Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CS(C)=O.C1C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(C(O)C(=O)O)cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)c2ccc(C(O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.9 g of the dipotassium salt of DL-α-hydroxy-4-carboxyphenylacetic acid (mp 201° ~ 203° C) in 40 ml of dimethylsulfoxide were added 6.2 g p-methoxybenzylchloride and stirred overnight at ambient temperature. 50 ml of ice-water were added to the reaction mixture, adjusted to pH 7.5 and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue was dissolved in 60 ml of 50% acetone. To the solution was added a phenolphthalein reagent and then dropwise a 2N-sodium hydroxide solution at 40° ~ 45° C with stirring. The reaction was continued until the red color was maintained for 5 minutes. Then acetone was removed under weakly reduced pressure. The aqueous layer was washed several times with ethyl ether, and then adjusted to pH 2.5 with a 20% hydrochloric acid solution after the addition of ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed several times with a small amount of an aqueous sodium chloride saturated solution, dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give an oily residue. The residue was dissolved in benzene and left overnight in an ice-box, yielding crystals of DL-α-hydroxy-4-(p-methoxybenzyloxycarbonyl) phenylacetic acid of 7.4 g (78.5%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.[C:20]([C:24]1[CH:25]=[C:26]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:27]([O:43][CH3:44])=[C:28]([NH:30][C:31]([C:33]2[S:37][C:36]3[C:38]([NH2:42])=[CH:39][CH:40]=[CH:41][C:35]=3[CH:34]=2)=[O:32])[CH:29]=1)([CH3:23])([CH3:22])[CH3:21].CNC>O=S(Cl)Cl.C1COCC1>[C:20]([C:24]1[CH:25]=[C:26]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[C:27]([O:43][CH3:44])=[C:28]([NH:30][C:31]([C:33]2[S:37][C:36]3[C:38]([NH:42][C:7](=[O:9])[C:5]4[CH:4]=[C:3]([C:10](=[O:12])[N:15]([CH3:16])[CH3:13])[CH:2]=[N:1][CH:6]=4)=[CH:39][CH:40]=[CH:41][C:35]=3[CH:34]=2)=[O:32])[CH:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCN(CC)CC
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4cncc(C(=O)N(C)C)c4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 22.1 %

Procedure:
A suspension of pyridine-3,5-dicarboxylic acid (43.5 mg, 0.26 mmol) in 2.5 mL of SOCl2 was refluxed for 2.5 h to give a light yellow solution. The excess SOCl2 was removed by distillation and the resulting solid was dissolved in 2 mL of dry THF. Triethylamine (0.12 mL, 0.86 mmol) and a solution of 7-aminobenzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (39 mg, 0.087 mmol) in 2 mL of THF was added and the reaction mixture was stirred 12 h. A solution of dimethylamine (2.0 M in THF, 1 mL, 2 mmol) was added and the reaction mixture was stirred for additional 5 h. The reaction mixture was then extracted with EtOAc and purified by reverse phase HPLC on a C18 column eluting with an acetonitrile-water gradient to provide 12 mg (24%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][CH:3]=1.N1C=CN=C1.CN(C)C=O.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>C(OC(=O)C)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ncc(Br)s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ncc(Br)s1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 104 %

Procedure:
A 100 mL round bottom flask is charged with (5-bromothiazol-2-yl)methanol (2.5 g, 12.9 mmol), imidazole (1.75 g, 25.8 mmol), dimethylformamide (25 mL), and chlorotriisopropylsilane (3.4 mL, 15.5 mmol). The reaction is stirred at room temperature under nitrogen for 72 hours. Contents are diluted with ethylacetate (150 mL), washed with 0.5M hydrochloric acid (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated under vacuum to afford the title compound (4.7 g): m/z (CI) M+H 350+352.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)Cl.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>CN(C=O)C.C(Cl)Cl>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-3-nitrobenzoic acid (10.0 g; 54.0 mmol), SOCl2 (20.0 mL; 270 mmol) and DMF (2-3 drops) was refluxed for 4 h, concentrated and the residue was dissolved in DCM (25 mL) and slowly added to a mixture of 4-bromoaniline (9.3 g; 54.1 mmol) and TEA (11.4 mL; 81.0 mmol) in DCM (50 mL) at 0° C. The mixture was stirred for 1 h at rt, concentrated, EtOAc was added and the organic phase was washed with aqueous NaHCO3, aqueous HCl (1 M), dried over Na2SO4, filtered and concentrated to give the sub-title compound. Yield: 18.0 g (98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[N:8]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[N:7]=1)=[O:5])[CH3:2].C[N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([CH2:64][CH2:65]N)=[N:63][C:59]=2[CH:58]=1>O1CCCC1.C(OCC)(=O)C>[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([CH:64]([NH:28][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][C:14]([N:8]4[C:9]5[CH2:13][CH2:12][CH2:11][C:10]=5[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]4)=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)[CH3:65])=[N:63][C:59]=2[CH:58]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2C(F)(F)F)c2c1CCC2
Reactant: NCCc1nc2cc(Cl)ccc2[nH]1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccc(C(=O)NC(C)c3nc4cc(Cl)ccc4[nH]3)cc2C(F)(F)F)c2c1CCC2
Yield: 52 %

