Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH2:6][C:5]([CH3:16])([CH3:15])[C:4]([OH:17])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)(C)Cc1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CC(C)(C)C(=O)O)c1
Yield: 68.1 %

Procedure:
The crude ethyl-3-(3-methoxyphenyl)-2,2-dimethylpropanoate (1.00 g, 4.23 mmol) was taken up in a solution of ethanol (50 mL) and sodium hydroxide (2 N, 10 mL). The reaction mixture was refluxed overnight and then concentrated under vacuum. The concentrated aqueous solution was acidified with hydrochloric acid (2 N) to pH 3-4 and extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate and evaporated to yield 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (600 mg) as a brown oil, which was used directly in the next step. MS m/z: 207 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CNC.[CH3:39][OH:40]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([O:40][CH3:39])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: CO
Agent: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCn1c(OC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropyl ethyl amine (0.05 g, 0.407 mmol) and 1M dimethyl amine in methanol (0.061 g, 1.36 mmol). The reaction mixture was heated at 50° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue obtained was purified by column chromatography to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one (0.005 g, 10%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.S(=O)(=O)(O)O.[C:13](#[N:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:13]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(-c2nnn[nH]2)cc1
Temperature: 97.5 °C
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 6.58 g (0.065 mole) of triethylamine and 52 ml of toluene. To the mixture were added 3.19 g (0.033 mole) of concentrated sulfuric acid with stirring. Further added were 5.16 g (0.050 mole) of benzonitrile and 4.23 g (0.065 mole) of sodium azide. The mixture was heated to a temperature from 95 to 100° C. to undergo a reaction for 7 hours. The same subsequent treatment as in Example 1 was conducted, giving 7.11 g (0.049 mole) of 5-phenyl-1H-tetrazole (yield 97.3% based on benzonitrile).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[S:16])=[CH:6][CH:5]=1.N>[Pd].CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[S:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCCNC(=S)Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: N
Solvent: CO
Product: COC(=O)c1ccc(OCCCNC(=S)Nc2ccccc2N)cc1
Reaction time: 4 h

Procedure:
A methanol solution (150 mL) of 36-3 (3.15 g, 8.08 mmol) was saturated with NH3. 10% Pd/C (2 g) was added and the mixture hydrogenated at 1 atm for 4 h. Filtration and concentration provided 36-4 as a purple solid.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[CH:28]=[CH:27][C:26]([S:23]([NH:22][C@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[C:6]([OH:39])=[O:5])(=[O:25])=[O:24])=[CH:31][CH:30]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 96.6 %

Procedure:
A solution of the title I compound, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (0.96 g, 1.69 mmol) in TFA (10 mL, 130 mmol) is stirred at RT for 2.5 h. The solution is concentrated under reduced pressure to give a white solid which is triturated from 20 mL of diethyl ether, collected by filtration and dried to give 837 mg (97%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid as a white solid: m.p. 179-181° C.; NMR(1:100 CD3OD/CDCl3) 1.65-1.86 (m, 4H), 3.63 (t, 3H, J=6.4), 3.93 (t, 3H, J=6.4), 7.39 (d, 2H, J=8.6), 7.47 (d, 2H, J=8.6), 7.60 (d, 2H, J=8.4), 7.65-7.68 (m, 2H), 7.76-7.79 (m, 2H), 7.86 (d, 2H, J=8.4); IR 1772, 1708, 1340, 1153; ESI-MS 511 (M−−1), 513 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes: ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1)(=[O:10])=[O:9].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].C(N(CC)CC)C>CN(C=O)C>[F:20][C:19]([S:18][C:14]1[CH:13]=[C:12]([N:11]2[C:23](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2S(=O)(=O)N1c1cccc(SC(F)(F)F)c1
Temperature: 100 °C
Yield: 140 %

