Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].N1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:4]([O:3][CH3:1])=[O:5])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
A solution of cis4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethy1-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an icewater bath as methyl chlorofomate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 601 (M++1); 1H NMR (coalescing mixture of conformers, CDCl3) δ0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3 (bm, 1H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H). [2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared in optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, using standard methods.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CC(O)=O.[Br:30]Br>O>[Br:30][C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Reaction time: 0.17 h

Procedure:
2-4 (0.73 g, 2.0 mmoles) was added to a 50% aqueous HOAc solution (40 ml) and after stirring at 0°-10° for 10 minutes, Br2 (0.32 g, 2.0 mmoles) was added dropwise. After stirring at 0°-10° for 3 hours, the reaction mixture was diluted with 150 ml H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (85)/acetone (15) to give pure 3-1, Rf 0.3.
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C1C=CC=CC=1.[C-:20]#[N:21].[Na+]>C1S(=O)(=O)CCC1>[C:1]([C:20]#[N:21])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O=C(Cl)c1ccccc1
Product: N#CC(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 99.1 %

Procedure:
72 g (0.5 mol) of sodium benzoate were mixed with 140.6 g (1 mol) of benzoyl chloride and 80 ml of tetramethylene-sulphone and 25 g (0.5 mol) of 98% pure sodium cyanide. After a stirring time of 20 minutes, an exothermic rise in the temperature to 85° C. was observed. It was now easier to stir the mixture. The subsequent reaction time was 2.5 hours at 150°-160° C. Working up gave the following yield: 65 g (99.3% of theory) of benzoyl cyanide; melting point 34° C.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]=[C:16]([NH2:21])[C:15]3[N:22]=[CH:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:14]=3[C:13]=2[CH:12]=1>C(O)(=O)C>[CH3:27][CH:26]([CH3:28])[CH2:25][N:24]1[C:14]2[C:13]3[CH:12]=[C:11]([N:10]4[CH:3]=[CH:7][CH:6]=[CH:5]4)[CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:21])[C:15]=2[N:22]=[CH:23]1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(N)cc3c21
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(-n4cccc4)cc3c21
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
2,5-Dimethoxytetrahydrofuran (1.6 mL of 95%, 12 mmol) was added to a suspension of 8-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 12 mmol) in acetic acid (60 mL), and the reaction was heated at reflux for one hour. The resulting dark brown solution was concentrated under reduced pressure, and the residue was mixed with water. The resulting mixture was made basic with the addition of ammonium hydroxide and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water, dried, and recrystallized from ethanol (100 mL). The crystals were collected in three crops. The first crop was dried for a day in a vacuum oven at 100° C. to provide 2.1 g of 1-(2-methylpropyl)-8-(1-pyrrolyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, mp 227.5–231.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[O-:27][CH2:28][CH3:29].[Na+].O>C(O)C>[CH2:28]([O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1)[CH3:29]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 65 °C

Procedure:
2-Chloro-6-(4-fluorophenyl-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) was added to freshly prepared sodium ethoxide (0.57 mMol) (from addition of sodium metal to ethyl alcohol) in ethyl alcohol (50 ml) and heated to 65° C. for 3.5 hours. The reaction mixture was cooled to room temperature. Water (3 ml) was added and the mixture was concentrated. The product was partitioned between water (50 ml) and ethyl acetate (50 ml). The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated to a solid. The product was purified by a silica gel chromatography to give a white solid: m.p. (DSC): 207.22° C. Anal. Calc'd. for C21H17N2O3SF (396.44): C, 63.62; H, 4.32; N, 7.07. Found: C, 63.56; H, 4.32; N, 6.88.
Reaction SMILES: [H-].[Na+].C1(S)C=CC=CC=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:22]C)=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([OH:22])=[C:15]([S:17]([NH:20][CH3:21])(=[O:18])=[O:19])[CH:16]=1
Reactant: CNS(=O)(=O)c1cc(Cl)ccc1OC
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cc(Cl)ccc1O
Yield: 64.2 %

