Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@:23]3([OH:41])[CH2:24][CH2:25][C@@H:26]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:18]1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:42]1(=[O:52])[N:46]([CH2:14][CH2:15][O:16][C@H:17]2[CH2:34][CH2:33][C@@:32]3([CH3:35])[C@H:19]([CH2:20][CH2:21][C@@H:22]4[C@@H:31]3[CH2:30][CH2:29][C@@:27]3([CH3:28])[C@:23]4([OH:41])[CH2:24][CH2:25][C@@H:26]3[C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)[CH2:18]2)[C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@]12CC[C@H](OCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](OCCN3C(=O)c4ccccc4C3=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 70.7 %

Procedure:
A solution of 0.29 ml of diethyl azodicarboxylate was added dropwise, under nitrogen, to a solution of 0.75 g of 3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, 0.28 g of phthalimide and 0.50 g of triphenylphosphine in 7 ml of tetrahydrofuran at room temperature. After 2 hrs the solvent was removed in vacuo, the crude product was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 to give 0.70 g of 3β-(2-phthalimidoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Br:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([CH2:25][Br:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CBr)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Diisopropylethylamine (0.99 ml, 5.6 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.37 g, 1.85 mmol) in DCM (20 ml) at room temperature. To this mixture was added 4-bromomethyl-benzenesulfonyl chloride (0.5 g, 1.85 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.56 g, 70% yield) as an off-white solid. Tr=2.12 min, m/z (ES+) (M+Na)+ 457.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][N:4]([NH:9]C(=O)C)[C:5](=[O:8])[NH:6][N:7]=1.Cl.Cl.[NH2:15][N:16]1[CH2:21][C:20](C)=[N:19]NC1=O.[CH3:24][OH:25]>>[NH2:9][N:4]1[CH2:3][C:2]([CH3:1])=[N:7][NH:6][C:5]1=[O:8].[NH2:15][C:16]1[C:24](=[O:25])[NH:4][N:19]=[N:20][CH:21]=1
Reactant: CC(=O)NN1CC(C)=NNC1=O
Reactant: CO
Agent: CC1=NNC(=O)N(N)C1
Agent: Cl
Product: Nc1cnn[nH]c1=O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A suspension is prepared of 39.9 g (0.234 mol) 6-methyl-4-acetylamino-4,5-dihydro-1,2,4-triazin-3-(2H)-one in 99 g 95% methanol. The suspension is heated to 45° C. and becomes a clear colourless solution. At between 45° and 50° C. a total of 15.4 g (0.421 mol) HCl are bubbled through this solution over a 2 to 3 hour period. After about 30% of the HCl has been added the reaction mixture is seeded with 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine hydrochloride. Thereafter 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine precipitates out continuously as the hydrochloride salt. After about 2 hours stirring, the maximum conversion of over 99% is reached. The reaction mixture is brought to pH 5 by the addition of 50% NaOH solution. The free aminotriazinone 4-amino-6-methyl-3-oxo-2,3,4,5-tetrahydro-1,2,4-triazine is formed in an amount of 29.7 g representing 14.3% by weight of the solution. This represents a yield of 99.2% of theory.
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=3[NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:6]=1.[O:29]=[C:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:15]=1)[NH:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][N:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:29])[CH2:35]3)[CH:6]=1)=[CH:19]2
Reactant: O=C1CNCCN1
Reactant: COC(=O)Cc1cccc(-c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)c1
Product: O=C1CN(CCc2cccc(-c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)c2)CCN1

Procedure:
2-[3-(7-Tetrahydropyran-4-ylamino-5-chloro-1H-indol-2-yl)-phenyl]-acetic acid methyl ester prepared in Example 132 and 2-oxo-piperazine were reacted according to the same procedures as Example 32 and Steps A and B of Example 36 sequentially to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[OH-].[Li+]>C1COCC1.CCOCC>[CH3:33][C:18]1[C:17]([CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:7]=[CH:8]3)=[CH:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc2c(ccn2CC(=O)O)c1
Yield: 82.7 %