Procedure:
A mixture of 2-amino-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide (52 mg, 0.15 mmol), 1,1′-carbonyldiimidazole (97 mg, 0.60 mmol) and triethylamine (41 μL, 0.30 mmol) in DMF (0.75 mL) was heated in a sealed tube for 5 h at 100° C. After concentration in vacuo, DCM and 1M aqueous HCl were added, the phases were separated, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography, eluting with 3% MeOH in DCM yielded the title compound (45 mg, 0.21 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].F[P-](F)(F)(F)(F)F.ClC1C=CC2N=NN(OC(N(C)C)=[N+](C)C)C=2C=1.Cl.[NH2:50][C:51]1([C:54]2[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52]1>[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:50][C:51]1([C:54]2[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=2)[CH2:53][CH2:52]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(COc2ccc(F)cc2)C1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(COc4ccc(F)cc4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A mixture of 5-chloro-2-(3-((4-fluorophenoxy)methyl)azetidin-1-yl)nicotinic acid (D113) (55.4 mg, 0.161 mmol), O-(6-Chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HCTU) (66.8 mg, 0.161 mmol) and N,N-disopropylethylamine (0.072 ml, 0.403 mmol) was stirred 30 min at room temperature. Methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (37.8 mg, 0.161 mmol) was added and the reaction mixture stirred overnight at room temperature. NH4Cl saturated solution (20 ml) was added and the mixture was extracted with ethylacetate (3×10 ml). The residue obtained after solvent evaporation was purified by SPE-Si cartridge (10 g) eluting dichloromethane. Collected fractions, after solvent evaporation, afforded the title compound (D163) (52.6 mg).
Reaction SMILES: [CH3:1][Mg]Br.Cl[C:5]1[C:6](=[O:12])[NH:7][N:8]=[CH:9][C:10]=1[Cl:11]>CCOCC>[CH3:1][C:5]1[C:6](=[O:12])[NH:7][N:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: C[Mg]Br
Solvent: CCOCC
Product: Cc1c(Cl)cn[nH]c1=O
Reaction time: 3 h

Procedure:
Into a 500 ml flask, 189 g of methylmagnesium bromide (1 mol/liter of an ether solution) was charged, and 10.0 g of 4,5-dichloro-3(2H)pyridazinone was gradually added thereto at a temperature of about 15° C. The mixture was stirred at a temperature of from 40° to 50° C. for about 3 hours. The disappearance of the starting dichloropyridazinone was confirmed by thin layer chromatography (developer; ethyl acetate:acetone =2:1, v/v), whereupon the reaction was terminated. The reaction solution was transferred to a separating funnel, and about 300 ml of a saturated sodium chloride aqueous solution was added thereto, and then the mixture was vigorously shaken. The aqueous layer was removed. The organic layer was washed with about 200 ml of water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The brown crystals thereby obtained were recrystallized from ethyl acetate to obtain 4.54 g of the above identified compound having a melting point of from 132° to 134° C. as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28](=[O:29])[NH:31][C@H:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][C@H:33]4[OH:41])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N[C@H]4c5ccccc5C[C@H]4O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-carboxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (1S,2R)-1-amino-indan-2-ol.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:8]([OH:11])[CH2:9][CH3:10])[C:3]([O:5]CC)=[O:4]>Cl>[NH2:1][C@@H:2]([C@H:8]([OH:11])[CH2:9][CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)CC
Agent: Cl
Product: CC[C@@H](O)[C@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
In a 35 ml microwave vial, ethyl (2S*,3R*)-2-amino-3-hydr oxy-pentanoate (0.078 g, 0.48 mmol) was dissolved in a 6.0 M HCl aqueous solution (7.0 mL) and stirred at 130° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the resulting yellowish solid was used without further purification in the following step. MS (ESI) m/z: 134 [M−H]+; (ESI) m/z: 132 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[C:6](Cl)[C:3]=1[C:4]#[N:5].[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)nc(Cl)c(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 2,4,5,6-tetrachloronicotinonitrile (7.6 g, 31.4 mmol) in MeOH/THF (230 ml/230 ml) was added zinc dust (4.0 g, 62.8 mmol) slowly at 0° C. and the saturated NH4Cl solution (105 ml) and the mixture was stirred for 30 minutes. TLC indicated that the reaction is complete. Saturated NH4OAc solution (180 ml) was added to the mixture and the mixture was allowed to stir at room temperature for 30 minutes. The mixture was filtered and was washed with EtOAc (500 ml). The filtrate was washed with brine and dried and concentrated to give a solid. ISCO column purification gave the title compound (4.63 g, 71%). 1H NMR (CDCl3): δ 8.97 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26].CN1CCOCC1>CO>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CC(=O)NCCN
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(=O)NCCNS(=O)(=O)c1ccc2nc(-c3c(C)n[nH]c3N)sc2c1
Yield: 43.9 %

