Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([NH:20][C:21](=[O:32])[NH:22][C:23]1[CH:24]=[C:25]([C:29]([OH:31])=O)[S:26][C:27]=1[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:29]([C:25]1[S:26][C:27]([CH3:28])=[C:23]([NH:22][C:21]([NH:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:32])[CH:24]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc(C(=O)O)cc1NC(=O)NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccccc2)cc1NC(=O)NCc1ccccc1
Yield: 96.6 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.24 g, 1.7 mmol), 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid from Step 3 (0.27 g, 0.9 mmol), and benzyl amine (0.1 g, 0.9 mmol) to afford 0.33 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid benzylamide. A sample of the crude product was stirred in 2 M aqueous KHCO3 for several hours, filtered off, rinsed with water, dried, and recrystallized from methanol to give product with a mp 180-181° C.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:17]1([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[NH:9][C:8]([N:20]1[CH2:21][CH2:22][N:17]([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][CH2:19]1)=[O:16]
Reactant: O=C(Nc1ncccn1)Oc1ccccc1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Product: O=C(Nc1ncccn1)N1CCN(Cc2cnc3ccccc3c2)CC1

Procedure:
The title compound was prepared from pyrimidin-2-yl-carbamic acid phenyl ester and 3-piperazin-1-ylmethyl-quinoline in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.72 (s, 1H), 8.10-8.02 (m, 1H), 8.43-8.41 (m, 2H), 7.69-7.66 (m, 2H), 7.50-7.40 (m, 2H), 6.82-7.70 (m, 1H), 3.81 (s, 2H), 3.42-3.38 (m, 4H), 2.41-2.36 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cl:19]Cl.Cl.N#N>O>[CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([Cl:19])[CH:6]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: ClCl
Agent: Cl
Agent: N#N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1Cl
Temperature: 20 °C
Yield: 57.3 %

Procedure:
99.1 g (0.5 mol) of isopropyl 4-methylphenyl sulfone in 180 g of 96% strength sulfuric acid are introduced into a 500 ml glass flask equipped with stirrer, condenser, gas inlet, thermometer and dropping funnel. At 70° C., about 140 g of chlorine are metered in over the course of 6 hours with vigorous stirring. After the reaction is completed, residual hydrogen chloride is eliminated by passing a N2 stream through the flask, 300 g of water are added dropwise and the mixture is allowed to cool to 20° C. in the course of 2 hours with stirring. The mixture is extracted four times each with 200 g of methylene chloride, the combined extracts are washed to neutrality using 5% strength NaHCO3 solution, dried with Na2SO4 and concentrated on a rotary evaporator. 66.7 g of 3-chloro-4-methylphenyl isopropyl sulfone are obtained (yellowish oil, content 94.3% by weight, corresponding to a yield of 54.1%, 1H-NMR (CDCl3): 7.3-7.9 (m, 3H); 3.23 (sp, 6.8 Hz, lH); 2.47 (s); 1.42 d, 6.8 Hz, 6H).
Reaction SMILES: C(O)C.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][C:14]#N)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[CH2:28](I)[CH:29](C)[CH3:30]>O>[CH2:14]([S:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2)[CH:29]([CH3:30])[CH3:28]
Reactant: CC(C)CI
Reactant: N#CSc1ccc2c(c1)CCN2
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: CC(C)CSc1ccc2c(c1)CCN2
Temperature: 50 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
An ethanol (14 mL) solution of indolin-5-yl thiocyanate (compound described in the document J. Med. Chem., 1998, vol. 41, p. 1598; 1.33 g, 7.55 mmol) was added to a solution of sodium sulfide nonahydrate (1.84 g, 7.66 mmol) in water (2.8 mL), and the mixture was stirred at 50° C. for 2 hours. To the reaction solution, an ethanol (2.4 mL) solution of isobutyl iodide (1.2 mL, 10.4 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. To the reaction solution, water was added, followed by extraction with ether three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-80:20-55:45, V/V) to obtain the title compound as brown oil (0.65 g, yield: 41%).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:22])[CH:11]=2)[N:6]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CO>[CH3:22][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([S:4][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]2=[O:21]
Reactant: Cc1ccc2nc(S)n(-c3ccccc3)c(=O)c2c1
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(SCc3ccccn3)n(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
9.5 ml Of 28% methanolic solution of sodium methoxide were added to a solution of 6.0 g of 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethylpyridine hydrochloride in methanol, the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. Crystals precipitated were collected by filtration and recrystallized from ethyl acetate to give 4.2 g (52.2%) of the title compound.
Reaction SMILES: [CH3:1][SiH:2]([CH3:7])[O:3][SiH:4]([CH3:6])[CH3:5].[CH:8]([Si:10]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:12])=[CH2:9]>>[CH3:12][O:11][Si:10]([O:15][CH3:16])([O:13][CH3:14])[CH:8]([Si:2]([CH3:7])([CH3:1])[O:3][SiH:4]([CH3:6])[CH3:5])[CH3:9]
Reactant: C=C[Si](OC)(OC)OC
Reactant: C[SiH](C)O[SiH](C)C
Product: CO[Si](OC)(OC)C(C)[Si](C)(C)O[SiH](C)C
Temperature: 65 °C
Yield: 93 %

