Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[S:3]Cl.[CH3:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:9]=1[C:10]([NH2:12])=[NH:11].[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[S:3][N:12]=[C:10]([C:9]2[C:8]([CH3:7])=[CH:16][C:15]([CH3:17])=[CH:14][C:13]=2[CH3:18])[N:11]=1
Reactant: Cc1cc(C)c(C(=N)N)c(C)c1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-c2nsc(Cl)n2)c(C)c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
2.2 g of trichloromethanesulfenyl chloride are introduced into a solution of 2 g of 2,4,6-trimethyl benzamidine in 16 ml of dichloromethane under an inert atmosphere at about -20° C., followed by the slow addition of 2 g of NaOH dissolved in 3.2 ml of water at about -10° C. After 1 hour at about -5° C., the precipitate formed is isolated and the organic phase is separated and washed with 6 ml of water. After being dried over K2CO3, it is concentrated under reduced pressure to give 2.8 g of the desired product in the form of an oil, which may be used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14](=[O:23])[CH2:15]CN3CCOCC3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:24](N)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][C:28]([C:6]([CH3:8])([CH3:7])[CH3:5])=[CH:27][CH:26]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:23])[CH3:15]
Reactant: NC(=O)c1ccccc1
Reactant: Nc1cc(-c2cccc(C(=O)CCN3CCOCC3)c2)ccn1
Product: CC(=O)c1cccc(-c2ccnc(NC(=O)c3ccc(C(C)(C)C)cc3)c2)c1

Procedure:
According to the same procedure for the preparation of 1-[3-(2-Amino-pyridin-4-yl)-phenyl]-3-morpholin-4-yl-propan-1-one, 4-tert-Butyl-N-{4-3-(3-morpholin-4-yl-propionyl)-phenyl]-pyridin-2-yl}-benzamide (12 mg, 30%) was obtained from N-[4-(3-Acetyl-phenyl)-pyridin-2-yl]-4-tert-butyl-benzamide (36 mg, 0.1 mmol). MS: m/z 472.3 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[Br:1][C:2]1[C:3]([O:14][CH2:21][O:22][CH3:23])=[C:4]([CH:7]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C=O
Reaction time: 72 h
Yield: 102.8 %

Procedure:
To a stirred solution of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (5.80 g, 22.6 mmol) (Intermediate 8) and potassium carbonate (4.10 g, 29.4 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added chloromethyl methyl ether (2.01 mL, 27.1 mmol) and the reaction mixture stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give 3-bromo-5-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (7.00 g, 100%+DMF) as a yellow oil.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][N:14]=1)(C)(C)C.[CH2:20](O)[CH2:21][OH:22].COC(OC)OC>C([O-])(O)=O.[Na+]>[CH3:16][C:15]1([C:12]2[O:11][C:10]([CH2:9][OH:8])=[N:14][CH:13]=2)[O:17][CH2:20][CH2:21][O:22]1
Reactant: CC(=O)c1cnc(C(C)(C)O[SiH2]C(C)(C)C)o1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(CO)o2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-5-yl]-ethanone (105 mg, 0.41 mmol) in ethylene glycol (0.46 mL, 8.22 mmol) was treated with trimethylorthoformate (0.09 mL, 0.82 mmol) followed by LiBF4 (8 mg, 0.08 mmol). The reaction mixture was heated at 95° C. until reaction completion. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with EA (2×10 mL). The combined org. extracts were washed with brine (20 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 EA-Hept) gave the title compound as a yellow oil. TLC: rf (4:1 EA-Hept)=0.25. LC-MS-conditions 02: tR=0.56 min; [M+H]+=186.55.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Cu]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 12.600000381469727 °C