Procedure:
the title compound (52 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), N-(2-aminoethyl)-acetamide (58 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 395.6 (M+1, 100%). Yield=43%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[NH:21][CH2:20][CH2:19]2.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:21]1[CH:22]2[CH2:25][CH2:26][N:18]([CH2:24][CH2:23]2)[CH2:19][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Reactant: C1CN2CCC(CC2)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(N2CCN3CCC2CC3)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
2-Chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (333 mg, 1.32 mmol), 1,4-diazabicyclo[3.2.2]nonane (57%, 195 mg, 0.88 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (58 mg, 0.093 mmol), sodium tert-butoxide (208 mg, 2.17 mmol) and toluene (1.55 mL) were added to a flame dried round bottom flask purged with nitrogen. The mixture was placed in an oil bath at 80° C. for 18 h and then cooled to RT. The mixture was filtered through a pad of celite and washed with chloroform and methanol. The filtrate was concentrated and the residue was purified by chromatography (Biotage, 12M) eluting with 8% methanol in chloroform with 20 drops of NH4OH per liter of eluent to afford 104 mg (34%) of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester: MS (Cl) m/z 343.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]1[C:2]([NH:1][C:24]([N:23]([CH3:27])[CH3:22])=[O:25])=[N:3][S:4][N:5]=1
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Yield: 30.1 %

Procedure:
To a solution of 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-dimethylformamide, 0.24 g of dimethylcarbamoyl chloride was added and the mixture was heated at 120° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain 0.19 g of 3-(2,6-dichlorophenyl)-4(3,3-dimethylureido)-1, 2,5-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([O:18]CC2C=CC=CC=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]([OH:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Yield: 72.9 %

Procedure:
Benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylate (10.03 g) [see Preparation 48] was dissolved in ethanol (200 ml) and hydrogenated over 10% w/w palladium-on-charcoal (2.0 g) at 60 psi (414 kPa) for 18 hours. The reaction mixture was then filtered through a plug of ARBOCEL (trade mark) filter aid and the filtrate evaporated under reduced pressure. The residue was azeotroped with dichloromethane to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid (5.50 g) as a white solid.
Reaction SMILES: [N+](C1C=CC(COC(NCCOC(C=CS[C:21]2[CH2:27][C@H:26]3[N:23]([C:24](=[O:31])[C@H:25]3[C@@H:28]([OH:30])[CH3:29])[C:22]=2[C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])=O)=O)=CC=1)([O-])=O.[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pd]>[OH:30][C@H:28]([CH:25]1[C:24](=[O:31])[N:23]2[CH:26]1[CH2:27][CH:21]=[C:22]2[C:32]([OH:34])=[O:33])[CH3:29]
Reactant: C[C@H](O)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC=CC(=O)OCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](O)C1C(=O)N2C(C(=O)O)=CCC12

Procedure:
The ester (e29) (150 mg) was dissolved in a mixture of dioxan (10 ml) and 0.05 M pH7 phosphate buffer (4.5 ml), and the solution was shaken with 5% palladium on charcoal (200 mg) in an atmosphere of hydrogen for 2 hours. The mixture was filtered over Celite, washed with water (20 ml), and the solution was then concentrated in vacuo to a volume of ca. 20 ml. The solution was washed with ethyl acetate (4×25 ml), and was then freeze-dried to afford (5R,6R)-3-[2-(Z)-2-aminoethoxycarbonyl)ethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (e30) as a solid; λmax. (H2O) 325 nm., σmax. (KBr) 1750, 1690 and 1565-1610 (br) cm-1. (The product contained ca. 5% of the corresponding E-isomer).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3][CH2:2]1.[C:8]1([N:14]2[C:19](=[O:20])[C:18]([Cl:21])=[C:17](Cl)[CH:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[C:8]1([N:14]2[C:19](=[O:20])[C:18]([Cl:21])=[C:17]([S:7][CH:4]3[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]3)[CH:16]=[N:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: SC1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1c(Cl)c(SC2CCCCC2)cnn1-c1ccccc1
Reaction time: 12 h

Procedure:
38.3 parts by weight of cyclohexylthiol were added dropwise to a mixture of 72.3 parts by weight of 1-phenyl-4,5-dichloropyridazin-6-one in 300 parts by volume of methylene chloride, 3 parts by weight of triethylbenzylammonium chloride, and 13.2 parts by weight of sodium hydroxide in 150 parts by volume of water at room temperature (20° C.), and the reaction mixture was kept at this temperature for 12 hours, while stirring vigorously. The organic phase was separated off, washed with twice 100 parts by volume of water, dried and then concentrated. The residue was recrystallized from ethylacetate. 61 parts by weight of 1-phenyl-4-(cyclohexylthio)-5-chloropyridazin-6-one of melting point 125°-127° C. were obtained (compound A1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH3:33]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:33])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@H:10]1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](F)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.930 g, 2.19 mmol) in anhydrous THF (15 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 5.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO3 solution (30 mL), and then extracted with EtOAc (3×30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc2O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as an off-white foam (0.767 g, 80%), which contained two diastereomers.