Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F-].C([N+:47]([CH2:56][CH2:57][CH2:58][CH3:59])([CH2:52][CH2:53][CH2:54][CH3:55])CCCC)CCC>O1CCOCC1.O>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:59]4[CH:55]=[CH:54][CH:53]=[C:52]5[C:58]=4[CH:57]=[CH:56][NH:47]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:27]1
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) was added {1-[1,1-dimethylethyl)(dimethyl)silyl]1-Hindol-4-yl}boronic acid (37 mg, 0.133 mmol), chloro[Z-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5.75 mg, 10.27 μmol) and potassium phosphate tribasic (65 mg, 0.308 mmol). The reaction mixture was heated under microwave irradiation at 100° C. for 40 min. The solvent was removed and the residue dissolved in 10% methanol in dichloromethane (2 ml) and purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The appropriate fractions were concentrated to give a brown gum which was treated directly with tetra-n-butylammonium fluoride (0.2 ml, 0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20° C. for 18 h. The solvent was removed and the residue dissolved in 1,4-dioxane (1 ml) and treated with 2M sodium hydroxide (1 ml) and allowed to stand at 20° C. for 48 h. The solvent was removed and the residue triturated with 10% methanol in dichloromethane then purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give a pale brown solid which was further purified by SCX SPE (1 g), eluting with 0.5M ammonia in 1,4-dioxane. The solvent was removed and the residue further purified by MDAP to give the title compound as a white solid (14 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34]3)=[O:22])=[CH:17][C:9]1=2
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC1CCc2ccccc21)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.95 (M+H+); retention time=0.99 minutes.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH:37]C=O)[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8].Cl.CO>O1CCCC1>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[C:7]([NH:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][CH:25]=[CH2:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCSC)c3csc(N)n3)[C@H]2SC1
Yield: 86 %

Procedure:
A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.95 g), conc.hydrochloric acid (0.324 g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.78 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 74.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (644 mg, 74%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)CCc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nccn1-c1ccc(F)cc1[N+](=O)[O-]
Yield: 47.8 %

Procedure:
1,4-Difluoro-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were heated at 100° C. for 64 hours. The reaction liquid was diluted with ethyl acetate and filtered. The filtrate was condensed under reduced pressure and subjected to silica gel chromatography (ethyl acetate) to provide 220 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH2:14][CH2:15][CH3:16])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]([C:11]([NH:13][CH2:14][CH2:15][CH3:16])=[O:12])=[CH:9][CH:8]=1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Yield: 91.5 %

Procedure:
The product from Example 127a (1.0 g, 2.99 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (834 mg, 92%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(#N)C.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:17]([C:21]([NH:23][CH2:24][C:25]3([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[C:16]([Cl:33])[CH:15]=[CH:14][C:13]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]([NH:23][CH2:24][C:25]4([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:22])=[C:16]([Cl:33])[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH2:3]1
Reactant: N[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reaction time: 1.58 h