Procedure:
To a solution of 4-cyanophenol (9.0 g, 75.55 mmol, commercially available) and anhydrous acetonitrile (120 mL) at ~0° C. under argon was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 14.0 mL, 93.61 mmol, 1.24 eq based on the input of 4-cyanophenol). A temperature increase to 12.6° C. was observed. After the solution had cooled to 0° C., copper bronze (cooper powder, 49.8 mg, 0.783 mmol, 0.0104 eq, 1.04 mol %) was added followed by the addition of a portion of the cuprous chloride in acetonitrile solution prepared above (600 μL, 15.49 μmole, 0.000205 eq., 0.0205 mol %). To the resulting mixture was added, dropwise over 12 minutes, 3-chloro-3-methyl-1-butyne (7.03 g, 68.54 mmol, 0.907 eq. based on the input of 4-cyanophenol). The resulting mixture was allowed to stir at 0° C. under argon. After stirring for 10 hours, the reaction mixture was filtered through a small pad of Celite (to remove the remaining copper bronze) using additional acetonitrile to complete the transfer and to wash the filter bed. The filtrate was concentrated at reduced pressure (bath temperature 40° C.) and the residue was partitioned between 1N HCl (100 mL) and toluene (400 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×60 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (10.68 g). Distillation of the crude material (bulb-to-bulb, ~70°-90° C., ~0.15 mm Hg) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (10.40 g).
Reaction SMILES: [CH2:1]([C:8]1([C:29]([OH:31])=O)[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:49])[NH:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH2:48])=[CH:43][CH:42]=1)=[NH:40])([CH3:35])([CH3:34])[CH3:33]>>[CH2:21]([O:20][C:18](=[O:19])[NH:17][C:14]1[C:13](=[O:28])[N:12]2[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:29](=[O:31])[NH:48][CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:39]([NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])=[NH:40])=[CH:42][CH:43]=3)[CH2:9][CH2:10][C:11]2=[N:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1cnc2n(c1=O)C(Cc1ccccc1)(C(=O)O)CC2)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)C2(Cc3ccccc3)CCc3ncc(NC(=O)OCc4ccccc4)c(=O)n32)cc1

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 21b (50 mg, 0.119 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 77 mg (quantitative) of intermediate 21c.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][OH:27].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][OH:27]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A stirred solution of 15.0 grams (0.056 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) and 15.0 grams (0.109 mole) of potassium carbonate in 200 mL of DMF was cooled to 0-4° C. and 8.4 grams (0.067 mole) of 2-bromoethan-1-ol was slowly added. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred during an 18 hour period. After this time water was added to the reaction mixture, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 17.1 grams of residual oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)acetic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)acetate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14]1([CH3:23])[C:15]([N:20]=[C:21]=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])=[O:22]
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Reactant: Cc1ccccc1N=C=O
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 70 °C
Yield: 90.5 %

Procedure:
The procedure of Leeson, P. D. et al., J. Med. Chem 35: 1954-68 (1992) was adapted. A suspension of 1-amino-1,4-dihydro-2,3-quinoxalinedione (37 mg, 0.21 mMol) in pyridine (2.5 mL) was stirred at 70° C. until dissolving was completed. To the solution was then added o-tolyl isocyanate (27.8 mg, 0.21 mMol, Aldrich), which was stirred at 60° C. for 2 h, then overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was washed by ether (2×2 mL) to give 59 mg of crude 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione (66% product; 30% tolyl-byproduct; 4% 1-amino-1,4-dihydro-2,3-quinoxalinedione by 1H NMR). Separated by chromatograph with silica gel (2 g) column, eluted with 100% benzene (20 mL) and benzene: acetone=1:1 (20 mL) and 100% acetone (20 mL) to remove most of impurity. The residue (43 mg of 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione) was washed with ethanol (2×2 mL) and ether (2×1 mL) to give 38 mg of pure 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione as a white powder (60%). Mp:decomposed from 265° C. IR (KBr, cm-1): 3375; 3237; 1718; 1693; 1675. NMR (1H, DMSO-d6) δ 2.161 (s, 3H); 6.996-7.380 (m, 8H); 8.530 (s, 1H), 9.343 (s, 1H); 12.155(s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1.O>CN(C)C=O>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Potassium phthalimide (0.580 g, 4.68 mmol) was added to a solution of toluene-4-sulfonic acid 2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethyl ester (compound of Reference Example 65; 0.661 g, 1.56 mmol) in N,N-dimethylformamide (10 ml), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water to give the title compound (0.577 g, 93%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:6]2[N:14]([CH2:15][O:16][CH3:17])[C:13]3[C:12]4=[N:18][CH:19]([CH2:21]OS(C)(=O)=O)[CH2:20][N:11]4[C:10](=[O:27])[N:9]([CH2:28][CH2:29][CH3:30])[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[K].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C=O>[CH:1]1([C:6]2[N:14]([CH2:15][O:16][CH3:17])[C:13]3[C:12]4=[N:18][CH:19]([CH2:21][N:36]5[C:32](=[O:42])[C:33]6[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=6)[C:35]5=[O:37])[CH2:20][N:11]4[C:10](=[O:27])[N:9]([CH2:28][CH2:29][CH3:30])[C:8]=3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN1C(=O)N2CC(COS(C)(=O)=O)N=C2c2c1nc(C1CCCC1)n2COC
Agent: [K]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N2CC(CN3C(=O)c4ccccc4C3=O)N=C2c2c1nc(C1CCCC1)n2COC
Temperature: 120 °C
Reaction time: 4 h
Yield: 104 %

