Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN=[N+]=[N-])C1

Procedure:
A solution of EXAMPLE 258A (1.66 g) and sodium azide (0.581 g) in anhydrous N,N-dimethylformamide (10 mL) was stirred at 90° C. for 4 hours. The mixture was cooled and concentrated to dryness. The residue was taken up in 5% aqueous sodium carbonate solution and extracted with methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give a solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[NH2:20]
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(N)Cc2ccccc2Br)cc1
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a suspension of 2-bromobenzyl bromide (500 mg, 2.00 mmol) and 4-methoxyphenylhydrazine hydrochloride (348 mg, 2.00 mmol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (1.38 g, 10.0 mmol). The reaction mixture was heated at 90° C. for 4 hours. The reaction was partitioned between water and methylene chloride. The methylene chloride was dried (MgSO4), concentrated and purified by SiO2 chromatography with 10-50% ethyl acetate/hexanes to give 298 mg of the title compound. LC-MS (C14H15BrN2O calculated 306) m/z 307 (M+H).
Reaction SMILES: [CH2:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:14]([O-:16])=[O:15]>O.CO>[N+:14]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:16])=[O:15]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Freshly distilled diethyl methylene-malonate (8.0 g, 0.046 mol) was added dropwise with stirring over a 10 min period to a solution of 16 g (0.1 mol) of nitroform in 25 ml of water and 40 ml of methanol at 0°-5°. The mixture was stirred 16 hrs at room temperature and was then extracted with 100 ml of methylene chloride. The methylene chloride solution was washed with 10% sodium bicarbonate and with water, dried over sodium sulfate and stripped of solvent under vacuum. Column chromatography on 200 g of silica gel (CCl4 --CH2Cl2), filtration through charcoal and removal of solvent gave 13.0 g (87%) of diethyl 2,2,2-trinitroethylmalonate, mp 24°-25°; NMR (CDCl3), 4.23 (q, 4 H, J=7 Hz, CH2CH3), 3.80 (m, 3 H, CH--CH2) and 1.33 (t, 6 H, J=7 Hz, CH3); IR (neat) 1730 (C=O) and 1600 (NO2) cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Yield: 16.3 %

Procedure:
Using 5-methylsalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][OH:22]>CCO.C(#N)C>[OH:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Solvent: CC#N
Solvent: CCO
Product: O=c1cc(-c2ccc(OCCO)cc2)oc2ncccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a 100 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.0 g, 4.18 mmol) in EtOH (10 mL) and acetonitrile (50 mL). 2-Chloroethanol (2.05 g, 25.0 mmol) was added slowly and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by column chromatography, using 2% MeOH in dichloromethane to afford 2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one (380 mg, 32% yield). MS (ES) m/z: 284.94 (M+1), 283.95 (M); Mp. 157-159° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([C:26](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)c1
Yield: 97 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole, and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 195 mg (97%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (175 mg), hydroxylamine hydrochloride (50 mg), potassium carbonate (70 mg), ethanol (1 mL), and water (1.5 mL) is heated under reflux for 2 h. The reaction mixture is concentrated in vacuo and chromatographed on silica gel (dichloromethane/methanol 92:8→60:40) to give the title compound. LC (method 5): tR=0.65 min; Mass spectrum (ESI+): m/z=417 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14]([O:21][C:22]([CH:24]1[CH2:36][C:35]2[C:34]3[C:29](=[C:30]([Cl:37])[CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]=2[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22]([CH:24]1[CH2:36][C:35]2[C:34]3[C:29](=[C:30]([Cl:37])[CH:31]=[CH:32][CH:33]=3)[N:28]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:27]=2[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)C1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cccc(Cl)c31)CC(C(=O)OCc1ccccc1)CC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Cesium carbonate (6.32 g, 19.2 mmol) and ethyl bromoacetate (1.16 ml, 10.2 mmol) are added to a stirred solution of 8-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid benzyl ester (2.17 g, 6.4 mmol) in dry DMF (20 ml). The reaction mixture is stirred at 60° C. for 3 h. The precipitate is filtered off and rinsed thoroughly with acetone. The filtrate is concentrated and the residue is purified by flash chromatography on silica gel (heptane/EtOAc 4:1) to afford pure title compound as a yellow solid (2.54 mg) in 93% yield. tR (LC-5) 1.14 min; ESI-MS (positive ion): m/z 426.16 [M+H]+ (calcd 425.91 for C24H24NO4Cl). 1H-NMR (CDCl3): 1.25 (t, J=7.0 Hz, 3H); 2.07 (m, 1H); 2.37 (m, 1H); 2.69 (m, 2H); 2.89 (m, 2H); 3.07 (dd, J=14.4, 4.4 Hz, 1H); 4.22 (q, J=7.3 Hz, 2H); 5.07 (d, J=18.2 Hz, 1H); 5.18 (s, 2H); 5.19 (d, J=18.5 Hz, 1H); 6.97 (t, J=7.9 Hz, 1H); 7.08 (dd, J=7.6, 0.9 Hz, 1H); 7.34 (m, 6H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2oc(Cl)nc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-chloro-5-methoxybenzoxazole (1 eq), 4-bromoaniline (2 eq) and diisopropylethylamine was refluxed in dimethylformamide. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave (4-bromophenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:28][N+:29]([O-])=O)[CH2:22][C:23](OCC)=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:28][NH:29][C:23](=[O:24])[CH2:22]2)([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCOC(=O)C1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A 11.45 g (25.26 mmol) portion of crude ethyl 3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]-4-nitrobutanoate was dissolved in 200 ml of ethanol to which was subsequently added 10 ml of Raney nickel under an atmosphere of nitrogen. After replacing nitrogen with hydrogen, this was stirred at 50° C. for 5 hours under an atmosphere of hydrogen. After cooling in an ice bath, the reaction solution was filtered through celite and then the solvent was evaporated under a reduced pressure to give 6.51 g (19.5 mmol) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:24])[NH:31][CH2:28][CH2:29][CH3:30])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: CCCN
Product: CCCNC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21

