Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])[CH:17]=[CH:18][O:19][CH3:20])[NH:13][C:12]1=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:23][CH:24](O)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26]>C(N(CC)CC)C.C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])[CH:17]=[CH:18][O:19][CH3:20])[N:13]([CH:24]([OH:23])[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:26])[C:12]1=[O:22])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC=CC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(COC(=O)C(O)O)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC=CC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc(OC)cc1
Yield: 92.3 %

Procedure:
A mixture of (3S ,4R) 3-((1R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-(4-methoxy-2-oxobut-3-en-1-yl)azetidin-2-one (100 mg, 0.3 mM), 4-methoxybenzyl dihydroxyacetate (72 mg, 0.33 mM) and 2 drops of triethylamine in benzene (5 ml) was heated at reflux for 1 hour. The solvent was evaporated and the product purified by subjecting to chromatography on silica, eluting with ether to give 4-methoxybenzyl 2-[(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-[4-methoxy-2-oxobut-3-en-1-yl]-2-azetidinone-1-yl]-2-hydroxy-acetate (147 mg, 93%). IR (film, NaCl) 3310, 1745.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[N:30][CH:29]=[C:28]([CH3:32])[N:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cncc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) in xylene (10 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (329 mg, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:28])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:28][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(C#N)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2ccc(C#N)cc2c1Br
Temperature: 60 °C
Yield: 99.5 %

Procedure:
A mixture of 193 (1.90 g, 7.09 mmol), NBS (1.41 g, 7.20 mmol) and K2CO3 (1.11 g, 8.50 mmol) in MeCN (20 mL) was heated at 60° C. under N2 for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with water (×2), brine and dried. Filtration through silica gel gave tert-butyl 1-bromo-7-cyano-2-naphthylcarbamate (194) (2.45 g, 100%) as a colorless powder. A sample was recrystallised (petroleum ether) to give colorless needles: mp 139-141° C.; 1H NMR (CDCl3) δ 8.58 (d, J=9.1 Hz, 1H), 8.54 (d, J=1.0 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.56 (dd; J=8.3, 1.4 Hz, 1H), 7.36 (br s, 1H), 1.57 (s, 9H); 13C NMR δ 152.3, 136.7, 132.5, 132.0, 131.4, 129.4, 128.3, 125.6, 122.4, 119.0, 111.3, 109.4, 81.9, 28.3. Anal. (C16H15BrN2O2) C, H, N, Br.
Reaction SMILES: C([C@@H]1COC(=O)N1C([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1)=O)C1C=CC=CC=1.[OH-].[Li+].[C:37]([O:40]CC)(=[O:39])C.Cl>C1COCC1.O>[C:31]([O:30][C:28]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C@H:16]([C:37]([OH:40])=[O:39])[CH2:17]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1

Procedure:
To a mixed solution of the compound (17.0 g) obtained in step 4 in THF (60 mL) and water (15 mL) was added at 0° C. 4N lithium hydroxide (35.1 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was acidified with 2N hydrochloric acid. The organic layer was dried, and the solvent was evaporated under reduced pressure to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (7.35 g) as a white powder.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[C:15]4[C:16](=[O:38])[N:17]([CH3:37])[C:18]([CH:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30]C)=[O:29])=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=5)[C:14]=4[CH:13]=[CH:12]3)[CH:7]=[CH:6][C:5]=12.[Li+].[OH-].Cl>O1CCCC1.CO>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[C:15]4[C:16](=[O:38])[N:17]([CH3:37])[C:18]([CH:27]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[C:28]([OH:30])=[O:29])=[C:19]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)[C:14]=4[CH:13]=[CH:12]3)[CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc4nonc4c3)c2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc3nonc3c2)cc1
Temperature: 70 °C

Procedure:
A mixture of the crude methyl 2-(1-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate in Tetrahydrofuran (THF) (1 mL) and Methanol (1 mL) was treated with 2M LiOH (1 mL, 2.000 mmol) and then heated to 70° C. for one hour. The mixture was cooled to 0° C., adjusted to pH <2 with 1N HCl and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min.) to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.77-7.85 (m, 1H) 7.52-7.59 (m, 1H) 7.41-7.49 (m, 2H) 7.36-7.41 (m, 1H) 7.29-7.34 (m, 2H) 7.05-7.13 (m, 1H) 6.09-6.19 (m, 1H) 5.87-6.02 (m, 2H) 5.46-5.52 (m, 1H) 3.66 (s, 3H) 2.45 (s, 3H) 1.00 (s, 9H); LCMS (m/z) ES+=501 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]([N+:24]([O-])=O)=[CH:15][C:14]=2[NH:13][C:12](=[O:27])[C:11]1=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[H][H]>CN(C=O)C.[Pt]=O.O>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]([NH2:24])=[CH:15][C:14]=2[NH:13][C:12](=[O:27])[C:11]1=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3ccccc3c21)OCC
Agent: O=[Pt]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc(N)c3ccccc3c21)OCC

