Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3C)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
In THF-methanol (1:1, 20 ml) was dissolved ethyl 2-(2-methylphenylamino)-6-benzothiazolylacetate (907 mg, 2.78 mmol). To the resulting solution was added 1.0M-NaOH (8.34 ml, 8.34 mmol), followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1.0N HCl. The crystals thus obtained were collected by filtration under reduced pressure, washed with water and dried at 60° C. under reduced pressure, whereby 2-(2-methylphenylamino)-6-benzothiazolylacetic acid (675 mg, 81%) was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 83%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[CH3:16][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:18]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:18][N:17]([CH3:16])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: CN(N)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: C=CCC(O)(CCNN(C)c1ccccc1)c1ccc(F)cc1
Temperature: 63 °C
Yield: 7.6 %

Procedure:
1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (58 mg, 0.25 mmol), 1-methyl-1-phenylhydrazine (500 mg, 4.09 mmol), and tetrabutylammonium iodide (92 mg, 0.25 mmol) were combined and heated in a microwave for 50 min at 63° C. The crude mixture was filtered and purified twice by chromatography on a silica gel cartridge eluted with an EtOAc/hexanes gradient to remove 1-methyl-1-phenylhydrazine. The residue was dissolved in Et2O and washed with 1 M aq HCl. The aqueous layer was treated with 1 M aq NaOH until a pH of 4 was reached, then extracted with Et2O. The organic layer was evaporated and the residue was further purified by preparative HPLC to provide 3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (6 mg). LC-MS Method 1 m/z=315 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:36])[CH:14]([CH3:35])[C:15]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:16])(C)(C)C>ClCCl>[CH3:35][CH:14]([C:15]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:16])[C:13]([OH:36])=[O:12]
Reactant: CC(C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (3 ml) was added to a solution of 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid tert-butyl ester (920 mg, 2.33 mmol) in dichloromethane (3 ml) and the mixture was stirred at r.t. overnight. The mixture was then taken up in more dichloromethane, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=339.3 (M+H+), (580 mg, 73%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](Br)[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH3:15]
Reactant: CCBr
Reactant: O=C(O)CCCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCO
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of 10-hydroxydecanoic acid (0.25 g, 1.33 mmol; 11-hydroxyundecanoic acid for compound 881 and 12-hydroxydodecanoic acid for compound 882), ethyl bromide (0.16 g, 1.46 mmol), and lithium carbonate (0.11 g, 1.46 mmol) in DMF (25 mL) was stirred at 70 C for 6 h. Then the product was extracted with ether (30 mL), and the ether solution was washed with 1 N NaOH aqueous solution (20 mL) and water (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 10-hydroxydecanoic acid ethyl ester (80 mg, 28%). This alcohol was coupled with 4-(3-adamantan-1-yl-ureido)butyric acid 822 by using EDCI/DMAP coupling reagent to give 880 (0.11 g, 60%) as a solid: 1H NMR (CDCl3) 1.24-1.32 (13H, m), 1.62-1.68 (10H, m), 1.80 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C27H46N2O5 [M+H]+ 479.34, found [M+H]+ 479.29; mp 60-61 C. Anal. Calcd for C27H46N2O5: C, 67.75; H, 9.69; N, 5.85. Found: C, 68.33; H, 9.92; N, 5.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:32]1([C:38](=[O:46])[CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][C:38]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[O:46])[CH2:41][CH2:42]3)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1ncccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 1) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H37N6O4Cl2 [(M+H)+] 651.2248, observed 651.2250.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[CH:6][CH:5]=1)#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(#N)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([Cl:16])(=[O:14])=[O:12])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(CS(=O)(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: CC#N
Product: N#Cc1ccc(CS(=O)(=O)Cl)cc1

