Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl[O-].[Na+].[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14](Br)=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10].C1(C)C=C(C)C=C(C)C=1.[C-]#N.[Na+].[CH2:31]([N:35]1C=CN=C1)CCC.C(N)CN>[Cu]I.O>[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]([C:31]#[N:35])=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CCCCn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Solvent: NCCN
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 500-mL four-necked flask equipped with a mechanical stirrer, thermocouple, condenser, side-arm addition funnel and sodium hydroxide/sodium hypochlorite scrubber was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (24.6 g, 0.10 mol, 99% purity) and mesitylene (100 g) while maintaining an atmosphere of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature and sodium cyanide (ground to a powder just prior to use) (6.2 g, 0.121 mol, assuming, 95% purity), copper(I) iodide (2.9 g, 0.015 mol, 98% purity) and 1-butyl-1H-imidazole (5.4 g, 0.0425 mol, 98% purity) were added, after which time the nitrogen inlet line was attached directly to the reaction flask. The reaction mixture was heated at reflux (about 166-170° C.) for 6 h, while venting through the scrubber. After cooling overnight, water (100 mL) was added to the reaction mixture and stirring was continued for 1 h. Ethylenediamine (0.09 g, about 0.015 mol, 99% purity) was added to the reaction mixture, and stirring was continued for an additional 3.5 h. The mixture was filtered, and the solid collected was washed with water (3×50 mL), mesitylene (50 g) and dried to a constant weight in a vacuum-oven at 55° C. to give the title compound as a light brown solid (19.0 g).
Reaction SMILES: Cl[C:2]([O:4]C)=[O:3].Br[C:7]1[CH:8]=[C:9]2[C:22]3[C:12]([CH2:13][C@@H:14]4[C@@H:19]([C:20]=3[CH:21]=1)[CH2:18][C@H:17]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:16][N:15]4[CH3:31])=[CH:11][N:10]2[Si](C(C)(C)C)(C)C>>[CH2:28]([N:25]([CH2:26][CH3:27])[C:24](=[O:30])[NH:23][C@H:17]1[CH2:18][C@H:19]2[C@@H:14]([CH2:13][C:12]3[C:22]4[C:9](=[CH:8][C:7]([C:2]([OH:4])=[O:3])=[CH:21][C:20]2=4)[NH:10][CH:11]=3)[N:15]([CH3:31])[CH2:16]1)[CH3:29]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: COC(=O)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(=O)O)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With methyl chloroformate and 3-(13-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: C(N(CCCC)CCCC)CCC.Cl[CH2:15][Si:16]([CH3:19])([Cl:18])[Cl:17].[Cl:20][SiH:21]([Cl:23])[Cl:22]>>[Cl:20][Si:21]([Cl:23])([Cl:22])[CH2:15][Si:16]([Cl:18])([Cl:17])[CH3:19]
Reactant: C[Si](Cl)(Cl)CCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Product: C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Yield: 30.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.115 g (0.62 mmol) of tri-n-butylamine, 1.0 g (6.2 mmol) of (chloromethyl)methyldichlorosilane, and 4.18 g (30.9 mmol) of trichlorosilane were reacted at 200° C. for 11 hrs. The resulting mixture was distilled to give 0.50 g of 1,1,1,3,3-pentachloro-1,3-disilabutane (yield; 6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:26])([F:25])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:26])([F:25])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Yield: 90.5 %

Procedure:
A solution of 3.methyl 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylate (4.0 g, 9.45 mmol) and LiOH (0.340 g, 14.18 mmol) in 10% H2O/MeOH (150 mL) was stirred at ambient temperature for 4 hrs. Solvent was removed via rotary evaporation, and the resulting residue was diluted with H2O (100 mL). The aqueous phase was adjusted to pH=5 with concentrated HCl. The resulting precipitate was collected, rinsed with water, rinsed with EtOAc, and dried under vacuum over P2O5 for 18 hrs to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylic acid 45J (3.5 g, 8.55 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (dd, J=9.85, 1.77 Hz, 1 H) 7.82 (d, J=9.60 Hz, 1H) 8.02 (d, J=9.60 Hz, 1 H) 8.51 (d, J=9.85 Hz, 1 H) 8.90 (s, 1 H) 8.97 (s,1 H). ESI-MS:m/z 4.09 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43])C1C=CC=CC=1.[H][H]>C(N(CC)CC)C.CO.[Pd]>[OH:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43]
Reactant: [H][H]
Reactant: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 3 h

