Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[C:24]([CH3:34])[CH:23]=1)[CH3:19]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(C)c1
Temperature: 105 °C
Yield: 62.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)—N-ethyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.286 mmol, 62.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H) 2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65 (m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz, 1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22]>C(O)C>[CH3:21][C:17]1[CH:18]=[CH:19][C:20]([NH:12][C:5]2[C:4]([Cl:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=2[F:11])=[C:15]([CH2:14][C:13]([OH:22])=[O:1])[CH:16]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)cc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Nc2c(F)cc(F)cc2Cl)c(CC(=O)O)c1

Procedure:
To a degassed solution of 1500 ml of absolute ethanol and 510 ml of 2N NaOH (1.02 mol) is added 150 g (0.51 mol) of N-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole. The resultant mixture is degassed and heated to 60-65° for 2 hours. Most of the ethanol is removed under reduced pressure and then 4500 ml of water is added to the residue which is then washed three times with 1500 ml of toluene. The aqueous layer is cooled to 0° and adjusted to pH 6 using 1.2 N HCl. The solid is filtered off and washed with 100 ml of water and dried. Recrystallization from ethyl acetate and heptane gives 5-methy-2-(2′,4′-difluoro-6-chloroanilino)phenylacetic acid of Example 1(g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:40][S:41](O)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:13]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3cc(OS(C)(=O)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 60 °C

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (105.7 mg, 0.23 mmol) in a vial. Add ethyl acetate (2 mL) and methanesulfonic acid (18 μL). Warm the resulting mixture to ˜60° C. with stirring. Add tetrahydrofuran (1 mL) to the resulting burnt orange solution with some dark brown gum on the bottom of the vial. Sonicate the resulting solution for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Carefully collect the resulting solids by vacuum filtration and wash the resulting cake with pentane (2×2 mL). Dry the resulting solids in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=161.90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24].C(OCC)(=O)C>ClCCl.CCCCCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH2:14][O:15][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2cc(Cl)ccc2Cl)CCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2cc(Cl)ccc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a stirred solution of [1-(2,5-dichlorophenyl)-cyclopentyl]-methanol (200) (23 g, 95.04 mmol) in dry dichloromethane (250 mL) was added dry triethylamine (26.42 mL, 190.083 mmol) slowly, then mesyl chloride (8.785 mL, 114.05 mmol) was added and the mixture was stirred for 16 h at room temperature. Silica thin layer chromatography was performed (10% ethyl acetate in hexane, Rf=0.5) After completion of the reaction, the mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was washed with brine, and dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified using normal silica gel (100-200 mesh) column chromatography using a gradient eluent of 2 to 10% ethyl acetate in hexane to get pure methanesulfonic acid 1-(2,5-dichlorophenyl)-cyclopentylmethyl ester (201) (24 g, 78.12%) as a white solid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[CH2:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCCCCCCCNC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.3 %

Procedure:
N-octyl-N′-phenylurea (10 g, 215 mmol) was dissolved in chlorosulfonic acid 925 g and stirred for 14 hours at ambient temperature. The reaction was poured into ice and extracted with ethyl acetate. The organic layer was washed with cold, dilute aqueous sodium bicarbonate, then dried (Na2SO4). The solvent was evaporated in vacuo to give the product as a white solid (11.46 g, 33 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20]O)[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20][Br:41])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C=CCO)cc1-c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-(3-hydroxyprop-1-en-1-yl)benzoate (17 g), triphenylphosphine (22.8 g; 87 mmol) and tetrabromomethane (28.8 g; 87 mmol) in dichloromethane (200 ml) was stirred at 0° C. for 1 hour. After filtration of the insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethanelpetroleum ether (30/70) to give methyl 2-(4-fluorophenyl)-4-(3-bromoprop-1-en-1-yl)benzoate as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][P:13](=[O:17])([OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1.[Br:20][O-].[Na+]>>[CH3:1][C:2]1[C:15]2[O:14][P:13](=[O:16])([OH:17])[C:12]3[C:7](=[CH:8][C:9]([Br:20])=[C:10]([CH3:18])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: [O-]Br
Reactant: Cc1cc(C)c2c(c1)-c1ccc(C)cc1P(=O)(O)O2
Agent: [Na+]
Product: Cc1cc(C)c2c(c1)-c1cc(Br)c(C)cc1P(=O)(O)O2

