Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]=[CH:5][CH2:6][C@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:35])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH3:26])[C:18]([O:27]CC2C=CC=CC=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:12]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:10]2([CH3:11])[C:9](=[O:35])[CH2:8]1)[C:21]1[CH:20]=[C:19]([O:25][CH3:26])[C:18]([OH:27])=[CH:17][C:16]=1[CH2:15][CH2:14]3
Reactant: COC(=O)C=CC[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OC)c(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCC[C@@H]1CC(=O)[C@@]2(C)CC[C@@H]3c4cc(OC)c(O)cc4CC[C@H]3[C@H]12
Yield: 1460 %

Procedure:
A solution of 4-(3-Benzyloxy-2-methoxy-17-oxo-estra-1,3,5(10)-trien-15β-yl)-but-2-enoic acid methyl ester (17.3 g, 2.36 mmol) in THF (440 ml) and MeOH (440 ml) was purged with H2 (balloon). Then Pd (10% on carbon, 50% H2O) (1.80 g) was added, and the mixture obtained was stirred under H2 pressure for over night. The reaction mixture was filtered over two filter papers and concentrated in vacuo to yield the desired compound (VIIβ-(C2-B)-3a-1) (13.8 g, 97%), which represents a compound falling under the scope of the present invention.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[C:17](=O)(O)[O-].[Na+]>Cl.CO>[CH3:17][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
The solution of 4.2 g (17.9 mmol) 4-nitro-3-(trifluoromethyl)benzoic acid (commercially available) in 5.1 mL 1.25 M hydrochloric acid in methanol was refluxed for 5 h. After cooling down to room temperature the solution was poured on saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers washed with brine, dried over magnesium sulfate and evaporated. After filtration the solvent was evaporated and the residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 60:40 v/v) to afford the title compound as a light yellow solid (90%) which was pure enough for the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Cl[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: COC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCn1cc(I)cn1
Temperature: 50 °C

Procedure:
To a mixture of 4-iodopyrazole (1.000 g, 5.155 mmol), Cs2CO3 (2.016 g, 6.186 mmol), and DMF (20 mL, 0.2 mol) was added methyl 3-chloropropanoate (758.1 mg, 6.186 mmol) at 0° C. The reaction was heated to 50° C. for 1 h. The material was transferred to a separatory funnel, diluted with EtOAc, and washed with water several times to remove DMF. The organic layer was dry-loaded onto silica gel, and column chromatography was used for purification, eluting with 3:1 Hexanes/EtOAc, affording the title compound as a clear liquid. MS (ES+): m/z=280.95 (100) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
(3RS)-3-tert-butoxycarbonylaminopiperidin-2-one (16.07 g) was dissolved in N,N-dimethylformamide (DMF, 350 ml) and the mixture was cooled to 0° C. Sodium hydride (3.6 g of a 50% dispersion in mineral oil) was added and then the mixture was stirred at 0° C. for one hour. A solution of ethyl bromoacetate (13.78 g) in DMF (20 ml) was then added. The mixture was stirred for 16 hours at ambient temperature, then cooled to 0° C. and ice added. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over Na2SO4 and concentrated by evaporation. The resulting oil was purified on silica eluting with 40% ethyl acetate/petroleum ether (60-80° C.) to give ethyl 2-[(3RS)-3-tert-butoxycarbonylamino-2-oxopiperidin-1-yl]acetate as a colourless oil (18.15 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.[Br:46][C:47]1[CH:52]=[CH:51][C:50](C2C=CC(OCCCCCCO)=CC=2)=[CH:49][CH:48]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][Br:46])=[CH:41][CH:40]=2)=[CH:37][CH:38]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: OCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of triphenylphosphine (3.46 g, 0.013 mol) and DEAD (2.30 g, 0.012 mol) in dry cold THF (100 ml) was added dropwise over 10 min to a solution of 4-bromo-4′-hydroxybiphenyl (3.00 g, 0.012 mol) and 4-bromo-4′-(6-hydroxyhexyloxy)biphenyl (2.20 g, 0.012 mol) (prepared as described in Example 4 step 2 above) in dry THF (50 ml) stirring at room temperature. The reaction mixture was left stirring overnight The reaction product was extracted into diethyl ether (2×200 ml), and the combined ethereal solutions were washed with water and dried (MgSO4). The crude product was adsorbed onto silica gel and purified by column chromatography [DCM-petroleum fraction (bp 40-60° C.), 1:6] and recrystallised from ethanol to give white crystals.
Reaction SMILES: C([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(OCC1C=CC=CC=1)=O.Cl.[H][H]>[Pd].C(O)C>[CH2:24]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12][NH:11][CH2:25]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCNCC12