Procedure:
A four-necked flask equipped with a reflux condenser, stirrer, addition funnel and thermometer was thoroughly purged with nitrogen. In the nitrogen blanket, the flask was charged with 134.3 g (1 mol) of 1,1,3,3-tetramethyldisiloxane and 0.026 g (0.1 mmol) of RhCl3.3H2O to form a mixture. The mixture was heated to 60-70° C. and maintained at the temperature. With stirring, 148.2 g (1 mol, equimolar to 1,1,3,3-tetramethyldisiloxane) of vinyltrimethoxysilane was added dropwise to the mixture from the addition funnel over 6 to 7 hours. After the completion of dropwise addition, the reaction mixture was maintained at 60-70° C. and aged for 1 to 2 hours, driving the reaction to completion. On vacuum distillation, a product having a boiling point of 92-95° C. at 1.3 kPa was collected. The 1-(trimethoxysilyl)ethyl-1,1,3,3-tetramethyldisiloxane product was obtained in a yield of 93%. On gas chromatography analysis, the product was identified to be a mixture of two isomers, alpha-adduct:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:13]1[CH2:18][CH:17]=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[CH2:23][C@H:24]4[C@@H:29]([C:30]=3[CH:31]=2)[CH2:28][CH2:27][CH2:26][NH:25]4)[CH2:15][CH2:14]1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:29]4[C:30]5[CH:31]=[C:19]([C:16]6[CH2:17][CH2:18][O:13][CH2:14][CH:15]=6)[CH:20]=[CH:21][C:22]=5[CH2:23][C@H:24]34)=[O:12])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: C1=C(c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)CCOC1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2nc[nH]c2c1)N1CCC[C@@H]2c3cc(C4=CCOCC4)ccc3C[C@@H]21
Yield: 69 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 1): tR=2.65 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[H-].[Na+].[NH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=1>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([NH:25][C:26]2[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: NC1=CC(=O)CC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reaction time: 21 h

