Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:21]3=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:45][C:34]([F:33])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: O=C(c1ccc(OCCCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCCCCN2CCC(NC(=O)C(F)(F)F)CC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
By customary procedures, 3-chloro-4-hydroxybenzoic acid was reacted with dodecylbromide in a mixed solution of ethanol and water containing sodium hydroxide to produce 3-chloro-4-dodecyloxybenzoic acid, and this acid was reacted with thionyl chloride to obtain 3-chloro-4-dodecyloxybenzoic acid chloride. Separately, 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone and 200 mg of 4-benzyloxybenzoic acid were dissolved in 200 ml of benzene, 190 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine were added to the solution, and a reaction was carried out at room temperature with stirring overnight. The reaction mixture was concentrated under a reduced pressure, and the concentrate was separated and purified by the silica gel column chromatography to obtain 120 mg of 2-(4'-benzyloxybenzoyloxy)-5-hexyl-δ-valerolactone. This compound was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2-(4'-hydroxy-benzoyloxy)-5-hexyl-δ-valerolactone. The obtained compound was dissolved in 20 ml of benzene, and 200 mg of 3-chloro-4-dodecyloxybenzoic acid chloride described above, 200 mg of triethylamine and 20 mg of N,N-dimethylaminopyridine were added to the solution, and a reaction was carried out with stirring overnight. The reaction liquid was treated by customary procedures and the intended product was separated and purified by the silica gel column chromatography. Recrystallization from ethanol gave 80 mg of (2R,5S)-2-[4-(3'-chloro-4'-dodecyloxybenzoyloxy)-benzoyloxy]-5-hexyl-δ-valeerolactone ##STR127##
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:8]([CH3:9])[CH2:7][O:6][C:4]([NH:1][NH:2][C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5])=[O:5])([O-:18])=[O:17]
Reactant: NN
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(COC(=O)NNC(=O)OCC(C)c1ccccc1[N+](=O)[O-])c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of hydrazine (0.32 mL, 10.25 mmol) in DCM (20 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (5.0 g, 20 mmol) in methylene chloride (25 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated and the residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 1.46 g (3.26 mmol 32% yield) of di-(2-(2-nitrophenyl)propoxycarbonyl)hydrazine. 1H-NMR (300 MHz, DMSO-d6): δ 9.06-8.73 (d, 1 H, CONH), 7.84 (d, J=7.8 Hz, 1 H, Ar—H), 7.63 (m, 2 H, Ar—H), 7.48 (m, 1 H, Ar—H), 4.20 (m, 2 H, CH2), 3.39 (m, 1 H, CH), 1.26 (d, J=6.9 Hz, 3 H, CH3). 13C-NMR (75 MHz, DMSO-d4): δ 156.19 (OCOR), 149.85 (C ipso to NO2), 136.53 (C ipso to CH(CH3)CH2OCOR), 132;91 (C para to NO2), 128.52.(C para to CH(CH3)CH2OCOR), 127.76 (C ortho to CH(CH3)CH2OCOR), 123.77 (C ortho to NO2), 67.86 (CH2OCOR), 33.30 (CH), 17.99 (CH3). Mass analysis (MALDI-TOF): calculated for C20H22N4O8 446.42, found 446.24 (C20H22N4O8Na 469.38 is the major peak). TLC: 5% methanol in chloroform, Rf=0.7.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][NH:30][CH3:31].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH3:29][N:30]([CH3:31])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: CNC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 85.7 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), dimethylamine hydrochloride (198 mg, 2.42 mmole), N-ethyldiisopropylamine (564 ul, 3.23 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4,1-trimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (138 mg, 85.7%) as a white solid. Mp.: 237-240° C. MS: m/z=399.2 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O=[C:12]1[CH2:17][CH2:16][N:15](C(OCCCC)=O)[CH2:14][CH2:13]1.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCOC(=O)N1CCC(=O)CC1
Reactant: NNc1ccccc1Br
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)CCNC3
