Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:27]([C:30]1[S:31][C:32]([C:35](O)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:27]([C:30]1[S:31][C:32]([C:35]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:36])=[CH:33][N:34]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1ncc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.694 g) in DMF (13 mL) was treated with triethylamine (1.3 mL), followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.406 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g). The resulting mixture was stirred at RT for 16 h. DMF was removed in vacuo. The residue was taken up in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution (2×40 mL), water (40 mL) and brine (40 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The viscous orange oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a viscous orange oil. Yield 0.765 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)oc2ccccc12
Yield: 54 %

Procedure:
The title compound was prepared from ethyl 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetate (0.988 g, 1.94 mmol), and sodium hydroxide (3.9 mL, 3.9 mmol) in ethanol (15 mL) in substantially the same manner as described in Step 2 of Example 2. Purification by flash chromatography on acid treated (phosphoric acid) silica gel using 10-40% ethyl acetate in hexane as an eluant and subsequent crystallization from acetonitrile furnished the title compound as a light yellow solid (0.504 g), mp 146-147° C. Mass spectrum (+APCl, [M+H]+) m/z 481. 1HNMR (400 MHz, DMSO-d6): δ13.15-13.3 (br s, 1H), 8.45 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=9.0 Hz), 8.15 (d, 1H, J=9.5 Hz), 8.0-8.05 (m, 2H), 7.70-7.75 (m, 1H), 7.4-7.5 (m, 3H), 5.05 (s, 2H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C25H21BrO5.0.30 H2O: Calculated: C, 61.69;H, 4.47; N, 0.00. Found: C, 61.63;H, 4.12; N, 0.07.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:36]3[CH2:37][CH2:38][CH:33]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:34][CH2:35]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCCC2)CC1
Reaction time: 0.5 h

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (100 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then 4-(piperidin-1-yl)piperidine (144 mg) was added thereto, followed by stirring for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:2 to 1:8). The solvent was evaporated under a reduced pressure to give a residue, which was then dried in vacuum to provide 4-(piperidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide as a crude product.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:30][CH:29]=2)[C@H:10]([O:47][CH2:48][C@H:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:9]1)=O)(C)(C)C.Cl>CO>[OH:56][C@H:49]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:48][O:47][C@H:10]1[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COCCOC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1
Agent: Cl
Solvent: CO
Product: COCCOC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1

Procedure:
In analogy to the procedure described in example 1 (l) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the 2-[3-[4-[(3S,4R, 5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile as colorless foam; MS: 671 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>C(O)CCC>[CH2:12]([NH:15][C:4]1[NH:3][C:2]([Cl:1])=[N:10][C:9]2[C:5]=1[N:6]=[CH:7][N:8]=2)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: CCCNc1[nH]c(Cl)nc2ncnc1-2
Temperature: 75 °C

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 0.09 ml (1.1 mol) of propylamine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 2 hours 30 minutes.
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[CH:16][CH3:17])[C:11]([O:13]CC)=[O:12])[N:9]=1)(=O)C.[OH-].[K+].Cl>O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[CH:16][CH3:17])[C:11]([OH:13])=[O:12])[N:9]=1
Reactant: CC=C(C(=O)OCC)c1csc(NC(C)=O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC=C(C(=O)O)c1csc(N)n1
Reaction time: 0.75 h

