Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:83][C:84]([N:86]1[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1)=[O:85].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:53]2[CH:54]=[C:55]3[CH:61]=[CH:60][N:59]([CH3:62])[C:56]3=[N:57][CH:58]=2)[C:16]([C:18]2[CH:19]=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:83][C:84](=[O:85])[N:86]4[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]4)=[CH:29][C:28]=3[C:34]([N:36]3[C@H:45]([CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)=[O:35])[N:21]3[C:26]=2[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(O)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Reactant: O=C(CO)N1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCC(=O)N5CCCCC5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The compound of Step D (3.0 g, 2.9 mmol) is dissolved in 100 mL of toluene. 1.53 g (5.8 mmol) of triphenylphosphine and 0.62 g (4.3 mmol) of 2-hydroxy-1-(1-piperidyl)ethanone are added thereto. The mixture is heated to 50° C., and then 1.01 g (4.3 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is stirred at 50° C. for 1 hour and is then allowed to return to ambient temperature before adding 1 mL of trifluoroacetic acid. After stirring overnight at ambient temperature, the mixture is successively washed with water, saturated NaHCO3 and brine solution. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography over silica gel (dichloromethane/ethanol 98/2) to yield the expected compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][SH:11])[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1.[OH-:14].[NH4+:15]>O>[CH3:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][S:11][S:11][CH2:10][C:7]2[C:6]([CH:12]=[CH2:13])=[CH:5][N:15]=[C:3]([CH3:2])[C:8]=2[OH:14])[C:6]([CH:12]=[CH2:13])=[CH:5][N:4]=1
Reactant: C=Cc1cnc(C)c(O)c1CS
Reactant: [NH4+]
Reactant: [OH-]
Agent: Cl
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CSSCc1c(C=C)cnc(C)c1O

Procedure:
2-Methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride (9 g.) is dissolved in 50 ml. water and treated with 2 N ammonium hydroxide to about pH 9. Air is bubbled through the solution for 24 hours. The precipitated bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl]disulfide is collected on a filter and dried, m.p. 178°-180° (dec.).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:20]=[CH:1][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Yield: 74.3 %

Procedure:
A solution of tert-butyl 2-formylpyrrolidine-1-carboxylate (4 g, 20 mmol) and (carbethoxymethylene)triphenylphosphorane (7 g, 20 mmol) in THF was stirred at room temperature for 2 hr. Then the mixture was concentrated and purified by column chromatography to give 4 g of desired product. MS (ESI): 270 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1.O.[C:23](OCC(Cl)(Cl)Cl)(=[O:26])[CH2:24][CH3:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19][C:23](=[O:26])[CH2:24][CH3:25])[C@@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([O:20][CH3:21])[N:3]=1
Reactant: CCC(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(OC)nc(N)nc32)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 23 h

Procedure:
2-Amino-6-methoxy-9-(β-D-arabinofuranosyl)-9H-purine (1.0 g, 3.3 mmol) (prepared as described in European Patent Application No. 294 114) was suspended in 40 ml of pyridine that contained 300 μL of H2O and 2 ml of trichloroethyl propionate (Trichloroethyl propionate was synthesized by addition of 19 ml of propionyl chloride (Aldrich) over 30 minutes to 19.1 ml of trichlorethanol (Aldrich) in 40 ml of pyridine at 0° C.). The product was purified by successive washing with 2×100 ml aliquots of H2O, 5% NaHCO3, and H2O. 1H NMR (200 MHz, CDCl3, 4.74 (s, 2H, Cl3CH2-), 2.49 (q, 2H, J=7.6 Hz, CH3CH2CO2-), 1.21 (t, 3H, J-7.6 Hz, CH3CH2CO2-). The reaction was initiated with 0.100 g of subtilisin (Sigma Chemical Co., St. Louis, Mo., P-5380, lot No. 38F-0356), whch had been activated by dissolving 1 g of the enzyme in 20 ml of 0.1M potassium phosphate at pH 7.8 and lyophilizing to dryness. After stirring for 23 hours at 40° C., the reaction was quenched by filtering off the enzyme and the solvent was removed in vacuo. The crude product was purified by chromatography on a 4.5×25 cm silica gel column with CH2Cl2 :CH3OH (9:1) as eluant. Product fractions were pooled and lyophilized from water to yield 0.76 g of the desired product as a white powder: m.p. 124° C.; TLC Rf =0.43 (silica gel; CH2Cl2 :CH3OH (9:1); UV λmax (ε, mM-1 cm-1) at pH 7.0, 2.78 nm (9.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH:21](OCC)[O:22]CC)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(O)=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH:21]=[O:22])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O)OCC
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: O=CCN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of 1.00 g (2.53 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2,2-diethoxy-ethyl)-[1,4]diazepan-5-one in 10 ml of toluene was treated at RT with 5.22 ml formic acid and 1.5 ml water. The reaction was stirred for 1.5 h, evaporated and neutralized with aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (EtOAc) to yield 0.37 g (45%) of the title compound as off-white foam. MS: 321.3 (MH+, Cl).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:25]3[CH:26]=[C:27]4[O:32][CH2:31][O:30][C:28]4=[CH:29][C:24]=3[CH2:23][CH:22]([CH3:33])[N:21]([C:34](=[O:37])[CH2:35]Cl)[N:20]=2)=[CH:15][CH:14]=1)([O-])=O>C(O)C>[NH2:10][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:25]3[CH:26]=[C:27]4[O:32][CH2:31][O:30][C:28]4=[CH:29][C:24]=3[CH2:23][CH:22]([CH3:33])[N:21]([C:34](=[O:37])[CH2:35][NH:5][CH3:3])[N:20]=2)=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCl)OCO3
Agent: CN
Solvent: CCO
Product: CNCC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Yield: 53.5 %

