Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:13]2[C:8](=[C:9]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+]>O.C(O)C>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][CH:5]2[OH:4]
Reactant: CC(=O)OC1CCc2c(-c3cccs3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1CCc2c(-c3cccs3)cccc21
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To 3.5 g (0.014 mole) of 4-(2-thienyl)-1-indanyl acetate was added a solution of 1.1 g (0.019 mole) of potassium hydroxide in 19.5 mL of water and 39 mL of ethanol. The reaction mixture was stirred for three hours at 60°-70° C., then for 16 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give an oil residue. The oil was slurried in 75 mL of water for one hour, causing the oil to solidify. The solid was washed with water, air dried, then recrystallized from toluene to give, in three crops, 2.4 g of 4-(2-thienyl)-1-indanol, m.p. 101°-103.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:21])=[N:14][C:15]([O:19][CH3:20])=[N:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24]Cl)[C:6]=2[C:5]([C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([O:28][CH3:29])=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:17]([CH3:18])=[N:16][C:15]([O:19][CH3:20])=[N:14][C:13]=3[CH3:21])[CH2:24][CH2:23][CH2:22][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A mixture of methyl 4-chloro-1-(3-chloropropyl)-2-[(2-methoxy-4,6-dimethylpyrimidin-5-yl)amino]1H-benzimidazole-7-carboxylate (560 mg, 1.28 mmol) and potassium carbonate (1.92 mmol) in N,N-dimethylformamide (5.6 mL) was stirred at 80° C. for 1 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (504 mg, 1.25 mmol, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: CCOC(=O)CCBr
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 166.8 %

Procedure:
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (320 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was mixed with ethyl 3-bromopropionate (0.187 mL, 1.47 mmol) and potassium carbonate (244 mg, 1.76 mmol) at room temperature and stirred at 80° C. for 4 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (453 mg, quant.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([O:28][CH:29]([CH3:31])[CH3:30])[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:32])[CH3:16])=[CH:22][C:23]=2[O:28][CH:29]([CH3:31])[CH3:30])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(C)Oc1cc(OCCN(C)C)ccc1N
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN(C)C)cc2OC(C)C)c1C(=O)OC
Yield: 47 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), 4-(2-dimethylaminoethoxy)-2-isopropoxyphenylamine (1.5 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (60 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 1.3 g of the product at 96:4 methylene chloride-methanol, in 47% yield; 1H NMR (CDCl3) δ 1.31 (d, J=6.1 Hz, 6H), 2.96 (d, J=4.8 Hz, 6H), 3.41-3.47 (m, 2H), 3.87 (s, 6H), 4.47-4.51 (m, 3H), 6.45 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 7.07 (dd, J=6.0 Hz, J=2.5 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.20-7.18 (m, 2H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=O)=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([Cl:27])=[O:24])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
15 g (0.05 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole and 36.43 g (0.31 mol) of thionyl chloride in 400 ml of benzene were heated under reflux for 3 h. The cooled mixture was filtered and concentrated. This gave 11.95 g (approximately 76%) of the title compound which was used for subsequent reactions without any further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH:14]=[CH2:15])[CH:5]=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:2]=[CH2:3].C([CH:18]1[O:22][C-:21]=[N:20][C:19]1=[O:23])=C>C(O)C>[CH:1]([N:20]1[C:19](=[O:23])[CH2:18][O:22][CH-:21]1)=[CH2:2].[CH2:1]([N:4]([CH:5]=[CH:6][CH:7]=[C:8]([C:9]#[N:10])[C:11]#[N:12])[CH2:13][CH:14]=[CH2:15])[CH:2]=[CH2:3]
Reactant: C=CC1O[C-]=NC1=O
Agent: C=CCN(C=CC=C(C#N)C#N)CC=C
Solvent: CCO
Product: C=CN1[CH-]OCC1=O

Procedure:
25 g of intermediate (A) and 25 g of vinyloxazolidone were dissolved in 150 ml of ethanol and added with 2.5 g of AZBN. The mixture was heated to reflux for 24 hours in a flask provided with stirrer and reflux condenser. At the end, it was cooled, precipitated in ether, washed and dried. The yield was 14.5 g of a product soluble in water and dimethylformamide, containing about 45% w/w of aminoallylidenmalononitrile moieties.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7](O)=[O:8])[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([Cl:18])=[O:8])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Solvent: ClCCl
Product: CCOc1ccc(C(=O)Cl)cc1OCC