Procedure:
2.41 g of the epoxide of example 1 were solved in 36 ml of dimethylsulfoxide under a protective gas, and 360 mg of sodium hydrid were added. To this stirred suspension was added 1.71 g of 3-amino-cyclopent-2-en-1-one (Chem. Ber. 103, 2403 [1970]) in portions. After 21 hours, the reaction solution was worked up in an aqueous manner and extracted with ethyl acetate. The usual further processing and recrystallisation of the product obtained from ethyl acetate yielded white crystals having a m.p. of 174°-176° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:22])[C:20]=3[CH3:21])=[N:11][C:10]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[NH:30]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45].[NH2:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:23][C:10]1[N:11]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:22])[C:20]=2[CH3:21])[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4C)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2nc(N[C@@H]3CCCC[C@@H]3N)nc3c2C(=O)NC3)cnn1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (1S,2R)-2-(6-(2,4-dimethoxybenzyl)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)cyclohexylcarbamate obtained above in TFA (2 mL) was stirred at 70° C. for 2 h. The mixture was subsequently purified by reverse phase preparative HPLC. The fractions were collected and concentrated to give a TFA salt of the title compound as a white solid (0.5 mg). 1H NMR (500 MHz, CD3OD) δ ppm 1.59 (br s, 2 H), 1.67-2.02 (m, 6 H), 2.66-2.72 (m, 3 H), 3.67 (br s, 1 H), 3.85 (s, 3 H), 4.29 (s, 2 H), 4.50-4.64 (m, 1 H), 8.64 (br s, 1 H). [M+H] calc'd for C17H23N7O, 342; found, 342.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.CCCCCC.C([Al]CC(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1>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.[Cl-].[Zn+2].[Cl-].O.O1CCCC1>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](/[C:8](/[Si:9]([CH3:10])([CH3:12])[CH3:11])=[CH:7]/[C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:32][CH:31]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)s1
Reactant: COc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[Al]CC(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(/C(=C/c2ccc(C)s2)[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
In a nitrogen atmosphere, (5-methyl-2-thienylethynyl)trimethylsilane (1.0 g, 5.2 mmol) was added to a hexane solution (1.0 mol/L) containing diisobutylaluminum (6.0 ml, 6.0 mmol), followed by stirring at room temperature for 24 hours. The mixture was added to a tetrahydrofuran solution, which contained Pd(PPh3)4 (0.3 g, 0.26 mmol), zinc chloride (1.0 g, 7.3 mmol), and p-methoxyiodobenzene (1.7 g, 7.3 mmol), and which had independently been prepared in another container, followed by stirring in an nitrogen atmosphere at 65° C. for 24 hours. The solution obtained was cooled to room temperature, and water was then added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated sodium chloride solution and then dried with magnesium sulfate, followed by filtration. The filtrate was concentrated using a rotary evaporator. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1). Thus, (Z)-(1-(4-methoxyphenyl)-2-(5-methyl-2-thienyl)-ethenyl)trimethylsilane (1.0 g, 3.44 mmol) was obtained in a yield of 66%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCCc1c(OC)ccc(C(=O)OC)c1OCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OC)ccc(C(=O)O)c1OCOC
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
The methyl 2-methoxymethoxy-3-n-propyl-4-methoxybenzoate (31.9 g) was dissolved in methanol (280 ml), and 10% aqueous solution of sodium hydroxide (70 ml) was added thereto. The mixture was agitated at 60° C. for 4 hours and then at room temperature for another 80 hours. The reaction mixture was concentrated to about one third of the original volume in evacuated atomosphere, cooled to 0° C., acidified by adding 2N aqueous hydrochloric acid thereto, and then extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere to produce 2-methoxymethoxy-3-n-propyl-4-methoxybenzoic acid (28.8 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:47][C:48]1[N:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([NH:55][CH2:54][C:51]3[CH:50]=[N:49][C:48]([CH3:47])=[N:53][CH:52]=3)=[O:23])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:3]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Reactant: Cc1ncc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylic acid (350 mg, 1.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (430 mg, 2.2 mmol), 1-hydroxybenzotriazole hydrate (170 mg, 1.1 mmol), CH2Cl2 (50 mL) were added (2-methylpyrimidin-5-yl)methanamine (210 mg, 1.7 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.2 mmol). The mixture was stirred at room temperature for 4 h, and then washed with water and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 20-60% MeCN/water[10 mM Et2NH]) to yield a white solid.
Reaction SMILES: C([O:8][C:9](=[O:17])[NH:10][CH2:11][CH2:12][C:13](O)([CH3:15])[CH3:14])C1C=CC=CC=1.[H-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][C:13]1([CH3:14])[O:17][C:9](=[O:8])[NH:10][CH2:11][CH2:12]1
Reactant: CC(C)(O)CCNC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCNC(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
(11.6 g, 48.9 mmol) (3-Hydroxy-3-methyl-butyl)-carbamic acid benzyl ester (Example 72, step 1) was dissolved in THF (250 ml) and sodium hydride (60%, 5.2 g, 108 mmol, 2.2 equiv.) was added in portions. The mixture was stirred for 3 hours at room temperature. 5 ml saturated NaHCO3 solution was added carefully and the mixture was evaporated with isolute to dryness. The crude product was purified by flash chromatography by directly loading the residue onto a silica gel column and eluting with an ethyl acetate:methanol gradient 100:0 to 90:10. The desired 6,6-dimethyl-[1,3]oxazinan-2-one (3.2 g, 51% yield) was obtained as a yellow solid, MS: m/e=130.1 (M+H+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].Cl>C(OCC)(=O)C>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reaction time: 1.5 h

Procedure:
3 g of the tripeptide derivative obtained under (7) are mixed with 60 ml of 0.4 N HCl in ethyl acetate and the reaction mixture is left for 90 minutes at 25° C. It is then evaporated to dryness and the residue (H-Met-Leu-Gly-OMe hydrochloride) is dried for 24 hours over sodium hydroxide at 0.01 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([O:22][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 5 °C
Yield: 78.9 %

