Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[C:38]([NH:46][C@H:47]([C:52](O)=[O:53])[CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:38]([NH:46][C@H:47]([C:52]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:53])[CH2:48][CH:49]([CH3:50])[CH3:51])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCC1CCCN1Cc1ccc(Cl)cc1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NCC1CCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCl (23 mg), HOBt (16.2 mg) and triethylamine (15.2 μL) were added to a chloroform (1 mL) solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mL), and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), washed with a 2 M aqueous solution of NaOH (0.75 mL×2), filtered through a PTFE membrane, thereby dried and concentrated to provide 2-[(N-benzoylleucyl)aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 344) (74 mg, quantitative). The purity was determined by RPLC/MS (85%). ESI/MS m/e 442 (M++H, C23H32ClN3O2).
Reaction SMILES: [Cl:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([Br:13])[CH:3]([C@H:5]1[C@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])[Br:4].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([Br:13])[CH:3]([C@H:5]1[C@H:7]([C:8]([Cl:23])=[O:9])[C:6]1([CH3:12])[CH3:11])[Br:4]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Yield: 94 %

Procedure:
14 g of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethyl-cyclopropane-1-(R,S)-carboxylic acid were dissolved in 100 ml of carbon tetrachloride, 75 g of thionyl chloride were added and the mixture was heated to the reflux temperature for 4 hours. The solvent and excess thionyl chloride were then stripped off in vacuo. 13.7 g (77.8% of theory) of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethyl-cyclopropane-1-(R,S)-carboxylic acid chloride were obtained as a viscous oil. ##STR14##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nncc3cc(Br)ccc23)CC1
Temperature: 120 °C

Procedure:
6-Bromo-1-chlorophthalazine (18 mg, 74 umol) and 1-(methylsulfonyl)piperazine (91 mg, 554 μmol) were dissolved in dichloromethane/methanol when the reaction mixture was concentrated by evaporation under a nitrogen line. The concentrate was heated to 120° C. for 6 h to give the title compound. MS (ES+): 373 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13].[NH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=1[CH3:23].CC(C)([O-])C.[K+]>CN(C)C(=O)C.O>[NH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([O:22][C:6]2[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=2)=[CH:17][C:16]=1[CH3:23]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNc1cc(Oc2cc(C)c(N)c(C)c2)ccc1[N+](=O)[O-]
Temperature: 77.5 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
To a solution of 2,4-dichloronitrobenzene (3.0 g) in N,N-dimethylacetamide (30 ml) was added a 40% aqueous solution of methylamine (4.9 g) at room temperature, and the resulting mixture was stirred at 75-80° C. for 1.5 hours. To the reaction mixture were added 4-amino-3,5-dimethylphenol (2.2 g), potassium t-butoxide (3.5 g), and N,N-dimethylacetamide (15 ml), and the resulting mixture was stirred at the same temperature for 3 hours. After stirring, water (60 ml) was added to the reaction mixture, and the resulting mixture was cooled gradually to room temperature. The crystalline solid precipitated was collected by filtration and dried in vacuo to afford the title compound (3.0 g, yield: 67%) as a yellow crystalline solid.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]=[C:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCOC(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(c2ccccc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.5 %

