Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:29](=[O:31])[CH3:30])[C@@H:7]([CH3:22])[CH2:8][N:9]2[S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3ccc(Br)cc32)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
A 2-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirring, and thermocouple was charged with (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (45.0 g, 118 mmol), dichloromethane (900 mL), and pyridine (14.32 mL, 177 mmol). The mixture was cooled to 0° C. and acetyl chloride (10.07 mL, 142 mmol) was added slowly while maintaining the internal temperature below 10° C. The reaction mixture was held cold (ca. 30 min) and then warmed to rt. After 1 h, the reaction was diluted with dichloromethane (200 mL), and the solution was washed with 1 M aqueous HCl (2×100 mL) and water (100 mL). The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (eluting with 3:1 dichloromethane-ethyl acetate) to afford (S)-1-(6-bromo-2-methyl-4-tosyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (54.15 g, 108%), which contained 4.1 wt % ethyl acetate, as a colorless to yellow oil. MS (ESI, pos. ion) m/z 424 [M+1]+.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][CH:4]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: [N-]=[N+]=NC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 3-azido-1-(p-nitrobenzyloxycarbonyl)azetidine (2.15 g, 7.76 mmol) (obtained as described in Reference Example 54(3)) in acetonitrile (65 ml) was added triphenylphosphine (2.14 g, 8.14 mmol), and the mixture was stirred in an oil bath (70° C.) for 2 hours. After checking the disappearance of the raw materials, sodium sulfate decahydrate (2.62 g, 8.14 mmol) was added thereto and then the reaction mixture was stirred for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give 3-amino-1-(p-nitrobenzyloxycarbonyl)-azetidine (1.87 g, yield 96%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C(=Cc1ccccc1)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 5-hydroxyindole (0.25 g) in acetonitrile (10 mL) was added cesium carbonate (1.22 g) and cinnamyl bromide (0.37 g). The suspension was stirred under nitrogen at ambient temperature overnight. Cesium salts were removed by filtration and washed with acetone. The residue left on concentrating the combined filtrate and washings was chromatographed over silica eel with a mixture of ethyl acetate and hexanes and crystallized from ether with hexanes to give 0.23 g of the title compound. MS CI (MH+)=250
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:31])=[CH:33][CH:34]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(=O)c5ccccc5)cc4)cc23)CC1
Yield: 74.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 30.0 mg (0.131 mMol) 4-(benzoyl)benzoic acid, 14.4 mg (75%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]=1[C:4]#[N:5].[OH-:21].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]=1[C:4]([NH2:5])=[O:21]
Reactant: N#Cc1c(Cl)cccc1Oc1cnc2ccccc2c1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(Cl)cccc1Oc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.18 g of 2-chloro-6-(quinolin-3-yloxy)-benzonitrile was dissolved in 5 ml of 80% sulfuric acid and the mixture was stirred for 3 hours at 100° C. After being neutralized with an aqueous solution of sodium hydroxide, the liquid was separated with ethyl acetate, the organic layer was concentrated and 1.03 g of 2-chloro-6-(quinolin-3-yloxy)-benzamide (Compound Number 20) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[N:20]O)[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1.Cl[CH:23]=[CH:24][C:25]#[N:26]>O1CCCC1.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]([C:25]#[N:26])=[CH:23][NH:20][C:15]=2[C:16]([F:19])([F:18])[F:17])=[CH:10][CH:9]=1
Reactant: N#CC=CCl
Reactant: ON=C(Cc1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Potassium-t-butoxide (2.46 g, 0.022 mol) is added in portions to a solution of 3-(p-chlorophenyl)-1,1,1-trifluoro-2-propanone oxime, (E)-, or (Z)-(4.75 g, 0.02 mol) in tetrahydrofuran (20 mL) at such a rate that the temperature if maintained at 25°-30° C. (ice-water bath). The resulting solution is stirred for 15 minutes and then added dropwise to a solution of β-chloroacrylonitrile (1.75 g, 0.02 mol) in tetrahydrofuran (15 mL) at 15°-10° C. over 1/2 hour. The ice bath is removed and the reaction mixture is stirred for 1 hour, diluted with water, made acidic with a small amount of dilute HCl and extracted with ether. The combined ether extracts are washed with water and brine and dried (Na2SO4). Concentration in vacuo gives an oil which is dissolved in methylene chloride and filtered through a bed of flash column silica gel (30 mL size) and washed with an ethyl acetate/methylene chloride mixture (1:1). The filtrate is evaporated and the residual semi-solid is crystallized from methylene chloride/hexanes to give the title product as a yellow solid (2.10 g): mp 162.5°-164.0° C. IR (Nujol) 3200, 2250 cm-1, 1H NMR (DMSO-d6) δ7.42, 7.56 (AB, JAB =8.3 Hz, ArH), 8.03 (s, 1H, 2H); 19F NMR δ-51.2; 13C NMR δ94.2 (C-3), 115.0 (CN), 116.6 (q, 2JCF =38.3 Hz, C-5), 120.6 (q, 1JCF =268.7 Hz, CF3), 127.0 (q, 3JCF =3.5 Hz, C-4), 128.6 (C-2') 129.1 (C-1'), 129.7 (C-2), 130.8 (C-3'), 133.4 (C-4').
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.O>C1C=CC=CC=1>[CH3:18][CH:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCCC(C)Oc1ccc(CO)cc1