Procedure:
4-Methyl-benzenesulfonyl chloride (5.51 g; 29 mmol; 1.0 eq.) was added portionwise to a solution of 1,4-Dioxa-spiro[4.5]decan-8-ol (4.44 g; 28 mmol; 1.0 eq.) in anhydrous Pyridine (13.5 mL) maintained at 5° C. with an ice bath. The reaction mixture was then allowed to warm to RT and stirred O/N. It was then quenched by addition of water and diluted with EtOAc. Organic phase was washed with a 1N HCl solution, saturated NaHCO3 solution and brine. It was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6.9 g of a pale yellow oil. Purification by flash chromatography on silica (heptane/EtOAc 60:40) afforded the title compound as a white powder (4.7 g, 52%). HPLC (Condition A): Rt 4.04 min (purity 100%). MS (ESI+): 330.3
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5].[C:28]([OH:32])(=[O:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[C:28]([O:32][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5])(=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)O
Reactant: CCCC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A suspension of (134) (5.8 g, 14.7 mmol), propionic acid (1.64 mL, 22.0 mmol) and Ag2CO3 (6.07 g, 22.0 mmol) in chloroform (80 mL) was stirred at room temperature. The reaction was judged complete by TLC after 5 hours. The reaction mixture was then filtered through a pad of Celite, the filtrate washed with brine and dried over Na2SO4. Filtration and evaporation gave a crude product, which was purified by flash chromatography on silica gel, eluting with 15% ethyl acetate in hexane, to afford 2.5 g of title compound (135). (CDCl3, 400 MHz): δ 0.95 (t, J=7.4 Hz, 3H), 1.12 (t, J=7.4 Hz. 3H), 1.54-1.37 (in, 12H), 1.72 (m, 2H), 2.33 (m, 4H), 3.16 (dd, J=6.8, 4.4 Hz), 5.10 (s, 2H), 5.33 (t, J=6.8, 1H), 6.72 (t, J=5.8 Hz), 7.33 (m, 5H).
Reaction SMILES: C(O[CH:7]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O1C=CC(CO)=C1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:16][C:13]2[CH:15]=[CH:7][O:11][CH:12]=2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: OCc1ccoc1
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1ccoc1
Temperature: 90 °C

Procedure:
N,N-Dimethylformamide dineopentyl acetal (1.8 ml) was added to a stirred mixture of 5-chloropyrimidin-2-one (522 mg) and 3-furanmethanol (0.48 ml) in dry N,N-dimethylformamide (10 ml) under nitrogen and the mixture was then heated at 90° C. After 11/4 h the reaction mixture was evaporated to dryness and then the residue was dissolved in ethyl acetate (200 ml) and the solution washed with water (3×50 ml), dried (MgSO4) and concentrated to ca 15 ml by which time crystallisation had occurred. The suspension was cooled and then the crystals collected and recrystallised from ethyl acetate to give white crystals of the title pyrimidinone (288 mg), m.p. 161.5°-162° C., λmax (EtOH) 333 nm (ε 2,340), λinf 245 nm (ε 4,000).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=1[NH2:12])=[O:4].ClS([N:17]=[C:18]=[O:19])(=O)=O.Cl.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:11][S:10][C:8]1[S:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([NH:12][C:18]([NH2:17])=[O:19])[N:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1sc(SC)nc1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1sc(SC)nc1NC(N)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In 150 mL methylene chloride, 4-amino-2-methylthio-5-thiazolcarboxylic acid methyl ester (0.05 mol) was dissolved and cooled to −78° C. under nitrogen gas. Stirring, 0.07 mol (1.4 eq) of chlorosulfonyl isocyanate was added slowly to give a brown solution. The reaction was warmed slowly to 0° C. and a white precipitate forms. After 30 minutes, the solution was evaporated under vacuum, resuspended in 40 mL of 6N hydrochloric acid (4 eq) and heated to 100° C. After 30 minutes, the solution was cooled to room temp, neutralized with saturated sodium carbonate followed by saturated sodium bicarbonate. The white solid was isolated by filtration to give methyl 2-(methylthio)-4-ureidothiazole-5-carboxylate 76.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][NH:21][C:22](=O)[CH3:23])=O)=[CH:16][CH:15]=1>ClC1C=CC=CC=1Cl>[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:22]([CH3:23])=[N:21][N:20]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)NNC(C)=O)cc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nnc(C)n2-c2ccccc2)cc1

Procedure:
Using the procedure of Step B in Example 1, 26.3 ml of aniline, 150 ml of o-dichlorobenzene, 4.65 ml of phosphorus trichloride and 10 g of N-(4-methoxybenzoyl)-N'-acetyl-hydrazine [prepared by process of J. Org., Vol. 19 (1954), p. 194-201] were reacted to obtain 7.1 g of 3-(4-methoxyphenyl)-4-phenyl-5-methyl-4H-1,2,4-triazole melting at 140°-141° C.