Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CC(C)=O>[CH2:30]([O:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Yield: 64.8 %

Procedure:
To a suspension of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [prepared according to WO09/049851] (67.0 g, 211.7 mmol) in acetone (900 ml) was added potassium carbonate (35.1 g, 254.1 mmol), followed by benzyl bromide (35.3 ml, 50.7 g, 296.4 mmol) dropewise. The suspension was stirred at reflux for one hour, then poured on ice water and ethyl acetate. The resulting precipitate was filtered off, dissolved in methylene chloride, dried over sodium sulfate, concentrated and dried over phosphorus pentoxide under vacuum at 50° C. overnight to afford a first crop of product as a white solid (55.8 g). The layers of the mother liquor were separated, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, filtered and dried to further deliver 22.6 g of product. Yield: 78.4 g of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.4) as a solid, mp 184-186° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:15].I[CH2:18][C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:12][CH2:18][C:19]([OH:21])=[O:20])=[C:6]([Cl:13])[C:5]=2[Cl:14])[CH:10]([CH3:11])[C:2]1([CH3:1])[CH3:16]
Reactant: CC1c2cc(O)c(Cl)c(Cl)c2C(=O)C1(C)C
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1c2cc(OCC(=O)O)c(Cl)c(Cl)c2C(=O)C1(C)C

Procedure:
A mixture of 2,2,3-trimethyl-5-hydroxy-6,7-dichloro-1-indanone (6.1 g., 0.025 mole), iodoacetic acid (5.58 g., 0.03 mole) and potassium carbonate (4.14 g., 0.03 mole) in acetone (80 ml.) is refluxed for 20 hours. The acetone is evaporated and the residue is dissolved in water and acidified with hydrochloric acid. The (1-oxo-2,2,3-trimethyl-6,7-dichloro-5-indanyloxy)acetic acid which separates is filtered, rinsed with water and dried.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]([Cl:12])([Cl:11])[CH2:9][OH:10].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:10][CH2:9][C:8]([Cl:12])([Cl:11])[Cl:7])=[O:4]
Reactant: OCC(Cl)(Cl)Cl
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(F)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 26 g of 2,2,2-trichloroethanol were introduced into a round-bottomed flask placed in an ice bath. 17 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 50 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 2,2,2-trichloroethanol was 52%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 67%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C@H:8]2[O:28][C@H:27]([CH2:29][O:30]CC3C=CC=CC=3)[C@@H:18]([O:19]CC3C=CC=CC=3)[C@@H:9]2[O:10]CC2C=CC=CC=2)[N:3]=1>CO.Cl.[Pd]>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C@H:8]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:18]([OH:19])[C@@H:9]2[OH:10])[N:3]=1
Reactant: Cc1cc(C)n([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(C)n([C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)n1
Reaction time: 20 h

Procedure:
1 g of Pd-black is pre-hydrogenated for 2 hours in 25 ml of absolute methanol. Then 3 g (6.0 mmoles) of 3,5-dimethyl-1-(2,3,5-tri-O-benzyl-α-D-arabinofuranosyl)pyrazole are added in 25 ml of absolute methanol and 0.8 ml of concentrated hydrochloric acid. Hydrogenation is carried out for 20 hours at room temperature. Then the catalyst is filtered off and the reaction mixture is fed onto a column with 20 g of amberlite IRA-402 in the OH⃝ -form for neutralisation and is eluated with methanol. After drawing off the solvent, a colorless syrup (which cannot be used for crystallization) remains. For purification therefore the substance is only dissolved in methanol and boiled up with active charcoal. The preparation is then thoroughly dried with a continuously running oil pump. Yield: 1.35 g (99%); Rf (silica gel, acetone): 0.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(c1)Cn1ccnc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)Cn1ccnc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]-benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]-benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred for 3 hours at room temperature and worked up to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[CH:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][SH:19])=[CH:16][CH:15]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[CH:18]([S:19][CH:18](/[CH:12]=[CH:11]\[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#Cc1ccc(OC)cc1OC
Agent: [Na]
Product: COc1ccc(/C=C\C(SC(/C=C\c2ccc(OC)cc2OC)c2ccc(F)cc2)c2ccc(F)cc2)c(OC)c1

Procedure:
A solution of 2,4-dimethoxyphenylacetylene (0.02 mol), 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethoxystyryl-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[C:16]#[N:17].Cl>C1(C)C=CC=CC=1>[C:1]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[C:16]#[N:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1csc(N)c1C#N
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1csc(NC(=O)c2ccccc2)c1C#N
Yield: 81.6 %