Procedure:
175 mg (0.37 mmol) {5-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester and 0.75 ml 1N lithium hydroxide solution were stirred in 2 ml THF at RT for 2 h. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in ether/heptane 1:19 and the resulting crystals were filtered off to give 135 mg of pure {5-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: [C:1]([C@H:6]1[O:10][C@H:9](C(=O)C)[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[C:1]([C@H:6]1[O:10][C@@H:9]([O:23][C:21](=[O:22])[CH3:17])[CH2:8][O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H]1OC[C@@H](C(C)=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1OC[C@H](OC(C)=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% meta-chloroperbenzoic acid (mCPBA) (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resultant suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-Hexanes) to give the title compound (11% yield) which displayed the following spectral characteristics; 1H NMR (CDCl3): δ 1.31 (t, 3H, J=7.2 Hz), 2.07 (s, 1H), 4.15 (d of d, 1H, J=4.5, 9.1 Hz), 4.21-4.29 (m, 3H), 5.42 (s, 1H), 6.39 (d of d, 1H, J=2.4, 4.5 Hz); 13C NMR (CDCl3): δ 14.05, 20.97, 29.69, 71.34, 94.04, 99.80, 167.19, 170.11.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (4.12 g) was dissolved in dichloromethane (120 ml) and triethylamine (3 ml) and methanesulfonyl chloride (1.35 ml) were added to the solution, followed by stirring the resulting solution at 0° C. for 1.5 hours. The reaction mixture was then poured into 1N hydrochloric acid and the resultant was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and with saturated saline, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure. The residue was recrystallized from n-hexane/ethyl acetate to obtain the desired compound (5.25 g, yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6].[H-].[Na+].[C:25]([O:29][C:30]([N:32]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[N:32]([CH2:33][CH2:34][O:22][C:20]1[CH:19]=[C:4]([C:5](=[O:6])[N:7]([CH:16]([CH3:17])[CH3:18])[CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:21]=1)[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)N(CCc1nnnn1C)C(=O)c1cc(O)cc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C(=O)OC(C)(C)C)c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCc1nnnn1C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Reaction time: 88 h
Yield: 23.8 %

Procedure:
To a solution of 3-chloro-5-hydroxy-N-isopropyl-N-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-benzamide (0.070 g) in DMF (2.0 ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0.010 g) and after 10 min was added toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester (0.120 g). The reaction was stirred for 88 h and the sovent removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 1M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (4:1 v/v) and 24:1 dichloromethane:methanol (24:1 v/v), to give the title compound as a colourless gum (0.028 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20](N4CCN(C(=O)C)CC4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.NC1C=CC([C:37]([OH:39])=[O:38])=CC=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:37]([OH:39])=[O:38])=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Product: NCC1CCN(c2nc(Nc3ccc(C(=O)O)cc3)ncc2F)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 4-aminobenzoic acid. MS 346.2 (M+H); UV 215.8, 275.8, 292.8 nm.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:20](O)(=[O:22])[CH3:21]>C(O)C.[OH-].[OH-].[Pd+2]>[C:20]([O:19][CH2:18][CH:16]1[CH2:15][NH:14][CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OCC1CNC1
Reaction time: 72 h

Procedure:
(1-Benzhydrylazetidin-3-yl)methanol (1.81 g, 7.16 mmol) was dissolved in ethanol (50 mL), and acetic acid (0.82 mL, 14.32 mmol) and 10% palladium hydroxide/carbon (1.2 g) were added at room temperature. The mixture was stirred for three days under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and the reaction liquor was concentrated under reduced pressure, to obtain the title compound as an oily matter. This compound was used in the subsequent reaction without being subjected to further purification.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[N:22][CH:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(Cl)n3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cncc(Cl)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(6-chloro-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.11 g, 0.30 mmol) in THF (3 mL) was added a solution of LiOH (0.036 g, 1.5 mmol) in water (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-chloro-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as an off white solid (0.05 g, 50%). mp 187.2-188° C. 1H NMR (400 MHz, DMSO-d δ 12.34 (s, 1H), 9.26 (s, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 5.55 (m, 1H), 3.10 (dd, J=15.60, 2.80 Hz, 1H), 2.32 (s, 3H), 2.16 (m, 1H). MS (ESI) m/z: 333 (M−1)−. HPLC purity: 98.97% (Maxplot), 99.14% (220 nm).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[C:24]2[S:23][C:22]([SH:25])=[N:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:24]2[S:23][C:22]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][CH2:6]3)=[O:4])=[N:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nc2cccc(Cl)c2s1
Product: O=C(CSc1nc2cccc(Cl)c2s1)N1CCCc2ccccc21
Yield: 46 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 7-chlorobenzo[d]thiazole-2-thiol as the nucleophile to yield 26 as a white solid (46%): MS m/z: 375 (M+H)+. Anal. Calcd. For, C18H15ClN2OS2: C, 57.67; H, 4.03; N, 7.47; S, 17.11; Cl, 9.46. Found: C, 57.50; H, 3.99; N, 7.47; S, 17.36; Cl, 9.52.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[C:16][C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:18]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]>CCOC(C)=O.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]2[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][N:20]=[C:19]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:18]=2)[CH2:6][CH2:7][CH2:8]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Reaction time: 8 h

