Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:19])[CH:3]=1.[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][NH:26][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH3:11])[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([CH3:19])[CH:3]=1)[CH3:22]
Reactant: Cc1cc(Cl)nc(NCC(C)OC(C)C)c1[N+](=O)[O-]
Reactant: CN(C)CCCN
Product: Cc1cc(NCCCN(C)C)nc(NCC(C)OC(C)C)c1[N+](=O)[O-]

Procedure:
5.75 parts of 6-chloro-2-isopropoxypropylamino-4-methyl-3-nitropyridine, 5 parts of dimethylaminopropylamine and 20 parts of alcohol are heated at 90° to 100° C for 12 hours. The excess amine and alcohol are distilled off in vacuo and the residue is extracted with chloroform. After distilling off the solvent from the chloroform solution, 6-dimethylaminopropylamino-2-isopropoxypropylamino-4-methyl-3-nitropyridine is obtained as a yellow substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[NH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1O
Temperature: 60 °C

Procedure:
10.9 g of o-aminophenol and 100 ml of acetic acid were placed in a 300 ml round-bottom flask, followed by addition of 10.2 g acetic anhydride under ice-water cooling. The mixture was heated at 60° C. for one hour to complete the reaction, resulting in formation of 2-acetaminophenol. 23.4 g gaseous chlorine was then passed into the reaction mixture at a temperature of 80°-90° C. and the resulting reaction solution was cooled and evaporated under reduced pressure to leave 24.9 g of yellow crystals of 2-acetamino-4,5,6-trichlorophenol which melted with decomposition at 200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH2:18].[C:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)([OH:21])=[O:20]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[NH:18][C:29](=[S:30])[NH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:19]([OH:21])=[O:20]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=C(O)c1cccc(N=C=S)c1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 4-methoxy-3-amino-N-phenyl-benzamide (0.73 g, 3.0 mmol) and 3-carboxyphenyl isothiocyanate (0.54 g, 3.0 mmol) in ethyl acetate (60 mL) was warmed briefly to 50° C. and then allowed to stand overnight at room temperature. The mixture was then rewarmed to 50° C., filtered, and concentrated to dryness. Trituration of the residue in ethyl acetate followed by filtration afforded the product (1.083 g); m.p. 196-197° C.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[N+](=[CH2:22])=[N-]>O1CCOCC1>[C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([O:15][CH3:22])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1

Procedure:
N-Carbobenzyloxy-4-hydroxy-L-proline [12.4 g. (0.047 mole)] is esterified with diazomethane in dioxane-ether as described in JACS, 79, 191 (1957). To avoid freezing of the dioxane the addition of the diazomethane solution is begun at 10° and completed at 0°-2°. The yield of nearly colorless viscous oil is 14.6 g. (100%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.[NH:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[N:15]=[CH:14]1>>[C:18]([C:16]1[N:15]=[CH:14][N:13]([CH:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([O:11][CH3:12])=[O:10])[CH:17]=1)(=[O:19])[NH2:20]
Reactant: NC(=O)c1c[nH]cn1
Reactant: COC(=O)C(O)c1ccccc1
Product: COC(=O)C(c1ccccc1)n1cnc(C(N)=O)c1

Procedure:
Methyl α-(4-carbamoyl-1-imidazolyl)phenylacetate was prepared from methyl mandelate and 4-imidazolecarboxamide obtained in Preparation 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)Cl.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.3 g, 1.2 ml (10 mmol) of Dimethyl-1,3-dioxolane-4-methanol, 3.7 g (3.0 mmol, 3.0 eq) of 4-Dimethyl amino pyridine dried for one hour was added and dissolved with 100 mL of CH2Cl2. Thereafter, 2.3 g (12 mmol, 1.2 eq) of p-Toluenesulfonyl chloride was added, then, [the solution] was stirred for the first 30 minutes dipped in cold water at room temperature under argon atmosphere (colorless transparent). After stirring for 18 hours, the disappearance of the raw materials was checked by TLC, liquid separation was carried out with a separating funnel (organic solvent: CDCl3) and the oil layer was dried with anhydrous Na sulfate. An hour later, cotton plug-filtered and concentrated with an evaporator, [the solution] was the target compound was isolated by silica gel column chromatography (CHCl3→CHCl3:MeOH=100 to 10:1) to obtain an oily liquid (2) (pale yellow transparent to colorless transparent). The obtained liquid was dried overnight and an NMR measurement was carried out. (yield: 1.85 g, 8.3 mmol; yield 83%)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:11][N:8]1[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=[N:9]1
Reactant: CCOC(=O)c1cnn(C)c1-n1cccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1-n1cccn1
Yield: 101.4 %

