Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:26]2[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]2=[O:30])=[CH:17][CH:16]=1
Reactant: CN1C(=O)CNC1=O
Reactant: CC(C)Cn1nnc2c(Br)c(-c3ccc(CCl)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CN4CC(=O)N(C)C4=O)cc3)ccc21
Temperature: 50 °C

Procedure:
4-Bromo-5-[4-(chloromethyl)phenyl]-1-(2-methylpropyl)-1H-benzotriazole (170 mg, 0.449 mmol), 3-methylimidazolidine-2,4-dione (102 mg, 0.898 mmol) and potassium carbonate (186 mg, 1.347 mmol) were combined in acetonitrile (3 ml) and heated at 50° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane and filtered. The filtrate was washed with aqueous saturated ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (acetone/dichloromethane gradient), providing the titled compound as white solid: 1H NMR (500 MHz, d6-DMSO): 1H NMR δ 8.00 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 4.60-4.57 (m, 4H), 3.97 (s, 2H), 2.90 (s, 3H), 2.34-2.27 (m, 1H), 0.93-0.88 (m, 6H) ppm. LRMS m/z (M+H) 455.9 and 457.9 found, 456.1 and 458.1 required.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.Cl.[CH2:39]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:39]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:49][C:31](=[O:33])[C@@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
HOBt (4 equivalents, 540 mg, 4 mmol), N-methylmorpholine (3 equivalents, 3 mmol), N-tert-butoxycarbonyl-D-leucine (1.0 equivalent, 230 mg, 1 mmol; Bachem), EDC (2 equivalents, 380 mg, 2 mmol) and again N-methylmorpholine (2 equivalents, 2 mmol) are added successively at −10° C. to a solution of L-leucine benzyl ester hydrochloride (1.1 equivalents, 300 mg, 1.1 mmol; cf. T. Wakamiya, M. Kamata, S. Kusumoto, H. Kobayashi, Y. Sai, et al., Bull. Chem. Soc. Jpn., 1998, 71, 699-710) in dichloromethane p.a. (30 ml). The reaction mixture warms slowly (about 12 h) to RT, whereby complete conversion of the amine component is observed by means of HPLC. The reaction mixture is concentrated in vacuo, taken up in acetonitrile and purified by means of preparative HPLC (Method 13). 362 mg (80% of theory) of the title compound are obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[S:29][C:22]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(-c3ccncc3)sc12
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Tereakis(triphenylphosphine)palladium (54 mg, 0.05 mmole) was added to a solution of 4-(tributylstannyl)pyridine (0.432 g, 1.17 mmole) and 7-chloro-2-iodothieno[3,2-b]pyridine (0.347 g, 1.17 mmole) in DMF (5 ml). The reaction mixture was stirred at reflux for 3h, cooled to room temperature. The mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (50 ml) and CH2Cl2 (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 30–60% EtOAc in hexane to give pale yellow color solid (0.103 g, 36%); 1H NMR (300 MHz, CDCl3) δ 8.61 (1H, d, J=5.1 Hz), 7.95 (1H, s), 7.66 (2H, m), 7.44 (2H, m), 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 481.10.
Reaction SMILES: Br.[NH2:2][C:3](=[O:24])[CH:4]([OH:23])[CH:5]([NH:12]C(=O)OCC1C=CC=CC=1)[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1>C(O)(=O)C>[NH2:12][CH:5]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH:4]([OH:23])[C:3]([NH2:2])=[O:24]
Reactant: NC(=O)C(O)C(Cc1cccs1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NC(=O)C(O)C(N)Cc1cccs1
Reaction time: 2 h
Yield: 131.3 %