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of (2-bromophenyl)hydrazine hydrochloride (2.24 g, 10.0 mmol; Aldrich) and tent-butyl 4-oxopiperidine-1-carboxylate (1.99 g, 10.0 mmol; Aldrich) was combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) in a sealed tube and stirred at 100° C. for 18 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between NaOH (1.0 M, 200 mL) and CH2Cl2 (3×200 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 50-80% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.86-2.94 (m, 2H), 3.24 (t, J=5.9 Hz, 2H), 4.04 (t, J=1.5 Hz, 2H), 6.89 (t, J=7.8 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.33 (dd, J=8.0, 0.8 Hz, 1H); MS (APCI) m/z 292/294 (M+CH3CN+H)+.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[N:12]1([CH2:17][CH2:18][NH2:19])[CH:16]=[CH:15][N:14]=[N:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH:16]=[CH:15][N:14]=[N:13]1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: NCCn1ccnn1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Yield: 79 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2.0 g, 13.06 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (1.76 g, 15.67 mmol) to give 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (2.55 g, 79%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)=[CH:15][C:14]([NH2:30])=[CH:13][N:12]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([NH:30][C:14]3[CH:13]=[N:12][C:11]([CH3:10])=[C:16]([NH:17][C:18]4[N:23]=[C:22]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=[CH:20][N:19]=4)[CH:15]=3)=[O:45])=[CH:47][CH:48]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: CCN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cnc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (47 μL, 0.27 mmol) was added into a solution of 2-Methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (15 mg, 0.054 mmol), 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid (16.1 mg, 0.61 mmol), BOP (33.4 mg, 0.76 mmol) in DMF (1.5 mL). The reaction mixture is stirred at rt under argon atmosphere overnight. The reaction mixture was then purified by Waters semi-preparative HPLC to the final product. MS (ESI+) m/z 509.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1NCc2ccccc21
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2ccccc2CN1Cc1ccc(CBr)cc1
Yield: 49.3 %

Procedure:
2,3-Dihydroisoindol-1-one (350 mg, 2.63 mmol), 1,4-bis-bromomethylbenzene (3.78 g, 14.3 mmol), Cs2CO3 (3.60 g, 11.1 mmol), in acetonitrile (20 mL), was stirred together at room temperature for 5 hours and 80° C. for 20 minutes. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (30% EtOAc/Hexanes) to afford a white solid (410 mg, 49%). 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 1H), 7.49-7.55 (m, 2H), 7.37-7.42 (m, 3H), 7.28-7.31 (m, 2H), 4.82 (s, 2.03), 4.49 (s, 2H), 4.31 (s, 2H).
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.O>[N:23]([C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)=[N+:24]=[N-:25]
Reactant: C[C@]12C=CC(=O)C=C1[C@H](Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1[C@@H](N=[N+]=[N-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 6β-bromoandrosta-1,4-diene-3,17-dione (5.0 g) in 250 ml of dimethylformamide, 1,15 g of powdered sodium azide dissolved in 14 ml of water are added and the mixture is warmed to 100° C. and maintained with stirring at the same temperature for 120 minutes. The entire mixture is then poured into 1 l of water and extracted with four 200 ml portions of ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride solution and dried. The solvent is then removed in vacuum to yield a crude product which is purified by chromatography on Al2O3 (neutral activity) with ethyl acetate:n-hexane 40:60 as eluant so obtaining 3.4 g of pure 6α-azido androsta-1,4-diene-3,17-dione. The analytical sample was crystallized from methanol, m.p. 168°-170° C.; [α]D20° +93.2° (c=1, CHCl3); U.V. (95% EtOH) λmax=244; ε=17,420; N.M.R. (CDCl3) δ: 0.98 (3H, s); 1.3 (3H, s); 4.31 (1H, ddd); 6.44 (1H, dd); 6.26 (1H, dd); 7.02 (1H, d). Following analogous procedure the 6β-azido androsta-1,4-diene-3,17-dione can be prepared, starting from 6α-bromo androsta-1,4-diene-3,17-dione.