Procedure:
After adding 29.4 g (0.21 mole) of benzoyl chloride, a mixture of 36 g (0.2 mole) of 2-amino-3-cyano-4-tert.-butyl-thiophene and 200 ml of toluene was boiled until the evolution of hydrogen chloride had ended (4 hours). Thereafter, the reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue was recrystallized from methanol. 46.4 g of 2-benzoylamino-3-cyano-4-tert.-butyl-thiophene of melting point 130° C. were obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C>ClCCl>[C:38]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:4]([CH3:15])[CH:5]=2)[CH2:14][CH2:13]1)(=[O:40])[CH3:39]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(C)=O)CC5)cc4C)c3)ccc21
Reaction time: 2 h
Yield: 46 %

Procedure:
(S)-Methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (20 mg, 0.04 mmol) was dissolved in 2 mL of dichloromethane, followed by addition of acetic anhydride (5 mg, 0.05 mmol) and triethylamine (12 mg, 0.12 mmol). The reaction solution was stirred for 2 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound (S)-methyl 2-(6-((4′-((1-acetylpiperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 6a (10 mg, yield 47.0%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[OH:4][CH2:3][CH:2]([NH:1][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[C:5]([OH:7])=[O:6]
Reactant: NC(CO)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)NC(CO)C(=O)O)cc1

Procedure:
In analogy to example 2, DL-serine was reacted with 4-toluenesulfonyl chloride to give 3-hydroxy-2-(toluene-4-sulfonylamino)-propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[C:13]3[S:12][C:11]([NH:10][CH2:9][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:15][C:14]3=[O:16])[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18]
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (example 10c, 38.1 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one as a light brown solid: 52.3 mg (72.4%), MS: m/e 452 (MH+).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:27]1[N:35]=[C:22]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[CH:20][CH:21]=3)[CH2:13][N:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9]2)[O:23][N:26]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 50 mg (56% of theory)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOC(C)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 95 °C

Procedure:
(3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)octahydropyrano[3,4-c]pyrrole (example 2: 646 mg, 1.35 mmol) was combined with 1,3-cyclopentanedione (200 mg, 2.03 mmol) and PTSA (26 mg, 0.135 mmol). Toluene (15 mL) was added to the reagents and the vessel was heated to 95° C. for 1 hr. The reaction was diluted with EtOAc and washed twice with 2N NaOH. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted with a 1 to 5% linear gradient of (10% NH4OH-methanol)/DCM which furnished the title compound. 1H-NMR (CD3OD): δ 1.38 (d, 3H, J=7.0 Hz), 2.20-2.44 (m, 4H), 2.55-2.84 (m, 3H), 2.80-3.24 (m, 2H), 3.34-3.80 (m, 3H), 4.24-4.34 (m, 1H), 4.42 (dd, 1H, J=2.5, 8.0 Hz), 4.78-4.92 (m, 1H), 5.09 (q, 1H, J=7.0 Hz), 6.96-7.02 (m, 2H), 7.20 (dd, 2H, J=6.05, 8.5 Hz), 7.39 (s, 2H), 7.76 (s, 1H) ppm. MS: (MH)+558.
Reaction SMILES: [I:1]I.N[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8].[O-]S([O-])=O.[Na+].[Na+]>CC#N.O>[I:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: II
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(I)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
To a stirring mixture of 23.0 g (90.6 mmol) of I2 and 5.4 mL (45.5 mmol) of tert-butylnitrile in 40 mL of CH3CN at 35° C. was added 5.0 g (30.3 mmol) of methyl 3-amino-4-methylbenzoate in 4 portions. Stirring was continued with cooling to r.t. in the dark (light off only). After 2.5 h, 400 mL of Na2SO3 in H2O was added gradually. The layers were separated, and the organic layer was washed with 80 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 5.7 g of methyl 3-iodo-4-methylbenzoate as a red liquid with some impurity in approximately 68% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:40](O)[CH3:41]>S(=O)(=O)(O)O>[CH2:40]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)[CH3:41]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 3.5 h

Procedure:
700 mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid was added. The reaction solution was boiled for 3.5 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 480 mg. MS (ES+): m/e=586.4 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:13][CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].[OH-].[Na+].C(O)C>O>[OH:16][C:15]1[C:14]([C:18]([NH2:20])=[O:19])=[N:13][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:12])[N:17]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: NC(=O)C(N)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(C(N)=O)c(O)nc1O
Reaction time: 0.67 h