Procedure:
Prepared analogously to Example 1g from 4-[3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-3-trifluoromethylbenzoic acid, TBTU, triethylamine, and (5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 52%; Rf value: 0.40 (silica gel; ethyl acetate);C26H23ClF3N5O3 (545.95); mass spectrum: (M+H)+=546.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[C:6]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:18]([O-])=O.[Na+].N([O-])=O>C(OCC)(=O)C>[CH2:16]([O:15][C:6]([CH:7]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([C:3]#[N:2])[N:5]=[N:18]1)=[O:14])[CH3:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: N#CCN
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1N=NC(C#N)C1C(=O)OCC
Temperature: 24 °C
Reaction time: 3 h

Procedure:
To a 500 ml, 3-neck, round bottom flask containing a cold (0° C.) slurry of 46.26 g (0.5 mol) of aminoacetonitrile hydrochloride and 32.74 ml (0.2 mol) of diethyl fumarate in 200 ml of ethyl acetate, were added dropwise, over one hour, an aqueous solution of sodium nitrite (34.5 g of sodium nitrite dissolved in 90 ml of water). The temperature of the reaction mixture was maintained between 0° C. and 5° C. during nitrite addition and then warmed to room temperature (24° C.), where the mixture was stirred for about 3 hours. The organic layer was separated from the aqueous layer and then stirred at room temperature overnight to provide a solution of title compound dissolved in ethyl acetate.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO.C(N(CC)CC)C>[C:13]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To dichloromethane (500 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then trimethylsilyl chloride (180.91 g) was added to the suspension in 10-15 minutes at ambient temperature. The reaction mixture was refluxed at 35° C. to 40° C. for 20 minutes and then it was cooled to ambient temperature. To the reaction mixture, a solution of triethyl amine (168.50 g) in dichloromethane (50 ml) was added in 30-45 minutes at 25° C. to 30° C. The mixture was refluxed for 45 minutes at 35° C. to 40° C. and then cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25° C. to 30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for 3 hours under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40° C. to 45° C. The crude product obtained was washed with water (750 ml) and filtered. The filtered product was further washed with 5% citric acid solution (750 ml) and filtered. The solid product obtained was partitioned between water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with hexanes (200 ml) and dried to obtain the titled product. Yield=135 gm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1COCC1.[Na]>CO>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ncccc1CO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2CO)CC1

Procedure:
The product from Step 1 and 1-(tert-butyloxycarbonyl)piperidin-4-one are heated together in a solvent such as THF or methanol. The cooled mixture is treated with sodium cyanpborohydride to give 1-(tert-butyloxycarbonyl)-4-(3-hydroxymethyl-2-pyridylamino) piperidine.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].Cl[C:37](OC1C=CC([N+]([O-])=O)=CC=1)=[O:38].[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>C1COCC1>[CH2:49]([N:51]([CH2:52][CH3:53])[C:37]([NH:33][C:32]1[CH:31]=[CH:30][C:29]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][C:15]([C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]6[CH2:28][CH2:27][CH2:26][CH2:25]6)=[CH:21][CH:22]=5)=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:35][CH:34]=1)=[O:38])[CH3:50]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CCNCC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37.2 %