Procedure:
70 ml of 30% HBr in glacial acetic acid were added to 11 g of phenylmethyl [3-amino-2-hydroxy-3-oxo-1-(2-thienylmethyl)propyl]carbamate (29.66 mmol) in 30 ml of glacial acetic acid. After about 2 hours, the mixture was concentrated and the resulting residue was stirred firstly with cyclohexane and then with dichloromethane. 7.8 g of the title compound were obtained as hydrobromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][C:9]([C:15]([OH:17])=[O:16])=[CH:8]2)=[O:4]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([C:15]([OH:17])=[O:16])[CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C=C(C(=O)O)CO2
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C(=O)O)CO2
Temperature: 80 °C
Reaction time: 48 h
Yield: 84.7 %

Procedure:
A mixture of ester XXXII (2 g, 8.5 mmol) and 300 mg of Pd (OH)2 in 20 mL of MeOH was stirred in an autoclave at 80° C. for 48 h under 40 psi of H2. Then the reaction mixture was filtered, and concentrated to give 1.7 g of chroman-3,6-dicarboxylic acid 6-methyl ester XXXIII (Yield 85%). MS: calc'd 237 (MH+), exp 237 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(I)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-iodophenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(1-(4-chlorophenyl)-3-(4-iodophenyl)-3-oxopropyl)malonate was obtained as beige coloured solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])=[CH:28][CH:27]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 54b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.2 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:23](=[O:25])[CH3:24])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of (4-phenyl-cyclohexyl)-acetic acid ethyl ester (15 g, 61 mmol, 1.0 equiv) in 200 Ml DCM was added aluminum trichloride (16 g, 122 mmol, 2.0 equiv) portionwise over 15 min. Acetyl chloride (4.7 Ml, 67 mmol, 1.10 equiv) was then added dropwise via syringe. The homogeneous solution was allowed to stir at 0° C. for 2 h, then carefully quenched with 300 Ml ice water. The mixture was extracted with DCM (3×150 Ml), and the organic extracts were washed with saturated bicarbonate and brine solution. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (q, J=11.96 Hz, 2 H) 1.20 (t, J=7.20 Hz, 3 H) 1.40-1.51 (m, 2 H) 1.84 (d, J=11.12 Hz, 4 H) 1.76-1.87 (m, 1 H) 2.17 (d, J=6.82 Hz, 2 H) 2.50 (s, 3 H) 4.07 (q, J=7.07 Hz, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.81 (d, J=8.08 Hz, 2 H); (M+H)+ 289.1.
Reaction SMILES: [C:1]1(S(O)(=O)=O)[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](S(O)(=O)=O)[C:5]=2[CH:4]=[C:3](S(O)(=O)=O)[CH:2]=1.[N+]([O-])(O)=O>S(=O)(=O)(O)O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: c1ccc2ccccc2c1

Procedure:
The industrially important 8-nitronaphthalene-1,3,5-trisulphonic acid is prepared by nitrating the naphthalene-trisulphonic acid mixture which is obtained in the trisulphonation of naphthalene with sulphuric acid and oleum and which contains naphthalene-1,3,5-trisulphonic acid as the main constituent, with nitric acid using sulphuric acid as the solvent (see F.I.A.T. Final Report No. 1016, pages 42-44). According to this process, the hot solution, of the naphthalenetrisulphonic acids in sulphuric acid, which has a temperature of 90° C. and is obtained in the trisulphonation of naphthalene is transferred to the nitration kettle and, after cooling to 60° C., diluted with water and nitrated with mixed acid (86% of nitric acid, 12% of sulphuric acid and 2% of water) at 30° to 35° C. The nitration mixture is subsequently stirred at 40° C. for 1 hour. As a repetition of the process has shown, the yield of 8-nitronaphthalene-1,3,5-trisulphonic acid is only about 46%, relative to the naphthalene-1,3,5-trisulphonic acid employed (see Example 16 of the present Application).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:15])[CH3:14])[CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]/[CH:27]=[C:28]1/[C:29]2[CH:42]=[C:41]([C:43]([OH:46])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:30]=2[O:31][CH2:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:13]([CH3:14])[CH3:15])[CH:8]2[CH2:12][CH2:11][N:10]([CH2:25][CH2:26][CH:27]=[C:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:33]=4[CH2:32][O:31][C:30]4[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of (4-chloro-benzyl)-isopropyl-pyrrolidin-3-yl-amine (0.68 mmol, 1.7 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.8 mmol, 2 eq) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.4 mmol, 1.0 eq) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 0.85 (6H, d), 1.50-1.90 (10H, m), 2.10-2.60 (8H, m), 3.50 (3H, m), 5.30 (2H, br, s), 6.10 (1H, t), 6.80 (1H, dd), 7.10-7.40 (8H, m), 7.50 (1H, d), 8.50 (1H, dd). ESI-MS m/z: 546 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)(Cl)=O.[N-:14]=[N+:15]=[N-:16].[Na+]>>[N:14]([CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[N+:15]=[N-:16]
Reactant: OCc1ccncc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccncc1F

