Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
A process according to claim 1, in which (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one is treated with tert-butyldimethyl chlorosilane in the presence of 4-dimethylaminopyridine in an organic solvent and the (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldi methylsilyl-azetidin-2-one (III) is isolated.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:20]([O-])([OH:22])=[O:21].C(O)(=O)C.N([O-])=O.[Na+]>O>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]=2[CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C)cccc2C)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2c(C)cc([N+](=O)[O-])cc2C)cc1

Procedure:
The sulfonamide intermediate of Example 4 (6.9 g, 0.025 mole) was added to a solution of 6.3 ml of concentrated nitric acid in 50 ml of water, followed by addition of 50 ml of glacial acetic acid and 0.18 g of sodium nitrite. The mixture was heated at reflux for one hour, then poured into 100 ml of water. The crude product thus isolated was recrystallized from ethanol to give 6.5 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([OH:20])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:27][CH2:28][OH:29]>Cl.Cl.CCO>[CH2:28]([O:29][C:11](=[O:19])[C@H:10]([OH:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)[CH3:27]
Reactant: CCO
Reactant: CC(C)(C)C(=O)N1C(=O)[C@H](O)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 92.5 °C

Procedure:
(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-hydroxypyrrolidin-2-one (56 g, 0.156 mol) was dissolved in EtOH (700 mL) and 12N HCl (700 mL). The mixture was heated to 90-95° C. for 20 hours. The mixture was concentrated on an 80° C. water bath under reduced pressure. EtOH (100 mL) was added to the residue, and the resulting mixture was filtered to yield a yellow solid. This solid was suspended in 3N HCl/EtOH (800 mL). The mixture was refluxed for 3 hours. The solution was concentrated to a reduced volume (˜200 mL volume), and ether (200 mL) was added. The resulting slightly yellow solid was filtered and dried under reduced pressure to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (43 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH:33]([CH3:35])[CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:36]([Cl:38])=[O:37])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH:33]([CH3:35])[CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cncc(O)c1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-hydroxynicotinic acid (10 g, 71.9 mmol) in MeOH (100 mL) was added sulfurous dichloride (1 mL) drop wise over 5 min. The resulting mixture was stirred at room temperature overnight. The resulted solution was added 100 mL of NaHCO3. The precipitate was filtrated and washed with MeOH for several cycles to give 8.5 g of A031-2 (75% yields), which was used for the nest step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 43.6 %

Procedure:
2-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.60 g, 44%). 1H NMR (CD3COCD3): δ 8.30 (d, 1H), 7.86 (m, 3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O)=[O:14])[CH3:11].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][C:16]=1[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NCc2ccc(F)cc2)CCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzylamine (12.1 g, 97.5 mmol) was added to a solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (15.25 g, 97.6 mmol) in toluene (225 mL) at 23° C. Glacial acetic acid (6.15 mL, 107 mmol) was then added, producing a large amount of white solid. The reaction mixture was heated to 70° C. in an oil bath, whereupon most of the solids dissolved. After stirring for 2 h at 70° C., a Dean-Stark apparatus and reflux condenser were fitted to the reaction flask and approximately 40 mL of liquid (predominantly toluene) was removed by distillation over 45 min (oil bath temperature=145° C.). The mixture was allowed to cool to 23° C. and was used in the next step. A small aliquot of the crude reaction mixture was concentrated in vacuo to afford the desired product, 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester as an orange oil: 1H NMR (CDCl3) δ: 1.28 (3H, t, J=7.5), 1.79-1.86 (2H, m), 2.51-2.56 (4H, m), 4.15 (2H, q, J=6.9), 4.34-4.36 (2H, m), 6.98-7.03 (2H, m), 7.19-7.23 (2H, m), 7.73 (1H, bs).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15]I>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([NH:1][CH3:15])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CI
Product: CNc1cc(OC)cc(OC)c1C(N)=O
Temperature: 110 °C
Yield: 5 %

Procedure:
2-Amino-4,6-dimethoxybenzamide (0.5 g, 2.55 mmol) and methyl iodide (0.17 mL, 2.81 mmol) were mixed in a closed bomb and heated at 110° C. for 14 h. The compound was washed with a dichloromethane-methanol mixture. After removing the solvent, the crude was purified by silica gel column chromatography (40 g) employing 1-5% methanol in dichloromethane to give 2,4-dimethoxy-6-methylamino-benzamide (0.027 g, 50.4%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:10]1[N:15]=[C:14](O)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C>[C:6]([C:10]1[N:15]=[C:14]([Cl:3])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Temperature: 40 °C
Yield: 85 %