Procedure:
In 2.0 mL of water are suspended 0.65 mL of diethyl-2-oxomalonate and 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.85 mL of 5 mol/mL sodium hydroxide is added thereto. The resulting solution is stirred for 40 minutes. Then, at ambient temperature, 2.55 mL of 5 mol/mL sodium hydroxide is added to the solution, which is then stirred for an additional 30 minutes. Ethanol is added to the reaction mixture and the precipitate is collected by filtration to obtain 0.24 g of 3,5-dihydroxy-6-ethoxycarbonyl-2-pyrazinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:44][N:45]([CH3:59])[CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][C:51]=1[O:57][CH3:58]>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:54][C:53]2[CH:55]=[CH:56][C:50]([O:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:59])[CH3:44])=[C:51]([O:57][CH3:58])[CH:52]=2)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: COc1cc(N)ccc1OCCCN(C)C
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(NC(=O)c2cc(C#N)c(Sc3c(Cl)cncc3Cl)s2)ccc1OCCCN(C)C

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (100 mg, 0.3 mmol) from step C of example 203, 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (126 mg, 0.33 mmol) and 4-(3-dimethylaminopropoxy)-3-methoxy-aniline (96 mg, 0.36 mmol) from the above. The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (15.0 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.33 (1H, s), 8.85 (2H, s), 8.24 (1H, s), 7.29 (1H, m), 7.18 (1H, m), 6.94 (1H, m), 3.94 (2H, m), 2.34 (2H, m), 2.14 (6H, s), 1.84 (3H, s), 1.81 (2H, m). MS m/z: 537.17, 539.15 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].O.Cl.CO[CH:18](OC)[CH2:19][CH:20](OC)OC>CO>[N:1]1([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:20]=[CH:19][CH:18]=[N:2]1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c(-n2cccn2)nc2ccccc12
Yield: 70.2 %

Procedure:
A mixture of 35.2 g (0.2 mole) of 2-hydrazino-4(3H)-quinazolinone, 250 ml of water, 30 ml of methanol and 36.6 ml of concentrated hydrochloric acid is stirred with 36.08 g (0.22 mole) of 1,1,3,3-tetramethoxy-propane at 40° C. The desired product precipitates after a short time from the solution initially formed. After a reaction of one hour in total at 40° C., 29.8 g of 2-(1H-pyrazol-1-yl)-4(3H)-quinazolinone (melting point 148°-50°) are isolated.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].S(=O)(=O)(O)O.[CH3:29][S:30][CH2:31][CH2:32]O.[OH-].[Na+]>O1CCOCC1.CN(C)C=O>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]3[NH:5][C@H:4]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:3]([OH:23])[C@H:2]([O:1][CH2:32][CH2:31][S:30][CH3:29])[C:11]=3[CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: CSCCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CSCCO[C@@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, dissolved in 30 ml of dioxane and 5 ml of dimethyl-formamide, is admixed with 0.63 g of concentrated sulfuric acid and 1 g of 2-methylmercaptoethanol. The mixture is stirred at RT for 3 h, poured into ice-water (200 ml), adjusted to pH 8 using 2 N aqueous sodium hydroxide solution and extracted three times with methylene chloride. The solvent is stripped off under reduced pressure and the oily residue that remains is purified on silica gel (mobile phase: diethyl ether). This gives 80 mg of the title compound of m.p. 118-9° C. (diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:26]2[CH2:31][CH2:30][CH:29]([CH:32]([CH3:38])[C:33]([O:35]CC)=[O:34])[CH2:28][CH2:27]2)=[N:4][CH:5]=[C:6]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])=[N:14][N:15]=2)=[O:10])[CH:7]=1.C[Si](C)(C)[O-].[K+].O.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][CH:29]([CH:32]([CH3:38])[C:33]([OH:35])=[O:34])[CH2:30][CH2:31]2)=[N:4][CH:5]=[C:6]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])=[N:14][N:15]=2)=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C)C1CCN(c2ncc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2C)CC1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2nnc(Nc3cc(F)c(F)cc3F)o2)cnc1N1CCC(C(C)C(=O)O)CC1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Ethyl 2-(1-{3-methyl-5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridine-2-yl}piperidin-4-yl)propanoate (Example 692) (70 mg; 0.13 mmol) was dissolved in dry THF (2.0 mL), treated with potassium trimethylsilanolate (167 mg; 1.30 mmol) and placed in a Biotage ‘Initiator’ microwave. The reaction was heated at 90° C. for 35 mins., monitoring by LCMS, as a yellow precipitate formed. The reaction was incomplete (˜9% ester remained). A further portion of potassium trimethylsilanolate (17 mg) was added and the reaction was returned to the microwave for 15 mins. Very little more reaction was seen (ie ˜5% of starting ester remained). The resulting yellow suspension was treated with water (3 mL) and acidified, to about pH 2, with dropwise addition of aq. 1M HCl. With vigorous stirring for ˜15 mins, a white precipitate formed which was filtered, washed with water and dried under vacuum at 60° C. to give the title compound (45 mg; 79% yield).