Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](=[O:22])[CH:20]=[CH2:21].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)c1ccc(Cl)s1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7.35 g (27.1 mmol) of 2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63, Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1 mmol) in DCM (10 mL) slowly at 0° C. over 20 min. Then the reaction was allowed to warm to ambient temperature. After being stirred at 25° C. for two days, the reaction mixture was diluted with DCM and washed with 2N HCl, water and sat. aq. NaCl solution. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (220 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provided the title compound as a light-yellow oil. Mass Spectrum (ESI) m/z=357 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: C1COCCN1
Product: Cc1cc(-c2cc(CN3CCOCC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 92, 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and morpholine were reacted to yield the title compound as a slightly yellow oil (yield: 97.4%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5]Cl.[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:3][O:4][CH3:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.7 %

Procedure:
Sodium hydride (214 g, 4.90 mol) and chloromethyl methyl ether (394 g, 4.90) were gradually added to a solution of 2-tert-butylphenol (700 g, 4.67 mol) in dimethylformamide (3000 ml) while cooling on ice and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and then the organic layer was washed with water and brine in that order and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1013 g) as a light yellow oil.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40]([CH:45]=O)[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]>C1COCC1.CCCCCC>[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40](/[CH:45]=[CH:5]/[CH2:4][CH2:3][OH:2])[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](C=O)CC[C@]12C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](/C=C/CCO)CC[C@]12C
Temperature: -25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of 23.0 g of (3-hydroxypropyl)triphenylphosphonium bromide in 280 ml of anhydrous THF cooled at -25° C., 36.0 ml of 1.6N n-butyllithium in n-hexane were added dropwise under a nitrogen atmosphere and the mixture was stirred at -25° C. for 1 hr. A solution of 3.20 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-3a-hydroxy-5-formyl-7a-methylperhydroindene in 32 ml of anhydrous THF was added and the reaction mixture was kept at -20° C. for 4 hrs, then warmed to room temperature and stirred for 3 hrs. The mixture was diluted with 5% aqueous NaH2PO4.H2 O, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/chloroform/acetone 6:2:2 to give 2.23 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-hydroxy-1-butenyl)-7a-methylperhydro-inden-3a-ol from which, by reaction with tert-butyldimethyl-chlorosilane, following the procedure, described in Prepn. 1, 2.94 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-tert-butyldimethylsilyl-oxy-1-butenyl)-7a-methylperhydroinden-3a-ol were obtained as a white foam.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C

Procedure:
25.08 g (0.079 mol) of N-tert-butyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide are dissolved in 1000 ml of MeOH. 0.50 g of Pd-C (10%) is added and the mixture is shaken under a hydrogen atmosphere (1 atm) until the uptake of hydrogen has finished. The catalyst is separated off and the solvent is removed by distillation. The residue is induced to crystallize by stirring with a little ethyl acetate. The resulting N-tert-butyl-5-amino-2-methoxycarbonylbenzenesulfonamide (18.3 g; 80.9% of theory) melts at 193° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:15][CH:14]=1>>[O:5]1[CH2:4][CH:3]1[CH2:1][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:15][CH:14]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(-c2nc(C(F)(F)F)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1csc(-c2ccc(OCC3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5 ml of epichlorohydrin and 0.5 g of potassium carbonate is heated under reflux. 0.5 g of 2-(4-hydroxyphenyl)-4-(trifluoromethyl)-thiazole is added in one portion and the reaction mixture is then heated under reflux for a further 15 minutes. After cooling, the mixture is filtered, the filtrate is concentrated by evaporation in a rotary evaporator and the residue is taken up in 6 ml of dichloromethane; 100 mg of tetrabutylammonium hydrogen sulphate and 6 ml of 2N sodium hydroxide solution are added to the solution and the whole is stirred for 3 hours at room temperature. The organic phase is separated off, washed and dried and finally the solvent is removed in a rotary evaporator. The residue is crystallised from ether/hexane yielding 2-[4-(2,3-epoxypropoxy)-phenyl]-4-(trifluoromethyl)-thiazole having a melting point of 97°-98°.