Procedure:
The product of Example 129B, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 153 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH2:22]1COCC1.C[Mg]Br.Cl>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:22])[CH:12]=[C:13]([S:15]([F:19])([F:18])([F:20])([F:17])[F:16])[CH:14]=1
Reactant: CON(C)C(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (980 mg) was dissolved in abs. THF (50 ml) and methylmagnesium bromide solution (2.1 ml; 3 M solution in diethyl ether) was added dropwise at 0° C. with stirring. After addition was completed, the ice bath was removed and the mixture was stirred at RT for 1 h. To complete the reaction, more methylmagnesium bromide solution (0.3 ml) was added and the mixture was stirred for a further 2 h. After storage overnight in a refrigerator, the reaction mixture was treated with 1 N hydrochloric acid with cooling. After addition of water and ethyl acetate, it was extracted a further two times with ethyl acetate, and the combined organic phases were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of chromatography on silica gel (n-heptane/ethyl acetate 100/0 to 50/50 in 30 min). The product-containing fractions were combined, the solvent was removed and the residue was dried in a high vacuum. 650 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:15])[F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[O:20][N:19]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 5-bromo-2-methyl-4-(trifluoromethyl)-1H-indole and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.44 (s, 2H), 6.58 (s, 1H), 5.41 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:22]([C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28])=[N+:23]=[N-:24]>C1COCC1>[C:1]([O:5][C:6]([C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[N:22]=[N+:23]=[N-:24])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A stirred solution of (2S)-5-oxo-proline tert-butyl ester (T. Kolasa and M. J. Miller, J. Org. Chem., 1990, 55, 1711-1721) (1.13 g, 6.13 mmol) in anhydrous THF (15 mL) was treated at −78° C. with LDA (9.19 mmol) and the reaction was stirred for 15 min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (6.13 mmol) in anhydrous THF (5 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated to give an oil which was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (1.67 g, 82%): 1H NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 2.14 (1H, m), 2.43 (1H, m), 2.55 (1H, m), 2.69 (1H, m), 4.79 (1H, dd, J 9.2, 3.2 Hz), 7.19-7.22 (2H, m), 7.36 (1H, m), 7.49 (1H, m). 13C NMR (100 MHz, CDCl3) δ 22.1 (CH2), 28.3 (CH3), 31.9 (CH2), 59.3 (CH), 83.0 (C), 118.7 (CH), 125.0 (CH), 127.9 (C), 129.1 (CH), 131.9 (CH), 137.9 (C), 167.5 (C), 170.2 (C), 173.6 (C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[N:10]([CH3:11])[N:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cn1ncc2ncc(Br)cc21
Reactant: OB(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc2ncc(-c3cccc(Br)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (120 mg, 0.566 mmol) and 3-bromophenylboronic acid (136 mg, 0.679 mmol) in degassed 1,4-dioxane (6 mL) and water (2 mL) was added K2CO3 (391 mg, 2.83 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol). The reaction mixture was heated at 90° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C13H10BrN3: 288.01 (M+H+); Found: 288.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[F-:13].[K+]>CS(C)=O>[Cl:8][C:7]1[C:2]([F:13])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: [F-]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ncc(C(F)(F)F)cc1Cl
Temperature: 120 °C
Yield: 92.7 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (800 g) was added to a stirred mixture of anhydrous potassium fluoride (320 g) and anhydrous dimethylsulphoxide at 110° C. then heated at 120° C. for 2 hours and fractionally distilled under reduced pressure to give 3-chloro-2-fluoro-5-trifluoromethylpyridine (685 g) in a yield of 92% (98% purity).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[C:4]([CH2:19][CH3:20])[N:3]=1.[CH3:21][NH2:22]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:22][CH3:21])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[C:4]([CH2:19][CH3:20])[N:3]=1
Reactant: CN
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCc1nc(N)nc(N)c1-c1ccc(NC)c([N+](=O)[O-])c1
Yield: 92 %