Procedure:
To a solution of 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid ethyl ester (340 mg, 1.54 mmol) in CH3OH (5 mL) and water (55 mL) was added LiOH (41 mg, 1.71 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (300 mg, quantitative), which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:32]([O:33][CH3:34])=[CH:31][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH:7]=1)[N:15]=[CH:14][C:13]([C:18]#[N:19])=[C:12]3[NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[I-].[Na+]>COCCOC>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[NH:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]([O:33][CH3:34])=[CH:31][C:9]=3[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl

Procedure:
Following procedure 1 of Example 17, a mixture of 0.105 g (0.20 mmol) of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.3 mL of morpholine and 0.01 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 7 hours. The resulting solid is purified by silica gel chromatography, utilizing a 98:2 to 94:6 gradient of methylene chloride/methanol to give 0.089 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 205-208° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>C1COCC1.C(OCC)(=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:37]4[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (294 mg, 0.553 mmol) and Pd(PPh3)4 (32 mg, 0.0277 mmol) are placed in a side-armed test tube and flushed with N2. Tetrahydrofuran (6.0 mL) and 1M aq potassium carbonate (0.6 mL) are added followed by a solution of 4-cyanobenzeneboronic acid (122 mg, 0.830 mmol) in THF (2.0 mL). After stirring at 70° C. for 8 hr the reaction is cooled, then dissolved in ethyl acetate, washed with water (2×10 mL), with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography eluting with heptane-10 to 40% ethyl acetate. Product containing fractions are combined and concentrated to afford 4-[1-(4′-cyanobiphenyl-4-yl)-3-formyl-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. TLC (heptane-30% ethyl acetate); RT=0.13; ESI/MS 451 [M-C(CH3)3]; NMR (CDCl3) 10.30 (1H, s); 8.28 (1H, d, J=9 Hz); 7.84 (6H, m); 7.55 (2H, d); 7.29 (3H, m); 3.34 (8H, m); 1.44 (9H, s).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2)(=[O:26])[CH3:25]
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2cnc(C3CC(C)NC(c4ccccc4)C3)[nH]c1-2
Temperature: 110 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A mixture of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (50 mg, 0.17 mmol), acetic anhydride (Aldrich Chemical Company) (168 mg, 1.64 mmol, 9.7 eq), K2CO3 (227 mg, 1.64 mmol, 9.7 eq) and 4-N,N-dimethylaminopyridine (2.6 mg, 0.021 mmol, 0.12 eq) in anhydrous DMF (2.0 mL) was stirred under N2 at 110° C. overnight. After cooling to the room temperature, the reaction was quenched by the addition of saturated NaHCO, (5 mL) and extracted with CHCl3 (3×30 mL). The organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 13 mg (22%) of the title compound as an off-white solid. Mp: 188-190° C. 1H NMR (CDCl3; 400 MHz): δ 11.43 (s, 1), 7.61 (d, 2, J=7.4), 7.43 (t, 2, J=7.4), 7.37 (t, 1, J=7.4), 4.88 (br s, 2), 4.06 (br s, 2), 2.58 (s, 3), 2.11 (s, 3), 1.73 (br s, 6). MS m/z: 335 (M+1), 333 (M−1). HRMS (NBA-NaI) m/z Calcd for M+H, C20H22N4O: 335.1888. Found: 335.1872.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:2][O:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([N:11]([CH3:10])[CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CNCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: ClCOc1ccncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N(C)CCOc2ccc(CC3SC(=O)NC3=O)cc2)ncn1
Temperature: 100 °C

Procedure:
A starting mixture consisting of 2.9 g (0.02 mol) 4-chloromethoxypyrimidine and 5.6 g (0.02 mol) 5-[4-(2-methylaminoethoxy)-benzyl]-thiazolidine-2,4-dione in 60 ml DMF and in the presence of 17 g NaHCO3 is heated at 100° C. for 24 h. Once the reaction completed, the mixture is poured onto 600 ml water and it is extracted with 4×200 ml AcOEt.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OO)(=[O:3])C.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]#[N:14])[CH:7]=1.O>C(O)(=O)C>[CH:10]1[CH:11]=[N+:6]([O-:3])[CH:7]=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=1
Reactant: N#CCc1cccnc1
Reactant: CC(=O)OO
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1ccc[n+]([O-])c1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
The title compound is prepared in accordance with the procedures as outlined in S. Okuda et al., J. Am. Chem. Soc., 81, 740, (1959). Peracetic acid (38%, 40 mL, 0.2 mol) is added to a stirred solution of 3-pyridylacetonitrile (15.0 g, 127 mmol) in acetic acid (75 mL) and the reaction is heated at 95° C. for 24 hr, then stirred at room temperature for 24 hr. Water is added and the solvents are removed. More water (100 mL) is added and again removed. This process is repeated with toluene and with ether to give (1-oxypyridin-3-yl)acetonitrile as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([NH:13][NH2:14])=[O:12])=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[C:15](OCC)(OCC)(OCC)[CH3:16].N12CCCN=C1CCCCC2>C(O)CCC>[Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:15]([CH3:16])=[N:14][N:13]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: NNC(=O)c1ccc2occ(Br)c2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Yield: 22.9 %