Procedure:
1.03 g (15.3 mmol) of methylamine hydrocdhloride and 2.64 ml (18.3 mmol) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 140 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was dissolved in 30 ml of chloroform, washed with 20 ml of 4% NaOH solution, then 2×20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the process of Example 16 and the product obtained was purified by column chromatography (adsorbent: Kieselgel 60, eluent: methanol--benzene 4:1). The crude product obtained was triturated with 5 ml of ethyl acetate at 25° C. to obtain 0.60 g (53.6%) of the aimed product, m.p. 198°-200° C. (weak decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5](I)[S:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]2=[N:10][C:9]=1[CH3:23].N1C=[CH:27][N:26]=[N:25]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][NH:36][C@H]1CCCC[C@@H]1NC>C(Cl)Cl.[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([N:26]2[CH:27]=[N:36][CH:35]=[N:25]2)[S:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]2=[N:10][C:9]=1[CH3:23]
Reactant: c1c[nH]nn1
Reactant: CN[C@H]1CCCC[C@@H]1NC
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3Cl)c(C)nc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-n4cncn4)cc3Cl)c(C)nc12
Temperature: 112 °C
Yield: 71.4 %

Procedure:
To a solution of 3-(3-chloro-5-iodo-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.65 mmol), 1H-triazole (0.047 g, 0.69 mmol), CuI (0.0062, 0.033 mmol), Cs2CO3 (0.45 g, 1.37 mmol) and DMF (3 mL) is added (1S,2S)-(+)-N,N′-dimethylcyclohexane-1,2-diamine (0.014 mL, 0.098 mmol). The solution is heated at 112° C. overnight, diluted with CH2Cl2 (10 mL) and filtered thru Celite® and concentrated. The residue is purified by ISCO flash chromatography (30%-40% EtOAc gradient furnish the title compound (0.028 g, 0.070 mmol, 11%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.75-1.92 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.35 (m, 1H), 6.72 (s, 1H), 7.22 (s, 1H), 8.10 (s, 1H), 8.50 (s, 1H). LC/MS (m/z): calcd. for C19H21ClN6S (M+H)+: 401.1; found: 401.2.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[C:18]1([CH:24]2[CH2:30][CH2:29][C:28](=O)[O:27][C:25]2=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[C:18]1([CH:24]([CH2:30][CH2:29][C:28]2[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]3[CH:16]=[CH:15][C:14]4[CH2:13][CH2:12][CH2:11][NH:10][C:9]=4[N:8]=3)[N:17]=2)[C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(c2ccccc2)C(=O)O1
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Solvent: C1COCCO1
Product: O=C(O)C(CCc1nc(CCCc2ccc3c(n2)NCCC3)no1)c1ccccc1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18–2.37 (2H, comp. band); 2.42–2.55 (1H, comp. band); 2.74–2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23–7.39 (5H, comp. band); 7.51/7.55 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:52][O:53][C:54](=[O:59])[C@H:55]([OH:58])[CH2:56][NH2:57]>CN(C=O)C.C(N(C(C)C)CC)(C)C.O>[CH3:52][O:53][C:54](=[O:59])[C@H:55]([OH:58])[CH2:56][NH:57][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 0.75 h