Procedure:
A mixture of 3.0 g. of 3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 2 g. of hydrogen chloride, 3 g. of 10% palladium on carbon and 200 ml. of ethanol is hydrogenated on a Parr apparatus for 18 hours at 46 p. s. i. hydrogen pressure. The catalyst is filtered and the filtrate is concentrated. The residue is recrystallized from ethanol to give 0.55 g. of the product as the hydrogen chloride salt, m.p. 288°-290°.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][NH:7][C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>CC(O)C>[CH3:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C@@H:6]([CH3:9])[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl) piperazine-1-carboxylate. To a solution of (2S,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate hydrochloride (1.17 g, 4.67 mmol, Acesys Pharmatech, A1653, Sample ID 119-99-18) in 2-Propanol (20 mL) was added 4-chloro-3-nitropyridine (1.11 g, 7.00 mmol, Alfa Aesar, Ward Hill, Mass.) and DIPEA (4.06 mL, 23.33 mmol). The mixture was heated and stirred at 85° C. for 2 h. Additional DIPEA (0.81 mL, 4.67 mmol) was added and the heat was raised to 90° C. The mixture was stirred at this temperature for 18 h. The mixture was then cooled to RT and concentrated. The residue was diluted with EtOAc (150 mL) and washed with water (15 mL) followed by brine (15 mL) and then dried over MgSO4. The crude material was purified by silica gel chromatography (30-70% EtOAc in hexanes) to afford (2S,5S)-tert-butyl 2,5-dimethyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (918 mg, 2.73 mmol, 59% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 337.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1 H), 8.38 (d, J=5.9 Hz, 1 H), 6.99 (d, J=6.1 Hz, 1 H), 4.12 (dd, J=14.0, 4.4 Hz, 1 H), 3.99-4.07 (m, 1 H), 3.94 (dt, J=10.8, 5.5 Hz, 1 H), 3.23 (dd, J=13.5, 9.4 Hz, 1 H), 2.98 (dd, J=14.1, 10.8 Hz, 1 H), 2.77 (dd, J=13.5, 5.7 Hz, 1 H), 1.46 (s, 9 H), 1.16 (d, J=6.3 Hz, 3 H), 1.13 (d, J=6.1 Hz, 3 H).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:4]=4)[CH:38]=[N:39][CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1
Reactant: N#Cc1ccc(CO)cc1OCCCCc1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(4-phenyl-butoxy)-benzonitrile from step 2 (100 mg, 0.36 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23 Step 5 (188 mg, 0.36 mmol) in CH2Cl2 (2 ml) was added DIEA (136 μl, 0.78 mmol) followed immediately by the addition of Tf2O (90 μl, 0.53 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (2 ml) and heated to 60° C. for several hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C:9]1[S:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=2[N:8]=1)=[O:16]
Reactant: Cc1cccc2sc(N)nc12
Reactant: O=C(Cl)c1cccnc1Cl
Product: Cc1cccc2sc(NC(=O)c3cccnc3Cl)nc12

Procedure:
Using 4-methyl-benzothiazol-2-ylamine and 2-chloronicotinic acid chloride the title compound was obtained as a yellow solid (50% yield), MS: m/e=304 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]([CH3:34])[C@H:9]([NH:29][C:30](=[O:33])[O:31][CH3:32])[C:10](=[O:28])[N:11]1[C@H:16]([C:17]2[NH:18][C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][N:21]=2)[CH2:15][C@@H:14]2[C@H:12]1[CH2:13]2>CO>[C:22]([C:19]1[NH:18][C:17]([C@@H:16]2[CH2:15][C@@H:14]3[C@@H:12]([CH2:13]3)[N:11]2[C:10](=[O:28])[C@@H:9]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:8]([CH3:34])[CH3:7])=[N:21][CH:20]=1)#[CH:23]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Potassium carbonate (34.3 mg, 0.248 mmol) was added to a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (200 mg, 0.497 mmol) in methanol (5 mL) and the reaction was flushed with nitrogen, sealed and then heated at 50° C. for 4 h. and then stirred at rt overnight. The reaction was concentrated to dryness and then purified on a BIOTAGE® Horizon (12 g SiO2, 70-90% EtOAc/hexanes) to yield methyl (S)-1-((1R,3S,5R)-3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (151 mg) as a yellow glass. LC-MS retention time 1.788 min; m/z 331.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1)(=O)C>O.CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH:20]=[O:21])=[CH:12]1
Reactant: CC(=O)OCCCCn1cc(C=O)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cn(CCCCO)c2ncccc12
Temperature: 60 °C
Yield: 78 %

