Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:43])=[C:21]([S:23]([N:26](CC2C=CC(OC)=CC=2OC)[C:27]2[S:28][CH:29]=[N:30][N:31]=2)(=[O:25])=[O:24])[CH:22]=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([S:23]([NH:26][C:27]3[S:28][CH:29]=[N:30][N:31]=3)(=[O:24])=[O:25])=[C:20]([F:43])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)ccn1

Procedure:
The title compound was prepared from 2-(2-aminopyridin-4-yl)-4-chlorophenol, (Preparation 721) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247) using a method analogous to that used in Preparation 669. Purification by semi-preparative HPLC using 15-100% MeOH/H2O yielded the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:15]2)[CH:3]=1.O.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[OH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:15]2)[CH:3]=1
Reactant: COc1ccc2c(Cl)cc(-n3ccc(NC(C)C)n3)nc2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(NC(C)C)n3)nc2c1
Temperature: 130 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
A mixture of [1-(4-chloro-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (0.52 g, 1.6 mmol) and sodium acetate monohydrate (1.0 g) in acetic acid (5 mL) was stirred at 130° C. for 2 d. The mixture was concentrated and then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes), affording [1-(4-hydroxy-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (0.09 g, 19%). LC/MS=299.1 (M++1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccncn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccncn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-4-carboxamide
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 7.4 g. (24.5 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine and 2.0 g. of 10% palladium-on-carbon in 150 ml. of ethanol and 75 ml. of ethyl acetate is stirred under one atmosphere of hydrogen for 2.5 hours. The reaction is filtered through diatomaceous earth and evaporated. Crystallization of the residue from ether-pentane gave 4.6 g. (62%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1>C(Cl)Cl.O>[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][CH:2]4[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]4[C:14]([O:16][CH3:17])=[O:15])=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1N
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 3.5 h
Yield: 69.1 %

Procedure:
The 1-tert-butyl 3-methyl 4-amino-1,3-pyrrolidinedicarboxylate (0.10 g, 0.41 mmol) was combined with the acid chloride from step (501b) (0.10 g, 0.32 mmol) in methylene chloride (15 mL) and water saturated sodium bicarbonate (15 mL). The reaction was stirred for 3.5 h, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (30:60, v:v) to give the 1-tert-butyl 3-methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-1,3-pyrrolidinedicarboxylate (0.120 g, 70%) as a solid, MS (M+H)+=543.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:10]=[C:8]1[NH:7][C:6]2[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2oc(=O)[nH]c2c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo benzoxazolinone (1 g, 4.7 mmol) in DMF (15 mL), were added Zn(CN)2 (1 g, 9.4 mmol) and Pd(PPh3)4. The reaction was stirred at 150° C. for 24 h. The reaction progress was monitored by TLC (100% EtOAc). The reaction was diluted with EtOAc (10 mL) and filtered through Celite® brand filter agent. The organic layer was concentrated and purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.6 (br s, 1H), 7.5 (dd, J=1.8, 8.4 Hz, 1H), 7.3-7.4 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 21 from 1-(4-trifluoromethoxyphenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3′-carboxylic acid ethyl ester (140 mg, 0.31 mmol, see step (b) Example 9) and 2-chloro-5-(trifluoromethyl)pyridine (112 mg, 0.62 mmol). Yield 87 mg (47%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 45 h
Yield: 58.7 %

