Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2](OS(C)(=O)=O)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[CH3:14][NH2:15].O>CN(C)C(=O)C.CCOCC>[CH3:1][C@@H:2]([NH:15][CH3:14])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7]
Reactant: CC(C)=CCC[C@@H](C)OS(C)(=O)=O
Reactant: CN
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CN[C@H](C)CCC=C(C)C
Temperature: 50 °C
Yield: 90 %

Procedure:
(S)-Methanesulfonic acid 1,5-dimethyl-hex-4-enyl ester (2) (3.21 g, 15.56 mmol) was dissolved in N,N-dimethyl-acetamide (55 mL), 40% methylamine in water (54.9 mL, 622 mmol) was added at RT using a heavy-walled reaction vessel (150 mL) with teflon screw cap. The reaction vessel was sealed, stirred, and heated at 50° C. for 64 h after which the reaction mixture was cooled to 5° C., and the system was opened to monitor the reaction by TLC. The reaction mixture was diluted with Et2O (320 mL), shaken, the organic layer was washed with water (4×100 mL), brine (100 mL), dried with MgSO4, and solvent was concentrated to give the titled compound as an oil (1.974 g, 90%). TLC sample was prepared by taking an aliquot (100 uL) of reaction mixture, diluting with EtOAc (100 uL), washing with brine (500 uL), TLC organic layer. TLC, Hexane-EtOAc, 75:25, product, Rf 0.35. DCM-7 N NH3-MeOH, 90:10, 3 Rf, 0.45 (developed with KMnO4 stain). H1 NMR (CDCl3): • 5.10 (m, 1H), 2.52 (m, 1H), 2.40 (s, 3H), 1.99 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.49 (m, 2H), 1.31 (m, 1H), 1.04 (d, 3H, J=6.0 z).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[C:12]2[CH:19]=[CH:18][NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)=[O:4].N[C:21]1C=C(C)SC=1C(OC)=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:21])=[CH:8][C:9]=1[NH:10][C:11]1[C:12]2[CH:19]=[CH:18][NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)=[O:4]
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: COC(=O)c1sc(C)cc1N
Product: COC(=O)c1sc(C)cc1Nc1ncnc2[nH]ccc12
Yield: 45 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester using methyl 3-amino-5-methylthiophene-2-carboxylate instead of methyl 3-amino-2-thiophenecarboxylate and obtained in 45% yield (HPLC: 99%, RT: 6.89 min). 1H NMR (DMSO-d6) 12.40 (br s, 1H), 10.58 (br s, 1H), 8.44 (s, 1H), 7.96 (br s, 1H), 7.47 (dd, J=3.1, 2.6 Hz, 1H), 6.63 (dd, J=3.3, 1.5 Hz, 1H), 3.82 (s, 3H), 2.55 (s, 3H); MS (m/z) 289 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:22][CH2:23][CH:24]=O)[CH:16]=[C:17]([F:21])[C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:22][CH2:23][CH:24]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[C:17]([F:21])[C:18]=1[O:19][CH3:20]
Reactant: COc1c(F)cc(CCC=O)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(OC)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (5.168 mmol) and 3-(3,5-difluoro-4-methoxy-phenyl)-propionaldehyde (1.034 g; 5.168 mmol) afforded 8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.73 min.; [M+H]+=448.42 g/mol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][C:29]([F:32])([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:33])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][C:38]1[N:43]=[CH:42][C:41]([C:44]2[CH:56]=[CH:55][C:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:46][C:45]=2[CH3:57])=[CH:40][C:39]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:39]4[CH:40]=[C:41]([C:44]5[CH:56]=[CH:55][C:47]([C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[CH:46][C:45]=5[CH3:57])[CH:42]=[N:43][C:38]=4[O:37][CH3:36])=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][C:29]([F:32])([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:33])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 13, 200 mg, 0.348 mmol), tert-butyl 4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate (INTERMEDIATE 31, 173 mg, 0.452 mmol) and potassium carbonate (144 mg, 1.04 mmol), in 1,4-dioxane (2 mL) and water (2.000 mL) was degassed, and refilled with nitrogen. Then, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (11.3 mg, 0.017 mmol) was added, and the reaction was stirred at 45° C. for 2 hours. It was directly applied to preparative reverse phase HPLC, eluting with 10% to 100% acetonitrile in water, to give the title compound for step A as a white solid after lyophilization. LCMS (M+H)+: 794.05.
