Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]=[C:9]([NH:11][C@H:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[S:10][C:6]=2[CH:5]=1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O.C(OCC)(=O)C>[CH2:20]([S:22]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([O:3][CH3:2])[CH:19]=[CH:18][C:7]=3[N:8]=2)[CH2:13]1)(=[O:24])=[O:23])[CH3:21]
Reactant: COc1ccc2nc(N[C@H]3CCCNC3)sc2c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(OC)cc3s2)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-6-methoxy-N-(piperidin-3-yl)benzo[d]thiazol-2-amine hydrochloride salt (2.0 g, 5.95 mmol), ethylsulfonyl chloride (1.13 ml, 11.91 mmol) and DIPEA (4.11 ml, 23.8 mmol) in NMP (25 ml) was heated at 55° C. for 16 hours 50 min. The reaction mixture was allowed to cool down to room temperature and diluted with water (150 ml) and ethyl acetate (150 ml). After stirring vigorously for 1 hour the separated organic layer was washed with water (3×100 ml), saturated sodium bicarbonate solution (3×100 ml), water (100 ml) and brine (100 ml) and dried over sodium sulfate. Concentration in vacuo and purification by flash chromatography over silica gel with ethyl acetate:hexane (20:80-100:0) provided (S)—N-(1-(ethylsulfonyl)piperidin-3-yl)-6-methoxybenzo[d]thiazol-2-amine as tan solid. Yield: 1.22 g. ES/MS m/z 356.0 (MH+), Rt=2.12 min.
Reaction SMILES: [S:1]1[C:5](=[O:6])[NH:4][C:3](=[O:7])[S:2]1.[CH2:8](Br)[CH:9]=[CH2:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:4]1[C:3](=[O:7])[S:2][S:1][C:5]1=[O:6])[CH:9]=[CH2:8]
Reactant: O=c1[nH]c(=O)ss1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCn1c(=O)ssc1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 111.8 %

Procedure:
Next, 4.0 g of the above 1,2,4-dithiazolidine-3,5-dione, 4.0 g of allyl bromide and 5.8 g of potassium carbonate were suspended in 65 ml of acetone, and the suspension liquid was stirred at room temperature for 6 hours, and then filtered. Then, the residual obtained by concentrating the filtrate was purified with a column to yield 5.8 g of N-allyl-1,2,4-dithiazolidine-3,5-dione. The N-allyl-1,2,4-dithiazolidine-3,5-dione was dissolved in 4.5 ml of chloroform, and 50 mg of 2,2′-azobisisobutylonitrile was added to this solution. The solution thus obtained was stirred at 60° C. for 4 days, and then 100 ml of acetone was added to the solution to precipitate a powder-like substance. The powder-like substance was recovered, washed with ethanol several times, and dried under a reduced pressure to yield 2.8 g of an allyl polymer. The reaction concerned is shown in the following formula (VII), G in formula (VII) being the allyl polymer. An infrared absorption spectrum of the allyl polymer G is shown in FIG. 5.
Reaction SMILES: COC1C=C(C(C2C=CC=CC=2)=O)C=C(OC)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OP(CC#N)(=O)OCC)C.O1[C:45]2[CH:46]=[CH:47][C:48]([C:50]([C:54]3[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH3:63])[CH:55]=3)=[CH:51][C:52]#[N:53])=[CH:49][C:44]=2OCC1>C1COCC1>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([C:50]([C:48]2[CH:49]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:51][C:52]#[N:53])[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=O)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccccc2)c1
Yield: 89 %