Procedure:
(S)-3 aminopyrrolidine (96 ml) and acetonitrile (300 ml) were charged to a vessel containing 2,6-Dichloro-N-((1-hydroxycycloheptyl)methyl)quinoline-5-carboxamide (300.0 g), potassium carbonate (249.0 g) and acetonitrile (2400 ml). The reaction mixture was heated under refux for 20 hours. Water (6900 ml) was charged at 20° C. to 25° C. The mixture was stirred for 95 minutes and filtered. The filter cake was washed with water (1200 ml) and acetonitrile (1200 ml). The filter cake was dried at 40° C. for 48 hours to provide the title compound as a yellow solid (283 g).
Reaction SMILES: [Li]CCCC.[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16].Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH2:21]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20][CH2:19][CH2:18][C:16]#[C:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]#[CH:6]
Reactant: BrCCCCOC1CCCCO1
Reactant: C#CCCCCCCCC#C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCCCCCCCC#CCCCCOC1CCCCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
n-BuLi (4.86 mL of 2.5 M in hexanes, 12.16 mmol) was added dropwise to a −78° C. solution of undec-1,10-diyne (2.0 g, 13.51 mmol) in dry tetrahydrofuran/HMPA (105 mL, 6:1) under an argon atmosphere. After 30 min, the reaction mixture was warmed to −10° C. over 2 h and maintained at this temperature for 20 min, then re-cooled to −75° C. To this was added a solution of 2-(4-bromobutoxy)-tetrahydropyran (2.4 g, 10.14 mmol) in dry THF (15 mL). The resulting mixture was warmed to room temperature over 3 h, maintained at this temperature for 12 h, then quenched with sat. aq. NH4Cl (25 mL). After 20 min, the mixture was extracted with ether (2×125 mL). The combined ethereal extracts were washed with water (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 5% EtOAc/hexanes as eluent to give 2-(pentadeca-5,14-diynyloxy)tetrahydropyran (1.97 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.58 (t, J=2.5 Hz, 1H), 3.82-3.89 (m, 1H), 3.71-3.78 (m, 1H), 3.43-3.53 (m, 1H), 3.36-3.47 (m, 1H), 2.01-2.20 (m, 6H), 1.93 (t, J=2.5 Hz, 1H), 1.27-1.81 (m, 20H). Lit. ref: F. Slowinski; C. Aubert; M. Malacria Eur. J. Org. Chem. 2001: 3491.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:7]([S:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[N:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:3][C:4]1[C:8]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[C:7]([S:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[N:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)=[N+:29]=[N-:30]
Reactant: CC(C)n1nc(CCl)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(CN=[N+]=[N-])c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 120 mg of 4-[3-chloromethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazol-4-ylmethyl]pyridine hydrochloride in 1 ml of anhydrous dimethylformamide stirred at room temperature was added 85 mg of sodium azide. The mixture was stirred for 1 h. The mixture was partitioned between diethyl ether and water then extracted three times. The combined extracts were reduced under reduced pressure to give 120 mg of 4-[3-azidomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazol-4-ylmethyl]pyridine as a yellow oil which was used without any further purification. Mass spectrum (ESI) 433 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1>ClCCl>[N:8]1([C:5](=[O:7])[CH3:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCCN2
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Acetic anhydride (55.5 g; 1.05 equiv.) was slowly added dropwise, at 0° C., to a solution of 1,2,3,4-tetrahydroquinoline (69 g; 1 equiv.) in 690 ml of dichloromethane. The reaction mixture was stirred for 30 minutes at room temperature and, when the conversion was complete, was washed with cold water and sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. 1-(3,4-Dihydroquinolin-1(2H)-yl)ethanone (85 g; 94.4%) was obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18]O)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:32].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][Br:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (3-benzyloxy-4-nitrophenyl)-methanol (11.0 g, 0.042 mol) in anhydrous THF is added triethylamine (8.7 g, 0.86 mol). The mixture is cooled to −20° C., followed by the addition of methanesulfonyl chloride (5.8 g, 0.051 mol) and then stirred at −20° C. for 45 min. To this mixture is added lithium bromide (37.3 g, 0.43 mol) in anhydrous THF (40 mL) over 40 min followed by stirring at RT for 2 h. The suspension is concentrated under reduced pressure and diluted with EtOAc and water. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2.CI>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([O:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH:26]([CH3:41])[C:27]([N:29]([CH3:3])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[O:28])=[CH:23][CH:22]=1)[CH:14]=[N:13]2
Reactant: CCCCCC
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)N(C)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A mixture of 0.23 g (5.7 mmol) of a 60 percent NaH/oil dispersion and 10 ml of hexane was stirred under N2 for 10 minutes. The hexane was decanted off, replaced with 20 ml of DMF and a solution of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide in 20 ml of DMF was added dropwise over a period of 30 minutes. The mixture was stirred at ambient temperature for 1.5 hours when a solution of 1.45 g (10 mmol) of methyl iodide in 10 ml of DMF was slowly added. The mixture was stirred at ambient temperature for 2 days and then quenched by cautious addition of a few drops of acetic acid and then water. The mixture was poured into water, extracted with three portions of ether and the combined organic layers dried over MgSO4 and evaporated to dryness. The residue was taken up in hot methylcyclohexane, treated with charcoal and filtered and then allowed to cool to give 1.03 g (50 percent) of the above-named product as colorless crystals, m.p. 137°-139° C. (Compound 41)
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[C:12]1([CH:18]([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:12]1([CH:18]([O:23][C:24]2[CH:25]=[C:26]([CH:27]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCCc2ccccc2)c(OC(c2ccccc2)C(F)(F)F)c1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)C(=Cc2ccc(OCCc3ccccc3)c(OC(c3ccccc3)C(F)(F)F)c2)SC1=S
Temperature: 25 °C
Reaction time: 84 h
Yield: 40.6 %

Procedure:
A solution of rhodanine-3-acetic acid (87 mg, 0.46 mmol, 1 eq), 3-(1-phenyl-2,2,2-trifluoroethoxy)-4-(2-phenylethoxy)benzaldehyde (183 mg, 0.46 mmol, 1 eq) and sodium acetate (112 mg, 1.37 mmol, 3 eq) in acetic acid (2 mL) was heated to 150□C and stirred for 3.5 days. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (50 mL) and the two layers separated. The organic layer was washed with 1M HCl (2×50 mL), and loaded onto silica. Elution with ethyl acetate:methanol (4:1) gave a yellow gum. This was dissolved in hot ethyl acetate and filtered (to remove some insoluble material). The filtrate was allowed to cool to room temperature and diethyl ether added. This gave a suspension which was again filtered. The filtrate was evaporated and the residue redissolved in diethyl ether. Addition of petroleum ether to the solution gave a precipitate which was filtered off. The mother liquor was evaporated and the resulting gum was crystallized from diethyl ether and petroleum ether to give the product as a yellow powder (107 mg, 41%) mp 170° C.: 1H NMR (d6 DMSO) δ 7.67 (s, 1H, C═C—H), 6.17 (q, 1H, J 6.5 Hz, CHCF3), 4.70 (s, 2H, CH2CO2H), 4.33 (t, 2H, J 5.9 Hz, OCH2CH2Ph), 3.09 (t, 2H, J 6.2 Hz, OCH2CH2Ph).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[O:22][CH3:23])C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(CCCCC(=O)O)ccc1O