Reaction SMILES: Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCN(CCCC(N[C:30]1[CH:31]=[C:32](/C=C/C2C=CC=CC=2Cl)[N:33]=[C:34]2[CH:39]=[C:38](Cl)[CH:37]=[CH:36][C:35]=12)C)CC>[Cu]Cl.O1CCOCC1.O1CCCC1.C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:33]1[C:34]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCN(CC)CCCC(C)Nc1cc(/C=C/c2ccccc2Cl)nc2cc(Cl)ccc12
Agent: Cl[Cu]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: c1ccc2ncccc2c1

Procedure:
The reaction of substituted o-aminobenzonitrile (10) and β-ketolactone (14) can be carried out in an alcohol in the presence of an acid such as hydrochloric acid at room temperature, or in a solvent such as toluene or benzene and in the presence of a condensing agent such as p-toluenesulfonic acid under heating. The cyclization of enamine compound (15) is carried out in a solvent such as tetrahydrofuran, 1,4-dioxane, or the like in the presence of a base (e.g., potassium carbonate) and copper (I) chloride at room temperature to the refluxing temperature. The dehydration-condensation reaction of aminoquinoline compound (16) and compound (6) for producing quinoline derivative (Ia) may be carried out in the absence of a solvent, by tube at 100°-200° C. The reactive derivative of lower fatty acid to be reacted with compound (Ia) may be carboxylic acid anhydride, carboxylic acid halide, or the like, and the reaction can be effected in the presence of a base such as pyridine, triethylamine, or the like at room temperature to 100° C. ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][S:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([NH:20][CH:30]4[CH2:32][CH2:31]4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cc(NC3CCSCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(NC3CC3)cc(NC3CCSCC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A solution of N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (27 mg, 0.048 mmol) in DCM (0.5 mL) was treated with TFA (1.0 mL, 12.98 mmol) and stirred at room temperature for 1 hour and then concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 254 nm). The product (retention time=36.913 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.9 mg, 8.33%). HPLC Rt=4.481 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=443.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]2[N:10]([C:11](=[O:21])[NH:12][C:13]3[CH2:20][CH2:19][NH:18][CH2:17][C:14]=32)[N:9]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC>[C:22]1([CH2:28][C:29]([N:18]2[CH2:19][CH2:20][C:13]3[NH:12][C:11](=[O:21])[N:10]4[N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:16]=[C:15]4[C:14]=3[CH2:17]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)nn13)CNCC2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)N1CCc2[nH]c(=O)n3nc(-c4ccccc4F)nc3c2C1
Yield: 85 %

Procedure:
A mixture of 2-(2-fluorophenyl)-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one (0.57 g, Example 15) and phenylacetylchloride (3 mL) is heated under nitrogen at 120° for 4 hours. The mixture is diluted with ether (30 mL) and the solid collected, washed with ether and air dried to afford pure 9-phenylacetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one, m.p. 310°-313°, in 85% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:9][N:8]=1)[CH3:2]>CO.C1COCC1.C(O)(C(F)(F)F)=O.[Pd]>[CH3:30][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])=[N:8][CH:9]=2)[CH:18]=[C:17]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pd/C (10.0 mg, 9.40 mol) was added to a solution of ethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]prop-2-enoate (96.0 mg, 0.224 mmol) in MeOH (2.00 mL) and THF (1.00 mL). One drop of TFA was added to the reaction mixture and was purged and flushed with argon (3×). The reaction mixture was stirred for 4 hours at room temperature under an atmosphere of hydrogen. The mixture was filtered through CELITE and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:7 ethyl acetate in hexanes) to afford ethyl 3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. C22H22F3N4O2 [M+H]431. found 431.
