Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
275 mg (1.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 289 mg (1.00 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.00 mmol) DIPEA were stirred overnight in 10 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH:16]1[CH2:21][CH2:20]OCC1.O.[Cl-].[Na+].O>C1COCC1>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:21]3[CH:20]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 127.4 %

Procedure:
4-Fluoro-3-nitroaniline (1, 1 g, 1 equiv.) and morpholine (1.67 g, 3 equiv.) were dissolved in THF (10 mL). The reaction mixture was heated at reflux overnight. After cooling, water/brine (10 mL) was added, the mixture was agitated, and the layers were separated. The organic phase was dried over sodium sulfate, and the solvent was removed via rotary evaporation. The material was purified by flash chromatography using 0-40% gradient of heptane/EtOAc to give 800 mg of 3 as an orange-red solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COc1cc(Cn2c(Oc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 64.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (275 mg, yield: 64.8%).
Reaction SMILES: BrC[CH2:3][C:4]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)OCCO1.[C:17](=O)([O-:19])[O-:18].[Ca+2].C(N)=O>O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH3:3])[C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(CCBr)OCCO2)cc1
Agent: [Ca+2]
Solvent: NC=O
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of 2-(bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (2.87 g; 10 mmol), calcium carbonate (1.2 g; 12 mmol), formamide (44 ml) and water (4 ml) is heated at 120° C., under stirring, for 6 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.67 g; 8.3 mmol; yield 83%), m.p. 55°-57° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)=O.[CH3:13][NH:14][CH3:15].C([BH3-])#N.[Na+].O>CO>[CH3:13][N:14]([CH2:1][C:3]1[CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][CH:7]=1)[CH3:15]
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cc(CN(C)C)c[nH]1
Temperature: 20 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a mixture of ethyl 4-formylpyrrole-2-carboxylate (8.8 g, 52.7 mmol) and dimethylamine (2 M in THF, 40 mL, 1.5 equiv) in methanol (60 mL) was added sodium cyanoborohydride (3.3 g, 1 equiv) in portions and the mixture was stirred for 3 h at 20° C. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and dried over Na2SO4. Evaporation of solvent afforded a crude, which was purified by column chromatography on silica gel, eluted with MeOH-DCM (1:9) to afford ethyl 4-dimethylaminomethyl-pyrrole-2-carboxylate as a solid (7.8 g, 76%). MS (ES): 392 (MH+) 197.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][S:7]([C:10]1[N:14]=[CH:13][NH:12][N:11]=1)(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29].O>C(#N)C>[CH3:26][N:27]([CH3:32])[S:28]([N:12]1[CH:13]=[N:14][C:10]([S:7]([O:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=2)(=[O:8])=[O:9])=[N:11]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Oc1cccc(C(F)(F)F)c1)c1nc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)n1
Yield: 97.4 %

Procedure:
1.0 g of 3-(3-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 1 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate was added, and 0.59 g of dimethylsulfamoylchloride was gradually added at room temperature while stirring them. Then, they were refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.33 g of the titled compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[C:11]([NH:13][C:14](=[N:17]CCSCC1N=CNC=1)SC)#[N:12]>C(O)C>[C:11]([NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[NH:17])#[N:12]
Reactant: CSC(=NCCSCc1c[nH]cn1)NC#N
Reactant: NCCSCc1c[nH]cn1
Solvent: CCO
Product: N#CNC(=N)NCCSCc1c[nH]cn1

Procedure:
4-((2-Aminoethyl)thiomethyl)imidazole is reacted with dimethyl-N-cyanoimidodithiocarbonate according to the procedure of Example 3(c)(i) and the resultant N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-S-methylisothiourea treated with ammonical ethanol according to the procedure of Example 5 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cnc(N2CCOCC2)cc1N
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a stirred solution of 27.5 g (132 mmol) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine in 400 ml acetone was added dropwise 19.5 ml (145 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 90 min before being cooled to room temperature and poured onto 400 ml hexane and stirred for 5 min. The resulting crystals were collected by filtration, washed with hexane and dried to afford 32.5 g (66%) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as a brown crystalline solid. ES-MS m/e (%): 373 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:54][S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([C:4]2[N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[S:55][CH3:54])[N:3]=2)[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[CH:45]=1)[CH3:48]
Reactant: CSc1ccccc1B(O)O
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3SC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C