Procedure:
A suspension of 7.60 g (12.98 mmol) (S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 0.76 g 10% Pd/C in 2 mL triethylamine and 150 mL MeOH was hydrogenated at RT and 2620 hPa hydrogen pressure for 16 h. To complete the reaction a further 0.38 g 10% Pd/C were added and the mixture was again hydrogenated for 3 h at RT. The catalyst was filtered off through Celite and the filtrate was concentrated by evaporation i.vac. The product was further reacted without purification.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][NH2:25])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl>[C:28]([NH:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:27])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:26])(=[O:30])[CH3:29]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylquinoline (100 mg), acetic anhydride (35 ml), pyridine (60 μl) and methylene chloride (2 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (138 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Product: O=C(Nc1ccc(-n2ccncc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
71.1 Using general method G, 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:13]([O-])([OH:15])=[O:14]>>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Product: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To ice cold conc. sulphuric acid (360 mL) was added fuming nitric acid (180 mL) dropwise followed by (ii) (60 g, 0.26 mol) dropwise over 15 min. The reaction mixture was stirred for 10 min and then allowed to warm to RT. After 30 min, the reaction mixture was heated at 45° C. for 2 h and then at 50° C. for 3 h and then allowed to cool to RT. The reaction mixture was then poured carefully over ice-water and the organics were extracted into chloroform (500 mL). The volatiles were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:n-hexane (gradient elution from 5% to 30% v/v) to give (iii) (5.1 g, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCc1c[nH]c2ccc(Cl)cc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.7 %

Procedure:
A mixture of 4-(5-chloroindol-3-yl)butyric acid (1.50 g), benzyl bromide (1.10 g) and potassium carbonate (0.987 in N,N-dimethylformamide (12 ml) was stirred at 25° C. for 4.5 hours. The mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was chromatographed on silica gel (40 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give benzyl 4-(5-chloroindol-3-yl)butyrate (1.40 g) as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25]CC)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[CH2:30][CH2:31]NC.C([Al](CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23](=[O:25])[CH2:30][CH3:31])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCNC
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following General Procedure O, 5-phenyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid ethyl ester (Compound 29, 292 mg, 0.71 mmol) in toluene (5 ml), N,N′-dimethylethylenediamine (DMEDA, 76 mg, 0.86 mmol) and triethylaluminum (2.4 ml, 0.35 mmol, 1 M in hexane) were reacted to produce the title compound as a oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.BrC[CH2:29][O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][CH2:29][O:30][CH3:31])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-otolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with 2-bromoethylmethylether in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=454.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH2:12]Cl.C1(C)C=CC=CC=1.[P:21]([S-:27])(=[S:26])([O:24][CH3:25])[O:22][CH3:23].[NH4+]>CO>[P:21]([S:27][CH2:12][C:3]1[N:4]=[C:5]2[S:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Cl:1])(=[S:26])([O:24][CH3:25])[O:22][CH3:23]
Reactant: O=c1c(Cl)c(CCl)nc2sccn12
Reactant: COP(=S)([S-])OC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COP(=S)(OC)SCc1nc2sccn2c(=O)c1Cl
Reaction time: 6 h

Procedure:
The compound of EXAMPLE 2 (7 g) and 100 ml of toluene was stirred and heated to 70°. To this mixture was added, dropwise, a solution of 14 g ammonium dimethyl phosphorodithioate in 200 ml methanol. The resulting mixture was kept at 70° for 6 hours, then the methanol was distilled off. Toluene (400 ml) was added, and the mixture was washed with water, separated, dried and evaporated under reduced pressure. The solid which remained was washed with toluene and filtered. The solid, m.p. 125°-130°, weighed 2.5 g.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[F:30][C:31]([F:41])([F:42])[C:32]1[CH:33]=[C:34]([NH:38][C:39]([N:23]2[CH2:24][CH2:25][N:20]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:27][CH:26]=3)[CH2:21][CH2:22]2)=[O:40])[CH:35]=[CH:36][CH:37]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(Cc2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Yield: 69.7 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 15 ml of methylene chloride is added dropwise a solution of m-trifluoromethylphenyl isocyanate (0.935 g, 0.005 mol) in 10 ml of methylene chloride under nitrogen at room temperature. After complete addition, the resultant suspension is stirred at room temperature for 1 hour. This is then filtered and the white residue which is precipitated is washed with methylene chloride and dried. This is re-crystallized from methanol to give 2 g (68%) of white crystalline 1-[[[3-(trifluoromethyl)phenyl]amino]carbonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzyl]piperazine of melting point 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:10]([N+:21]([O-])=O)[CH:9]=1)=[O:6].[OH-].[Na+]>Cl.CO.[Zn]>[NH2:21][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1
Reactant: O=C(Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(NC(=O)c2cccc(Cl)c2)cc(Oc2cccnc2)c1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Compound 1 (710 mg, 1.92 mmol, 1.00 eq) was dissolved in 1N HCl in MeOH (22 mL) and zinc (377 mg, 5.77 mmol, 3.00 eq) was added. The reaction was stirred for 1 hour and additional zinc (251 mg, 3.84 mmol, 2.00 eq) was added to drive the reaction to completion as determined by TLC. The reaction was neutralized with 1N NaOH, filtered and extracted with CH2Cl2 (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 555 mg (85%) of the title compound as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.37 (dd, J=2.7, 0.8 Hz, 1H), 8.34 (dd, J=4.3, 1.7 Hz, 1H), 7.93 (t, J=1.8 Hz, 1H), 7.84 (dt, J=7.9, 1.2 Hz, 1H), 7.63 (ddd, J=8.1, 2.1, 1.0 1H), 7.52 (t, J=7.8 Hz, 1H), 7.43 (m, 2H), 6.94 (t, J=1.8 Hz, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.00 (t, J=2.1 Hz, 1H), 5.37 (s, 2H); ES-MS [M+1]+: 340.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:12][C:13](=[O:19])[CH2:14][CH:15]([CH3:18])[CH2:16]Cl)=[O:5])[CH3:2].[I-].[Na+].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[N:12]1[CH2:16][CH:15]([CH3:18])[CH2:14][C:13]1=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)CC(C)CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@H]1N1CC(C)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
cis-2-(4-Chloro-3-methyl-butyrylamino)-cyclohexanecarboxylic acid ethyl ester (895 mg) was dissolved in absolute DMF (20 ml) under argon at RT. Sodium iodide (463 mg) and sodium hydride (55%) (270 mg) were added; a white suspension was obtained. The mixture was then stirred for 2 hours at room temperature. The reaction mixture was poured into ice/water containing saturated NH4Cl solution and the aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (CH2Cl2/MeOH/NH3 95/5/0.5) to give the product as a 1:1 mixture of epimers as a light yellow liquid (402 mg). MS (ESI): 254.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CC1CCCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH:23]2[CH3:28])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1CCCN1
Product: CC1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-methylpyrrolidine and isolated as white solid (13.0 mg, 70%). MS(m/e): 385.4 (MH+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([O:47][C:48](OC3C=CC([N+]([O-])=O)=CC=3)=[O:49])[CH2:43][CH2:42]2)=[O:40])=[O:30])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([O:47][C:48](=[O:49])[NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:43][CH2:42]2)=[O:40])=[O:30])=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCCCC1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)NC2CCCCC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.5 %