Procedure:
In cold (˜0° C.) POCl3 (20 mL) was dropped triethylamine (0.55 mL) with stirring. To this was added in parts ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 9.72 mmol). The mixture then warmed to 40° C. and stirred under Argon for 1 hour. The mixture was evaporated until free of POCl3, diluted with CHCl3 (100 mL) and poured carefully into ice (300 mL). The solution was stirred until it reached RT. The organic phase was separated, washed with sodium bicarbonate (100 mL), water (100 mL), dried (Na2SO4) and concentrated in vacuo to give ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (2.0 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 4.34 (q, J=6.8 Hz, 2H), 1.33 (s, 9H), 1.27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 243.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]=[O:23])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:23])[CH:28]=[CH2:29])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a 1 L 3-neck round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (7.96 g, 21.9 mmole) and THF (260 mL). The resulting slurry was cooled to −78° C., and vinylmagnesium bromide (175 mL, 1.0 M in THF) was added dropwise over 30 minutes. The mixture was stirred at −78° C. for 2 hours, then warmed to -10° C. over 30 minutes and maintained at −10° C. for an additional 2 hours. The reaction was then quenched by addition of saturated aqueous ammonium chloride (200 mL), and extracted into EtOAc (2×200 mL). The organic layers were collected, washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to provide 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 91%) as an orange-yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.52 (br s, 1H), 10.38 (br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.24 (td, 1H, J1=9.1 Hz, J2=11.7 Hz), 6.02 (ddd, 1H, J1=5.9 Hz, J2=10.6 Hz, J3=17.2 Hz), 5.41 (app d, 1H, J=5.5 Hz), 5.33 (dt, 1H, J1=1.6 Hz, J2=17.2 Hz), 5.17 (dt, 1H, J1=1.2 Hz, J2=10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z): 393 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: Nc1cc(O)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (4.76 g, 30 mmol) and 3-amino-4-chlorophenol (4.31 g, 30 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.15 g, 30 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate (80 mL), and the mixture was washed successively with water (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate (15 mL)/n-hexane (15 mL), and the precipitated crystals were collected by filtration, washed with diisopropyl ether (20 mL), and dried under reduced pressure to give the title compound (6.74 g, 85%) as brown crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH2:10][O:11][CH3:12])[CH:9]=1.[Mg].CN(C)[CH:17]=[O:18]>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH2:10][O:11][CH3:12])[CH:9]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: COCc1cc(Br)cc(COC)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCc1cc(C=O)cc(COC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Grignard solution was prepared from 13.4 g (54.7 mmol) of 3,5-bis(methoxymethyl)bromobenzene, 3.25 g (134 mmol) of magnesium, and 60 ml of tetrahydrofuran (hereinafter abbreviated as “THF”) in a reaction vessel of 200 ml. Subsequently, 30 ml (387 mmol) of dimethylformamide (DMF) was added dropwise into this solution at 0° C. and further agitated at room temperature for 3 hours after completion of the addition. Solvent was removed from the obtained reaction liquid by reduced pressure and 2N hydrochloric acid was added. The obtained reaction mixture was extracted 3 times with 50 ml of diethyl ether and the organic layer was collected and dried with anhydrous magnesium sulfate after rinsing with water. Residues obtained by the removal of solvent were purified by silica gel column chromatography to obtain 8.36 g (43.0 mmol) of the target 3,5-bis(methoxymethyl)benzaldehyde as a viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][Br:31])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a heterogeneous, refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was quickly added N-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run to near 50% completion. Additional benzoyl peroxide (12 mg, 0.05 mmol) was added, and the reaction checked after another 1 hour. The reaction was still not complete, and so more benzoyl peroxide (4 mg, 0.017 mmol) was added. After 30 minutes, the reaction was completed. The mixture was cooled to 23° C. and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 4:1) to provide the product (yield: 530 mg, 74%). 1H NMR (300 MHz, CDCl3) δ 3.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.67-7.74 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7 Hz, 2H), MS (APCI+) m/z 437 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O.[CH3:25][N:26]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([NH:34][C:35]2[CH:43]=[C:42]([Sn](C)(C)C)[CH:41]=[C:40]3[C:36]=2[CH:37]=[N:38][N:39]3S(C2C=CC=CC=2)(=O)=O)=[O:33])=[N:27]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH:4]=[CH:5][NH:6]2)=[C:2]([C:42]2[CH:41]=[C:40]3[C:36]([CH:37]=[N:38][NH:39]3)=[C:35]([NH:34][C:32]([C:28]3[C:29]([CH3:31])=[CH:30][N:26]([CH3:25])[N:27]=3)=[O:33])[CH:43]=2)[CH:10]=1)#[N:12]
Reactant: N#Cc1cc(Br)c2ccn(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c2c1
Reactant: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn(C)nc1C(=O)Nc1cc(-c2cc(C#N)cc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
4-Bromo-1-[(4-nitrophenyl)sulfonyl]-1H-indole-6-carbonitrile (70 mg), 1,4-dimethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-3-carboxamide (51 mg) and Pd(PPh3)4 (22 mg) were weighed to a microwave vial and DMF (1 ml) was added. The reaction was heated at 120° C. for 1 h, then cooled and passed through a silica (1 g) cartridge, which had been pre-washed with methanol and washed through with methanol:DCM. The solvent was dried under nitrogen blowdown. The residue was purified using MDAP (method K but using an isocratic 50:50 solvent mix over 10 min). Purified fraction was dissolved in methanol (1 ml) and 2M NaOH (aq) (2 ml) was added and the reaction left at RT over the weekend. The reaction was neutralised using 2M HCl (aq) and dried under nitrogen blowdown. The residue was taken into water and extracted into ethyl acetate. The ethyl acetate was passed through a hydrophobic frit, then through an SAX cartridge pre-conditioned with ethyl acetate. The solvent was evaporated by nitrogen blow down to give title compound, 12 mg.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[N:29]O)[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH2:29])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=NO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -40 °C