Procedure:
To a cloudy mixture of 4-(1-ethyl-4-{2-[4-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline (350 mg, 0.76 mmol) in dry THF (8 mL) was added 4-nitrophenyl chloroformate (168 mg, 0.83 mmol). The resultant slurry was stirred at room temperature for 45 min and diethylamine (0.32 mL, 3.03 mmol) was added. After 1 h, the reaction was concentrated under reduced pressure and diluted with 1N NaOH and EtOAc. The aqueous layer was extracted with three portions of EtOAc followed by 5% MeOH in EtOAc and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by Gilson reverse phase HPLC (MeCN/H2O with 0.1% TFA) to provide 159 mg (32%) of the title product as a bis-TFA salt (yellow solid). ESMS [M+H]+: 562.4
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:55]2[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[3-fluoro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.18 g, 0.43 mmol) that was obtained in Example 20 (20b), carbon tetrabromide (0.22 g, 0.65 mmol), triphenylphosphine (0.17 g, 0.65 mmol), methyl 3-azetidinecarboxylate hydrochloride (99 mg, 0.65 mmol), N,N-diisopropylethylamine (0.22 mL, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.14 g) in a yield of 64% as a pale yellow oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.COCCOC>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.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:21]=[CH:22][CH:23]=[CH:24]4)[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: OB(O)c1ccc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3ccc4ncccc4c3)nc(OC)n2)cc1
Yield: 71 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (150 mg, 0.51 mmol, Intermediate (8) prepared as described in Example 2 step 1), quinoline-6-boronic acid [176 mg, 1.02 mmol, Intermediate (22)], Cs2CO3 (590 mg, 1.81 mmol) tetrakis(triphenylphosphine)palladium (0) (59 mg, 0.051 mmol), ethylene glycol dimethyl ether (4 mL) and water (1 mL) is placed in a microwave tube, sealed and evacuated and flushed with argon three times and irradiated in a microwave oven at 140° C. for 10 minutes. The reaction mixture is partitioned between EtOAc and water. The organic phase is separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residual solid is subjected to flash column chromatography on silica gel eluting with a mixture of EtOAc and heptane. The material is recrystallized from MeOH to afford [2-(4-methoxy-phenyl)-ethyl]-(2-methoxy-6-quinolin-6-yl-pyrimidin-4-yl)-amine [140 mg, 71%, Example 10(a)] LCMS: RT=5.97 minutes, MS: 387 (M+H). IC50=0.6 nM
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][N:31]([CH3:48])[CH3:30])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.01 g, 9%). LCMS: 517.30 (M+1)+; HPLC % 98.12 (@254 nm) (Rt; 3.972; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.34-7.36 (m, 2H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4 Hz), 3.84 (d, 2H, J=10.8 Hz), 3.42 (s, 2H), 3.02 (m, 2H), 2.66 (m, 1H), 2.63 (s, 3H), 2.50 (3H merged in solvent peak), 2.23 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: BrC[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[C:20](=O)([O-])[O-].[K+].[K+].[NH2:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>C(#N)C>[CH:27]1([NH:26][CH2:20][CH:4]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)[CH3:3])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: NC1CCc2ccccc21
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: [K+]
Solvent: CC#N
Product: CC(CNC1CCc2ccccc21)Oc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1-aminoindan, and acetonitrile essentially as described above in example 48. Purity by LC/MS (APCI)=97%, [M+H]+=391.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[Cl:10].C(O[Na])(C)=O>CCO.[Pd]>[Cl:10][C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][CH:2]=1
Reactant: CC(=O)c1cc(Cl)c(Br)s1
Agent: [Pd]
Agent: CC(=O)O[Na]
Solvent: CCO
Product: CC(=O)c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a solution of 28-2 (3.20 mg, 13.36 mmol) in EtOH (70 mL) was added 10% Pd/C (2.50 g) and AcONa (1.10 g, 13.36 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 h, filtered, and the filtrate was concentrated. The resultant residue was dissolved in EA (100 mL) washed with sat. NaHCO3 (40 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE/EA=30/1 to 5/1) to afford 28-3 as a yellow oil (1.32 g, yield: 62%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.O>CN(C)C=O.C(OCC)(=O)C>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][N:9]3[C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:10]3(=[O:12])=[O:11])[CH2:24][CH2:25]2)=[O:37])=[CH:35][CH:34]=1
Reactant: O=S1(=O)Nc2ccccc2-c2ccccc21
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCN2c3ccccc3-c3ccccc3S2(=O)=O)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A solution of 6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (1.7 g) in dry N,N-dimethylformamide (15 cc) is added dropwise to a suspension of sodium hydride (0.25 g, 80% suspension in oil) in N,N-dimethylformamide (5 cc). After 30 minutes' stirring, a solution of 1-(3-chloropropyl)-4-(4-fluorobenzoyl)piperidine (2.1 g) in N,N-dimethylformamide (15 cc) is added. The reaction mixture is heated to 100° C. for 40 minutes and is then cooled and poured into a mixture of water (150 cc) and ethyl acetate (150 cc). The organic phase is washed with water (3×50 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.06-0.2-mm particle size, 2-cm diameter, 25-cm height) and eluted with a mixture of cyclohexane and ethyl acetate (50--50 by volume), 30-cc fractions being collected; fractions 7 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from ethanol (40 cc); the crystals obtained are filtered off, washed with ethanol (5 cc) and dried. 6-[3-(4-(4-fluorobenzoyl)-1-piperidyl)propyl]-6H-dibenzo[c,e]-1,2-thiazine 5,5-dioxide (1.8 g) is obtained, melting at 114° C.