Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 5-bromo-2-nitropyridin (30.0 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40.0 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28.0 g, 148 mmol). The mixture was stirred at 65° C. overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried in vacuo. It was then further purified by silica-gel column chromatography eluting with 20:1 petroleum ether/ethyl acetate and then with dichloromethane to afford 339a as a yellow solid (17.0 g, 37%). MS-ESI: [M+H]+ 309.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CC(=O)Nc1ccc(OCCn2c(C)cc3c(Cl)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.89 (d, J=1.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 6.73 (d, J=8.9 Hz, 2H), 4.62 (t, 2H), 4.19 (t, 2H), 2.48 (s, 3H), 1.95 (s, 3H); MS (ES) m/z 368 (M+1).
Reaction SMILES: C[Al](C)C.[C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Si:18]([O:25][CH2:26][C:27]#[C:28][C:29](OCC)=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:12]1([N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:29](=[O:30])[C:28]#[C:27][CH2:26][O:25][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C#CCO[Si](C)(C)C(C)(C)C
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 1.4 mL Me3Al (2.0M in hexanes) in 3.6 mL anhydrous CH2Cl2 under N2 was added 0.49 g of diphenylamine in one portion. After stirring 30 min, 0.35 g ethyl 4-(t-butyldimethylsilyloxy)-2-butynoate in 0.4 mL CH2Cl2 was added dropwise. The reaction was stirred overnight at room temperature, then heated in an oil bath at 35° overnight. The reaction was quenched by the addition of a few drops of 1N HCl, diluted with H2O, and extracted with CH2Cl2. The combined organics were with H2O and brine and dried over Na2SO4. Filtration, evaporation, and flash chromatography with a 10-15% Et2O/hexanes gradient provided 0.31 g of product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:16][C:13]2[S:14][C:15]3[C:7]([CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=3[N:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a stirred suspension of 450 mg (1.69 mmol) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine and 0.41 ml (5.07 mmol) pyridine in 10 ml dichloromethane at 0° C. was added 0.28 ml (2.20 mmol) phenyl chloroformate and stirring continued at room temperature for 16 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 acetone/heptane) followed by trituration in ether and hexane afforded 630 mg (96%) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester as a white solid. [α]D20=+13.6° (c=0.32, CHCl3), ES-MS m/e (%):387 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1NCCN1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 32 %

Procedure:
Imidazolidin-2-one (2.0 g; 23.23 mmol) was dissolved in dimethyl sulfoxide (DMSO; 30 ml). Potassium carbonate (3.10 g; 23.23 mmol), potassium iodide (0.95 g; 5.80 mmol) and 4-benzyloxybenzyl chloride (5.4 g; 23.23 mmol) were added thereto. The mixture was heated at 100° C. for 3 hours (h). Cooling to RT was followed by partition between water (100 ml) and ethyl acetate (EtOAc, 100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3×; 30 ml). The combined organic phases were washed with saturated NaCl solution (80 ml) and dried over MgSO4. The solvent was removed under reduced pressure in a rotary evaporator. Trituration of the residue with EtOAc (10 ml) triturated resulted in 1-(4-benzyloxybenzyl)-imidazolidin-2-one (2.10 g; 7.43 mmol). MS: 283.15 (M+H); Rt: 1.38 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@@H:33]1[CH:34]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:34][CH:33]1[CH2:36][CH2:37][CH2:38][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of triphenylphosphine (31.7 g, 120.8 mmol) and carbon tetrabromide (20.0 g, 60.3 mmol) in methylene chloride (450 mL) at 0° C. was added dropwise a solution of N-(tert-Butoxycarbonyl)-D-prolinal (6.0 g, 30.1 mmol) in methylene chloride (50 mL). Upon complete addition of the aldehyde, the cooling bath was removed and mixing continued for an additional 30 minutes at ambient temperature. The mixture was poured into saturated sodium bicarbonate solution (600 mL) and the organic layer was extracted, dried over sodium sulfate anhydrous, concentrated in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-butyl 2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=300. 1H NMR (CDCl3, 400 Mhz) 6.37 ppm (s, 1H), 4.36 (s, 1H), 3.5-3.4 (m, 2H), 2.2-2.1 (m, 1H), 1.88-1.82 (m, 2H), 1.77-1.71 (m, 1H), 1.56 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH3:60])=[CH:55][CH:54]=1>ClCCl.CCN(C(C)C)C(C)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[O:50])[N:59]([C:56]3[CH:57]=[CH:58][C:53]([Cl:52])=[CH:54][CH:55]=3)[CH3:60])=[CH:44][C:43]=2[F:51])[CH2:34][CH2:33]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: CNc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
PyBroP (606 mg, 1.3 mmol) was added to a solution of 4-[3-(4-carboxy-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39 (382 mg, 11.0 mmol) in dichloromethane (20 ml) and DIEA (to pH9). The mixture was stirred for 1 h at room temperature then (4-chloro-phenyl)-methyl amine (156 mg, 1.1 mmol) was added. The mixture was stirred for 2 days at room temperature then solvents were concentrated in vacuo. The residue was dissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (210 mg, 41%).
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[NH:5][C:4](=[O:6])[CH:3]2[CH2:7][CH2:8][CH2:9][N:2]12.[C:12]1([S:18][CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([S:18][CH2:19][N:5]2[S:1](=[O:11])(=[O:10])[N:2]3[CH2:9][CH2:8][CH2:7][CH:3]3[C:4]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NS(=O)(=O)N2CCCC12
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: O=C1C2CCCN2S(=O)(=O)N1CSc1ccccc1
Yield: 65.8 %