Reaction SMILES: C(OC(N[CH:12]1[NH:16][C@@H:15]([CH3:17])[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[O:13]1)=O)C1C=CC=CC=1.[OH2:27].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:27][C:12]([NH:16][C@@H:15]([CH3:17])[C:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[O:18])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H]1NC(NC(=O)OCc2ccccc2)OC1(O)c1ccc(F)cc1F
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
In tetrahydrofuran (70 mL) was dissolved (4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12, and water (50 mL) and conc. hydrochloric acid (20 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:35].[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=[O:35])=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 4-[6-(4-cylopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile (2.0 g, 6.3 mmol) dissolved in THF (40 mL) was added DIBAL-H (25 mL, 1 N) at −40° C. The mixture was stirred 2 h at −40° C. and then CH3OH (15 mL), water (100 mL) and 1 N NaOH (15 mL) was added at −40° C. The mixture was extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1.7 g (51%) of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzaldehyde.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:20]([N:22](CC)CC)C.CN>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:22][CH3:20])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CCc1nc(NC)sc1C(=O)NC(C#N)c1cccs1
Yield: 89 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.58ml of methylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 4 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.77g (Yield 89%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:30]([O:29][C:27]([CH:26]1[CH2:32][CH2:33][N:23]([C:17]2[C:12]3[CH:11]([CH3:20])[C:10](=[O:21])[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:22])[C:13]=3[N:14]=[C:15]([CH3:19])[N:16]=2)[CH2:24][CH2:25]1)=[O:28])[CH3:31]
Reactant: Cc1nc(Cl)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2nc(C)nc3c2C(C)C(=O)N3c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (7.5 g), ethyl isonipecotate (4.7 g), N,N-diisopropylethylamine (3.8 g) in ethanol (35 mL) was heated at reflux for 12 hours. The reaction mixture was stirred at room temperature to afford a solid. The solid was collected by filtration and washed with cold ethanol to give 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid ethyl ester (7.7 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][C:30](Cl)=O.[OH-].[Na+]>C1COCC1>[CH3:27][O:28][CH2:29][C:30]1[NH:20][C:18](=[O:19])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide (0.564 g, 2.0 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add dropwise pyridine (0.325 mL, 4.0 mmol) and methoxyacetyl chloride (0.365 mL, 4.0 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and stir at 50° C. for 3 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and purify by column chromatography to give 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].C(N(CC)CC)C.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:30]([C:33]1[CH:34]=[C:35]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-3 step (ii) (240 mg), triethylamine (0.12 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (204 mg) were dissolved in acetonitrile (5 ml), and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 35 mg (9%); mp 218-219° C., MS APCI+ve 493 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][NH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][O:34][NH:35][CH3:36].CCN(CC)CC>C(Cl)Cl>[CH3:33][O:34][N:35]([CH3:36])[C:8]([C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)=[O:10]
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a suspension of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (8.0 g, 1.0 eq), EDCI (13.2 g, 1.2 eq) and HOBt (9.3 g, 1.2 eq) in 150 mL CH2Cl2 were added N-methoxymethanamine hydrochloride (6.8 g, 1.2 eq) and Et3N (26.2 g, 4.5 eq). The reaction mixture was stirred at rt overnight, concentrated, and purified by column chromatography to give the desired product (6.3, 60% yield). 1H NMR (400 MHz, CDCl3) δ 12.79 (s, 1H), 7.40 (d, J=6.8 Hz, 1H), 6.77 (s, 1H), 6.43 (dd, J=6.8 Hz, 1.6 Hz, 1H), 3.62 (s, 3H), 3.34 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:20]=O>O>[OH:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[CH2:20][NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6]2
Reactant: C=O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 8 h

Procedure:
(S)-2-Amino-3-(3,4-dihydroxy-phenyl)-propionic acid (90 g) was suspended in 0.8 L water, then 18.2 mL concentrated sulfuric acid in 0.5 L additional water was added with stirring. Formaldehyde solution (136 mL, 37 wt %) was then added while stirring and the mixture was stirred 18 hours at rt. It was quenched by addition of 24.4 g NaOH in 0.5 L water, dropwise over 1 h while cooling. The resulting mixture was stored overnight at 4° C., and the solid that formed was collected by filtration, washed with hot water (70° C.), cooled again and collected by filtration. The solid was treated with 0.5 L MeOH and evaporated, then stored under vacuum overnight to give 65 g desired product. 1H NMR (400 MHz, MeOH-d4): 6.64 (s, 1H), 6.59 (s, 1H), 4.29-4.21 (m, 3H), 3.29-3.21 (m, 1H), 3.11-3.01 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])(O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1.S(Br)([Br:26])=O.Cl>C(#N)C.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Br:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[N:6][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OC(Cn1cncn1)(c1ccc(Cl)cn1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Clc1ccc(C(Br)(Cn2cncn2)c2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Chloropyrid-2-yl)-1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol (0.55 g, 1.49 mmoles) was stirred in acetonitrile (20 ml) and thionyl bromide (0.4 g, 1.92 mmoles) was added. After 1 hr. at room temperature, a small amount of starting material remained (as shown by t.l.c.) and thus a further 0.1 g of thionyl bromide was added and the solution was stirred overnight at room temperature. The acetonitrile was then removed by evaporation under reduced pressure and the residue was basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3×40 ml). The combined organic extracts were dried over magnesium sulfate and evaporated and the residue was flash chromatographed on silica (230-400 mesh), eluting with ethyl acetate:hexane (1:3, v:v) to give an oil which was dissolved in dry ether and treated with ethereal hydrogen chloride. The white solid which precipitated (0.23 g) was recrystallized from isopropanol/diisopropyl ether to give the title compound as white crystals, 0.112 g (16%), m.p. 130° -150° C.