Procedure:
42 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is dissolved in 250 ml of benzene and, with stirring, treated dropwise with 50 g of 70% bis(2-methoxy-ethoxy)sodium aluminum hydride. The reaction solution is further stirred at 25° C. for 5 hours and thereafter treated with water. The organic phase is separated off, dried under sodium sulfate, carefully filtered (using a filter aid) and evaporated under reduced pressure. There is obtained a residual of p-[(1,5-dimethylhexyl)oxy]benzyl alcohol; B.P. 180°-182° C./1.0 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].Br[CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Temperature: -17 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5.0 g, 24.5 mmol) in DMF (100 mL) was added potassium bistrimethyl silyl amide (49 mL of 0.5 M solution in toluene, 24.5 mmol) at 0° C. The reaction mixture was stirred for 20 minutes and was cooled to −17° C. A solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1 (A) (6.9 g, 27 mmol) in DMF (50 mL) was added dropwise so the internal temperature remained below −15° C. The reaction mixture was stirred at −16° C. for 1 hour, was warmed to room temperature and was diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and was concentrated. The resulting pale brown solid was triturated with ether to obtain 3.2 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide as a white powder. The filtrate was concentrated and the residue was triturated with ether/hexanes. The solid was collected by filtration to give a second crop of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (3.4 g). MS 380.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].C([Li])(CC)C.[C:15](=[O:17])=[O:16]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:17])=[O:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C=O
Agent: [Li]C(C)CC
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
Accordingly, the invention also provides a process for the preparation of N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamine, characterized in that in the first stage a) according to the invention 2-bromo-5-chlorotoluene is reacted with a secondary or tertiary organolithium compound, particularly preferably sec-butyllithium, and CO2 to give the first intermediate 4-chloro-2-methylbenzoic acid, in stage b) a methylsulfonyl group is introduced by reacting 4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfite and methyl iodide to give the corresponding intermediate 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
The 1-benzyl-4-aminopiperidine prepared in Example 30 was treated with p-chlorobenzoyl chloride in a similar manner to that described in the same example and the product converted to a salt.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1>C(#N)C>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2)[S:32]([C:29]1[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=1)(=[O:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: O=C1NCCc2cc(NCc3ccccc3)ccc21
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3=O)n1
Temperature: 150 °C
Yield: 14 %

Procedure:
To a stirred solution of 6-benzylamino-3,4-dihydro-2H-isoquinolin-1-one (45 mg, 0.18 mmol) and pyridine (31 μl, 0.39 mmol) in anhydrous acetonitrile (1 ml) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (70 mg, 0.39 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The solvent was evaporated in vacuo and the crude residue purified by preparative tlc (5% methanol in dichloromethane) to afford the title compound as a yellow solid (10 mg, 14%). HPLC retention time 3.83 min. Mass spectrum (ES+) m/z 397 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)/C=C/c1cccc(OC)c1

Procedure:
A mixture of (E)-3-(3-methoxyphenyl)acrylic acid (3.56 g, 20 mmol). K2CO3 (3.1 g, 22 mmol), and iodomethane (4.0 g, 28 mmol) in acetone (20 mL) was heated to 70° C. for 16 hours. The mixture was concentrated and partitioned between water and ethyl acetate to afford the crude title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[NH2:16][C@@H:11]1[C:10](=[O:17])[N:9]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][C@@H:8]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1CCC2CCCCC(N)C(=O)N21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CCCC[C@H]2CC[C@@H](C(=O)O)N2C1=O
Reaction time: 8 h