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[C:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[C:16]([CH2:17][C:18]([F:20])([F:19])[F:21])=[CH:15][C:14]([I:1])=[CH:13][C:12]=1[CH3:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(CC(F)(F)F)c1OCc1ccccc1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(I)cc(CC(F)(F)F)c1OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of iodine (1.52 g, 6.0 mmol) dissolved in CHCl3 (80 mL) was added dropwise to a stirred mixture of 2-benzyloxy-1-methyl-3-(2,2,2-trifluoro-ethyl)-benzene (2.1 g, 6.0 mmol), silver trifluoroacetate (1.33 g, 6.0 mmol) in CHCl3 (20 mL). After the addition was complete the reaction mixture was stirred for 1 hour. The mixture was filtered through a pad of celite washing with CH2Cl2. The filtrate was washed with satd Na2S2O3, brine, dried over Na2SO4 and concentrated to a pale yellow solid (1.68 g). LCMS: APCI−VE=405
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20]([F:23])([F:22])[F:21])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2C(F)(F)F)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccccc2C(F)(F)F)nc1-c1ccnn1-c1ccccc1
Yield: 12 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[2-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (crude 785 mg, 2.33 mmol) in 20 mL of methanol was added phenylhydrazine (377 mg, 3.50 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-[2-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (105 mg, 12% for two steps) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:17][CH2:15][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A stirred mixture of 2,5-difluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 244, 5.07 g, 20.3 mmol), N-bromosuccinimide (freshly recrystallised and dried, 4.71 g, 26.4 mmol) and azobisisobutyronitrile (0.05 g, 0.30 mmol) in 1,2-dichloroethane (100 mL) was heated at reflux under nitrogen whilst being irradiated with light from a lamp. After 2 hours, additional azobisisobutyronitrile (0.05 g, 0.30 mmol) was added and the reaction heated under reflux for 2 hours more. The reaction mixture was cooled to room temperature and evaporated in vacuo. The resulting residue was partitioned between brine (200 mL) and EtOAc (2×150 mL). The combine organic extracts were dried over magnesium sulphate and concentrated in vacuo to yield a pale yellow oil which solidified on standing (7.88 g). The solid was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to afford the title compound as a white solid (3.71 g, 56%):
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[C:39]([O:56][CH3:57])=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44](I)[C:43]2=[O:55]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:44]3[C:43](=[O:55])[C:42]4[C:47](=[C:38]([Br:37])[C:39]([O:56][CH3:57])=[CH:40][CH:41]=4)[O:46][C:45]=3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1Br
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1Br
Yield: 40 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-7-methoxy-2-phenyl-chromen-4-one (198 mg, 0.434 mmol) was reacted to give the title compound (100 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 8.27-8.22 (d, 1H), 7.53-7.19 (m, 9H), 7.08-7.03 (d, 1H), 5.06 (s, 1H), 4.06 (s, 3H), 2.58-1.76 (m, 6H), 1.46-1.18 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Yield: 91.1 %

Procedure:
A solution of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate (165.0 g, 401.2 mmol) in acetonitrile (3.3 L) and isopropanol (990 mL) and 5% platinum on carbon (13.2 g) were added to a Parr vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 139.29 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]carbamate as a yellow solid. The product was suspended in a mixture of dichloromethane (4 mL/g) and chloroform (8 mL/g), and the suspension was divided into two equal portions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH:6]=[N:22][NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Solvent: CCO
Product: CCOC(=O)C(C=NNc1ccccn1)c1cccnc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.90 g (15.0 mmol) of the compound from Example 2A and 1.72 g (15.8 mmol) 2-pyridylhydrazine are dissolved in 75 ml ethanol and the mixture is stirred at RT for 4 d. The reaction mixture is freed from the solvent on a rotary evaporator and the residue is chromatographed over silica gel 60 (mobile phase: methylene chloride→methylene chloride/methanol 10:1→methylene chloride/methanol 2:1). The product fractions are combined and the solvent is removed on a rotary evaporator. After drying in vacuo, 3.95 g (93% of th.) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:3]=1.N#N.[Na].Cl.[CH3:40][OH:41]>O>[CH3:40][O:41][C:3]1[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:9]=[C:10]2[CH:2]=1