Procedure:
A solution of cyclohexylamine (442 mg, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature for approximately 48 hours. The reaction mixture was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.92 g of a waxy yellow solid. Purification of the solid on silica gel (230-400 mesh) using 20% ethyl acetate-methylene chloride as the eluent gave 884 mg (47%) of the title compound as a white crystalline solid, mp 138°-142° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.Br[CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:42][S:39]([CH2:38][CH2:37][CH2:36][N:22]1[C:21](=[O:24])[N:5]2[CH:6]=[C:7]([C:8]3[N:12]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)[N:11]=[CH:10][CH:9]=3)[C:2]([CH3:1])=[C:3]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:4]2=[N:23]1)(=[O:41])=[O:40]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCCBr
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(CCCS(C)(=O)=O)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 70 mg. 0.152 mmol) and 1-bromo-3-methanesulfonyl-propane (53 mg, 0.264 mmol) using a similar method to that employed for Example 11 (27 mg).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[CH:31]=[N:30][CH:29]=[N:28][C:27]=3[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([F:44])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:44][C:19]1[N:18]=[C:17]([NH:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:32]2[CH:31]=[N:30][CH:29]=[N:28][C:27]=2[NH:26][CH:25]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncncc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To {6-fluoro-5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (67, 27 g, 42.5 mmol) in 700 mL of acetonitrile, triethylsilane (67.8 mL, 425 mmol) and trifluoroacetic acid (32.7 mL, 425 mmol) were added. The reaction was stirred at 50° C. overnight, solvents removed under vacuum, and the residue taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum and purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (P-0105, 4.5 g, 12.38 mmol, 29.2% yield).
Reaction SMILES: Br[C:2]([F:6])=[C:3]([F:5])[F:4].Cl[Si:8]([CH3:19])([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1.C([Li])(CC)C.C1CCCCC1.Cl>CCOCC>[F:6][C:2]([Si:8]([CH3:18])([CH3:19])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[C:3]([F:5])[F:4]
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Reactant: FC(F)=C(F)Br
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCOc1ccc([Si](C)(C)C(F)=C(F)F)cc1
Temperature: -65 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A -30° C. solution of bromotrifluoroethylene (7.15 g, 0.044 mol) in ether is treated with p-(chlorodimethylsilyl)phenetole (9.54 g, 0.044 mol), cooled to -65° C., treated dropwise with a 1.3M solution of sec-butyllithium in cyclohexane (34.2 mL, 0.044 mol) while maintaining the temperature below -60° C., stirred at -65° C. for 5 hours, stirred at room temperature overnight, cooled to 0° C., treated with dilute hydrochloric acid, and diluted with ether. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue which is distilled to give the title product as a clear liquid (7.66 g, bp 84°-92° C./0.8 mm Hg).