Procedure:
To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH2Cl2 was added SOCl2 at room temperature; the reaction was refluxed for 1.5 h and the mixture concentrated under reduced pressure to yield 3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of the 3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirred for 12 h at room temperature. The mixture was poured into 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuum. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured into an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH2Cl2:MeOH (9:1) to yield the product as white solid in 67% yield (150 mg). 1H NMR (400 MHz, CDCl3): δ 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1350.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][S:15][CH3:16].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14][S:15][CH3:16]
Reactant: CSCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CSCC(CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfanyl)propan-2-yl]carbamate (from Step 3 of PrepEx 4.11) (10.0 g, 28.6 mmol) in ethanol (150 mL) was added dropwise hydrazine hydrate (15.7 g, 286 mmol) at 0° C. and then the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was heated to reflux. After two hours, the reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give tert-butyl [1-amino-3-(methylsulfanyl)propan-2-yl]carbamate. MS ESI calc'd. for C9H21N2O2S [M+H]+ 221. found 221. 1H NMR (400 MHz, CD3OD) δ 3.66-3.63 (m, 1H), 2.83-2.79 (m, 1H), 2.64-2.50 (m, 3H), 2.12 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[K+].Br[C:13]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>O.[Cu]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:13]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ccccc1S
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 104.8 %

Procedure:
2-Methoxythiophenol (9.9 ml, 81.29 mmol) was added to a solution of KOH (18.24 g, 325.18 mmol) in water (80 ml) degassed for 15 minutes. 2-Bromo-5-nitrobenzoic acid (20.0 g, 81.29 mmol) and copper bronze (258 mg, 4.06 mmol) were added to the reaction mixture, which was refluxed overnight. The reaction was stopped and the mixture was filtered through a celite pad and washed with 2M NaOH then water (50 ml). The filtrate was acidified (pH 1) with concentrated HCl. The precipitate formed was filtered and dried overnight in a vacuum oven (50° C.) to give the crude title compound (26.0 g) as a pale yellow solid. The product was used without further purification.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[S:5][N:4]=1.Cl[C:17]1[CH:18]=[C:19](C=CC=1)[C:20](OO)=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[S:5][N:4]=[C:3]([O:21][CH2:20][C:19]#[C:18][CH3:17])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nsc(-c2cccc(F)c2F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC#CCOc1nsc(-c2cccc(F)c2F)n1
Reaction time: 7 h

Procedure:
3-Methylthio-5-(2,3-difluorophenyl)-1,2,4-thiadiazole was dissolved in 14 ml of chloroform, and 279 mg of m-chloroperoxybenzoic acid (65%<) was added thereto. The mixture was stirred for 7 hours with ice-cooling, and allowed to stand at room temperature overnight. Then, the reaction mixture was added to an aqueous sodium bicarbonate solution, and layers were separated. The organic layer was concentrated. Further, toluene was added to the residue, and the mixture was concentrated. To the resulting residue were added 2 ml of N,N-dimethylformamide and 59 mg of 2-butyne-1-ol, and 59 mg of sodium hydride (60% oily) was added thereto with ice-cooling. The mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 3 hours. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was purified by silica gel column chromatography to obtain 95 mg of 5-(2,3-difluorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (16) of the present invention).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21]C(=O)C)=[C:4]([F:25])[CH:3]=1>CO.B(F)(F)F>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH2:21])=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Agent: FB(F)F
Solvent: CO
Product: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of 20 ml of boron trifluoride methanol complex methanol solution and 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide was stirred for 3 hours at temperature from 60 to 70° C. Thereafter, the reaction solution was concentrated, the residue was diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated, and the resulted residue was purified by column chromatography concentrated to obtain 0.87 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[N:19]=[N:18][C:17]([NH:20][NH2:21])=[CH:16][C:15]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCCl>[Cl:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:16][C:17]2[N:18]([C:2](=[O:4])[NH:21][N:20]=2)[N:19]=1
Reactant: NNc1cc(N2CCOCC2)c(Cl)nn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1[nH]nc2cc(N3CCOCC3)c(Cl)nn12
Yield: 172.1 %