Procedure:
0.3 mmol of (6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester in 10 ml of DMF z.A. is dissolved, and 10 mg of platinum oxide catalyst, which was previously saturated with hydrogen, is added. It is hydrogenated with hydrogen for three hours at normal pressure and room temperature. The catalyst is suctioned off on Celite, the mother liquor is diluted with water and the precipitate that is produced is suctioned off. 44% of theory of (6-amino-2,3-dioxo-1,2,3,4-tetrahydro-benzo[f]quinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained. The latter is described as in Example 1e) or saponified according to standard conditions with HCl to (6-amino-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxalin-1-yl)-methanephosphonic acid (or to its hydrochloride, respectively).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1Oc1cc(Cl)ccc1C2
Temperature: 25 °C

Procedure:
A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1 M., 38 ml.) is added slowly to a solution of 3-chloro-5-methoxyxanthone (15 g.) in tetrahydrofuran (200 ml.). The mixture is refluxed for 2 hours, cooled to room temperature and poured into water. The precipitate is filtered, dried and recrystallised from methanol to give 3-chloro-5-methoxyxanthene, m.p. 106°-108° C.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:9][C:7]1[CH:8]=[C:3]2[C:4]([C:11]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:12]=3[C:13](=[O:14])[O:15]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of methyl 2-(2,4-dimethoxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-(1), 43.5 g, 137 mmol) in anhydrous methylene dichloride (250 mL) was cooled to −78° C., boron tribromide (96.2 g, 384 mmol) was added thereto, then the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −50° C. and methanol (300 mL) was added thereto. The resulting precipitates were filtered off with methanol to give the titled reference compound (18.0 g) as a yellow solid. (Yield 51%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.OS(O)(=O)=O.[C:29]([OH:32])(=[O:31])[CH3:30]>>[CH3:20][C:6]1[CH:5]=[C:4]([CH2:30][C:29]([OH:32])=[O:31])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(CC#N)cc2C)cc1C(C)C
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc(Oc2c(C)cc(CC(=O)O)cc2C)cc1C(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetonitrile (0.75 g, 2.42 mmol) in acetic acid (7 mL) was added a 50% solution of H2SO4 (14 mL). The reaction mixture was heated at 105° C., for 3 h, cooled to room temperature and poured into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetic acid as a brownish solid (0.62 g, 85%, m.p.: 118-120° C.): 1H NMR (300 MHz, CDCl3): δ 7.11 (s, 2 H), 6.82 (d, J=2.7 Hz, 1 H), 6.80 (d, J=8.7 Hz, 1 H), 6.37 (dd, J=3.3, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.61 (s, 2 H), 3.38-3.25 (m, 1 H), 2.11 (s, 6 H), 1.17 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:1); Rf=0.2.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:22][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
Boc-D-methionine (34.2 g, 0.137 mole) and L-leucine methylester hydrochloride (25.0 g, 0.137 mole) was dissolved in 450 ml of methylene chloride and triethylamine (19.15 ml, 13.9 g, 0.137 mole) was added. Dicyclohexylcarbodiimide (62 ml of a 0.5 g/ml solution in CH2Cl2, 0.15 mole) was then added followed by stirring at room temperature overnight. The mixture was filtered and the filtrate was extracted with three 150 ml portions of dilute citric acid and three 150 ml portions of 1N sodium biocarbonate. After drying with sodium sulfate, the solution was concentrated in vacuo. Chromatography of the crude material on silica gel eluting with ethyl acetate-hexane (1:1; 2:1) followed by ethyl acetate gave pure product which crystallized from ethyl acetate-hexane to give 28.4 g of product (53%), m.p. 61°-64°. The nmr spectrum was consistent with the expected structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(Cl)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cl)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 0.90 g (2.532 mmol) of the product of Example 2 in 10 mL of DMF was added 0.127 g (3.165 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperatue and then 0.38 mL (3.165 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/liexanes to provide 0.44 g (39%) of the desired product as white crystals. CI Mass Spec: 446 (M+H).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: SCc1ccccc1
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(N)[n+](CCCC)c(SCc2ccccc2)c1C#N
Temperature: 100 °C
Yield: 49.4 %