Procedure:
A solution of methyl {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.085 g, 0.17 mmol) in THF (3 mL) was treated with 1N NaOH (1.5 mL) and the biphasic mixture was stirred at room temperature for 45 hours. Et2O was then added and the organic layer siphoned off. The remaining aqueous layer was cooled to 0° C. and acidified with 6N HCl. The separated solids were collected by suction and rinsed with water. Drying under high vacuum at 45° C. for 5 hours gave {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetic acid (0.050 g, 56% yield) as an off-white powder.
Reaction SMILES: C([N:4]([CH:23]1[CH2:25][CH2:24]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([F:22])=[CH:7][CH:6]=1)(=O)C.Cl>CO>[CH:23]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A solution of 21.9 g (63 mmole) of 4-[6-(acetylcyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 170 ml of 15% hydrochloric acid and 235 ml of methanol was refluxed for one hour and allowed to stir at room temperature for 18 hours. The methanol was removed in vacuo and the aqueous acid was made basic with 1.0N sodium hydroxide to pH 10.5. The mixture was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 17.6 g of the title compound, mp 68-70° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[N:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C>C(O)CCC>[CH2:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 160 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (42 mg) obtained in Step A, 4-(morpholin-4-yl)aniline (39 mg) and acetic acid (11 μL) in 1-butanol (2 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[CH:10][C:9]=1[O:18]COC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CO>[CH2:1]([C:8]1[C:9]([OH:18])=[CH:10][CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cccc(OCOC)c1Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(O)c1Cc1ccccc1
Yield: 100.6 %

Procedure:
A solution of 13 (214 mg, 0.74 mmol) in MeOH (6.20 mL) was treated dropwise with 3 M HCl (0.22 mL, 5.92 mmol), then heated to reflux for one hour. Water (10 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 14 as a red amorphous solid (149 mg, 99%). 1H NMR (CDCl3, 400 MHz) 7.31 (d, J=6.6 Hz, 4H), 7.25-7.19 (m, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.44 (d, J=8.1 Hz, 2H), 4.82 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].[N:23]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([N:26]1[CH2:27][CH2:28][N:23]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:24][CH2:25]1)=[O:21]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.29 g, 1.0 mmol, Example 21C) in CH2Cl2 (15 mL) was added benzyl piperazine-1-carboxylate (0.22 g, 1.0 mmol) under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2.0 mmol) and 4-(dimethylamino)pyridine (0.012 g, 0.1 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; CH3OH/CH2Cl2, 2:98 eluant) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.43-7.16 (m, 15H), 5.14 (s, 2H), 4.19 (s, 2H), 3.64-3.23 (m, 10H), 2.81 (t, J=6.5, 2H); MS (DCI+) m/z 414 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:16]=[C:15]([OH:17])[C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Oc1cc(O)c2ccccc2c1)C(F)(F)F
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12

Procedure:
4-Hydroxy-2-naphthyl trifluoromethanesulfonate (100 mg, 0.34 mmol), 4-(trifluoromethoxy)phenyl boronic acid (0.14 g, 0.68 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) in DME/2M K2CO3 (1/1) were heated at reflux under an argon atmosphere. After approximately 2 hours the solution was cooled and partitioned between aqueous 1N hydrochloric acid and ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 3.94 min. (M+H)=305
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(F)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
3.7 g (13 mmol) of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 20 ml of sulfuric acid, and 0.9 g (14 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water and then, dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 4.2 g (yield: 98%) of the desired product. Melting point: 115-118° C. 1H-NMR (400 MHz, CDCl3) δ value: 3.71(3H,s), 6.81(1H,d), 7.13(1H,t), 7.57(1H,d), 8.43(1H,m)ppm.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[N:12]=1)=[O:10])[CH3:7]>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[C:16]([O:17][CH2:18][CH3:19])=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:30][CH:31]=2)[N:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)OCC)c(OCC)c(N3CCOCC3)n2)cc1
Yield: 25.2 %

Procedure:
Ethyl isocyanate (0.012 ml, 1.4 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in toluene (2 ml) and the mixture was reacted overnight at 80° C. The reaction mixture was extracted with EA, washed with brine. The crude was purified by chromatography to give a product (12 mg, 25.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1)[S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCCCCCNCc1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccccn1