Reactant: CCOC(=O)CCCCCCn1cc(Br)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CO
Agent: Cl
Agent: N#N
Agent: [Na]
Solvent: O
Product: COc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2n1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising ethyl 7-(7-bromo-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (step 1) (50 mg, 0.094 mmol) in anhydrous MeOH (1 ml) was degassed with N2 and treated with sodium (10.75 mg, 0.468 mmol). After stirring at room temperature for 30 minutes, the mixture was heated to 120° C. using microwave radiation for 1 hour. The mixture was diluted with water (20 ml) and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane followed by 10% MeOH in EtOAc afforded the titled compound as an orange solid;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
(R)-N-benzyloxycarbonyl-tyrosine methyl ester was reacted in a manner analogous to that described in Example 3 with t-butyl bromoacetate in the presence of potassium carbonate to give N-benzyloxycarbonyl-3-[p-(tert-butoxycarbonylmethoxy)phenyl]-D-alanine methyl ester. The colorless oil was hydrogenated in methanol, after addition of 5% palladium/carbon, in a shaking apparatus at room temperature under atmospheric pressure, obtaining, after filtration and removal of the solvent, 3-[p-(tert-butoxycarbonylmethoxy)phenyl]-D-alanine methyl ester in the form of a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1S
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A solution of 6-nitrobenzothiazole (5 g, 27.7 mmol) in ethanol (50 mL) was treated with mono hydrazine hydrate (19 g, 388 mmol). The reaction mixture was stirred for 3 h at 25° C. and concentrated in vacuo. The resulting red oil was taken up in ethyl acetate, carefully acidified with 0.1 M aqueous hydrochloric acid solution until the solution turned light yellow. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting orange solid was triturated with diethyl ether and dried in vacuo to afford the desired product, 2-amino-5-nitro-benzenethiol (4.1 g, 23.9 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz, Acetone-d6) δ 6.43 (bs, 2H), 6.82 (d, 1H, J=8.7 Hz), 7.65 (d, 1H, J=2.2 Hz), 7.88 (dd, 1H, J1=8.9 Hz, J2=2.7 Hz). LC-MS (ESI) calcd for C6H6N2O2S [M+H+] 171.01. found 193.20 [M+Na+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([C:33](O)=[O:34])=[N:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:26]3[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:24][N:25]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1noc2ccccc12
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3noc4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[d]isoxazole-3-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=477.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].CCN(C(C)C)C(C)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid (254.5 mg, 1.9 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (500 μL, 2.9 mmol) was added followed by benzyl chloroformate (410 μL, 2.9 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)[C:29]#[N:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[C@H:38]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[C:26]([F:25])[CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Yield: 66.8 %

Procedure:
In the same manner as that described in Example 1(iii) above, a reaction was carried out using 1.02 g (2.84 mmol) of (2R,3R)-2-(2,5-difluorophenyl)3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 8(vi) above], 571.6 mg (2.84 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile and 594.5 mg (3.13 mmol) of p-toluenesulfonic acid monohydrate and the reaction product was purified by chromatography on a silica gel (75 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 1.03 g (yield 66%) of the title compound as a colorless non-crystalline solid.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[N:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[OH:8]
Reactant: [H][H]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
0.34 g. of 1-benzyloxy-2-[(2,6-dichlorophenyl)-imino]imidazolidine is hydrogenated under normal pressure in 5 ml. of ethanol and 2 ml. of 1 N hydrochloric acid in the presence of 0.05 g. of palladium-on-charcoal (5%). After the uptake of hydrogen has ended, the catalyst is filtered off and the solution is evaporated. The residue is dissolved in water and the solution is adjusted to pH 10 with caustic soda solution and extracted, first with methylene chloride and then with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, m.p. 196°, is obtained. Recrystallization from methanol/acetonitrile raises the melting point to 215°.