Procedure:
Triphosgene (750 mg, 2.5 mmol) was added to a stirred solution of 6-chloro-5-(morpholin-4-yl)pyridazin-3-ylhydrazine (1.42 g, 6.2 mmol) in 1,2-dichloroethane (60 ml) at room temperature under nitrogen. The mixture was then stirred and heated at reflux for 22 hours. Upon cooling the precipitate was collected by filtration. The solid was washed with diethyl ether and then dried in vacuo to give 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one (1.1 g, 67%) which was used without further purification. Data for the title compound: 1H NMR (250 MHz, d6-DMSO) δ3.02-3.05 (4H, m), 3.72-3.76 (4H, m), 7.19 (1H, s), 12.57 (1H, br s); MS (ES+) m/e 256, 258 [MH+].
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([C:2](=[O:1])[CH3:4])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (114 mg, 0.211 mmol) in DCM (2.11 mL) at 0° C. was treated with pyridine (0.051 mL, 0.63 mmol) and acetic anhydride (0.040 mL, 0.42 mmol). The reaction mixture was stirred for 30 min at 0° C. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered, and purified by HPLC Method B, using a 40% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (39.7 mg, 32.3%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.96 (m, 2H), 2.12 (m, 2H), 2.18 (s, 1.3H), 2.20 (s, 1.7H), 2.73 (t, J=5.9 Hz, 0.8H), 2.83 (t, J=5.9 Hz, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.80 (m, 4H), 4.45 (dt, J=7.0, 3.6 Hz, 1H), 4.57 (app d, 2H), 6.05 (m, 1H), 6.86 (m, 1H), 6.96 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.15 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 468.4.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:35][C:10]1([CH3:36])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccccc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 88.8 %

Procedure:
To a stirred mixture solution 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.1 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (850 mg, 90%) as a white solid: LC/MS m/e calcd for C29H33N3O2 (M+H)+: 456.61, observed: 456.2.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=1.C(=O)(OC(C)(C)C)[NH2:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH2:22][C:16]1[CH:15]=[C:14]([O:13][C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[Cl:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:19]=[CH:18][N:17]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(Cl)c2)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cl)c(Oc2ccnc(N)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A flask was charged with ethyl 4-chloro-3-(2-chloropyridin-4-yloxy)benzoate (16.347 g, 52.369 mmol), tert-butyl carbamate (18.405 g, 157.11 mmol), potassium phosphate (12.228 g, 57.606 mmol), and toluene (150 mL). The flask was degassed with nitrogen, and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (3.0302 g, 5.2369 mmol) and tris(dibenzylideneacetone)dipalladium (0) (2.3978 g, 2.6185 mmol) were added. The flask was degassed again, and degassed water (40 mL) was added. The reaction was heated at 90° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate and concentrated. TFA (100 mL) was added and the mixture was stirred overnight, then concentrated, treated with sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography eluting with 20-25% ethyl acetate in hexanes and then ethyl acetate to provide the desired product (5.75 g, 37.510% yield) as yellow oily semi solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:8])[O:3]1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:38])[O:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1>C(Cl)Cl>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:27]([O:28][CH2:29][C:30]3[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=3)=[O:38])[CH2:14][CH2:13]2)=[O:8])[O:3]1
Reactant: O=C(NCCC1CCNCC1)c1c[nH]c(=O)o1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-oxo-N-(2-(piperidin-4-yl)ethyl)-2,3-dihydrooxazole-5-carboxamide (step 3) (210 mg, 0.76 mmol) was suspended in DCM (2 ml). DIPEA (265 μl, 1.52 mmol) was added and the reaction mixture sonicated to aid dissolution. 3,5-dichlorobenzyl carbonochloridate (182 mg, 0.76 mmol) in DCM (2 ml) was added and the mixture was left stirring vigorously at RT overnight. The resulting mixture was diluted with DCM and washed with citric acid (emulsion formed). Brine was added and organics were separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica eluting with 75-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=O.[O-:23][C:24]#[N:25].[Na+]>C(O)(=O)C>[CH:3]1([CH2:12][N:1]2[C:2]3[C:3](=[CH:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:25][C:24]2=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: N#C[O-]
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2c(-c3ccc(C(C)C)cc3)nc(=O)n(CC3CCCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 50 mg (0.126 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1 ml acetic acid are added 8 mg (0.126 mmol) sodium cyanate. After stirring for 24 h at rt the solvent is evaporated and the residue is extracted with dichloromethane/0.1 M NaOH. Recrystallisation from ether/hexanes yields the title compound.