Procedure:
A suspension of 66.3 (48 mg, 0.06 mmol), 2-(methylthio)phenylboronic acid (12.5 mg, 0.2 mmol), Na2CO3 (28 mg, 0.24 mmol) in 3:1 DME/H2O (2 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 5 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The crude product of Intermediate 93.1 used as is for the next step. LCMS (4 min gradient) RT=4.87 min, 816.3 (M+H).
Reaction SMILES: [Na].Br.Br[CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>C(O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:4][CH2:5][NH2:6])=[CH:10][CH:9]=1
Reactant: NCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: Br
Agent: [Na]
Solvent: CCO
Product: NCCSc1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
A solution of sodium metal (22.5 mg, 0.98 mmol) in ethanol (2.0 mL) was treated with 2-bromoethylamine hydrobromide (100.0 mg, 0.49 mmol) and 4-chlorobenzenethiol (71.0 mg, 0.49 mmol), heated to 75° C. for 18 hours, and concentrated. The concentrate was partitioned between water (2.0 mL) and diethyl ether (5.0 mL) and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 188 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]2[CH:14]=[CH:15][N:16]=[C:10]2[CH:9]=1.[F:17][C:18]([F:29])([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O.C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[F:17][C:18]([F:29])([F:28])[CH2:19][N:5]1[N:4]=[N:3][C:7]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[N:6]1
Reactant: c1cn2ccc(-c3nn[nH]n3)cc2n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1nnc(-c2ccn3ccnc3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
Sodium hydride (60 mg, 1.5 mmol) was added to a stirred suspension of 7-(2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (250 mg, 1.3 mmol) in dry DMF (4 ml) under a nitrogen atmosphere. After 1 h, Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (1.16 g, 5 mmol) was added, followed by 18-crown-6 (260 mg, Immol). The reaction mixture was stirred at room temperature for 18 h then quenched with water and extracted with EtOAc (×2). The combined organic extracts were washed with brine (×1), dried (Na2SO4), filtered and the solvent removed in vacuo. Purification via silica column chromatography (0-2% 2M NH3MeOH/CH2Cl2) afforded the product (138 mg). MS: [M+H]+ 269.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 529.1.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH:23]1([C:12]2[CH:13]=[C:14]3[C:15](=[CH:20][C:11]=2[CH2:10][C:9]2[CH:26]=[CH:27][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=2)[C:16](=[O:17])[N:29]([C@@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[OH:35])[CH2:21]3)[CH2:24][CH2:25]1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(C3CC3)cc2CN1[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate (0.11 g), trans-2-aminocyclopentanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.07 g) in THF (2.20 mL) was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.20 mL) and THF (2.20 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.06 g).
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.[CH3:12][CH:13]([OH:15])[CH3:14].O>N1C=CC=CC=1>[CH:13]([O:15][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:14])[CH3:12]
Reactant: CC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 4-methyl-benzenesulfonyl chloride (3.8 g) was added to a solution of 2-propanol (6.12 ml) in pyridine (6.6 ml). The reaction mixture was stirred at 0° C. for 2 h and then at 20° C. for 16 h. The reaction mixture was poured into water (150 ml) and extracted with dichloromethane. The combined organic phases were washed with 3M aqueous HCl and sat. NaHCO3. After drying (MgSO4) and concentrating in vacuo, the title product was obtained as a pale yellow oil. Yield: 2.89 g. MS-ESI: [M+H]+=215.
Reaction SMILES: [CH2:1](N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:30])([OH:29])[OH:28])C)=[O:23])[CH3:21])=O)C1C=CC=CC=1>CO>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([P:27](=[O:28])([OH:30])[OH:29])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])[CH3:21]
Reactant: NCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)P(=O)(O)O