Procedure:
8.4 parts by weight and ethyl 2-(2-acetamidothiazol-4-yl)-2-butenoate are added to a solution, warmed to 90° C., of 18.8 parts by weight of potassium hydroxide in 168 parts by volume of water. The solution is stirred for 45 minutes at the same temperature, cooled and brought to pH 3.6 with concentrated hydrochloric acid, with cooling.
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[N:11]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][C:20]3[CH:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:19]2=3)[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[N:11]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][S:21][C:20]3[CH:24]=[C:25]([NH:28][C:7]([C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)=[NH:8])[CH:26]=[CH:27][C:19]2=3)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc2c(c1)SCCN2CCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)SCCN2CCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (1.239 g, 4.34 mmol) was added to a mixture of 4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.572 g, 2.172 mmol) in EtOH (20 mL). The reaction was stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (30 mL). The mixture was then extracted with CH2Cl2 (50 mL), and the aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (CH2Cl2 then 5% (2M NH3 MeOH)/CH2Cl2). The collected fractions gave compound 11 as light brown viscous liquid (0.71 g, 88%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.6 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.08-7.06 (m, 1H), 6.67 (t, J=8.7 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 6.32 (brs, 2H), 3.57-3.53 (m, 2H), 3.39-3.34 (m, 2H), 3.03-3.00 (m, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.50 (brs, 4H), 1.68 (brs, 4H); ESI-MS (m/z, %): 375, 373 (MH+, 47), 278, 276 (100), 98 (21).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1B1OCC(C)(C)CO1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:46]=1[C:55]1[CH:60]=[CH:59][N:58]=[N:57][CH:56]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:18])=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:53])([F:54])[F:52])=[CH:47][C:46]=1[C:55]1[CH:60]=[CH:59][N:58]=[N:57][CH:56]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(B3OCC(C)(C)CO3)c(C#N)c2)c(OC)c1
Reactant: FC(F)(F)c1ccc(CBr)c(-c2ccnnc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 65 °C

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 29, 100 mg, 0.19 mmol) in tetrahydrofuran (2 mL) was added a 2 M aqueous solution of potassium carbonate (270 μL, 0.54 mmol) and 4-[2-(bromomethyl)-5-(trifluoromethyl)phenyl]pyridazine (Preparation 33, 57 mg, 0.18 mmol). The solution was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium (0) (20.8 mg, 0.018 mmol). The reaction mixture was heated at 65° C. for 6 hours. The reaction mixture was cooled to ambient temperature and partitioned between a saturated aqueous solution of ammonium chloride (5 mL) and ethyl acetate (2×10 mL). A saturated aqueous solution of sodium chloride was added to aid the separation. The combined organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a brown oil. The material was purified by silica gel column chromatography (ISCO™ companion, 12 g column, 0-30% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a foam.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:18]>C1C=CC=CC=1>[NH:18]1[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][N:15]=[N:16]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)C#N
Solvent: c1ccccc1
Product: CCOC(=O)c1nnn[nH]1

Procedure:
A solution of tributyltin azide (6.65 g) and ethyl cyanoformate (1.98 g) in dry benzene (25 ml) was heated at reflux for 48 hours. The benzene was removed under reduced pressure and the residue was dissolved in an excess quantity of a dry solution of hydrogen chloride in ethanol. The mixture was allowed to stand, and then the ethanol was removed in vacuo on the rotary evaporator to give a red oil. Chromatography of this oil on a column of silica gel, eluting with a mixture of methanol and chloroform (1:9 v/v), gave ethyl tetrazole-5-carboxylate, identical with samples prepared by the other methods as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]([C:21](=[O:22])[CH2:20][Cl:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CCc1ccc(Nc2c(C)cc(Cl)cc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CCc1ccc(N(C(=O)CCl)c2c(C)cc(Cl)cc2Cl)cc1
Temperature: 100 °C

Procedure:
N-(2′,4′Dichloro-6′-methylphenyl)-4-ethylaniline (4.83 g as a mixture with the byproduct N,N-di-(4-ethylphenyl)-2′,4′-dichloro-6′-methylaniline) is dissolved in 4.18 g of chloro acetylchlorid and heated to 100° C. for 1.5 h. The mixture is cooled, diluted with toluene (50 ml) and extracted with aqu. sodium bicarbonate. The organic phase is evaporated to dryness and chromatographed on silica (75 g) eluting with toluene to afford unreacted N,N-di-(4-ethylphenyl)-2′,4′-dichloro-6′-methylaniline and N-(2′,4-dichloro-6′-methylphenyl)-N-chloroacetyl-4-ethylaniline (2.95 g). A crystallised sample melts at 83-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2)nc1
Temperature: 80 °C