Procedure:
A suspension of 1.1 g (5.02 mMol) of the sodium salt of 4-cyanobenzenemethanesulphonic acid in 20 ml of acetonitrile was mixed with 1.2 g (5.76 mMol) of phosphorus-(V)-chloride and then refluxed for 24 hours. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. Yield; 0.8 g (74% of theory). The product was used in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2[N:10]=N[CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].COC(=O)C1C=C[C:22]([Cl:25])=NC=1Cl>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[N:10][C:22]([Cl:25])=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Product: CCOC(=O)c1oc2nc(Cl)ccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2,6-dichloronicotinic acid methyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: C(O[CH:5]1[CH2:31][C:30](=[O:32])[CH:29]([CH2:33][CH:34]=[CH2:35])[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][C:50]2([O:62][SiH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:55][CH2:54][CH:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]([O:60][CH3:61])[CH2:51]2)[CH:6]1[CH3:77])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[CH2:33]([CH:29]1[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][C:50]2([O:62][SiH:63]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH2:55][CH2:54][CH:53]([C:56]([CH3:58])([CH3:59])[CH3:57])[CH:52]([O:60][CH3:61])[CH2:51]2)[CH:6]([CH3:77])[CH:5]=[CH:31][C:30]1=[O:32])[CH:34]=[CH2:35]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3(O[SiH](c4ccccc4)c4ccccc4)CCC(C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3(O[SiH](c4ccccc4)c4ccccc4)CCC(C(C)(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 14-acetoxy-17-allyl-12-[2-(4-tertbutyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (43.8 mg) in tetrahydrofuran (1.5 ml) was added potassium carbonate (ca 100 mg) at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with diethyl ether and the resulting solution was washed with a saturated aqueous ammonium chloride, water and an aqueous sodium chloride successively, and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 3:2 v/v) to give 17-allyl-12-[2-(4-tertbutyl-diphenylsilyloxy-3-methoxycyclohexyl)-1methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:25])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.4 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.4 g) and triethylamine (1.0 g) in dichloromethane (40 ml) were added tridecanoyl chloride (2.0 g) and dimethylaminopyridine (0.2 g). The solution was stirred at room temperature for about 20 hours and thereto was added dilute aqueous hydrochloric acid solution. The organic layer was separated by a funnel and distilled to remove the solvent. The residue was washed with n-hexane and dried to obtain the titled compound (about 1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCOC(=O)c1cc2ccc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(F)cc2n1CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A 1.0 g portion of ethyl 6-fluoro-2-indolecarboxylate was dissolved in 50 ml of dimethylformamide, mixed under ice-cooling with a suspension consisting of 0.3 g of 60% sodium hydride and 10 ml of dimethylformamide, stirred at the same temperature for 30 minutes, further mixed with 5.0 g of N-(2-bromoethyl)phthalimide and then stirred for 24 hours while gradually returning to room temperature. After terminating the reaction by adding water, this was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated. The thus obtained residue was applied to a silica gel column chromatography and developed with a hexane-ethyl acetate (9:1) mixed solvent, thereby obtaining 0.74 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)=CCOc1ccc(Br)cc1C

Procedure:
Using essentially the same procedure as Example 5-20, Step 1, 4-bromo-2-methylphenol (1.00 g, 5.35 mmol), cesium carbonate (3.48 g, 10.7 mmol) and 4-bromo-2-methyl-2-butene (0.75 mL, 6.42 mmol) afforded the desired product as a pale-yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:17][C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:50][C:51]([O:58][CH2:59][C:60]#[CH:61])([CH3:57])[C:52]([O:54][CH2:55]I)=[O:53]>C1COCC1>[CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([N:17]([CH2:55][O:54][C:52](=[O:53])[C:51]([CH3:50])([O:58][CH2:59][C:60]#[CH:61])[CH3:57])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: C#CCOC(C)(C)C(=O)OCI
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCOC(C)(C)C(=O)OCN(C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)[C@@H](CC(C)C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a light yellow solution of (S)-4-methoxybenzyl 4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanoate (2.16 g, 4.0 mmol) in THF (15 mL) at −50° C. was added KHMDS solution (1 M in THF, 5.0 mL, 5.0 mmol) dropwise maintaining the internal reaction temperature below −50° C. The mixture was stirred for 10 min and a solution of iodomethyl 2-methyl-2-(prop-2-ynyloxy)propanoate (1.58 g, 5.6 mmol) in THF (5.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with methanol (3 mL) and then diluted with ethyl acetate. The resulting mixture was washed with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (hexanes/ethyl acetate=9:1 to 7:3) to afford compound (major spot, 1.9 g, 68.5% yield) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C@:9]([CH3:29])([C:25]([F:28])([F:27])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F