Procedure:
The title compound of Step B was prepared from 7-(4-pyrazol-1-yl-benzylamino)-heptanoic acid methyl ester, of Step A, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.06 (m, 1H), 8.80 (dd, 1H), 8.10 (m, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.65 (d, 2H), 7.48 (m, 1H), 7.36 (d, 2H), 6.46 (d, 1H), 4.38 (s, 2H), 3.62 (s, 3H), 3.14 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.36 (m, 2H), 1.25 (m, 4H); MS 457 (M+1).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH:19]=1)[C:14](=[O:38])[NH:13][C:12]2=[O:39].CO.[NH4+].[Cl-]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)[CH2:30][CH2:31]3)=[O:25])[CH:19]=1)[C:14](=[O:38])[NH:13][C:12]2=[O:39]
Reactant: COc1cccc2c(=O)[nH]c(=O)n(Cc3cccc(C(=O)N4CCN(c5ncccn5)CC4)c3)c12
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3cccc(O)c32)c1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A solution of BBr3 (4N in DCM, 10 mL, 40 mmol) was added dropwise to a mixture of 8-methoxy-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione (60 mg, 0.13 mmol) in DCM (25 mL) at −70° C. The mixture was warmed to room temperature and stirred at r.t overnight. After cooled at ice-bath, 10 mL MeOH was added dropwise and then NH4Cl (a.q.) was added. The mixture was extracted by DCM (50 mL×2), the combined organic layer was dried to give crude product which was purified by TLC (DCM/MeOH=20:1) to give the target product (7.64 mg, 13.1% yield). 1H NMR (DMSO-d6): 11.64 (s, 1H), 10.34 (s, 1H), 8.36 (d, J=4.8 Hz, 2H), 7.51 (dd, J=6.8 and 2.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.27-7.23 (m, 3H), 7.10-7.03 (m, 2H), 6.65 (t, J=4.7 Hz, 1H), 5.63 (s, 2H), 3.85-3.53 (m, 8H). MS: m/z 459.4 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]C(=O)C)[CH2:20][C:21](OC)=[O:22])[CH2:14][C:15](OC)=[O:16])(=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][SH:33])[CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CC(CCCCCCCCSC(C)=O)C(CCCCCCCCSC(C)=O)CC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCCC(CCCCCCCCS)C(CCO)CCCCCCCCS
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a flame-dried 20 mL vial fitted with a screw-top septa cap was charged with dimethyl 3,4-bis(8-(acetylthio)octyl)hexanedioate (1 equiv, 0.34 mmol, 187 mg, mixture of stereoisomers) and THF (4.5 mL). DIBAl-H (12 equiv, 4.1 mmol, 2.7 mL of a nominally 1.5 M solution in toluene) was added dropwise. The reaction was stirred for 3 h at rt, quenched by careful addition of 2 N HCl (5 mL), diluted with 10 mL sat. aq. NH4Cl (10 mL), and extracted with Et2O (3×15 mL). The combined organic layers were washed with brine (1×15 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (35% EtOAc/Hex) to afford rac-3,4-Bis(8-mercaptooctyl)hexane-1,6-diol (41 mg, 30%) and meso-3,4-Bis(8-mercaptooctyl)hexane-1,6-diol (49 mg, 49%). TLC rac-Rf=0.57 (50% EtOAc/Hex), meso-Rf=0.38 (50% EtOAc/Hex); rac: 1HNMR (400 MHz): δ 3.60-3.79 (4H), 2.54 (q, 4H, J=7.3 Hz), 1.14-1.68 (38H); 13CNMR (100 MHz): δ 61.6, 35.8, 34.0, 33.7, 30.7, 30.0, 29.5, 29.1, 28.3, 28.0, 24.6; FTIR: 3323, 2922, 2852, 1463, 1051, 722 cm−1; HRMS-ESI: calc. for C22H46NaO2S2 (M+Na)+: 429.2837. found: 429.2825; meso: 1HNMR (400 MHz): δ 3.59-3.76 (4H), 2.54 (q, 4H, J=7.3 Hz), 1.87 (bs, 2H), 1.08-1.68 (36H); 13CNMR (100 MHz): δ 61.9, 36.7, 34.0, 33.8, 30.7, 30.0, 29.5, 29.1, 28.4, 28.0, 24.7; FTIR: 3329, 2922, 2852, 1463, 1051, 721 cm−1; HRMS-ESI: calc. for C22H46NaO2S2 (M+Na)+: 429.2837. found: 429.2829.