Procedure:
To a solution of 5-chloro-2-(6-chloropyridin-3-yl-carbonylamino)-N-(5-chloropyridin-2-yl)benzamide (Intermediate E-2, 0.42167 g, 1 mmol) in 10 mL of DME was added phenyl boronic acid (0.134 g, 1.1 mmol) and an aqueous solution of potassium phosphate (0.6 mL, 1 molar solution). The reaction mixture was degassed and tetrakistriphenyl-phosphine palladium (60 mg) was added. The mixture was heated at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, saturated sodium bicarbonate, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by RPHPLC [ethyl acetate/hexane (3:7)]. Yield=0.280 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][O:11][CH2:12]3)[C:5]([Cl:16])=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.C(O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:16][C:5]1[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)=[N:3][C:2]([C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=2)=[N:7][C:6]=1[N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][O:11][CH2:12]2
Reactant: Clc1nc(N2C3CCC2COC3)c(Cl)c(N2C3CCC2COC3)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc(N3C4CCC3COC4)c(Cl)c(N3C4CCC3COC4)n2)cc1
Yield: 61.3 %

Procedure:
To a solution of 8,8′-(2,5-dichloropyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane) (1.0 g, 2.7 mmol) in 1:1 ethanol:toluene (10 mL) was added 4-aminophenylboronic acid pinacol ester (0.7 g, 3.2 mmol), 2.0M solution of sodium carbonate (1.2 mL) and tetrakis(triphenylphosphine) palladium (0) (0.3 g, 10 mol %). The reaction was refluxed under nitrogen overnight. The reaction was cooled and water was added (75 mL) and the mixture was extracted 3 times with ethyl acetate. The organics were separated and dried over magnesium sulfate, then filtered through Magnesol™ and concentrated in vacuo to an oil. The crude product was purified via silica gel column with hexanes/ethyl acetate to yield the title compound as a white solid (0.708 g). MS m/z=428 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][C:42]=1[Cl:43])[NH:39][N:38]=[C:37]2[C:44]([OH:46])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO>[Cl:43][C:42]1[CH:41]=[C:40]2[C:36]([C:37]([C:44]([OH:46])=[O:45])=[N:38][NH:39]2)=[CH:35][C:34]=1[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3)cc12
Temperature: 130 °C
Yield: 19.3 %

Procedure:
A suspension of 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg, 0.025 mmol) and potassium acetate (135 mg, 1.38 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to afford the title compound (23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)+. Retention time=2.19 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([CH3:11])=[CH:9][S:10][C:3]=12.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]=[C:23]([NH:26][C:27]3[N:32]=[CH:31][C:30]([S:33]CCC(OC)=O)=[CH:29][C:28]=3[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[S:24][CH:25]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].CC([O-])(C)C.[K+]>CS(C)=O>[CH3:11][C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([S:33][C:30]3[CH:29]=[C:28]([O:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:27]([NH:26][C:23]4[S:24][CH:25]=[C:21]([CH:18]5[CH2:19][CH2:20][N:15]([C:12](=[O:14])[CH3:13])[CH2:16][CH2:17]5)[N:22]=4)=[N:32][CH:31]=3)=[C:3]2[S:10][CH:9]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Reactant: Cc1csc2c(Cl)ccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc5c(C)csc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
7-chloro-3-methylthieno[3,2-b]pyridine (0.072 g, 0.39 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (Example 3, Step B, 0.20 g, 0.39 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes under nitrogen. KOtBu (0.13 g, 1.2 mmol) was added and the reaction stirred at ambient temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography of the crude material gave the title compound (0.100 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.03-2.09 (m, 2H), 2.11 (s, 3H), 2.51 (s, 3H), 2.66-2.73 (m, 1H), 2.83-2.90 (m, 1H), 3.15-3.22 (m, 1H), 3.88-3.94 (m, 1H), 4.70-4.73 (m, 1H), 6.51 (s, 1H), 6.75 (d, 1H), 7.05 (d, 2H), 7.17-7.25 (m, 2H), 7.36-7.40 (m, 3H), 8.30 (d, 1H), 8.48 (d, 1H), 8.84 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][NH:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][N:5]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1[nH]ncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C#N)n2)CC1
Yield: 60.7 %

Procedure:
4-bromo-2H-pyrazole-3-carbonitrile (500 mg), potassium carbonate (522 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (975 mg) in acetonitrile (15 ml) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethylacetate, washed with water and brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford. tert-butyl 4-(4-bromo-3-cyano-pyrazol-1-yl)piperidine-1-carboxylate (627 mg) The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.74 (dd, 1H), 1.78 (dd, 1H), 1.98-2.08 (m, 2H), 2.90 (bs, 2H), 3.95-4.11 (m, 2H), 4.46-4.57 (m, 1H), 8.45 (s, 1H).