Procedure:
To a mixture of tetrahydropyrrolo[1,2-b]1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (5.0 g, 28.4 mmol) suspended in 150 ml of toluene was added phenylthiomethyl chloride (6.76 g, 42.6 mmol) and tetrabutylammonium bromide (0.91 g). The resulting mixture was refluxed for 6 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (25%-30% ethyl acetate in hexane) to afford 5.58 g (66%) of 2-phenylthiomethyl-tetrahydropyrrolo[1,2-b]1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (Formula VI: R1 =H; R2 and R3 together =-(CH2 )3 -) as a solid, m.p. 90.5°-91.5° C.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].C(N(CC)CC)C.[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl.Cl>CN(C=O)C>[CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[N:4]([CH3:5])[S:19][C:18]([Cl:22])([Cl:21])[Cl:17]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=N[N+](=O)[O-])N(C)SC(Cl)(Cl)Cl
Yield: 57.1 %

Procedure:
To a cooled, stirred mixture of S,N-dimethyl-N'-nitroisothiourea (1.0 g), triethylamine (0.68 g) and DMF (10 ml) was added 1.2 g of trichloromethanesulfenyl chloride dropwise at 3°-7° C. After stirring at the same temperature for 1 hour, the mixture was poured into 50 ml of 2N hydrochloric acid and the resulting mixture was extracted with toluene (50 ml). The toluene layer was washed with water (50 ml), dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (8:1). The fractions containing the desired product were concentrated to afford 1.1 g of S,N-dimethyl-N'-nitro-N-trichloromethanesulfenylisothiourea as a pale yellow crystal, m.p. 75°-78° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][C:8]1([CH3:11])[CH2:10][O:9]1>>[CH3:7][C:8]([OH:9])([CH3:11])[CH2:10][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: CC1(C)CO1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CC(C)(C)O

