Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[CH:9])[CH2:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCCC)CC>[Pd].Cl[Pd]Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(NC(C)C)(C)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:4][CH:3]=1
Reactant: C#CC1CC=C(C)CC1
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu+2]
Agent: [Pd]
Solvent: CCCNCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1ccc(C#CC2CC=C(C)CC2)cc1
Temperature: 25 °C

Procedure:
To a round-bottom flask equipped with a stirbar is added acetylene 4F (R=methyl) (2 g), 4-bromoanisole (3.40 g), palladium catalyst (made by mixing together 29.11 g triphenylphosphine, 3.28 g PdCl2, and 200 mL dipropylamine; refluxing the slurry for 3 hours to get a yellow slurry; cooling to room temperature; adding 3.69 g copper (II) acetate monohydrate; refluxing 1 hour; cooling and storing in the freezer) (330 mg), and diisopropylamine (80 mL). A stream of dry nitrogen is bubbled through this solution for 15 minutes to degas it, and the solution is then refluxed under a nitrogen atmosphere for 5 hours. The cooled solution is poured onto silica gel and eluted with 1:1 hexanes:ethyl acetate to give the product. The methyl group may be removed using the conditions used for deprotection of methyl ether 2F.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Temperature: 80 °C
Yield: 71.6 %

Procedure:
1-t-Butoxycarbonyl-4-piperidinol (5.0 g 24.88 mmol) in dry dimethylformamide (60 ml) was treated with sodium hydride (60% 2.99 g 74.75 mmol) at room temperature under argon and then with 2-chloropyridine hydrochloride (4.1 g 27.33 mmol). Then mixture was heated at 80° C. overnight. After cooling the reaction was carefully quenched with water (5 ml) and then diluted with more water (20 ml) and extracted with ethyl acetate (30 ml). The organic solution was washed with sat. sodium bicarbonate, dried (MgSO4) and evaporated to give 1-t-butoxycarbonyl-4-(2-pyridoxy)piperidine (4.96 g 72%).
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1.C(O)C.[OH-].[Na+]>O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH:13]=2)=[CH:18]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCOC2CCCCO2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
15.6 ml of 6 N hydrochloric acid were added to a mixture of the product of Step A and 156 ml of 95% ethanol and the mixture was stirred for 31/2 hours under an inert atmosphere and was then poured into one liter of water. 10 ml of sodium hydroxide were added to the mixture which was then filtered. The recovered crystals were washed with water and dried under reduced pressure to obtain 4.068 g of 4-(1H-indol-3-yl)-3,6-dihydro-1-(2H)-pyridine-ethanol melting at 164°-165° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH3:29])[CH:22]=[O:23]>>[CH2:28]([NH:27][C:26]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17])[CH3:29]
Reactant: CCNc1ccc(C=O)cc1Br
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Product: CCNc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CC(=O)N2CC
Yield: 53 %

Procedure:
The intermediate 4-ethylamino-3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 3-bromo-4-ethylamino benzaldehyde. 53% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.31 (s, 3 H), 1.35 (s, 3 H), 2.08 (s, 3 H), 2.53 (s, 2 H), 3.27 (m, 2 H), 4.02 (q, J=7.5 Hz, 1 H), 6.75 (d, J=8.7 Hz, 1 H), 6.83 (s, 1 H), 7.21 (s, 1 H), 7.52 (s, 1 H), 7.81 (d, J=8.4 Hz, 1 H), 9.76 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:47][CH2:48][CH2:49][C:50]1([OH:53])[CH2:52][CH2:51]1)(=O)=O>CC(N(C)C)=O>[OH:53][C:50]1([CH2:49][CH2:48][CH2:47][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]5[C:23](=[O:35])[N:24]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:25]([CH3:28])[C:26]=5[CH3:27])=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:52][CH2:51]1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Yield: 62.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (277 mg, 0.593 mmol), Cs2CO3 (560 mg, 1.724 mmol, Aladdin), and 3-(1-hydroxycyclopropyl)propyl methanesulfonate (334 mg, 1.724 mmol) in DMA (10 mL). The title compound was purified by a silica gel column chromatography (67:30:1:2 (v/v/v/v) EtOAc/CH2Cl2/CH3OH/Et3N) to afford the title compound as a white solid (210 mg, 62.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH2:12]([N:11]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:24][N+:21]([O-:23])=[O:22])=[C:3]([O:2][CH3:1])[CH:10]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCN(CC)c1ccc(C=O)c(OC)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 44 %

Procedure:
A solution was prepared by dissolving 30 grams (0.14 mol) of 2-methoxy-4-(N,N-diethylamino)benzaldehyde in 150 ml of nitromethane, and added with 4 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystals was obtained. The yield was 44%.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][CH:14]=[C:13]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]=2[CH:12]=1)(=[O:5])=[O:4].[OH:21][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23]>C(OCC)(=O)C>[CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][CH:14]=[C:13]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]=2[CH:12]=1)(=[O:5])=[O:4].[O-:23][C:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:21]
Reactant: CCCCCCCCCC(=O)O
Agent: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN(C)C)c2c1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)[O-]
Temperature: 25 °C