Procedure:
A suspension of 2,4-Diamino-5-(4-chloro-3-nitro phenyl)-6-ethylpyrimidine (nitropyrimethamine) (10 g) in aqueous methylamine solution (40%; 200 ml) was refluxed for 48 hours with the further addition of methylamine solution (100 ml) after 24 hours and 36 hours. An orange colour slowly developed and the consumption of starting material was monitored by t.l.c. After cooling and dilution with water, the crystalline product was collected and recrystallized from aqueous DMF to yield orange prisms of 2,4-Diamino-5-(4-methylamino-3-nitrophenyl)-6-ethylpyrimidine (9.0 g. 92%), m.p. 262°-265° C. (Elemental analysis: C, 53.9; H, 5.9; N, 29.3%; calculated: C, 54.2; H, 5.6; N, 29.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:20][CH3:21]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:20][CH3:21])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
To a solution of (3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) (1.50 g, 6.63 mmol) in 25 ml of DMF was added a 60% suspension of sodium hydride in mineral oil (207 mg, 8.62 mmol, 1.3 equiv.). The suspension was stirred for 45 minutes at room temperature (gas evolution), then iodoethane (1.34 g, 0.696 ml, 8.62 mmol, 1.3 equiv.) was added and the mixture was stirred at room temperature overnight. After concentration in vaccuo and workup with ethyl acetate/water, 1.60 g of a yellow oil were obtained containing mineral-oil drops which was directly used in the next step without further characterization.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](O)=[O:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[N:21]1[C:26](C)=CC=C[C:22]=1C.CNC>ClCCl.CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](=[O:8])[N:21]([CH3:26])[CH3:22])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Reactant: Cc1cccc(C)n1
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1sc(Cl)nc1C(=O)N(C)C
Temperature: 45 °C
Yield: 76 %

Procedure:
To a stirred solution of 2-chloro-5 (ethoxy carbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 2 g, 8.01 mmol) in dry dichloromethane (20 mL) was added oxalyl chloride (1.37 mL, 16.02 mmol) and 2 drops of dry dimethylformamide. The reaction mixture was heated to 45° C. for 90 minutes. After the completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dry dichloromethane (20 mL) and was cooled to 0° C., then 2,6-lutidine (0.97 mL, 8.4 mmol) was added followed by addition of N,N-dimethylamine (2 M solution in tetra hydro furan, 4.19 mL, 8.4 mmol). After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate (2×50 mL). The organic layer was washed with 1 N hydrochloric acid, water and brine (1×50 mL), and concentrated after drying over anhydrous sodium sulfate to afford 1.6 g (72.7%) of the title compound as a thick syrup.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([Si](C)(C)C)[O:12][C:9]2=[CH:10][N:11]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:12]1[C:9]2=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=[C:8]2[CH:14]=[CH:13]1
Reactant: CC(=O)OCc1cc2cc([Si](C)(C)C)oc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCc1cc2ccoc2cn1
Yield: 90.3 %

Procedure:
[2-(Trimethylsilyl)furo[2,3-c]pyridin-5-yl]methyl acetate (1.3 g, 4.9 mmol) was dissolved in ethanol (50 ml) and treated with potassium carbonate (0.82 g, 5.9 mmol) and heated under reflux for 18 hrs. The mixture was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was dried, filtered and evaporated to yield the title compound (0.66 g).