Procedure:
The title compound was prepared according to the method described for Preparation 146 using 2-methyl-1H-imidazole and 2,2-dimethyloxirane.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2ccccc2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), Phenylacetic acid (38.2 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-[4-fluoro-1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80.2 mg, 71.2% yield) as a white solid. LC-MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 3.89 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 5.79-6.20 (m, 2H), 7.10-7.42 (m, 7H), 7.95 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[CH:22][C:21]=1[Cl:37].[CH:38]1[C:43]([N:44]=[C:45]=[S:46])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C=O)C>[Cl:37][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:45]([NH:44][C:43]1[CH:42]=[C:41]2[C:40](=[CH:39][CH:38]=1)[C:50]1([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[O:58][C:59]3[C:60]1=[CH:61][CH:62]=[C:63]([OH:65])[CH:64]=3)[O:49][C:47]2=[O:48])=[S:46]
Reactant: NCCOCCOCCOc1c(Cl)cc(Nc2ccccc2C(=O)O)cc1Cl
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1Nc1cc(Cl)c(OCCOCCOCCNC(=S)Nc2ccc3c(c2)C(=O)OC32c3ccc(O)cc3Oc3cc(O)ccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N,N-Diisopropylethylamine (10 μL, 0.057 mmol) was added to a solution of the compound 4 (1.9 mg, 0.0035 mmol) and fluorescein isothiocyanate (FITC) (1.2 mg, 0.003 mmol) in DMF (1.0 ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (silica gel, 1-20% methanol/methylene chloride) to give the desired compound 5 (1.5 mg, 52% yield); 1H NMR (CD3OD, 400 MHz) δ 8.14-8.10 (m, 1H), 7.88 (dd, 1H, J=2.0 Hz, 8.0 Hz), 7.80-7.62 (m, 2H), 7.34-7.30 (m, 1H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 3H), 6.86-6.78 (m, 1H), 6.72-6.64 (m, 3H), 6.54-6.50 (m, 2H), 4.21-4.04 (m, 4H), 3.92-3.66 (m, 8H); HRMS (ESI+) m/z: calcd for C40H33Cl2N3O10S+H+ 818.1342; found 818.1328 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>ClCCl>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:2]=[C:20]=[O:21])=[CH:19][CH:18]=1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=NCc1ccc(C(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To 4-(aminomethyl)benzoic acid, benzyl ester, hydrochloride salt, prepared as in Example 5, step C (288 mg, 1.04 mmol) at 0° C. was added saturated aqueous NaHCO3 (15 ml) and dichloromethane (20 ml). After 20 minutes stirring was ceased and the two layers were allowed to separate. Phosgene (20% solution in toluene, 1.1 ml, 2.18 mmol) was added rapidly to the lower layer and stirring resumed immediately. After 1 hour the organic layer was isolated. The aqueous layer was extracted with dichloromethane (3×20 ml). The four organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound (261 mg, 94%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH3:9])=[N:6][CH:7]=1.Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(O)cn1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccccn2)cn1
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A mixture of (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide (30 mg, 0.088 mmol), 2-(bromomethyl)pyridine hydrobromide (22 mg, 0.088 mmol), and cesium carbonate (115 mg, 0.35 mmol) in DMF (3 mL) was heated at 90° C. overnight. After cooling, the mixture was filtered through a pad of celite, washed with dichloromethane, the filtrate was concentrated, and the residue was purified by SCX cartridge to give 34 mg (89% yield) of (R)-N-(1-(5-(pyridin-2-ylmethoxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)a cetamide as a clear colorless oil; LCMS (Method A) m/z: M+1 obs 432, M−1 obs 430
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:28]1([NH2:35])[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>CN1C(=O)CCC1>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:35][C:2]2[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:29][CH2:30]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Solvent: CN1CCCC1=O
Product: Cn1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide 18A (19.9 mg, 0.044 mmol) and trans-cyclohexane-1,4-diamine (47.6 mg, 0.417 mmol) in NMP (0.7 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and purified by preparative HPLC. The desired fraction was concentrated and lyophilized to give 18B (14.9 mg, 40%) as a brown solid. [M+H]=465. HPLC Peak Rt=2.263 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Na+].[Na+].C(B(CC)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C>COCCOC>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CCB(CC)c1cccnc1
Reactant: COc1ccc(Br)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cccnc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 855 %

Procedure:
A mixture of 5-bromo-2-methoxybenzaldehyde (10.00 g, 1.82 mmol) and tetrakis (triphenylphosphine)palladium (O) (2.10 g, 1.82 mmol, 3.9 mol %) in DME (filtered through Al2O3) (50 ml) was stirred at RT for 0.25 h. Sodium carbonate (2M, 50 ml, 0.10 mol %) and diethyl (3-pyridyl)borane (6.817 g, 46.36 mmol) were added, the mixture heated to reflux for 5.5 h then allowed to stand at RT overnight. The dark brown reaction mixture was partitioned between water (50 ml) and Et2O (100 ml) and the organic layer separated and combined with two further Et2O extracts (1×50 ml, 1×25 ml). The organic phase was extracted with 2N hydrochloric acid (2×50 ml) then the aqueous extract was basified with 3M NaOH and extracted with Et2O (1×150 ml, 2×50 ml). The combined organic extract was washed with brine (50 ml), dried (Na2SO4), concentrated in vacuo then submitted to column chromatography [SiO2; Et2O] to furnish the title compound (3.318 g) as a pale yellow solid (Found: C, 73.40; H, 5.20; N, 6.44. C13H11NO2 requires C, 73.23; H, 5.20; N, 6.57%.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.48 g) was added to a solution of 2-butyl-4-chloro-5-hydroxymethylimidazole (prepared as described in U.S. Pat. No. 4,355,040) (0.56 g) and 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (1.3 g) in DMF (15 ml) and the mixture was stirred under an atmosphere of argon at 60° C. for 5 hours. The mixture was cooled to ambient temperature, water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with satured sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (180 mg) as a pale yellow solid, m.p. 182°-186° C.; NMR (CDCl3) 0.87(t,3H), 1.32(m,2 H), 1.65(m,2H), 2.49(t,2H), 4.57(s,2H), 5.15(s,2H), 6.58(d,2H), 6.75(d,2H), 6.90(dd,2H), 7.36(dd,1H), 7.65(m,2H), 7.85(dd,1H), 8.00(dd,2H); mass spectrum (+ve FAB, DMSO/CH3OH/m-nitrobenzyl alcohol): 544 (M+H)+.