Reaction SMILES: [C:1]1([C:7]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[C:8]([CH:10]([C:16](OCC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[OH:17][C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:7]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[C:8](=[O:9])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
The product of Example 1E (4.51 g, 12.4 mmol) was treated with concentrated sulfuric acid (25 mL) and stirred at 25° C. for 3 hours. The mixture was then poured into a mixture of ice and water (500 mL) and stirred until all the ice melted. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with water and saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methyl t-butyl ether in hexane to afford the title compound (1.73 g, 44%). 1H NMR (300 MHz, CDCl3): δ 15.15 (d, J=13.24 Hz, 1 H), 8.18 (m, 1 H), 7.59 (m, 1 H), 7.40 (m, 2 H), 4.47 (m, 2 H), 2.25 (m, 2 H), 1.91 (m, 1 H), 1.70 (m, 1 H), 1.47 (q, J=7.23 Hz, 3 H), 1.25 (m, 1 H), 0.93 (m, 2 H), 0.67 (m, 7 H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH2:14]C.CC[O-].[Na+].Cl>CCO>[CH2:13]([O:16][C:17](=[O:23])[C:18](=[O:19])[CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: CCCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Treat a suspension of 4-methyl-3-nitro-benzonitrile (2.11 g, 12.5 mmol) and oxalic acid ethyl ester propyl ester (2.99 g, 18.7 mmol) in EtOH (80 mL) with NaOEt (21% w/w, 18.2 mL). Stir the mixture at 40° C. overnight. Quench the reaction with water and acidify with 1 M HCl solution. Concentrate to a residue and partition between EtOAc and water. Concentrate the organic layer and purify by silica gel chromatography to give the desired product 3-(4-cyano-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (3:1 keto/enol mixture) as a solid in 37% yield (1.21 g, 4.62 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[CH:25]1([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.N#N.[BH3-]C#N.[Na+]>CO.CC(O)=O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:33][C@@H:32]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([O:30][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:41])[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1C1CCC(=O)CC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Agent: N#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1C1CCC(N[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 6 (50 mg, 0.15 mmol) was added to a colourless solution of L-phenylalanine cyclopentyl ester (89 mg, 0.38 mmol) in MeOH (10 ml) at RT/N2 and stirred at RT for 1 h. AcOH glacial was added dropwise to adjust the pH to 6 followed by the NaCNBH3 (38 mg, 0.61 mmol). The resultant colourless solution was stirred at RT overnight and then carefully quenched with sat. NaHCO3 (20 ml) and extracted into CH2Cl2 (3×15 ml). The combined organic phases were washed with 2M HCl (2×20 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo giving a cream coloured solid. Purification by flash column chromatography (silica, gradient elution 40-100% EtOAc/heptane) gave the desired material, separable as two isomers, isomer 1 (Example 34) as a white solid (Yield=39 mg, 47%) LCMS purity 100%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.40-2.05 (16H, m), 2.85-3.10 (3H, m), 3.60-3.70 (1H, m), 4.55-4.65 (1H, m), 5.10-5.20 (1H, m), 5.70 (1H, d), 7.15-7.40 (7H, m), 7.45-7.50 (1H, m), 7.50-7.60 (2H, m) and isomer 2 (Example 35) LCMS purity 97%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.25-1.85 (12H, m), 1.95-2.20 (2H, m), 2.45-2.95 (4H, m), 3.00-3.10 (1H, m), 3.65-3.75 (1H, m), 4.55-4.65 (1H, m), 5.05-5.15 (1H, m), 5.65 (1H, d), 7.20-7.35 (7H, m), 7.40-7.50 (1H, m), 7.50-7.60 (2H, m) as a colourless film (Yield=15 mg, 18%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CS(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH:9]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 160 °C
Yield: 71.9 %

Procedure:
A mixture of potassium carbonate (1.5 g, 10.9 mmol), 3-bromophenol (1.73 g, 10.0 mmol) and bromoacetaldehyde diethyl acetal (1.5 ml, 9.67 mmol) in dimethylsulphoxide (10 ml) was heated at 160° C. for 1½ hours. The cooled reaction was partitioned between water (50 ml) and ethyl acetate (100 ml), and the phases separated. The aqueous layer was extracted with ethyl acetate (50 ml), the combined organic solutions washed consecutively with 1N sodium hydroxide solution, water (2×), brine and then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by medium pressure column chromatography on silica gel using an elution gradient of ether:pentane (0:100 to 5:95) to afford the title compound (2.01 g, 72%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:22]1([CH3:34])[CH:27]=[CH:26][C:25]([S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:32](=[O:33])[NH:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:34])=[CH:23][CH:24]=2)(=[O:29])=[O:30])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCC2CCSc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (300 mg, 1.44 mmol) in 7 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.22 ml, 1.6 mmol) and p-toluenesulfonyl isocyanate (312 mg, 1.586 mmol). The mixture was stirred at room temperature for 1.5 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:9 tert.butyl methyl ether/dichloromethane). The product was obtained in a yield of 250 mg (43%).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[O:8][C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)=O)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)o1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A solution of methyl 4-(5-acetylfuran-2-yl)benzoate (580 mg, 2.37 mmol) in ethanol (5 mL), and sodium hydroxide (6N, 1 mL) was heated at 70° C. for 30 minutes. The reaction mixture was cooled to rt and pH was adjusted (pH=4) with HCl (6N). The resulting precipitate was collected by filtration to give the desired 4-(5-acetylfuran-2-yl)benzoic acid (500 mg, 2.17 mmol, 91% yield) as a yellow/green solid. LCMS (ES): m/z 231 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C[CH2:31][N:32](CC)[CH2:33]C.CNC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:32]([CH3:33])[CH3:31])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and dimethyl amine (0.33 mL, 2.0 M solution in THF, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (75%) of the title compound as an off white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]1([NH2:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:6]1([NH:12][C:1](=[O:4])[CH:2]=[CH2:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccccc1
Reaction time: 3 h
Yield: 79 %

Procedure:
Acryloyl chloride (28.5 mL; 350 mmol) was added to a stirred solution of phenylamine (30 mL; 320 mmol) and TEA (56 mL; 400 mmol) in THF (1 L) at 0° C. The reaction mixture was stirred for 3 h, poured onto brine and extracted with diethyl ether. The organic layer was dried, concentrated and recrystallized from hexane:EtOAc (3:1) to give the sub-title compound in a 79% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].CCOC(C)=O.O>CN1CCN(C)C1=O.[Cu]I>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([C:24]#[N:25])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2C[C@@H]2CN(Cc3ccccc3)CCN12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 190 °C
Reaction time: 1.38 h

Procedure:
Mixture of (R)-2-Benzyl-8-bromo-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (25 mg, 0.067 mmol), CuCN (12.9 mg, 0.14 mmol) and CuI (3.7 mg, 0.29 mmol) in 1,3-dimethyl-2-imidazolidinone (1.5 mL) was stirred at 190° C. for 83 min in microwave. The reaction was cooled to RT and added EtOAc (20 mL) and H2O (5 mL). Filtered off the precipitate and rinsed with EtOAc (50 mL). The organic layer was separated and washed with brine (5 mL), dried over MgSO4, and conc in vacuo to give crude product. Purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to yield crude product as a yellow oil. MS (ESI) 318 (M+H).
Reaction SMILES: FC1C=CC2N=C([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)SC=2C=1.Cl[C:30]1[S:31][C:32]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:30]4[S:31][C:32]5[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:33]=5[N:34]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: FC(F)(F)c1cccc2nc(Cl)sc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(C(F)(F)F)c2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-7-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluoro-1,3-benzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.12-2.31 (m, 4H), 3.05-3.18 (m, 2H), 3.41 (d, J=12.8 Hz, 2H), 4.47-4.57 (m, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 8.12 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.57 (s, 1H), 8.60 (d, J=2.2 Hz, 1H). MS (ES+): m/z=445.08 [MH+]. HPLC: tR=2.38 min (ZQ2, polar—5 min).