Procedure:
Compound 18 (500 mg, 0.98 mmol) obtained in Example 18 was dissolved in N,N-dimethylformamide (10 mL), to the solution was added phthalimide potassium salt (485 mg, 2.62 mmol, 2.7 equivalents), and the mixture was stirred at 120° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After the reaction mixture was concentrated, the residue was crystallized from dichloromethane and diethyl ether to obtain the title compound (500 mg, 78%) as white crystals.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1>C(O)C>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([N:18]2[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1-c1cccc(C(F)(F)F)c1
Yield: 68.9 %

Procedure:
A solution of 21.4 grams of mucobromic acid and 13.3 grams of 3-trifluoromethylphenyl hydrazine in 60 milliliters of ethanol was stirred for about 10 minutes. The ethanol was removed by evaporation under reduced pressure, and then 40 milliliters each of glacial acetic acid and acetic anhydride were added to the reaction vessel. The acidic reaction mixture was heated at reflux for 4 hours. The reaction solvent was removed by evaporation under reduced pressure whereupon a solid precipitate formed. The solid was purified by recrystallization from ethanol. A yield of 20.7 grams of 1-(3-trifluoromethylphenyl)-4,5-dibromo-1,6-dihydro-6-oxopyridazine was obtained.
Reaction SMILES: CN1CCCC1=O.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:35]1[CH2:36][CH2:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:18]3[N:17]=[C:16]([NH:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1)[CH3:44]
Reactant: NC(=O)c1cnc(Nc2ccc(N3CCNCC3)cc2)nc1NCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5 ml portion of 1-methyl-2-pyrrolidone solution of 400 mg of 4-benzylamino-2-[(4-piperazin-1-ylphenyl)amino]pyrimidine-5-carboxamide was mixed with 0.12 ml of ethyl bromoacetate and 200 mg of potassium carbonate, followed by stirring at room temperature for 30 minutes. The reaction mixture was mixed with water, and the organic layer was extracted with ethyl acetate-THF mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the residue obtained by evaporating the solvent was washed with methanol to obtain ethyl[4-(4-{[5-(aminocarbonyl)-4-(benzylamino)pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetate as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].C(OC(=O)[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:68].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:68].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:12][C:6]2[CH:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])=[C:2]([OH:1])[C:7]=2[C:8]([F:9])([F:10])[F:11])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Reactant: CC(C)C(=O)c1ccc(O)c(C(F)(F)F)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Mechanically stir solutions of 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-2-methyl-propan-1-one (211 g, 850.1 mmol), (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (195 g, 821.8 mmol), and triphenylphosphine (212 g; 808.3 mmol) in toluene (9 L) in two separate 22-L Morton flasks. Treat solutions with diisopropyl azodicarboxylate (183 mL, 923 mmol) over a 60 min period, then stir over the weekend at room temperature. Combine the solutions and evaporate to a brown oil. Dissolve the oil in 1,4-dioxane (8 L), treat with 4N hydrogen chloride solution in 1,4-dioxane (3 L, 12 mole), and heat to 92° C. for 6 hrs (out-gassing and precipitation is observed at 52° C. during the warm up period). Cool to room temperature, filter the resulting solid and wash with dioxane, 30% dioxane in hexanes, and hexanes to provide the title compound (510 g, 78% yield) as a tan solid. HPLC Rt=4.71 min; 1H NMR (DMSO-d6) δ 14.00 (s, 1H), 8.4 (bs, 3H), 7.50 (ABq, J=12.0, 8.0 Hz, 4H), 6.92 (d, J=8.0 Hz, 1H), 5.37 (s, 2H), 4.0 (m, 2H), 3.73 (hept, J=4.0 Hz, 1H), 1.12 (d, J=4.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.10; MS (m/z): 368.0 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:15][O:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: [H][H]