Procedure:
(3,5-Dimethoxyphenyl)phenylmethanone (0.34 g, 1.40 mmol), lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 2.81 ml, 2.81 mmol), and cyanomethylphosphonic acid diethyl ester (0.44 ml, 2.81 mmol) in anhydrous THF (5 ml) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane) to give 3-(3,5-dimethoxy-phenyl)-3-phenyl-acrylonitrile as an oil (0.33 g, 89%): 1HNMR (DMSO-d6) δ 7.55-7.35 (m, 5H, Ar), 6.67-6.62 (2ts, 1H, Ar), 6.48-6.45 (2ds, 2H, Ar), 6.39 (s, 0.57H, double bond proton of one isomer), 6.34 (s, 0.43H, double bond proton of the other isomer), 3.76 (s, 3H, OCH3), 3.73 (s, 3H, OCH3); 13C NMR (CDCl3) δ 163.2, 163.1, 160.9, 160.9, 141.2, 138.9, 138.7, 137.0, 130.6, 130.2, 129.7, 128.8, 128.6, 128.5, 117.9, 117.8, 107.8, 107.0, 102.3, 102.2, 95.3, 95.1, 55.7, 55.6; Anal. Calcd. For C17H15NO2 (+0.03 H2O): C, 76.80; H, 5.71; N, 5.27. Found: C, 76.41; H, 5.40; N, 5.18.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]3[CH:27]=[CH:26][C:14]4[N:15]=[C:16]([NH:18][C@@H:19]5[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]5[OH:25])[S:17][C:13]=4[CH:12]=3)[C:6]=2[CH:28]=1.BrC1C=CC2N(CC3C=CC4N=C(N[C@@H:46]5CCCC[C@H:47]5[OH:52])SC=4C=3)C=NC=2C=1>>[OH:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([CH2:10][N:7]3[C:6]4[CH:28]=[C:2]([C:47](=[O:52])[CH3:46])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH:27]=[CH:26][C:14]=2[N:15]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)cc43)cc2s1
Product: CC(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2c1

Procedure:
1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanone was synthesized as a white powder (8 mg, 6%) using a procedure analogous to that described in Example 110, substituting (1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Steo 6 of Example 107 for (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol used in Example 110. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.24 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 5.58 (s, 2H), 4.75 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.61 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.34 (m, 4H); LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1)([O-])=O>CO.[Pd]>[NH2:4][C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1
Reactant: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c(cc1N)OCCO2
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of hydrazine monohydrate (1.0 mL, 21 mmol) in MeOH (3 mL) was added dropwise to a refluxing suspension of methyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (889 mg, 3.7 mmol) and palladium on carbon (10%, 220 mg) in MeOH (25 mL) under N2. After refluxing overnight, the resulting mixture was cooled to room temperature, filtered through celite and the filter cake was washed with MeOH. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 30% ethyl acetate in hexane to yield methyl 7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (390 mg, 50%). 1H NMR (CDCl3, 600 MHz) δ 7.19 (s, 1H), 6.17 (s, 1H), 4.24-4.22 (m, 2H), 4.17-4.15 (m, 2H), 3.82 (s, 3H); MS (ES+) m/z 210.1 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.CO>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:6][CH:7]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-tert-butylphenyl acetic acid methyl ester (10.0 g, 48.5 mmol) in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) was added 6 mol/L aqueous sodium hydroxide solution (16.2 mL, 97.0 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure and 6 mol/L hydrochloric acid was added thereto while cooling in ice, to adjust the pH to 4 to 5. A precipitated solid was collected by filtration to afford (4-tert-butylphenyl)acetic acid as a colorless powder (9.32 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](Br)=[C:9]([C:12]2C=C[C:15](F)=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2].C(OC(C1C2C(=CC=CC=2)N(C2C=CC=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Agent: CCOC(=O)c1c(C)n(-c2ccccc2)c2ccccc12
Product: CCOC(=O)c1c(CBr)n(-c2ccccc2)c2ccccc12

Procedure:
Prepared in analogy to that of 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-Methyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.21 (d, 1H), 7.6-6.9 (m, 8H), 4.89 (s, 2H), 4.47 (q, 2H, J=7.4 Hz), 1.50 (q, 3H, J=7.4 Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:35][C:36]([OH:40])([C:38]#[CH:39])[CH3:37].[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:40][C:36]([CH3:37])([CH3:35])[C:38]#[C:39][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a degassed solution of 4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144) (0.25 g, 0.56 mmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (40 mg, 0.06 mmol), CuI (11 mg, 0.06 mmol), N,N-diisopropylethylamine (0.45 mL, 2.52 mmol) and 2-methyl-3-butyn-2-ol (0.11 mL, 1.12 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl (15 mL) and water (5 mL), extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 30% EtOAc in hexanes to give a light brown solid. The solid was triturated with hot hexanes containing 1% MeOH and 5% EtOAc in hexanes to afford 150 mg (67%) of the title compound (241) as off-white solid. mp 186-187° C. 1H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.42 (s, 6H), 1.84 (s, 2H), 1.90 (s, 2H), 5.41 (s, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 9.29 (s, 1H). LCMS (ESI): m/z 401 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[O:5][C:6]1[C:7](=[O:33])[N:8]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19](C(OC(C)(C)C)=O)[N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]>C(O)(C(F)(F)F)=O>[Cl:37][C:35]1[CH:34]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:36]=1)[O:5][C:6]1[C:7](=[O:33])[N:8]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Cl)c3)c2=O)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(Oc2cc(Cl)cc(Cl)c2)c(C(F)(F)F)ccn1Cc1n[nH]c2ncccc12
Reaction time: 4 h