Procedure:
4-[2,4-Bis(tert-butyldimethylsilyloxy)phenyl]cyclohexanone oxime (120 mg) was dissolved in anhydrous methanol (10 ml) with stirring. The solution was cooled to −40° C., and nickel chloride hexahydrate (133 mg) was added. Stirring was continued for 10 min before sodium borohydride (42 mg) was added in one portion. The reaction mixture was stirred at −40° C. for 20 min and water (0.5 ml) was added. The reaction mixture was allowed to warm to room temperature with stirring. Silica gel was added and the solvent removed in vacuo. Purification via flash column chromatography (SiO2 eluting with CH2Cl2:MeOH:NH4OH, 44:50:6 v/v) afforded the desired product as a pale brown oil (83 mg, 71%) and a mixture of diastereoisomers. δH(CD3OD): 0.22 (6H, s), 0.27 (6H, s), 1.02 (9H, s), 1.08 (9H, s), 1.24-1.40 (1H, m), 1.42-1.57 (1H, m), 1.57-1.68 (1H, m), 1.71-1.90 (4H, m), 1.99-2.07 (1H, m), 2.84-2.98 (1H, m), 4.28-4.40 (1H, m), 6.34 (1H, d), 6.44 (1H, t), 7.04 (0.5H, d), 7.16 (0.5H, d); m/z (ES+) 436 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:24]([C:29](OC)=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19]3[S:21][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([OH:30])[N:20]=3)=[C:12]2[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1O
Temperature: 100 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride(3.45 g, 10.3 mmol) in DMF (100 mL), was added 94% dimethyl chloromalonate (2.79 mL, 20.6 mmol) and the mixture was stirred for 7.5 h at 100° C. The reaction mixture was allowed to cool to 50° C. and then was dropwise added water (100 mL). The resulting precipitate was collected by filtration and then washed with EtOH (20 mL) and diethyl ether (20 mL) to obtain methyl 2-[5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-4-hydroxy-1,3-thiazole-5-carboxylate as a orange solid, which was used in the next step without further purification. 1H-NMR (DMSO-d6, 300 MHz) δ 2.59 (3 H, s), 3.75 (3 H, s), 5.27 (2 H, s), 6.87 (1 H, dd, J=2.6, 7.6 Hz), 7.32-7.51 (3 H, m), 7.52-7.64 (2 H, m), 7.88 (1 H, d, J=2.6 Hz), 8.67 (1 H, d, J=7.6 Hz), 11.79 (1 H, br s).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[CH3:8][S:9](Cl)(=[O:11])=[O:10].O>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][S:9]([CH3:8])(=[O:11])=[O:10]
Reactant: OC[C@@H]1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1CCCO1

Procedure:
To a solution of (S)-1-(tetrahydrofuran-2-yl)methanol (7.95 g) in pyridine (35 ml) was added, at −15° C., methanesulfonyl chloride (7.47 g), and the reaction was stirred at 0° C. for 5 hours. After the addition of water, the mixture was extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 180.22 (C6H12O4S); MS (ESI): 181 (M+H+). Analogously, methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester was synthesized.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12](=[CH:11][C:10]3[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=3[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:22])[NH:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (240 mg) suspended in ethylene glycol (5 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (2 pellets) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and purified on a silica gel column using ethyl acetate:hexanes:glacial acetic acid 50:50:10 as eluent to give 45 mg (21%) of 3-[2-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.