Procedure:
To a solution of sodium hydride (60% in mineral oil, 90.24 mg, 2.25 mmol) in dry dimethyl formamide was added thiophenol (0.225 ml, 2.25 mmol) dropwise. To this was then added 5-Chloro-2-methoxy-N-methyl-benzenesulfonamide (531 mg, 2.25 mmol) followed by refluxing for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with a 1N sulfuric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel yielded the above titled compound (320 mg, 53% yield).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C.[OH-].[Na+]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:26](=[O:28])[CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)C1C(=O)N(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of N,N′-dibenzylethylenediamine (14.12 mL, 60.2 mmol) in acetonitrile (100 mL) was added diethyl bromomalonate (5.14 mL, 30.1 mmol), and the mixture was heated with an oil bath at 90° C. (reflux) for 7 hours. The solvent was evaporated to provide a residue that was dissolved in 1 M NaOH (aqueous), and the mixture was extracted with ethyl acetate twice, dried over Na2SO4, and the solvent was evaporated. The crude mixture was purified by silica gel chromatography (Analogix IntelliFlash 280, SF40-150) eluting with 15%-30% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38-7.20 (m, 10H), 4.54 (dd, J=15.0, 154.2, 2H), 4.20-4.10 (m, 2H), 4.03 (q, J=7.1, 1H), 3.96 (s, 1H), 3.61 (dd, J=13.5, 41.7, 2H), 3.27-3.14 (m, 2H), 3.05-2.95 (m, 1H), 2.60-2.52 (m, 1H), 1.23 (t, J=7.1, 3H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:26])=O.CN(C)C=O>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:26])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccncc1N(C(=O)C(F)(F)F)C1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccncc1N(C(=O)C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinic acid (350 mg, 1.1 mmol) in dry dichloromethane (15 mL) and oxalyl chloride (0.65 mL, 6.6 mmol, 6 eq) a drop of N,N-dimethylformamide was added. The mixture was stirred at room temperature for 1 h and then evaporated to dryness affording the crude title compound that was used as such for the next step.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([OH:32])[CH2:27]2)=[N:24][CH:25]=1>>[OH:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:24]=2)[CH2:27]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCCC(O)C2)nc1
Product: O=C(Nc1ccc(N2CCCC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-ol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[C:10]([C:12]1([C:18]2[N:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[C:5]([N:15]1[CH2:14][CH2:13][C:12]([C:10]#[N:11])([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=4)[C:31]=3[CH3:32])=[O:26])=[CH:22][N:23]=2)[CH2:17][CH2:16]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(C#N)(c2ccc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cn2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2-Bromo-2-methylpropanoic acid ethyl ester (193 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (455 mg) described in Reference Example 169 and potassium carbonate (276 mg) in N,N-dimethylformamide (3.3 ml) and stirred at 50° C. for 12 hours. Then, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) and potassium carbonate (276 mg) were added and stirred at 50° C. for 5 hours and at 80° C. for 3 hours. Further, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) was added and stirred at 80° C. for 3 hours. Water was added to the reaction solution, the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) as a white solid. MS (ESI) m/z: 570 (M+H)+. (2) Lithium borohydride (25 mg) was added to a solution of 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) in tetrahydrofuran (3.7 ml) and stirred at room temperature for 1.5 hours. Then, lithium borohydride (25 mg) was added and stirred at 80° C. for 2 hours. To the reaction solution, were added methanol (1.5 ml) and sodium borohydride (85 mg), and stirred at room temperature for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (35 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:13]=O)[C:11]=1[OH:12].[CH:16](B(O)O)=[CH:17][CH2:18][CH2:19][CH3:20].C(NCC1C=CC=CC=1)C1C=CC=CC=1.O>O1CCOCC1>[F:15][C:3]1[C:2]([F:1])=[C:11]2[C:10]([CH:13]=[CH:16][CH:17]([CH2:18][CH2:19][CH3:20])[O:12]2)=[C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=12
Reactant: CCCC=CB(O)O
Reactant: Cc1cc2c(C=O)c(O)c(F)c(F)c2o1
Agent: c1ccc(CNCc2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
4.0 g (18.9 mmol) of 6,7-difluoro-5-hydroxy-2-methylbenzofuran-4-carbaldehyde are stirred for 20 h at 90° C. together with 2.79 g (24.5 mmol) of 1-penteneboronic acid and 0.72 ml (3.73 mmol) of dibenzylamine in 95 ml of 1,4-dioxane. Water is added to the reaction mixture, which is then extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is firstly purified by column chromatography (SiO2, 1-chlorobutane) and subsequently crystallised from methanol, giving 4,5-difluoro-2-methyl-7-propyl-7H-furo[3,2-f]chromene as a yellow, crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1.OOS([O-])=O.[K+].CC[O:30][C:31](C)=[O:32]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:31]([O:32][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:21][CH:20]=1)=[O:30]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(C)=O
Agent: COc1ccc(C(=O)O)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To prepare 4-methoxybenzoic acid, 4-methoxybenzaldehyde (100 mg) was dissolved in DMF (10 mL), and OXONE (0.451 g) was added and stirred at room temperature for 3 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 4-methoxybenzoic acid in 31% yield and 4-methoxyphenol formate in 58% yield after purification by silica gel column chromatography. 4-Methoxyphenyl Formate: 1H NMR (CDCl3, 300 MHz): δ8.26 (s, 1H), 7.03 (d, 2H, J=9.0), 6.89 (d, 2H,J=8.9), 3.78 (s, 3H); 13C NMR (CDCl3, 75 MHz): 8176.7, 170.5, 79.9, 74.3, 31.4, 30.4, 28.2, 24.8, 23.9, 22.4, 20.9, 13.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C([Cl:13])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([Cl:13])=[O:7])[CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 0° C. solution of 3,3-dimethylcyclobutanecarboxylic acid (1.35 g, 10.5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (4.01 g, 31.6 mmol) and 1 drop of N,N-dimethylformamide. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was concentrated in vacuo to give crude 3,3-dimethylcyclobutanecarbonylchloride (1.54 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4]/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[SH:25][C@@H:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27](O)=[O:28]>C1(C)C=CC=CC=1>[O:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][NH:14][C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]2[N:5]([CH2:4][CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:27](=[O:28])[CH:26]([CH2:30][C:31]([OH:33])=[O:32])[S:25]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCOCC1
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)C(CC(=O)O)SC1c1cccc(F)c1NCCN1CCOCC1