Procedure:
To tert-butyl 3-{[3-(3,5-dichlorophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.625 g, 1.13 mmol) in a flask was added TFA (10 mL). This solution under an atmosphere of N2 was placed in an oil bath at 75° C. After 4 hours, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and washed with 50% aqueous sodium carbonate (50 mL). The aqueous layer was back extracted with ethyl acetate (100 mL) and the combined organic extracts were dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The resulting solid was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 13.65 (s, 1H), 8.54-8.52 (m, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.32-7.30 (m, 1H), 7.18 (dd, J=8.0 Hz, J=4.4 Hz, 1H), 7.06-7.04 (m, 2H), 6.63 (d, J=7.3 Hz, 1H), 5.54 (s, 2H). HRMS (M+1)=455.0289.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[CH2:5][O:12]1
Reactant: C=Cc1ccccc1F
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of o-fluorostyrene (5.0 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mol) in three portions. The reaction was allowed to warm to RT and stirred overnight. Sodium carbonate (8.68 g, 81.9 mmol) was added in portions and then 1M NaOH (ca. 10 mL) was added and the reaction was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.31 g (94%) of the title compound as a slightly tinted oil which was used without further purification. MS (ESI+) for C8H7FO m/z 138.1 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30]OS(C5C=CC(C)=CC=5)(=O)=O)[CH2:26][CH2:25]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1.[ClH:42]>CS(C)=O.C(#N)C>[ClH:42].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:25][CH2:26][CH:27]([CH2:30][C:1]#[N:2])[CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(c3nccnc3N3CCN(Cc4cnn(C)c4C)CC3)CC2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1c(CN2CCN(c3nccnc3N3CCC(CC#N)CC3)CC2)cnn1C
Temperature: 50 °C
Reaction time: 5.75 h
Yield: 101.4 %

Procedure:
Add sodium cyanide (78.46 mg, 1.60 mmol, 2.4 eq) to a solution of toluene-4-sulfonic acid 1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-ylmethyl ester (0.36 g, 0.667 mmol, 1 eq) in dimethyl sulfoxide (5 mL). Heat the solution to 50° C. with stirring for 5.75 hr. and then cool to room temperature. Add water (20 mL) and extract the aqueous layer three times with DCM (20 mL). Combine the organic extracts, dry over magnesium sulphate, filter and concentrate. Purify by flash chromatography on a 40 g silica gel column, eluting with a gradient of 2-10% methanol in DCM. Further purify by high pH reverse phase HPLC (UV guided). Dissolve this material (148 mg, 0.38 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous hydrogen chloride (190 μL, 0.38 mmol) and lyophilize to give {1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-yl}-acetonitrile hydrochloride (166 mg, 58%). MS (m/z): 395.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]4[O:41][C:40]5=[N:42][C:43]([N+:45]([O-:47])=[O:46])=[CH:44][N:39]5[CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[N+:45]([C:43]1[N:42]=[C:40]2[N:39]([CH:44]=1)[CH2:38][CH2:37][CH:36]([CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH:18]4[CH2:19][CH2:20][N:15]([CH2:13][C:18]5[CH:19]=[CH:20][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:16][CH:17]=5)[CH2:16][CH2:17]4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=1)[O:41]2)([O-:47])=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(c3ccc(OCC4CCn5cc([N+](=O)[O-])nc5O4)cc3)CC2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCN(CC4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution (1.5 ml) of 4-{4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazin-1-ylmethyl}piperidine-1-carboxylic acid tert-butyl ester (300 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, methylene chloride (1.5 ml) and triethylamine (1.5 ml) were added to the residue, and the result was stirred at room temperature for 5 minutes. After concentrating the reaction mixture under reduced pressure, methanol (3 ml), 4-(trifluoromethyl)benzaldehyde (130 mg), sodium cyanoborohydride (160 mg) and acetic acid (1 ml) were added to the residue in this order, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) and recrystallized from methanol to afford the title compound as a pale yellow powder (50 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:23])([CH3:22])[C:17](=[O:21])[NH:18]2)=[CH:14][C:13]=1[CH3:24].[CH2:27](I)[CH2:28][CH3:29]>>[F:26][C:2]([F:25])([F:1])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:22])([CH3:23])[C:17](=[O:21])[N:18]2[CH2:27][CH2:28][CH3:29])=[CH:14][C:13]=1[CH3:24]
Reactant: CCCI
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)NC(=O)C2(C)C
Product: CCCN1C(=O)C(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21

