 75 mg (45.7%) of the desired product as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 2.79 (t, J=6.80 Hz, 2H) 3.11 (s, 3H) 3.37-3.44 (m, 2H) 3.46 (s, 2H) 3.77 (s, 3H) 3.92 (t, J=5.85 Hz, 1H) 4.40 (br.s., 2H) 4.52-4.63 (m, 1H) 7.40-7.62 (m, 5H) 7.74 (d, J=13.22 Hz, 1H) 7.86 (s, 1H) 8.15 (s, 1H) 8.48-8.55 (m, 2H) 9.36-9.44 (m, 1H). MS: (M+H)+=626. MP=140-142° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:36])[C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N:10]([CH2:16][C:17]3[CH:34]=[CH:33][C:20]4/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[CH2:24][CH2:25][C:19]=4[CH:18]=3)[C:9]=2[CH:35]=1)=[O:4].[OH-].[Na+].Cl>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([CH3:36])[C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH3:15])[N:10]([CH2:16][C:17]3[CH:34]=[CH:33][C:20]4/[C:21](=[CH:30]/[C:31]#[N:32])/[C:22]5[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=5[CH2:24][CH2:25][C:19]=4[CH:18]=3)[C:9]=2[CH:35]=1)([OH:4])=[O:2]
Reactant: CCCc1nc2c(C)cc(C(=O)OC)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(C(=O)O)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Yield: 114.3 %

Procedure:
[step 2] (E)-[2-(6-Methoxycarbonyl-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (500 mg, 1.05 mmol) obtained in step 1 was dissolved in ethanol (7.5 mL), 2 mol/L aqueous sodium hydroxide solution (2.5 mL) was added, and the mixture was stirred under reflux for 30 min. The mixture was adjusted to pH 2 with 2 mol/L hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (554 mg) quantitatively.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13](OC)=[O:14].CSC1SC2C=C(C(OCC)=O)C=CC=2N=1>>[F:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:13][OH:14]
Reactant: COC(=O)c1ccc2nc(SC)sc2c1F
Agent: CCOC(=O)c1ccc2nc(SC)sc2c1
Product: CSc1nc2ccc(CO)c(F)c2s1

Procedure:
(7-Fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanol was synthesized as a white solid (249 mg, 69%) using a procedure analogous to that described in Step 3 of Example 36, substituting methyl 7-fluoro-2-(methylthio)benzo[d]thiazole-6-carboxylate from the previous step for ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate used in Example 36. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 5.39 (t, J=5.8 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H), 2.81 (s, 3H); LCMS (ESI) m/z 230 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4].[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4]
Reactant: O=C(CCl)NCCc1ccc2c(c1)OCO2
Reactant: NCCCO
Solvent: CCO
Product: O=C(CNCCCO)NCCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
To 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (0.45 g, 1.9 mmol) in ethanol (10 mL) was added 3-aminopropanol (0.72 mL, 9.4 mmol) (a compound of formula (Y9)). After heating the reaction in an oil bath at 60° C. for 1 day, the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent was removed in vacuo to give 0.44 g of 2-[(3-hydroxypropyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Y10).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14]C)[C:8]([O:12]C)=[N:9]2)=[C:4]([CH2:16][NH:17][C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH:3]=1>Br.C(O)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:12])[NH:9]2)=[C:4]([CH2:16][NH:17][C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH:3]=1
Reactant: COc1nc2cc(Br)cc(CNC(=O)c3ccco3)c2nc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12)c1ccco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 mg (0.79 mmol) of furan-2-carboxylic acid (7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-amide are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether, and the solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [NH2:1][N:2]([CH2:8][CH2:9][C:10]([OH:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3](=O)[O:4]CC.[CH3:19][N:20]=[C:21]=[S:22].CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[OH:18][C:10]([CH3:17])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8][N:2]1[C:3](=[O:4])[N:20]([CH3:19])[C:21](=[S:22])[NH:1]1
Reactant: CCCCCCC(C)(O)CCN(N)C(=O)OCC
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC(C)(O)CCn1[nH]c(=S)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl N-amino-N-(3'-hydroxy-3-methylnonyl)carbamate (1.812 g; 6.97 mmole), and methyl isothiocyanate (764 mg; 10.5 mmole) in dry toluene (25 ml) was heated under refulx for 2 hrs and then allowed to cool to room temperature. Potassium t-butoxide (1,56 g; 13.96 mmole) was added and the mixture stirred at 25° for 16 hr. The mixture was portitioned between water (100 ml) and ethyl acetate (100 ml) and acidified with 5 M HCl. The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml), dried (Na2SO4), and evaporated to dryness and chromatography of the residue on Kieselgel 60 (10 g) in chloroform gave 2-(3'-hydroxy-3'-methylnonyl)-4-methyl-1,2,4-triazolidine-3-one-5-thione as a gum (1.83 g; 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:42]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 36.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again, for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)benzamide (0.045 g, 36.9%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[OH:14].COC(C)(C)C>CCCCCCC.O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([Br:1])[C:7]=1[OH:14]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)ccc1O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: COC(=O)c1cc(OC)cc(Br)c1O
Reaction time: 0.62 h
Yield: 82.5 %

Procedure:
In the course of from 30 to 45 minutes, at 20°, with stirring, 43.9 g of bromine are added dropwise to a solution of 45.9 g of 2-hydroxy-5-methoxy-benzoic acid methyl ester in 125 ml of heptane. The reaction mixture is then stirred for a further 3 to 4 hours, then diluted with 110 ml of water and stirred for a further one hour and then 295 ml of heptane and 46 ml of tert-butyl methyl ether are added thereto. The mixture is then heated to from 50° to 55° and the aqueous phase is separated off. The organic phase is extracted twice with 114 ml of water each time and cooled to -20°. The crystals which precipitate are filtered off and dried under a high vacuum. 3-Bromo-2-hydroxy-5-methoxy-benzoic acid methyl ester is thus obtained; yield 82.5% of the theoretical yield.