Procedure:
A solution of sodium hydroxide (0.2 g, 17.5 mmol) in water (35 ml) was added to a solution of 1-(4-acetoxybutyl)-7-azaindole-3-carboxaldehyde (2.3 g, 8.8 mmol) in methanol (40 ml). The mixture was heated at 60° C. for 0.5 h, then the solvent was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water (50 ml:50 ml) and the water layer was separated out. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was used without further purification. Yield 78%. m.p. 90° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:6]=2[N:24]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a solution of 0.60 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-291) in 8 mL of dimethylformamide was added 0.83 g (0.0026 mole) of cesium carbonate, followed by 0.32 mL (0.0051 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 0.56 g of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:31])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[CH:20]=3)[NH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1
Solvent: Cc1ccccc1
Product: CN(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(C(N)=O)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
3-{3-[2-(Dimethylamino)acetylamino]phenyl}-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide was suspended in toluene (10 mL) and HCl gas was bubbled through the suspension for 15 min. The reaction was then stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.027 g, 13.5% yield over 2 steps): 1H NMR (CD3OD) 8.66 (s, 1H), 8.22 (t, 1H), 7.97 (dd, 1H), 7.75 (t, 2H), 7.63 (d, 2H), 7.51 (t, 1H), 3.21 (s, 2H), 2.41 (s, 6H); ES-MS (m/z) 338 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.O.NN>C(O)C.[Pd]>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1CCOc2cccc(Oc3ccc(N)cn3)c21
Temperature: 90 °C
Yield: 111.7 %

Procedure:
In a 50 mL round-bottomed flask 2-(4-methylchroman-5-yl)oxy-5-nitro-pyridine (Intermediate 212, 22.9 mg, 0.08 mmol) was dissolved in Ethanol (10 mL) to give a pale yellow solution. Pd/C (17.88 mg, 0.017 mmol) and hydrazine hydrate (0.4 mL, 4.15 mmol) were added. The reaction mixture was stirred at 90° C. The reaction mixture was filtered and evaporated in vacuo to give the title compound (22.9 mg) as a pale yellow oil.
Reaction SMILES: C([Mg]Br)C.[C:5]1([S:11][CH2:12][C:13]#[CH:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21]>CCOCC.O1CCCC1>[C:5]1([S:11][CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CCSc1ccccc1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCSc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.64 ml (12.48 g, 0.0936 mol) of a 3.8N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold solution of 13.2 g (0.089 mol) of 3-phenylthio-1-propyne (G. Pourcelot et al, vide supra) in 70 ml of anhydrous tetrahydrofuran. The temperature was maintained at 0°-5° C. Thereafter, the reaction mixture was stirred for 1 hour further at room temperature. Then, 440 mg of cuprous cyanide were added and the solution stirred for 20 minutes more. Then a solution of 7 g (0.0445 mol) of 1-bromo-2,5-hexadiyne in 20 ml of anhydrous tetrahydrofuran was added dropwise, maintaining the temperature between 0°-5° C. After the addition, the reaction mixture was stirred at room temperature for 3 additional hours, and then quenched with 150 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml) the combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and then with water,dried over sodium sulfate and evaporated. The crude material was purified by column chromatography on 150 g of silica gel, using hexane as eluant, to produce 9-phenylthio-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1(C(F)(F)F)CC1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 701 mg (2.58 mmol) of [1-(trifluoromethyl)cyclopropyl]methyl trifluoromethanesulphonate and 1.73 ml (1.73 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 13 ml of THF were reacted according to General Method 7B. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 40 g silica cartridge, flow rate 40 ml/min), giving the title compound. Yield: 295 mg (45% of theory)
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:26])([F:25])[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:11]=[C:10]([NH2:24])[CH:9]=1.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>>[N+:27]([C:9]1[C:10]([NH2:24])=[N:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:21])[F:23])=[CH:13][C:8]=1[C:7]([F:6])([F:25])[F:26])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(C(F)(F)F)cc(-c2ccccc2C(F)(F)F)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (10 mL) was placed in a 100 mL two-necked round-bottomed flask fitted with a magnetic stir bar and an internal thermometer and cooled to 0° C. 4-Trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (720 mg, 2.35 mmol, prepared as described in STEP C above) was added portion wise so that the internal temperature did not exceed 5° C. The resulting mixture was stirred at 0° C. for 1 h. Nitric acid (106 μL, 2.35 mmol) was added slowly, keeping the internal temperature below 10° C. The mixture was stirred an additional 2 h at 0° C., poured over ice water (100 mL), treated with 6 M aqueous NaOH to pH 10, and extracted twice with EtOAc (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a bright yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C13H7N3O2F6: 352.0 (M+H). Measured: 352.0.