Procedure:
Pd/C 10% (40 mg) was added to a solution of tert-butyl 4-(4-((4-((2-(1-(methoxycarbonyl)cyclobutyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A54 (33 mg, 0.052 mmol) in EtOAc (10 mL) and Et3N (0.5 mL). The mixture was stirred under a hydrogen atmosphere overnight and then filtered through Celite. The filter cake was washed with EtOAc (50 mL) and the volatiles were removed in vacuo to give the title compound A55 as a yellow oil (31 mg, 93%). LCMS-A: rt 8.013 min; m/z 639.3 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH:9]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O1CCCC1>[CH:9]1([NH:15][C:16]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N-hydroxysuccinimide (11.5 g, 0.1 mol) was dissolved in 200 g of sufficiently dried tetrahydrofuran. To the solution was added dropwise 12.5 g (0.1 mol) of cyclohexyl isocyanate, and then a catalytic amount of triethylamine was added. After stirring at room temperature overnight, the reaction solution was decolored with active carbon and concentrated. The deposited crystal was filtered and washed with a small amount of ether to obtain 18.0 g of N-(cyclohexylcarbamoyloxy)succinimide represented by the following formula. Yield: 81.5%.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][C:20]([N:8]1[CH:7]2[C:16]3=[C:3]([O:2][N:1]=[C:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=3)[CH2:4][CH2:5][CH2:6]2)=[O:21])[CH3:18]
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: CCN=C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCNC(=O)N1c2ccccc2-c2noc3c2C1CCC3

Procedure:
In 20 ml CCl4 were combined 5.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine and 9 ml ethyl isocyanate. The mixture was refluxed for two days. After the first day, 9 ml more ethyl isocyanate was added. The reaction mixture was then cooled in ice and the precipitate filtered. The precipitate was recrystallized from 1:1 DCM/hexanes and dried in vacuo at 80° C. to yield 3.91 g crystals, m.p. 189° C.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:36])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4F)c(F)c3)c2cc1C#N
Yield: 72 %

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) was added to 4.5 ml of toluene, and the mixture was heated to reflux. After then adding 2-fluorophenyl isocyanate (0.05 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene==1/1 to obtain 100 mg of the title compound as light brown crystals (72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:17]=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C.Cl[C:43]([C:45]1[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=1)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44]>ClCCl>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([C:45]3[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=3)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44])=[C:3]([C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH:17]=[CH:16][N:15]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 0 °C
Yield: 109.2 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide (100.0 mg, 0.23 mmol, 1.00 equiv) and N,N-diisopropylethylamine (0.2 mL) in dichloromethane (20 mL). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate 22d (74.0 mg, 0.27 mmol, 1.20 equiv) in dichloromethane (2.0 mL) with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was combined with the solution of the previous batch and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100˜100:1˜50:1). The product was obtained as 170 mg (70%) of a yellow solid.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:13]([OH:16])(=[S:15])[CH3:14]>>[C:13]([S:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])(=[O:16])[CH3:14]
Reactant: CC(O)=S
Reactant: C=CCCCC(CCC)C(=O)O
Product: CCCC(CCCCCSC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 2-propyl-6-heptenoic acid (1 g) and thioacetic acid (450 mg) was heated for 4 hours at 60° C. and allowed to stand overnight at ambient temperature in an air-tight container. Excess thioacetic acid was evaporated under reduced pressure to give oil of 7-acetylthio-2-propylheptanoic acid (0.9 g).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[I:8][C:7]1[C:2]([O:15][CH3:14])=[N:3][C:4]([CH3:13])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: C[O-]
Reactant: Cc1nc(Cl)c(I)c(C(F)(F)F)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)nc(C(F)(F)F)c1I
Yield: 57.3 %

Procedure:
4-Chloro-5-iodo-2-methyl-6-trifluoromethylpyrimidine (23.0 g) was dissolved in methanol (150 ml) and sodium methoxide (30% methanol solution, 12.8 g) was added under ice cooling with stirring. After stirring over night at room temperature, the solvent was removed under reduced pressure. The residue was mixed with water and extracted with benzene, and then benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The crude fraction was concentrated, and then washed with cold hexane to give 5-iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (13.0 g) as colorless crystalline solid, mp 44-45° C.