Procedure:
The intermediate 4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-6-yl)-benzaldehyde was prepared in a similar manner to example 21a using 4-trifluoromethoxy-3-(3,3,5-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzaldehyde (example 21b) and propyl iodide. 1H NMR (300 MHz, CDCl3, ppm): δ: 0.93(t, J=7.3 Hz, 3 H), 1.45(s, 6 H), 1.70(m, 2 H), 2.10(s, 3 H), 3.66 (m, 2 H), 6.63 (s, 1 H), 7.11 (s, 1 H), 7.52–7.55 (m, 1 H), 7.85 (m, 1 H), 7.98 (m, 1H), 10.05 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.B([O-])[O-].[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34](Cl)[N:33]=1)=[O:31])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:8]=2)[N:33]=1)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)n1
Reactant: CC1(C)OB(c2cccc(Oc3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Temperature: 90 °C

Procedure:
In a 50-ml vial with a screw-top septum, 2-[3-(4-fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.500 g, 1.59 mmol) was dissolved in 6 ml DME, 3 ml EtOH, and 6 ml water. The boronate was then treated with one equivalent of 4,6-dichloro-pyridine-2-carboxylic acid ethyl ester (Anichem), PdCl2(PPh3)2 (0.078 g, 0.11 mmol), and cesium carbonate (1.04 g, 3.18 mmol). The vial was purged with argon and heated to 90° C. for 10 hours, at which time the reaction was complete. The reaction mixture was diluted with 50 ml water and the aqueous layer acidified with about 10 ml 4N aq. HCl. The desired material was extracted with EtOAc (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by combiflash using a 40-gram silica column and a gradient of EtOAc (100% max) in hexane to provide 0.445 g of 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:4][CH:3]=1.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1>ClCCl>[CH2:25]([O:24][C:22](=[O:23])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:18][CH3:19])=[CH:6][CH:7]=1)=[O:27])[CH3:26]
Reactant: CCc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1ccc(-c2c(CC)sc3ncnc(N)c23)cc1
Yield: 64.8 %

Procedure:
A solution of Example 78A (0.065 g, 0.25 mmol), ethyl chloro(oxo)acetate (0.028 mL, 0.25 mmol), and pyridine (0.02 mL, 0.25 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight and partitioned between water and dichloromethane. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by silica gel column chromatography with 5% methanol/dichloromethane to provide 60 mg of the desired product. MS (ESI(+)) m/e 371(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.15 (t, J=7.46 Hz, 3H); 1.34 (t, J=7.12 Hz, 3H); 2.64 (q, J=7.46 Hz, 2H); 4.34 (q, J=7.12 Hz, 2H); 7.41 (d, J=8.48 Hz, 2H); 7.93 (d, J=8.82 Hz, 2H); 8.27 (s, 1H); 11.00 (s, 1H).
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([C:17]2[CH2:18][CH2:19][N:20]([O:23][CH3:24])[CH2:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[NH2:25]>>[C:1]1([C:13]2[CH:14]=[C:15]([CH:17]3[CH2:22][CH2:21][N:20]([O:23][CH3:24])[CH2:19][CH2:18]3)[CH:16]=[CH:11][C:12]=2[NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CON1CC=C(c2ccc(N)c(Br)c2)CC1
Reactant: OB(O)C1=CCCCC1
Product: CON1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Yield: 76.8 %

Procedure:
The title compound was then prepared according to Suzuki coupling procedure of Example 12, step (d) using cyclohex-1-enyl boronic acid (27.9 mg, 1.00 mmol) and 2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (as prepared above, 44 mg, 0.15 mmol) and chromatographed on silica (20-50% EtOAc/hexanes) afforded 2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (33 mg, 74%). Mass spectrum, (ESI, m/z): Calcd. for C18H26N2O, 287.2 (M+H). found 286.8.