Procedure:
A solution of 3-bromofuro[3,2-b]pyridine-5-carbohydrazide (0.16 g, 0.64 mmol) and triethyl orthoacetate (0.26 mL, 1.40 mmol) in n-butanol (3 mL) was heated under reflux for 1 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.096 mL, 0.64 mmol) was added to the reaction mixture, and the resulting mixture was heated under reflux overnight. After cooling, the precipitate was collected by filtration, purified by silica gel column chromatography (hexane/ethyl acetate=3/1), and recrystallized from hexane/ethyl acetate to give the title compound (41 mg, yield 23%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.O.[OH-].[Na+:34].Cl>CC(C)=O>[Na+:34].[Na+:34].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 2 °C
Reaction time: 10 h

Procedure:
A flask was charged with crude N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (4 g), water (28 ml) and NaOH (3 equivalents) at 25° C. Complete dissolution was obtained. The pH was corrected to 10.0 with HCl 1M and acetone (120 mL) was added drop wise over a period of 50 min. The obtained suspension was cooled to 2° C. in one hour, stirred at 2° C. for 10 hours and filtered. The solid was washed with acetone (30 mL) and dried at 40° C. under vacuum (18 mbar) for about 16 hours affording the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=1
Reactant: COC(=O)CCCCCCCCNc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b) the reaction is carried out with 2 g. (6.8 mmol) of 9-(4-methoxyphenylamino)-pelargonic acid methyl ester, 0.75 g (7.5 mmol) of triethylamine, 1.2 g (6.8 mmol) of 4-chlorobenzoic acid chloride and 80 cc. of ether. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:9]2([OH:32])[CH2:15][CH:14]3[N:16]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C1(P([N:47]=[N+:48]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>>[N:1]([CH2:2][C:3]1[C:4]([C:9]2([OH:32])[CH2:10][CH:11]3[N:16]([CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[N+:47]=[N-:48]
Reactant: NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Follow the procedure of Step 5 of Example 15, using the product from Step 4 (95.2 mg, 0.213 mmol), diphenylphosphoryl azide (67.4 mg, 0.245 mmol) and 1,8-diazabicyclo [5,4,0]undec-7-ene (52.96 mg, 0.32 mmol) to give the desired compound as the minor product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:16]2[NH:15][CH:14]=[C:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[CH:17]=2)=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cc(-c2c(Cl)cccc2Cl)c[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared as described in Journal of Organic Chemistry, 62: 2650 (1997) (incorporated herein by reference) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 168 mg of (2-chloro-pyridin-3-yl)-[4-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18]O)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2.S(Cl)(Cl)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CN3CCCC3)c[nH]c1=S)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A solution of (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18, in 20 mL of THP and 1 drop of DMF was cooled to between 0° and 5° C. and thionyl chloride (13.7M, 109 μL, 1.49 mmol) was added drop-wise under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 hours, under reflux for 0.5 hours and again at room temperature for 0.5 hours. The mixture then was cooled to between 0° and 5° C. and pyrrolidine (12.0M, 818 μL, 9.8 mmol) was added drop-wise. The mixture was stirred under reflux for 1.5 hours. The solvents were removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the dilution and the mixture was adjusted to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. Purification of the residue by column chromatography gave (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrrolidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol). [α]D25 =-10.96° (c=1.3, DMSO).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1I.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30]
Reactant: N#Cc1nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Temperature: 75 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylsulphenylphenyl)4-iodopyrazole (10 g) in dimethylformamide (45 ml) at room temperature was added triethylamine (34 ml), trimethylsilylacetylene (6 ml), cuprous iodide (0.4 g), and bis(triphenylphosphine)palladium(II) chloride (0.4 g). The mixture was heated at 75° C. for 6 hours. The cooled reaction mixture was evaporated to dryness and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water, then brine, and then dried (Na2SO4) and evaporated to give the crude product which was purified by column chromatography on silica gel (400 g) eluting with dichloromethane. Combination and evaporation of suitable fractions provided an oily solid which was further purified by column chromatography on silica gel (400 g) eluting with dichloromethane/hexane. Combination and evaporation of suitable fractions followed by recrystallisation of their residue from dichloromethane/hexane provided the title compound as a buff solid m.p. 165-169° C.