Procedure:
The crude 6-amino-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 18, obtained from the previous reaction is dissolved in a mixture of THF:water (3:1) (40 mL) and treated with a catalytic amount of LiOH. The reaction solution is allowed to stir overnight then concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: NCCCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (855 mg, 5.14 mmol), HOBt (701 mg, 5.14 mmol, 1.0 eq.) and 3-phenylpropylamine (0.969 ml, 6.68 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.16 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C([O-])(O)=O.[Na+]>COCCOC>[CH2:31]([O:30][C:28]([C:27]1[N:23]=[C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C:10]3[C:9]([F:24])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=3)=[CH:22][N:21]2[CH:26]=1)=[O:29])[CH3:32]
Reactant: COc1ccc(Cc2ccc(N)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(Cc3ccc(OC)c(-c4cccc(Cl)c4)c3F)ccc2n1
Yield: 27.3 %

Procedure:
Into a 20 mL vial with stir bar was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine (P-252, 565 mg, 1.65 mmol), ethyl bromopyruvate (0.52 mL, 4.12 mmol), and 5 mL of DME. The reaction was stirred at room temperature for 18 hours, then basified with NaHCO3 (aq. sat). The product was extracted with ethyl acetate and concentrated. Purification by flash column chromatography (5% acetone/dichloromethane) provided a tan solid which was triturated with ether to obtain 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (I-37) (198 mg, 27%) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27](C)[C:28]([OH:30])=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].[CH3:44]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC[C@@H](O)C>C(Cl)Cl>[OH:30][C@@H:28]([CH3:44])[CH2:27][NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:41])[C:9](=[O:40])[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:11]2=[N:15][CH:14]=1)(=[O:18])=[O:17])=[O:25]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@H](O)CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a stirred solution of (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (82 mg, 0.14 mmol) in anhydrous methylene chloride (1 mL) and HATU (82 mg, 0.21 mmol) was added DIPEA (73 μL, 0.42 mmol) and the mixture was stirred for 10 min at room temperature under nitrogen. (S)-1-Amino-propan-2-ol (0.21 mmol) was added and the mixture was stirred for 2 h at room temperature under nitrogen. The material was purified by column chromatography over silica gel to provide 62 mg of the title compound as a white solid (M+1, 631.2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:60][O:61][C:62](=[O:65])[CH2:63]Br>CCOCC.C(Cl)Cl>[C:62]([CH2:63][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:12]2[CH2:16][C@@H:15]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C@H:14]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH2:13]2)=[O:11])[CH:3]=[CH:2]1)([O:61][CH3:60])=[O:65]
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](c2ccsc2)C1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.126 g (0.258 mmol) of 1-(7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 6 mL of ether was added 0.082 g (0.31 mmol) of 18-crown-6 and 0.31 mL (0.31 mmol) of potassium t-butoxide (1M in t-BuOH). After stirring the reaction mixture at rt for 15 min, the reaction mixture was cooled to 0° C. and to it was added 0.034 mL (0.36 mmol) of methyl-2-bromoacetate. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with sat. NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated and purified by chromatography (silica, hexanes: acetone, 3:1) to give the title compound.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.N1CCCCC1>[CH:12](=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CC(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Reaction time: 24 h
Yield: 72.1 %

Procedure:
To a solution of 1,3-indandione (43.8 g) and piperidine (44 mg) in dry benzene (500 ml) was added benzaldhyde (31.8 g). The mixture was heated to reflux and the water generated was removed by Dean-Stark trap. After 24 hours, the mixture was evaporated to dryness. The residue was recrystallized from ethanol (200 ml) to give 2-benzylidene-1,3-indandione as a yellow solid (50.6 g).
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:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(NS(=O)(=O)c2ccccc2N)cnc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1OC
Yield: 49 %

Procedure:
The title compound (257 mg, 0.77 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide (486 mg, 1.57 mmol), 1,1′-carbonyldiimidazole (1.02 g, 6.29 mmol) and triethylamine (0.44 mL, 3.14 mmol) in DMF (3 mL) using the methods of (IntA14), step 3.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:3]([NH:2][S:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)(=[O:29])=[O:28])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(CC(=O)O)c1ccccc1O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.1 g of 3-amino-3-(2-hydroxyphenyl)propionic acid hydrochloride, prepared according to J. Agric. Food Chem., 1977, 25, 965, are dissolved in 25 ml of dioxane and 10 ml of 1N NaOH are added; 1.12 g of 2-naphthalenesulphonyl chloride are gradually added while maintaining the pH at 11.5-12 by addition of 1N NaOH. After stirring for 2 hours at RT, the reaction medium is diluted in water, washed with EtOAc (twice) and then acidified to pH=1.5-2 by addition of 6N HCl. The white precipitate formed is drained, washed with water and dried in order to obtain 0.82 g of the expected product, m.p.=190-200° C.