Procedure:
Example 128 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 1-propylamine to give the title compound (0.011 g).
Reaction SMILES: ClC1C=CC(S(N(C2C=C(Cl)C=CC=2Cl)[C@H](C)CCN2CCSC2[C:20]([OH:22])=[O:21])(=O)=O)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[C@H:43]([CH3:56])[CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH:50](CC(O)=O)[S:49][CH2:48]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.[OH-].[K+].[K+].[Br-]>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[C@H:43]([CH3:56])[CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH:50]([C:20]([OH:22])=[O:21])[S:49][CH2:48]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: C[C@H](CCN1CCSC1C(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](CCCN1CSC(CC(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Product: C[C@H](CCCN1CSC(C(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 45 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-(4-(5-carboxy-3-thiazolidinyl)-1(R)-methylbutyl)benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-(2,5-dichlorophenyl)-N-(4-(5-carboxymethyl-3-thiazolidinyl)-1(R)-methylbutyl)benzenesulfonamide with 50% aqueous KOH. Yield=45%; White powder: IR (KBr) 1467, 1350, 1167, 1094, 754, 622 cm−1; MS (ESI+), 537 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)CC1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)cc1
Temperature: 90 °C
Yield: 66.4 %

Procedure:
To a suspension of 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (250 mg, 0.78 mmol) in dioxane (8 mL) was added 4-((dimethylamino)methyl)cyclohexanamine (233 mg, 1.55 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (225 mg, 66%) as a yellow solid. ESI MS m/z 434 [C29H20BrN3O2+H]+
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1.O>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1.1 g (2.06 mmol) of 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride was dissolved in a mixture of 40 mL of tetrahydrofuran and 10 mL of water, then 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of n-hexyl chloroformate were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 mL of saturated saline solution and the resulting solution was extracted three times with 20 mL of dichloromethane. The extracts were dried over sodium sulfate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). Yield: 78% of theory, C35H42N6O5 (626.8); Rf value: 0.49 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=627; (M+H+Na)++=325; (M+2H)++=314.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example M3) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (60 mg).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1.Cl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.6 %

Procedure:
To a mixture of cyclopentylmethanol (8.7 g, 87 mmol) and 4-(dimethylamino)pyridine (0.5 g, 4.3 mmol) in dichloromethane (30 mL) and pyridine (30 mL) was added 4-methylbenzene-1-sulfonyl chloride (16.6 g, 87 mmol). The mixture was stirred at ambient temperature for 20 hours then diluted with 2 N aqueous HCl and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried with NaSO4, concentrated and the filtered thru a silica plug using hexanes:EtOAc (3:1) to afford the title compound (16.5 g, 64.9 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.12-1.27 (m, 2H), 1.47-1.61 (m, 4H), 1.64-1.78 (m, 2H), 2.12-2.30 (m, 1H), 2.45 (s, 3H), 3.90 (d, J=7.1 Hz, 2H), 7.32-7.36 (m, 2H), 7.76-7.81 (m, 2H); MS (DCI/NH3) m/z 272.1 (M+NH4)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(=O)(=O)(O)O.[CH3:16]O>ClCCl>[C:1]([O:10][CH3:16])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccccc1O
Reaction time: 18 h

Procedure:
Combine salicylic acid (19.4 g, 140.5 mmol), sulfuric acid (20 mL), and methanol (100 mL). Heat to reflux. After 18 hours, pour the reaction mixture into dichloromethane. Separate the layers and extract the aqueous layer twice with dichloromethane. Combine the organic layers and extract three times with 5%.aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter and evaporate invacuo to give methyl salicylate: Rf=0.60 (silica gel, 1/10 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].Cl>>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 561.1 [(M+H)+]; mp 268° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:7]=1.Br[CH2:25][CH:26]=[CH:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:25][CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1
Reactant: Clc1cc(Cl)cc(C=CCBr)c1
Product: COC(=O)CCc1cccc(CN(CC=Cc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1

Procedure:
Following the procedure described in Step A of Example 2, 3-[3-(benzenesulfonylamino-methyl)-phenyl]-propionic acid methyl ester was alkylated with 1-(3-bromo-propenyl)-3,5-dichloro-benzene to provide the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, 2H), 7.63 (m, 1H), 7.55 (m, 2H), 7.22 (m, 2H), 7.07 (m, 3H), 6.93 (s, 2H), 6.11 (d, 1H), 5.77 (m, 1H), 4.34 (s, 2H), 3.87 (d, 2H), 3.66 (s, 3H), 2.87 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:19](=[O:20])[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]#[N:10]
Reactant: Cn1cccc1C(=O)CC#N
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To the suspension of 12.9 of 1-methyl-β-oxo-2-pyrrolpropionitrile in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine, 10.7 g of phenylisocyanate are added while stirring. After all solids are dissolved, the dark red solution is allowed to stand 30 minutes at room temperature, 5 minutes on the steam cone and at room temperature overnight. The mixture is evaporated on the steam cone, the residue taken up in methanol and the solution poured into the mixture of 25 ml of 5 N hydrochloric acid and 600 ml of water. The light brown crystals formed are collected, washed with water, triturated with ethanol and recrystallized from about 2200 ml of methanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrol-propionitrile of the formula ##STR8## melting at 174°-175°.