Reactant: CO[C@@H]1CCN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-methoxypiperidin-3-ylcarbamate (1.37 g, 4.28 mmol) and 10% Pd/C (0.46 g, 0.43 mmol) in MeOH (20 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 18 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-methoxypiperidin-3-ylcarbamate (0.99 g, 100%) as a solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH:15](O)[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[O:26][CH3:27]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1ccc(C(O)CCCc2ccccc2)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C2CCCc3ccccc32)cc1C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
A 1M solution of titanium tetrachloride in toluene (74.1 mL, 74.1 mmol) was added dropwise to a solution of 2-methyl-4-(1-hydroxy-4-phenyl-1-butyl) anisole (5.0 g, 18.5 mmol) in methylene chloride. The mixture was stirred at room temperature for 3h, then the reaction was quenched by pouring into excess aqueous saturated sodium bicarbonate. After stirring for 5 min the mixture was extracted with ether, and the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with hexanes to afford 2.46 g of 2-methyl-4-(1-tetralinyl) anisole as a clear oil.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=[O:14])[C@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8]1.[CH3:22][CH2:23]O>>[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH2:22][CH3:23])=[O:14])[C@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8]1
Reactant: CCO
Reactant: O=C1CC[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1CCC(=O)C[C@H]1c1ccccc1
Reaction time: 14 h
Yield: 31 %

Procedure:
Sulfuric acid (0.073 ml, 1.375 mmol) was added to a mixture of (trans)-4-oxo-2-phenylcyclohexanecarboxylic acid (1.5 g, 6.87 mmol) in EtOH (15 ml). The reaction was aged at 77° C. for 14 h. The cooled reaction was quenched with NaOH (1/V) and extracted three times with CH2Cl2. The combined organic layers were dried under reduced pressure and purified via silica gel column chromatography (0-40% EtOAc:Hexanes) to afford ethyl(trans)-4-oxo-2-phenylcyclohexanecarboxylate (526 mg, 31%) as a colorless oil. MS ESI: [M+H]+ m/z 247.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[S:8]1(=[O:25])[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:10]2=[N:9]1.[Cl:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[C:33]([O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:17]3[C:10]4=[N:9][S:8](=[O:7])(=[O:25])[CH2:13][CH2:12][N:11]4[CH2:14][CH2:15][CH2:16]3)=[CH:19][CH:20]=2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O=S1(=O)CCN2CCCC(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Potassium carbonate (73.9 mg) was added to a mixture of 4-(2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (50 mg) and 2-chloro-4-fluorobenzonitrile (41.6 mg) in DMF (dry) (1 ml). The mixture was stirred at 60° C. under atmosphere overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was crystallized from MeCN-THF/IPE to give the title compound (32.2 mg) as colorless crystals.