Procedure:
Heated 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-morpholinoethyl)benzenamine (606 mg, 1.806 mmol) and (S)-2-mercaptosuccinic acid (282 mg, 1.878 mmol) in toluene (10 mL) at 80° C. for 1 day. Volatiles were removed on a rotary evaporator under high vacuum to give 2-(2-(2-(2-morpholinoethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid as a yellow gum which was carried on to the next step as is. LC/MS: 468.39 (M+1) Rt=diastereomers at 1.91 and 1.93 min (10-90% 3/5 min (grad/run) w/formic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.C=O.[C:25]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([CH3:25])[C:12]([CH3:14])([CH3:15])[CH2:13]2)=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: COc1ccc(C=C2CC(C)(C)NC(C)(C)C2)c([N+](=O)[O-])c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2CC(C)(C)N(C)C(C)(C)C2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
4-(4-methoxy-2-nitrobenzylidene)-2,2,6,6-tetramethylpiperidine (1.1 g; 3.23 mmol; 1 eq) is dissolved in MeOH (10 mL) then formaldehyde (0.19 g; 6.45 mmol; 2 eq) and sodium cyanoborohydride (0.41 g; 6.45 mmol; 2 eq) are added. The reaction mixture is stirred at room temperature overnight. The solvents are evaporated under reduced pressure and the residue obtained is taken up in EtOAc then a saturated aqueous solution of NaHCO3 is added. The organic phase is washed with brine, dried over MgSO4 and the solvent is evaporated under reduced pressure to afford 320 mg (31%) of the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 7.53 (d, J=2.6 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.49 (s, 1H), 3.87 (s, 3H), 2.22-2.15 (m, 6H), 1.20-1.10 (m, 6H), 1.00-0.90 (m, 6H). HPLC (max plot) 99.5%; Rt 2.84 min. LC/MS: (ES+): 319.1
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([O:23]C)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH3:22][NH:21][C:17]1[N:16]=[C:15]([C:13]2[CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[C:10](=[O:23])[NH:11][CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: C1CCNCC1
Reactant: CNc1nccc(-c2cnc(OC)c(NC(=O)c3ccc(Br)cc3)c2)n1
Solvent: CN1CCCC1=O
Product: CNc1nccc(-c2c[nH]c(=O)c(NC(=O)c3ccc(N4CCCCC4)cc3)c2)n1
Temperature: 160 °C
Yield: 45 %

Procedure:
4-Bromo-N-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)benzamide (50 mg, 0.121 mmol) was placed in a microwave tube equipped with a stirrer bar. NMP (1.5 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (22 mg, 45% yield). MS (ES+) m/e=405. 1H NMR (DMSO-d6) δH 1.54-1.61 (6H, m), 2.85 (3H, br s), 3.28-3.36 (4H, m), 6.95-7.12 (4H, m), 7.77 (2H, d), 8.00 (1H, s), 8.27 (1H, d), 9.02 (1H, br s), 9.09 (1H, s), 12.53 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].O>CC(C)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(F)ccc1OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluoro-2-methoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with cesium carbonate (8.3 g, 25.3 mmol) followed by 2-bromo-1-(4-bromo-phenyl)-ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room temperature for 2 h. Water (600 mL) is added slowly to the vigorously stirring solution. After stirring for 30 minutes, the precipitate is filtered off and washed with copious water to give 1-(4-bromo-phenyl)-2-(4-fluoro-2-methoxy-phenoxy)-ethanone (G-1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[C:35]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:36]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(N2CCCC2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(N2CCCC2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(pyrrolidin-1-yl)aniline in step 1. MS: 396.6 (M+H).