Procedure:
3.15 gms (0.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano pyridinium chloride (compound 6 - Table 1), 1.24 gms (0.01 mole) of benzyl mercaptan and 1.0 gm (0.01 mole) of triethylamine was dissolved in dimethylformamide and heated at 100°C for 1 hour. The dimethylformamide was evaporated off, ethanol added and 2.0 gms (50% yield) of 2-amino-6-benzylmercapto-1-n-butyl-4-n-butylamino-5-cyano pyridinium chloride (compound 75 - Table 5) crystallised out and was recrystallised from ethanol (MPt 145° - 147°C).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[C:3]([CH3:12])[CH:4]=[CH:5]2)=[N:9]1
Reactant: N#C[Cu]
Reactant: Cc1ccc2cn(C)nc2c1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2cn(C)nc2c1C#N
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,6-dimethyl-2H-indazole (1 equiv.) in NMP, was added CuCN (2 equiv.) and heated at 130 oC for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: [C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:31](=[N:37][OH:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[C:6]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:38][N:37]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=4)=[CH:23][CH:22]=3)[C:10](=[O:29])[C:7]=2[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#Cc1ccc(N2C(=O)c3[nH]nc(C(C)(C)C)c3C2c2ccccc2OC)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(N3C(=O)c4[nH]nc(C(C)(C)C)c4C3c3ccccc3OC)cc2)on1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a mixture of 3-t-butyl-5-(4-ethynylphenyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (1.51 g, 3.9 mmol), ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) and THF (4 mL), triethylamine (1.09 mL, 7.8 mmol) in THF (3 mL) was added dropwise under ice-cooling conditions, and the mixture was stirred at 0° C. for 4 hr. Ethyl 2-chloro-2-hydroxyiminoacetate (1.19 g, 7.8 mmol) was added, and further triethylamine (0.81 mL, 5.9 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at 0° C. for 2 hr and left stand overnight. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 3-t-butyl-5-[4-(3-ethoxycarbonyl-5-isoxazolyl)phenyl]-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]-pyrazol-6-one (1.26 g, 64%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-]>O1CCCC1.CC(=O)OCC>[F:18][C:2]1([F:1])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Into a solution of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (900 mg, 3.39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBH4 (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0° C. The resulting solution was stirred overnight at room temperature, then was diluted with EA and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate as reddish oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:30]=[C:31]([CH3:32])[C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (210 mg, 46%). MS (ISP) 444.3 [(M+H)+]; mp 194-195° C.
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=[CH2:3].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of nucleoside 2 (35.0 g, 7.31 mmol) in anhydrous pyridine (23 cm3) at 0° C. was added methanesulphonyl chloride (1.69 cm3, 21.89 mmol). The reaction mixture was stirred for 1 h at room temperature, water (100 cm3) was added and extraction was performed using dichloromethane (3×150 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×200 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane/methanol (99:1) as eluent to give 3 as a white solid material (3.64 g, 89%). δH (CDCl3) 8.95 (1 H, br s, NH), 7.71 (1 H, d, J 1.1, 6-H), 7.39-7.25 (10 H, m, Bn), 6.52 (1 H, d, J 8.0, 1′-H), 5.90 (1H, m, 2″-H), 5.34 (1 H, d, J 7.9, 2′-H), 5.20-5.09 (2 H, m, 3″-Ha, 3″-Hb), 4.91 (1 H, d, J 11.2, Bn), 4.68 (1 H, d, J 11.3, Bn), 4.64 (2 H, s, Bn), 4.33 (1 H, br s, 4′-H), 3.81 (1 H, dd, J 2.5, 11.1, 5′-Ha), 3.73 (1 H, dd, J 1.1, 11.1, 5′-Hb), 3.08 (1 H, dd, J 5.5, 5.7, 1″-Ha), 2.99 (3 H, s, CH3), 2.68 (1 H, m, 1″-Hb), 1.51 (3 H, d, J 0.8, CH3). δC (CDCl3) 163.4 (C-4), 150.8 (C-2), 137.9, 136.3 (Bn), 135.5 (C-6), 131.0 (C-2″), 128.8, 128.3, 127.5, 127.2 (Bn), 119.3 (C-3″), 111.6 (C-5), 84.1, 83.6, 82.4, 82.2 (C-1′, C-2′, C-3′, C-4′), 73.7, 68.9 (Bn), 66.2 (C-5′), 38.7 (CH3), 33.0 (C-1″), 11.9 (CH3) Found: C, 60.5; H, 5.8; N, 4.9. C28H32N2O8S requires C, 60.4; H, 5.8; N, 5.0%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]3[CH2:31][CH2:30]3)=[CH:21][CH:20]=2)[C:6]([S:9][C:10]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][CH2:11]2)=[N:7][N:8]=1>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]3[CH2:31][CH2:30]3)=[CH:21][CH:20]=2)[C:6]([S:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:11][CH2:12][CH2:13]2)=[N:7][N:8]=1
Reactant: CCOC(=O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.387 mL, 0.387 mmol, 3 eq) was added to a solution of ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate (61 mg, 0.129 mmol) in THF/methanol (2/1, 3 mL) and the mixture stirred at room temperature for 18 h. The mixture was acidified with HCL (1N aqueous, 0.645 mL, 0.645 mmol, 5 eq), concentrated, water (10 mL) added and extracted with diethyl ether (2×15 mL). The combined organic extracts were dried over calcium chloride and concentrated to give 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylic acid as an off-white solid (43 mg, 75%).