Procedure:
Sumatriptan base ((2.29g; 7.75 mmol) was dissolved in boiling ethyl acetate (300 mL) with stirring. Capric acid (1.33 g; 7.75 mmol) was dissolved in ethyl acetate (10 mL) and added to the sumatriptan base solution in one portion. The hot solution was stirred for a further 10 minutes and allowed to cool to room temperature. Evaporation of the solvent by rotary evaporation rave a pale yellow oil. Hexane (50 mL) was added and a white precipitate formed that was filtered off under vacuum. The precipitate was washed with hexane and allowed to dry at room temperature to give sumatriptan caprate as a pale yellow solid (2.79 g; 77.4%). The sumatriptan caprate was characterised by DSC and FT-IR. DSC gave a single, sharp endotherm with the onset at 94.6° C. The FT-IR differed significantly from that of the sumatriptan base.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:24]=[O:25])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.75 g, 6.85 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added nBuLi (3.3 mL, 1.2 equivalents, 2.5 M solution in hexanes). After stirring for 1 hour, dry N,N-dimethylformamide (796 μL, 1.5 equivalents) was added. The reaction mixture was stirred for 1 hour at −78° C. and then warmed slowly to room temperature. After a further 2 hours at room temperature the reaction mixture was poured onto ice-water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4])=[O:16])[CH:19]=[CH2:20]
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO)COCc1ccccc1
Yield: 94.2 %

Procedure:
A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ2.56 (br s, 1 H), 3.69 (m, 3 H), 3.88 (m, 2 H), 4.54 (s, 2 H), 4.58 (d, 2 H, J=5.6 Hz), 5.23 (dd, 1 H, J=10.4, 1.1 Hz), 5.33 (dd, 1 H, J=17.1, 1.1 Hz), 5.42 (m, 1 H), 5.93 (m, 1 H), 7.35 (m, 5 H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH3:15])=[CH:4][C:5](OCC1C=CC=CC=1)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:1][C:2]([F:17])([F:16])[C:3]([CH3:15])=[CH:4][CH2:5][OH:6]
Reactant: CC(=CC(=O)OCc1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 4,4,4-trifluoro-3-methylbut-2-enoate (1.87 g, 7.67 mmol) in diethyl ether (5 mL) was added dropwise to a suspension of LAH (291 mg, 1.67 mmol) in diethyl ether (10 mL). After stirring at −78° C. for 10 min and at 0° C. for a further 30 min, the reaction mixture was filtered through cotton, quenched with sodium potassium tartrate and stirred vigorously until layers separated. The aqueous phase was extracted with diethyl ether. The combined ethereal layers were dried (magnesium sulfate) and concentrated in vacuo to afford 4,4,4-trifluoro-3-methylbut-2-en-1-ol which was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(C)(C)COC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCC(C)(C)C)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid 2,2-dimethyl-propyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,2-dimethylpropyl chloroformate (131 μl, 0.89 mmol). The title compound was obtained as yellow powder (245 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:19](=[O:20])[N:18]([CH3:21])[N:17]=[N:16][C:15]=12)=O>Cl>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:11]1[N:12]=[CH:13][N:14]2[C:19](=[O:20])[N:18]([CH3:21])[N:17]=[N:16][C:15]=12
Reactant: Cn1nnc2c(C(=O)Nc3ccccc3N)ncn2c1=O
Agent: Cl
Product: Cn1nnc2c(-c3nc4ccccc4[nH]3)ncn2c1=O
Temperature: 25 °C
Yield: 2.8 %