Procedure:
9,10-Dihydro-1,3,7-trimethyl-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide (268 g) is treated with an aqueous solution of sodium hypobromite at 60° C. in the same manner as in Example 6, to give about 250 g of 9,10-dihydro-1,3,7-trimethyl-6-bromo-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide, exhibiting a phosphorus content of 8.7% (theoretical value: 8.77%), an acid value of 160 (theoretical value: 158,9) and a melting point of 260° C. or higher, which will be hereinafter referred to as CA-M1,3,7-B6.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:24][O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1>>[CH3:24][O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1ccc(Br)c(CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(OC)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-methoxy-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].CN(C)C=O.[H-].[Na+].Br[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH3:22])[N:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=O)[nH]n1
Reactant: CC(Br)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=O)nn1C(C)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a mixture of 5-formylpyrazole-3-carboxylic acid ethyl ester (5.42 g) and anhydrous dimethyl formamide (80 ml), 1.41 g of 60% sodium hydride oil suspension were added at 0° C. After 30 minutes, 6.30 g of 2-(1-bromoethyl)pyridine were added at 0° C. The mixture was stirred overnight at room temperature and 120 ml of water was added thereto. The mixture was extracted with ethyl acetate (3×300 ml). The combined organic solution was dried over sodium sulfate and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 2/1) to afford 4.0 g of 3-formyl-1-(1-(2-pyridinyl)ethyl)pyrazole-5-carboxylic acid ethyl ester as a viscous oil. NMR: 1.33 (t, 3H), 2.01 (d, 3H), 4.29 (m, 2H), 6.73 (q, 1H), 7.40 (s, 1H, 4-pyrazolyl H) 7.06, 7.19, 7.63, 8.57 (4 m, 4H, pyridyl H's), 10.04 (s, 1H, CHO). Also obtained was 535 mg of 5-formyl-1-(1-(2-pyridyl)ethyl)pyrazole-3-carboxylic acid ethyl ester as a viscous oil. NMR: 1.41 (t, 3H), 2.05 (d, 3H), 4.42 (q, 2H), 5.51 (q, 1H), 7.46 (s, 1H, 4-pyrazolyl H), 7.07, 7.17, 7.61, 8.54 (4 m, 4H, pyridyl H's), 9.88 (s, 1H, CHO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:28]([O:30][C:31](=[O:43])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:38][CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 200 mg (0.512 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 5 ml tetrahydrofuran were added 126 mg (0.563 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN 42806-90-6) and 124 mg (0.614 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. 106 mg (0.614 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the title compound as colorless solid (74%). MS (Turbo Spray): m/z=597.2 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][CH2:2][P:15](=[O:20])([O:18][CH3:19])[O:16][CH3:17]
Reactant: COP(OC)OC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: COP(=O)(CCN1C(=O)c2ccccc2C1=O)OC
Yield: 61.2 %

Procedure:
A mixture of 2-(2-bromoethyl)isoindoline-1,3-dione (7.62 g, 30 mmol) and trimethyl phosphite (100 g) was refluxed under N2 atmosphere for 10 hours. Concentration and purification through column chromatography on silica gel (100% EtOAc) gave the desired product as a white solid (5.2 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:15](=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[N:17]3)[N:14]=[C:13]([CH:25]=O)[CH:12]=1)(C)(C)C.Cl.[NH2:29][OH:30].[OH-].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl.O>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:15](=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[N:17]3)[N:14]=[C:13]([CH:25]=[N:29][OH:30])[CH:12]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C=O)nc2c1ccc1cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc(C=NO)nc2c1ccc1cccnc12
Temperature: 25 °C