Procedure:
To a mechanically stirred solution of the title compound of Example E (21 g, 0.085 mol) in 450 ml of pyridine was added hydroxylamine hydrochloride (8.83 g, 0.127 mol). After stirring for 4 days at room temperature the solution was concentrated in vacuo to give a solid which was chromatographed on silica gel eluting with 3% EtOH/CH2Cl2 to give the title compound (13.71 g, 61%) as a colorless powder: Anal calcd for C13H14N2O4 : C, 59.53; H, 5.40; N, 10.68. Found: C, 59.48; H, 5.47; N, 10.64. MS calcd for C13H14N2O4 262, found 262. DSC=153.2°-155.4° C. at 91.1 J/g.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]([CH2:38][C:39]#[CH:40])[CH3:37].C(NC(C)C)(C)C>O1CCCC1.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.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:40]#[C:39][CH2:38][N:36]([CH3:37])[CH3:35])=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
To a degassed solution of methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (480 mg, 0.818 mmol; prepared as described in example 53), N,N-dimethylpropargylamine (0.175 mL, 1.64 mmol) and diisopropylamine (0.539 mL, 3.85 mmol) in anhydrous tetrahydrofuran (10 mL), bis(triphenylphosphine)-palladium(II) dichloride (29 mg, 0.041 mmol) and copper(I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was stirred at ambient temperature over night under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)Nc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 56.6 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (37.8 mg, 0.11 mmol), 1-tert-butyl-4-isocyanatobenzene (1.2 eq, 0.13 mmol, 22.49 μl), and TEA (3 eq, 0.33 mmol, 45.99 μl) were added in methylene chloride. The reaction mixture was stirred for 12 hrs. The reaction mixture was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=1:1) to yield title compound (26.1 mg, 55%) as a white solid.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]([CH2:51][CH3:52])[CH2:49][CH3:50]>>[CH2:47]([N:48]([CH2:51][CH3:52])[CH2:49][CH2:50][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1)[CH3:46]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using (2-chloroethyl)-diethylamine hydrochloride. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 374.0 [M+H]+; single peak at tR=3.04 min (System 2).
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)CO>[Cl:19][C:15]1[CH:14]=[C:13]([C:12]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1cccc(Cl)c1
Solvent: OCCO
Product: NC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Temperature: 190 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
A suspension of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-3-chlorobenzamide (8.7 g, 0.029 mole) in 200 ml of ethylene glycol was heated at 190° C. for 40 minutes. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water to produce a white precipitate. The mixture was refrigerated and the precipitate was filtered, washed with water, and dried under high vacuum at room temperature overnight, then at 60° C. for 6 hrs. The sample was recrystallized from methanol-water (~40/60) and refrigerated. The crystalline precipitate was filtered, washed with water, and dried under high vacuum at room temperature overnight. The sample was redried under high vacuum at 60° overnight to give 5.48 g (66%) of title compound, mp. 245°-47° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11]OC(OC)OC.[CH3:18][C:19]1[C:20]([NH2:24])=[CH:21][S:22][CH:23]=1>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:11][NH:24][C:20]2[C:19]([CH3:18])=[CH:23][S:22][CH:21]=2)[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Reactant: Cc1cscc1N
Product: Cc1cscc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.85 g, 34 mmol) in trimethoxymethane (37 mL, 337 mmol) was heated to 90° C. under nitrogen. After 2 hours, a solution was 4-methylthiophen-3-amine (3.81 g, 34 mmol) was added (as a solution in trimethoxymethane (37 mL, 337 mmol). The reaction stirred at 90° C. for 6 hours and then was allowed to cool to room temperature and concentrated. The material was placed in the refrigerator where it solidified after two days to obtain the title compound (9 g, quantitative).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1csc(C)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1csc(C)c1OC