Procedure:
In a manner analogous to that given in Example 1 (b) but with ion-exchange in methanol, from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-alanylamino)-2-phenylethylphosphonic acid of melting point 250°-260° C (decomposition); [α]D20 = -40.3° (c = 0.21% in water).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2]
Reactant: [H][H]
Reactant: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCN1c2ncc(/C=C\c3ccccc3)cc2C(=O)N(C)c2cccnc21
Yield: 16.5 %

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-8-phenylethynyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.12 g, 0.34 mmol) was hydrogenated over Lindlar catalyst in ethanol under 50 p.s.i. of hydrogen. Workup and purification as described in Example 42 afforded 20 mg of the title compound as a yellow-orange oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:25]([S:28][CH2:29][CH2:30][C:31](Cl)=[O:32])(=[O:27])[CH3:26]>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[N:15]([C:31](=[O:32])[CH2:30][CH2:29][S:28][C:25](=[O:27])[CH3:26])[C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CC(=O)Oc1ccccc1C1N[C@H](C(=O)O)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C1SC[C@@H](C(=O)O)N1C(=O)CCSC(C)=O
Temperature: 25 °C

Procedure:
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 1.8 g of S-acetyl-3-mercaptopropanoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 2.8 g (70%), mp. 144°-145° C. (ethyl acetate-benzene), [α]D27 +109.0° (c=1.0, methanol).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 3-(trifluoromethyl)aniline. Title compound: ES-MS: 411.1 [M+H]+; tR=4.19 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [CH3:1][C@H:2](CC1CCCCC1)[C:3](Cl)=[O:4].[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)[CH3:15].C(Cl)(=O)CC.C([O-])(O)=O.[Na+]>C1COCC1.CCCCCC>[CH3:13][CH:14]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:3](=[O:4])[CH2:2][CH3:1])[CH3:15]
Reactant: C[C@H](CC1CCCCC1)C(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
α(R)-Methylcyclohexanepropionic acid chloride: Under argon, a 1.6M hexane solution of burylithium (100 mL, 160 mmol) was added to a cooled solution (-30° to -40°) of 4(S)-(1-methylethyl)-2-oxazolidinone (20.7 g, 160 mmol), see L. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989), in dry THF (200 mL). After 15 min, the mixture was cooled to -78° and propionyl chloride (14.2 mL, 163 mmol) was added. After 5 min at -78°, the reaction mixture was allowed to warm to 0°. The mixture then was treated with a saturated aqueous solution of NaHCO3 (500 mL). The resultant mixture was extracted with EtOAc (2 X). The combined organic extracts were dried (MgSO4) and concentrated to afford a yellow liquid. This material was purified by flash chromatography [SiO2, eluent: EtOAc-hexane (1:10 to 1:4)] to provide (4S)-(1-methylethyl)-3-(1-oxopropyl)-2-oxazolidinone as a clear liquid (10.9 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 4.46-4.41 (m, 1H), 4.29-4.19 (m, 2H), 3.03-2.86 (m, 2H), 2.43-2.33 (m, 1H), 1.17 (t, J=7.3 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=2)[N:26]=1
Reactant: OCC(O)Cc1nccn1CCCc1cccc(O)c1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)c1
Yield: 60.4 %

Procedure:
Using 3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (203 mg), 65% oily sodium hydride (29 mg) and 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (197 mg), the same reaction as Example 2 was carried out to yield the titled compound (220 mg).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([NH2:29])[CH3:28]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][NH:29][CH2:27][CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CCN
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CNCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and ethylamine, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.06 (m, 4 H), 3.18 (m, 4 H), 2.32 (q, J=7.4 Hz, 2 H), 2.15 (t, J=5.2 Hz, 2 H), 1.13 (m, 18 H), 0.839 (t, J=7.4 Hz, 3 H), 0.698 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50° C. Rf=0.1 (20% ether/CH2Cl2).