Procedure:
A solution of [2-(2-formyl-[1,10]phenanthrolin-4-yloxy)-ethyl]carbamic acid tert-butyl ester (0.52 g, 1.4 mmol) was stirred for 1 hour at room temperature in a mixture of trifluoroacetic acid (5 mL) and methylene chloride (10 mL). The solvent was removed and the residue was dried and redissolved in ethanol (5 mL). A solution of hydroxylamine hydrochloride (0.88 g, 12.7 mmol) in water (7 mL) was added followed by the addition of 10% NaOH until a white precipitate formed. The mixture was heated to reflux for 1 hour, cooled down to room temperature and the white precipitate filtered, washed with cold water and dried. The title compound was isolated as a pale solid (37.0 mg, 9%)
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:37]([CH2:39][Cl:40])=[O:38])[CH:34]([CH3:36])[CH3:35].Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:32][C@H:33]([C:37]([CH2:39][Cl:40])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)CCl
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ala-OH (1.60 g, 3.73 mmol) was then coupled to H-ValCH2Cl.HCl by a procedure substantially similar to that described for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl, above. The resulting product was crystallized from ethyl acetate:ether to yield 1.29 g of Z-Phe-Gly-Ala-ValCH2Cl (m.p. 143°-144°).
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:31])=[O:30]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: CS(=O)(=O)Cl
Product: CC(=O)C1=C(C)Nc2ccnc(OS(C)(=O)=O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 12 μl (0.15 mmol) of methanesulfonyl chloride. 10.4 mg (15% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=O.[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][C:11]([C:16]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([CH3:14])[CH3:6])=[CH:9][CH:10]=2)([CH3:18])[C:15]([OH:20])=[O:19])=[CH:10][CH:9]=1
Reactant: CN(C)c1ccccc1
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc(C(C)(C(=O)O)c2ccc(N(C)C)cc2)cc1
Yield: 69.8 %

Procedure:
Into 40 ml of 20% aqueous solution of sulfuric acid was dissolved 20 g of N,N-dimethylaniline. To the solution were added 8.4 g of pyruvic acid and 0.2 g of p-toluenesulfonic acid and the mixture was heated with reflux for 24 hours. The reaction mixture was, after cooled, diluted with 200 ml of water and adjusted to pH 6 with addition of 20% aqueous solution of sodium hydroxide. The precipitated crystal was collected by filtration which was 18.0 g (yield 70%) of 2,2-bis(4-dimethylaminophenyl)propionic acid, having a melting point of 152°~154° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCCCN(CCCC)c1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of N1,N1-di-n-butyl-2-fluorobenzene-1,4-diamine (1.10 g, 4.62 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (23 mL, 23 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (798 mg, 5.08 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:2) to give the title compound as pale yellow oil (800 mg, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:34][C:35]([F:51])([F:50])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45](C=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[B-]C#N.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:45]3[CH:44]=[CH:43][C:42]([C:39]4[CH:40]=[CH:41][C:36]([C:35]([F:34])([F:50])[F:51])=[CH:37][CH:38]=4)=[CH:47][CH:46]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@]1(CN2CCN(Cc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.7 g, 4.6 mmol), trifluoroacetic acid (10 ml) and methylene chloride (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). To the solution, 4′-trifluoromethylbiphenyl-4-carboaldehyde (2.3 g, 9.19 mmol), sodium cyanotrihydroborate (580 mg, 9.23 mmol) and acetic acid (0.55 ml, 9.62 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-2-methyl-6-nitro-2-[4-(4′-trifluoromethylbiphenyl-4-ylmethyl)piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (1.47 g, yield 63%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]([OH:17])[CH2:5][CH2:6]S2.C([O-])(=O)C.[Na+].O[O:24][S:25]([O-:27])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CO>[CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]([OH:17])[CH2:5][CH2:6][S:25]2(=[O:27])=[O:24]
Reactant: COC(=O)c1cc(C)c2c(c1C)C(O)CCS2
Reactant: O=S([O-])OO
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1C)C(O)CCS2(=O)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10 g (0.04 mol) of methyl 5,8-dimethyl-4-hydroxy-6-thiochromanecarboxylate and 4.9 g (0.06 mol) of sodium acetate were together added to 200 ml of methanol. The mixture was cooled to 0° C. and slowly admixed with a solution of 41.4 g (0.07 mol) of OXONE® (potassium peroxymonosulfate) in 200 ml of water. During the addition, the reaction temperature was kept below 6° C. The mixture was subsequently stirred at room temperature for 4 h and then diluted with 120 ml of water. The mixture was extracted with methylene chloride (3×200 ml), and the extract was dried over MgSO4 and concentrated using a rotary evaporator.