Procedure:
A solution of N-(2-aminophenyl)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (300 mg) in 3N HCl (15 mL) was heated at 90° C. overnight. After cooling to room temperature, the mixture was concentrated to dryness under high vacuum and the residue was dissolved in MeCN:MeOH. Triethylamine (170 μL) was added to the solution and the crude product was absorbed on silica and purified by flash chromatography using DCM:MeOH (95:5) as eluent to give 8 mg of the pure title compound as a green solid (3% yield). δH (DMSO d6): 13.0 (1H, s), 8.99 (1H, s), 7.73-7.75 (1H, d, J=7.5), 7.56-7.58 (1H, d, J=7.5), 7.23-7.27 (2H, m), 3.90 (3H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1COCC1>[OH:26][C@H:25]([CH2:27][NH:31][CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 292), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography, gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (82 mg, 68%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[S:17][C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.C(OCC)(=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:18]1[S:17][C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:20][CH:19]=1)=[O:23]
Reactant: O=C(O)c1cnc(-c2ccccc2)s1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
DIPEA (170 mg, 0.22 mL, 1.31 mmol) was added to a stirred solution of 2-phenyl-thiazole-5-carboxylic acid (90 mg, 0.43 mmol) in DMF (2 mL). HOBT (71 mg, 0.52 mmol) and EDCI (100 mg, 0.52 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (185 mg, 0.52 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 77.1 mg (35%) of 2-phenyl-thiazole-5-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.1%. 1H NMR (DMSO-d6): δ 9.0-8.9 (m, 1H), 8.54-8.5 (s, 1H), 8.0 (m, 2H), 7.9-7.64 (m, 3H), 7.6-7.5 (m, 4H), 4.24-4.1 (m, 2H), 3.8-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.[CH3:26][C:27]#[N:28].F[C:30]1[N:35]=[CH:34][C:33]([C:36]2[CH:50]=[CH:49][C:39]([O:40][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>C1COCC1>[O:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:40][C:39]2[CH:49]=[CH:50][C:36]([C:33]3[CH:32]=[CH:31][C:30]([CH2:26][C:27]#[N:28])=[N:35][CH:34]=3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1
Reactant: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A 3 L three-necked round-bottomed flask was equipped with mechanical stirrer, thermometer and adapter, additional funnel, and nitrogen inlet (on top of addition funnel, positive pressure through a bubbler). With a rapid stream of nitrogen going through the bubbler, the stopper was removed and the flask was charged with KHMDS (415.8 g, 2.08 mol) and then anhydrous THF (1 L). To the stirred and cooled (ice/methanol bath, internal temperature of solution was −8° C.) KHMDS/THF solution was added dropwise a solution of MeCN (70 g) in THF (110 mL) over a period of 22 min followed immediately by the relatively rapid (4 min) addition of a solution of 5 (79.06 g, 0.262 mol) in THF (400 mL), after which time the internal temperature of the reaction mixture had reached 10° C. With continued cooling (1 h) the internal temperature was −6° C. and by TLC the reaction appeared complete. After an additional 30 min (internal temperature of −3° C.), the reaction mixture was quenched with saturated brine (1 L) and diluted with EtOAc (500 mL). After removing the aqueous layer, the organic solution was dried (Na2SO4), filtered, and evaporated to dryness (to an oil) followed by completely dissolving in IPA (150 mL), diluting with heptane (300 mL), adding seed crystals (prepared by dissolving ˜100 mg of crude oil in IPA (˜150 mg) and diluting with heptane (˜2.5 mL)), and allowing to stand overnight. After stirring to break up the crystalline solid, the solid was filtered, washed with 250 mL 2:1 heptane/IPA and then multiple washes with heptane and air dried to give 64.38 g (yield of 76%) of title product 6 as a crystalline tan solid (LC purity of 99.3%). Another 5.88 g of less pure material was obtained from the filtrate.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].C1C=C[C:20]([N:23](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:19]C=1.C(N)C.C1COCC1>CN(C=O)C.O>[CH2:20]([NH:23][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[N:6]=1)[CH3:19]
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CCN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1nc(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of 3-nitro-6-(trifluoromethyl)-2(1H)-pyridinone (2.4 g, 11.5 mmol) in DMF (69 mL) was added sodium hydride (350 mg, 13.8 mmol). The reaction was stirred for 30 min at 45° C., cooled to room temperature and N-phenyltrifluromethanesulfonimide (4.9 g, 13.8 mmol) was added. After 1 h, a 2 M solution of ethylamine in THF (13 mL, 25 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×). The combined organic layer was successively washed water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 9:1) to give the desired compound (1.1 g, 41% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl.CO>[CH:1]1([CH2:7][N:16]2[C:17]3[C@:18]4([CH3:28])[C:25]([CH3:27])([CH3:26])[C@@H:21]([CH2:20][CH2:19]4)[C:22]=3[C:23](=[O:24])[N:15]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCCCC1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
A mixture of cyclohexylmethyl bromide (2.1 mL, 15 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 395 mg, 1.47 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) in N,N-dimethylformamide (4 mL) was heated in an oil-bath at 100° C. for 64 h. Additional quantities of in N,N-dimethylformamide (2 mL), cyclohexylmethyl bromide (2.1 mL, 15 mmol), and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) were added and the mixture was heated at 135° C. for 20 h. An additional quantity of cyclohexylmethyl bromide (2.1 mL, 15 mmol) was added and the mixture was heated at 135° C. for 6 days. The reaction mixture to cooled to room temperature and then diluted with dichloromethane (150 mL) and washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 15-100% ethyl acetate/hexanes and then held under high vacuum to give an orange gum. This was treated with charcoal in methanol in a warm water bath, and the resulting mixture was filtered, evaporated and held under high vacuum to give (4R,7S)-1-(cyclohexyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (22 mg, 4%) as a yellow gum. ES(+)-MS (M+H) 365.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:16]([O:17]C)=[N:15][S:14](=[O:20])(=[O:19])[N:13]=1.[OH-].[Na+]>CO>[OH:17][C:16]1[C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])=[N:13][S:14](=[O:19])(=[O:20])[N:15]=1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]cnc1CSCCNC1=NS(=O)(=O)N=C1O

Procedure:
When a methanolic solution of 3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide [prepared by the procedure of Step A of Example 1] is treated with a solution of sodium hydroxide in methanol by the general procedure of Example 17, Step B, the title compound is produced, mp 263°-265° (dec).