Procedure:
4-{[tert-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid was dissolved in DMF (10 mL) and HOBt (0.40 g, 2.93 mmol) and EDAC (0.52 g, 2.73 mmol) were added. The reaction mixture was stirred for 45 min. Then a solution of (R)-3-amino-2-hydroxypropionic acid methyl ester in DMF (8 mL) and diisopropylethylamine (0.46 mL) were added. The mixture was stirred overnight. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (75 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×30 mL), water: saturated sodium chloride (3×30 mL), dried with magnesium sulphate and concentrated in vacua. The residue was purified by column chromatography on silica gel (100 g) using mixtures of ethyl acetate and n-heptane (1 L (1:1) and 0.5 L (7:3)) as eluents to afford 0.77 g (R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxypropionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:37]=[CH:36][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:38])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:37]=[CH:36][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:38])[CH:21]=1)[CH2:9]/[C:10](=[N:40]\[OH:41])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)N[C@H]3CC[C@H](C(=O)O)CC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, trans-4-{4-[1-(2-chloro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-benzoylamino}-cyclohexanecarboxylic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 13% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=552.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[C:21]([O:24]C(=O)C)(=[O:23])C.N1C=CC=CC=1>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:19][C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)[C:10](=[O:12])[C:21]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C(=O)C(=Cc1ccncc1)c1ccc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
To mixture of (3,4-diChloro-phenyl)-acetic acid 10.3 g and pyridine-4-carbaldehyde 5.25 mL was added acetic anhydride 6 mL and pyridine 6 mL. The reaction mixture was heated to 120° C. for 2 hours and cooled down to room temperature. Water and ethyl acetate were added. The solid formed was filtered, washed with water and ethyl acetate and dried to afford the title compound 10.2 g as a light yellow solid. MS (ES+): 292 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[NH:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(C(C)C)C(C)C)C.Cl[C:33]([O:35][CH3:36])=[O:34]>ClC1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[NH:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(C)ccc1C)=C2O
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: COC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC12CCN(OC)CC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one and 0.14 ml of ethyl diisopropyl amine in 2 ml of chlorobenzene was added a solution of 66 mg of methyl chloroformate in 0.5 ml of chlorobenzene at 50° C. After stirring for 1 hour at 50° C., the reaction mixture was cooled to room temperature, diluted with 5 ml of chlorobenzene and washed with cold 5% aqueous sodium hydroxide and water. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel. Yield: 120 mg of carbonic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester methyl ester (title compound A1). This material was triturated with ethyl acetate/hexane, filtered and dried to afford a solid, mp: 186-188° C.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:10][S:11]([O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: OCC1(F)CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 37C (1.4 g), methanesulfonyl chloride (1.054 mL), triethylamine (2.99 mL), and 4-dimethylaminopyridine (0.051 g) in CH2Cl2 (20 mL) was stirred at 0° C. for 2 hours, concentrated and chromatographed on silica gel eluting with 30% ethyl acetate in hexanes to give the product.
Reaction SMILES: [CH2:1]([S:8][S:9][CH2:10][CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].[OH-:17].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1>[S:8]([CH2:1][CH2:2][CH:3]([NH:7][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[C:4]([OH:6])=[O:5])[S:9][CH2:10][CH2:11][CH:12]([NH:16][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:13]([OH:15])=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC(CCSSCCC(NC(=O)OCc1ccccc1)C(=O)O)C(=O)O)OCc1ccccc1
Temperature: 7.5 °C

Procedure:
L-Homocystine (200.0 g, 745.5 mmol, 1.0 eq.) is suspended in THF (1000 mL, 5.0 vol.) and cooled to 5-10° C. Addition of 20% sodium hydroxide (521.7 mL, 626.2 g, 125.25 g at 100%, 3.13 mmol, 4.2 eq.) is followed by addition of benzyl chloroformate (220.3 mL, 267 g, 1565.5 mmol, 2.1 eq.). Conversion is complete after a night at room temperature (L-Homocystine<1%). Extractions and washings of the organic layer with water leads to a yellow oil which is isolated in quantitative yield, and which slowly crystallizes as a yellowish solid at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH:21][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: NNc1ccccc1F
Reactant: Nc1cccc(F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Nc1cccc(F)c1C(=O)NNc1ccccc1F
Temperature: -12 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
2-Amino-6-fluorobenzoic acid (2.00 g, 12.89 mmol) was combined with 2-fluorophenylhydrazine hydrochloride (2.096 g, 12.89 mmol) and HOBt (3.949 g, 25.79 mmol) in dry THF (75 ml) and cooled to about −12° C. N-Methylmorpholine (2.835 ml, 25.79 mmol) was added, the mixture was stirred for 5 minutes, then EDC hydrochloride (2.66 g, 13.88 mmol) was added. The mixture was maintained at a temperature between −14 and −10° C. for 1 hour, then allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was cooled to 0° C., then filtered through CELITE® (diatomaceous earth). The filtrate was diluted with EtOAc, treated with saturated NaHCO3 and the layers separated. The organic layer was washed twice with 50% saturated NaHCO3 and then dried over MgSO4 and concentrated. The resulting solid was triturated with dichloromethane, filtered, rinsed with a very small amount of dichloromethane and dried. The filtrate from the trituration was re-triturated with a small amount of dichloromethane, filtered, rinsed with a tiny amount of dichloromethane and dried. The filtrate was concentrated to dryness, triturated with a small amount of Et2O, filtered, rinsed with a tiny amount of ether and dried. The three solids were combined to afford a total of 2.182 g (64%) of 2-amino-6-fluoro-benzoic acid N′-(2-fluoro-phenyl)-hydrazide (Intermediate 44) as an off-white solid. MS (APCI): (M−1)=262.0.
Reaction SMILES: [F:1][C:2]1[N:3]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10]S(C)(=O)=O)[N:6]=1.[Na].[CH3:35]O>>[F:1][C:2]1[N:3]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][CH3:35])[N:6]=1
Reactant: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CO
Agent: [Na]
Product: COCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole in MeOH was treated with sodium metal and stirred at 65°. Work-up as for the starting material of Example 9 gave 2-fluoro-4-(3-methoxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.87 (m, 2H); 2.45 (t, 2H); 3.26 (s, 3H); 3.33 (t, 2H); 6.21 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([NH2:37])[CH3:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][NH:37][CH2:35][CH3:36])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CNCC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A3) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.