Procedure:
The raw product obtained in Example 21 was dissolved in 500 ml of N,N-dimethylformamide and 22 g of 10% palladium on charcoal catalyst was added. The mixture was hydrogenated at 60° C. and normal pressure until the theoretical amount (3 mole) of hydrogen was consumed. After filtering the solvent was evaporated in vacuo to a great extent and the residue was dissolved in 1 l of dichloromethane and washed with 2 l of water. The product was extracted with 1.5 l of saturated NaHCO3 -solution. After acidification of the aqueous phase with hydrochloric acid the product was extracted with 1 l of dichloromethane. The solvent was distilled off in vacuo and the semisolid residue (180 g) was used to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:13]=[O:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(Cl)cc1F
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-chloro-2-fluorobenzamide (0.200 g, 1.26 mmol), EDC (10 mL) and oxalyl chloride (0.14 mL, 1.15 mmol) to afford 0.200 g of the product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16]C(OC(C)(C)C)=O)[CH2:11][O:12][CH:13]([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].CCOCC>CCOCC>[ClH:25].[CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH2:16])[CH2:11][O:12][CH:13]([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of the compound of Formula XIII(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid benzyl ester (2.11 g, 5.89 mmol) in ether (10 mL) was treated with 2M HCl/ether, and stirred at 0° C. for 2 hours. The reaction mixture was concentrated to dryness and triturated with hexane/ether to give the compound of Formula V(a) (S)-2-amino-3-difluoromethoxy-propionic acid benzyl ester hydrochloride salt (1.15 g, 69%) as a white powder. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.40-7.33 (m, 5H), 6.53 (broad s, 1H), 6.18 (wt, 1H), 5.25 (dd, 1H), 5.21 (dd, 2H), 4.53 (dt, 1H) 4.18 (td, 1H), 4.16-4.13 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C@H:19]([C:20]([NH:22][C@H:23]([C:42]([O:44]C)=[O:43])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[C:33]4[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=4[Cl:40])=[CH:27][CH:26]=3)=[O:21])[C:18]3[CH:17]=[N:16][N:15]([CH2:46][CH3:47])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[Li].O.Cl>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[C@H:19]([C:20]([NH:22][C@H:23]([C:42]([OH:44])=[O:43])[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:41])[C:33]4[C:38]([Cl:39])=[CH:37][N:36]=[CH:35][C:34]=4[Cl:40])=[CH:27][CH:26]=3)=[O:21])[C:18]3[CH:17]=[N:16][N:15]([CH2:46][CH3:47])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCn1ncc2c1CN(S(=O)(=O)c1cc(Cl)cc(Cl)c1)[C@@H]2C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)C(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCn1ncc2c1CN(S(=O)(=O)c1cc(Cl)cc(Cl)c1)[C@@H]2C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)C(=O)O
Reaction time: 2 h

Procedure:
A solution of 47 mg (0.063 mmol) of N-[(5-(3,5 -dichlorobenzensulfonyl)-1-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4 (S)-carbonyl]-4-(3′,5′-dichloroisonicotinoyl)amino-(L)-phenylalanine, methyl ester in 2 mL of MeOH and 0.5 mL of water was treated with 7 mg (0.167 mmol) of LiOH—H2O. After stirring for 2 hr the solution was acidified (pH 2) with 1.2 N HCl and concentrated in vacuo. The residue purified by preparative TLC on silica eluted with 94.5:5:0.5 CH2Cl2:MeOH:HOAc to yield N-[(5-(3,5-dichlorobenzensulfonyl)-1 -ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-4(S)-carbonyl]-4-(3′,5′-dichloroisonicotinoyl)amino-(L)-phenylalanine (35 mg) as a solid. LC-MS: m/e 727 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@:4](C1C=CC(Br)=CC=1)([NH:6][C:7]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH3:5].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:7]([NH:6][C@@H:4]([CH2:5][C:12]2[CH:17]=[CH:16][C:15]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:14][CH:13]=2)[C:3]([OH:2])=[O:26])=[O:8])[N:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@@](C)(NC(=O)c1cc2ccccc2cn1)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)c3cc4ccccc4cn3)C(=O)O)cc2)cc1
Yield: 164.1 %

Procedure:
3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was reacted with 4-methoxyphenyl boronic acid (76 mg, 0.5 mmol) as described in general procedure D yielding the title compound (84 mg, 82%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[OH2:20]>ClCCl>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]([C:15]#[N:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Reactant: O
Solvent: ClCCl
Product: N#Cc1c(-c2ccccc2F)nc(N)[nH]c1=O

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and water in dichloromethane. ES-MS m/e (%): 231 (M+H+, 100).