Procedure:
A solution of [(2R,5R)-5-(2-fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.98 g, 2.25 mmol) in isopropanol-THF 2:1 (24 ml) was hydrogenated over 5% Pd—C for 4 h at 50° C. The catalyst was filtered off over Celite and the filtrate was concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (hexane-EtOAc 1:1): Rf=0.42; HPLC RtH5=0.955 min; ESIMS: 406 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 6.82 (dd, 1H), 6.52 (m, 2H), 4.30 (dd, 1H), 3.97 (dd, 1H), 3.06 (br s, 2H), 1.58 (s, 3H), 1.48 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([NH2:7])=[S:6].C([O:10][C:11](=O)[CH2:12][C:13](=O)[CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>CO>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][C:13]1[N:7]=[C:5]([SH:6])[N:4]=[C:11]([OH:10])[CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)CCCOCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cc(CCCOCc2ccccc2)nc(S)n1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of sodium methoxide (3.48 g) in methanol (40 mL), cooled to 0° C., was added thiourea (3.56 g). The mixture was stirred until it dissolved, then 6-benzyloxy-3-oxo-hexanoic acid ethyl ester (8.52 g in 20 mL methanol) was added slowly. The solution was heated at reflux overnight, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in water (50 mL), acidified to pH 6 with acetic acid, and stirred for 1 h. The precipitate was filtered, washed successively with water (2×20 mL) and isopropanol (2×20 mL), then dried to afford 6-(3-benzyloxy-propyl)-2-mercapto-pyrimidin-4-ol as a white powder (7.94 g). MS m/z 277.1 (M+1), 100%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (10 g, 0.052 mol) in dry DMF (300 mL) cooled to 0-5° C. was added sodium methoxide (5.60 g, 0.1036 mol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (7.5 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[ClH:12].Cl.NC1C=C(CC(N)C)C=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[ClH:12].[NH:1]([C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)[C:25]([CH3:26])=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cc1cccc(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(CC(C)N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
15 gm of 1-(3'-amino-phenyl)-2-amino-propane were dissolved in glacial acetic acid, and ethereal hydrochloric acid was added to the solution. The resulting solution of 1-(3'-amino-phenyl)-2-amino-propane monohydrochloride was admixed with 15 ml of acetic acid anhydride, and the mixture was stirred for 10 minutes at room temperature. Thereafter, the reaction mixture was evaporated in a water aspirator vacuum, whereupon 1-(3'-acetamino-phenyl)-2-amino-propane hydrochloride crystallized out. Recrystallized from ethanol, the product had a melting point of 181°-183° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:29][SH:30]>>[CH3:25][O:26][C:27](=[O:35])[CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:29][S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)C(CS)NC(C)=O
Product: COC(=O)C(CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1)NC(C)=O
Yield: 30.9 %

Procedure:
2-Acetylamino-3-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl)-propionic acid methyl ester (156 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-acetylamino-3-mercapto-propionic acid methyl ester (354 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:18][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C1CCN(c2ncc(Cl)cn2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(5-Chloropyrimidin-2-yl)piperidin-4-one (1.5 g) is dissolved in anhydrous dichloromethane (25 mL) and cyclopropylamine (0.42 g) is added followed by glacial acetic acid (0.80 mL). Sodium triacetoxyborohydride (1.8 g) is then added in one portion under nitrogen and the resulting mixture stirred at r.t. for 17 h. The mixture is diluted with dichloroemthane (25 mL) and extracted with 3 M HCl (75 mL and 50 mL). The combined HCI layers are cooled on ice and 4 M NaOH (100 mL) is added in portions until the mixture is strongly basic (pH ˜14). The mixture is then extracted with dichloroemthane (150 mL and 100 mL) and the combined dichloromethane layers are dried over Na2SO4, filtered and concentrated to yield the title compound. LC (method 21): tR=2.57 min; Mass spectrum (APCI): m/z=253 [M+H]+.