Procedure:
Methyl 4-hydroxy-5-methyl-3-thiophenecarboxylate (34 g), potassium carbonate (37 g) and dimethyl sulphate (33.67 g) were stirred in anhydrous acetone (200 ml) at room temperature for 20 days. The reaction mixture was filtered and the solvent removed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:14][CH:15]=CC=3)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[N:6][CH:7]=1.FC(F)(F)C(=O)CC(C1OC=CC=1)=O.Cl.BrC1C=C[C:41]([NH:44][NH2:45])=NC=1.[OH-:46].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:14][C:15](=[O:46])[N:44]([CH3:41])[N:45]=3)=[CH:11][C:10]([C:18]([F:19])([F:20])[F:21])=[N:9]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccc(Br)cn2)n1
Reactant: NNc1ccc(Br)cn1
Reactant: [OH-]
Agent: Cl
Agent: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(C(F)(F)F)nn2-c2ccc(Br)cn2)oc1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Step-1: 5-Bromo-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine: A mixture of 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (7.0 g, 34.0 mmol) and 5-bromo-2-hydrazinylpyridine hydrochloride (7.62 g, 34.0 mmol) in acetic acid (20 mL) was stirred at 70° C. for 1.5 h. The reaction mixture was cooled to room temperature (RT) and then diluted with ethyl acetate (200 mL) and basified with aqueous sodium hydroxide solution (10%, pH 7-8). The resulting slurry was filtered and the filtrate was washed with water (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate-hexanes as eluent) to afford 10 g (82%) of the title compound as white semisolid. 1HNMR (400 MHz, CDCl3) δ 8.54 (brs, 1H), 8.02 (dd, J=2.5 & 8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 6.93 (s, 1H), 6.62 (d, J=3.5 Hz, 1H), 6.47 (dd, J=3.5 & 1.5 Hz, 1H); ESI-MS (m/z) 358, 360 [(MH)+, Br79,81].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>O1CCOCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CSCCCNCC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSCCCN(CC(=O)OC(C)(C)C)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a solution of N-(3-methylthiopropyl)glycine t-butyl ester (36.4 g, 0.166 mol) and triethylamine (20.2 g, 0.199 mol) in 300 ml of dioxane was added dropwise 3-acetylthio -2-methylpropanoyl chloride (30.0 g, 0.166 mol). After stirring at room temperature for 16 hours the mixture was filtered and concentrated to yield 52.9 g. Purification by medium pressure liquid chromatography eluting with 20% ethyl acetate in hexane gave 18.0 g (30%) of N-(3-acetylthio-2-methylpropanoyl)-N-(3-methylthiopropyl)glycine t-butyl ester as a colorless oil. Rf =0.19 (20% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[C:9](=[O:12])[N:8]([C@@H:13]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[C:5]2=[N:6][CH:7]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[C:9](=[O:12])[N:8]([C@@H:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[C:5]2=[N:6][CH:7]=1.[ClH:25]
Reactant: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(=O)n([C@@H]2CCNC2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL, 4 mmol) was added. The mixture was stirred at rt for 3 h and concentrated to give (R)-6-chloro-1-methyl-3-(pyrrolidin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one as its HCl salt (78 mg, 87%). Method 1 tR=0.77 min, m/z=253.
Reaction SMILES: [CH2:1]1COCC1.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>CN(C=O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16]([C:19](=[O:22])[C:20]([CH3:1])=[CH:21][N:23]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a mixture of THF (60 mL) and DMF (7.5 mL) at 0° C. under nitrogen was added oxalyl chloride (6.5 mL, 76.8 mmol) during which time a white precipitate formed. The temperature was slowly raised to room temp. and stirred for 1.5 hr. THF was distilled off from the reaction mixture under reduced pressure and under nitrogen. The gummy residue was further diluted with DMF (100 mL). A solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (5.0 g, 19.30 mmol) in DMF (50 mL) was added to the reaction mixture at room temperature. The reaction was heated at 115° C. for 2 hr. The reaction mixture was brought down to room temperature, then diluted with water (750 mL), and the mixture was extracted with ethyl acetate (2×750 mL). The combined organic layers were washed with brine (500 mL), dried, and concentrated under reduced pressure to yield 7-chloro-3-methyl-1-phenyl-1H-quinolin-4-one (4.25 g, 81.6%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 8.24 (d, J=8.8 Hz, 1H) 8.01 (s, 1H) 7.52-7.80 (m, 5H) 7.40 (dd, J=8.8, 1.8 Hz, 1H) 6.87 (d, J=1.8 Hz, 1H) 2.01 (s, 3H). MS calcd. for C16H12ClNO [(M+H)+] 270.0, obsd. 269.8.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:17])[CH2:15][OH:16])[C@H:9]([CH3:18])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][C:27]([Cl:33])=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[Cl:33][C:27]1[CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:24]([O:16][CH2:15][C:14]([N:10]2[CH2:11][C@H:12]([CH3:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH2:8][C@H:9]2[CH3:18])=[O:17])=[N:25][CH:26]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CO
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.90 g, 3.2 mmol) in toluene (20 mL) at 0° C. was added sodium hydride (0.18 g, 4.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 15 minutes, then 2,5-dichloro-3-nitro-pyridine (0.65 g, 3.38 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The reaction was quenched by the slow addition of water (5 mL) then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (1.25 g).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][Si:8]([O:11][CH3:12])([CH3:10])[CH3:9]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:7][Si:8]([O:11][CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CO[Si](C)(C)CCl
Reactant: CC(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CO[Si](C)(C)COC(C)=O
Temperature: 150 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
A mixture of 61.1 kg of Hydroseal G 400 H and 50 kg (609.4 mol) of sodium acetate was dried by heating at 150° C./2 mbar for 1 h. After cooling down to 112° C., the vacuum was broken with nitrogen, 3.76 kg (11.1 mol) of tetrabutylphosphonium bromide were added and the temperature was adjusted to 120° C. Then, under agitation, 76.8 kg (554 mol) of (chloromethyl)methoxydimethylsilane were metered in over 1 h. The mixture was subsequently stirred at the same temperature for a further 6 h. The product was then distilled out through a column at 20 mbar (head), 50-56° C. (head) and 70-145° C. (pot), while a further 36.7 kg of Hydroseal G 400 H were metered in during the distillation to ensure stirrability. The product (acetoxymethyl)methoxydimethylsilane (89.0 kg, 548.5 mol, 99% of theory; purity 99.5% (GC area %)) was obtained as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[C:32](Cl)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:32](=[O:34])[CH3:33])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[N:5]=[C:4]([C:28]([F:31])([F:29])[F:30])[N:3]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: CN(C)c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 30 °C

Procedure:
A solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide (0.5 g, 1.01 mmol, prepared according to the procedure described in PCT/IB03/02879), DMAP (0.01 g) and acetyl chloride (0.5 g, 6.36 mmol) were stirred at 30° C. TLC confirmed the completion of the reaction after 4 hours of stirring under the same conditions. Subsequently the resulting mass was poured onto the ice and the procedure described for example 14 was followed to afford the title compound (0.252 g, 46.41%, purity by HPLC 98.82%); m.p.: 230-235° C. 1H-NMR (DMSO-d6) δ: 1.87 (s, 3H), 3.17 (s, 3H), 7.51-7.53 (m, 2H), 7.66-7.67 (m, 2H), 7.8-7.82 (d, 2H), 7.9 (s, 1H), 7.99 (s, 1H), 12.14 (s, 1H, D2O exchangeable); IR (KBr) cm−1: 3150, 1720 and 1525; MS m/z: 533.7 (M+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:22][OH:23])=[CH:29][CH:28]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)nc1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (35 mg, 0.14 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (15 mg, 0.090 mmol) in acetonitrile (1.5 mL) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC ((100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to give a light yellow foam. LC-MS: 391.4 [M+H]+.