Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH2:17].[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)=[O:25]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1ccccn1
Yield: 28 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-2-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 28% yield: 1H NMR (300 MHz, CDCl3) δ 8.56-8.54 (m, 1H), 7.70-7.64 (m, 1H), 7.30-7.19 (m, 2H), 7.13-7.10 (m, 1H), 4.69 (d, J=4.6 Hz, 2H), 4.17-4.11 (m, 2H), 3.63-3.58 (m, 2H), 2.65 (s, 3H), 2.24-2.08 (m, 2H), 1.92-1.75 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.5, 155.8, 155.6, 152.3, 148.9, 136.7, 122.4, 121.9, 118.2, 44.6, 42.9, 42.3, 42.0, 31.8, 31.4, 30.9, 30.6, 20.2, 20.1, 17.3; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:17]([C:2]2[N:3]=[CH:4][C:5]([B:8]([OH:9])[OH:12])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: OC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: OB(O)c1ccc(N2CCC(O)C2)nc1
Temperature: 180 °C

Procedure:
To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (239 mg, 1 mmol) in NMP (2 mL) was added pyrrolidin-3-ol (174 mg, 2 mmol) and DIPEA (500 uL, 3 mmol), then the mixture was sealed in a microwave tube and heated in microwave reactor at 180° C. for 1.5 hours. TLC and LC-Ms showed the reaction had completed and the desired compound was detected. The reaction mixture was poured into 30 mL of H2O, and extracted with n-BuOH, washed with water and brine, concentrated and purified on TLC(CH2Cl2:MeOH=10:1) to give a white solid. MS (m/z): 209 (M+H)+
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:9][C:10](I)([F:12])[F:11].C1(S(C2C=CC=CC=2)=O)C=CC=CC=1.S(=O)(=O)(O)O.OO>S([O-])([O-])(=O)=O.[Fe+2]>[F:9][C:10]([F:12])([F:11])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: FC(F)(F)I
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 25 °C
Yield: 0.47 %

Procedure:
0.055 g (0.5 mmol) of uracil was weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with trifluoromethyl iodide. The following materials were added thereinto: 2.5 g of diphenyl sulfoxide, 0.027 ml of concentrated sulfuric acid, 0.1 ml of a 30% hydrogen peroxide aqueous solution and 0.15 ml of a 1.0 mol/l aqueous solution of iron(II) sulfate, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40° C. to 50° C. Thereafter, the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 0.47%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard.
Reaction SMILES: C1[O:3]C1.O[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=CC=2)(C)C)=[CH:7][CH:6]=1.C1OC1C.C(O)(=O)C1C=CC(C(O)=O)=CC=1.C(O)(=O)CCCCC(O)=O.C([Sn](=O)CCCC)CCC>>[CH:14]([CH:19]=[CH:18][C:17]([OH:20])=[O:3])=[CH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1
Reactant: C1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC1CO1
Agent: CCCC[Sn](=O)CCCC
Agent: O=C(O)CCCCC(=O)O
Product: O=C(O)C=CC=Cc1ccccc1

Procedure:
In a reaction vessel equipped with a condenser, a stirrer and a nitrogen inlet tube, 229 parts of ethylene oxide 2 mol adduct of bisphenol A, 529 parts of propylene oxide 3 mol adduct of bisphenol A, 208 parts of terephthalic acid, 46 parts of adipic acid, and 2 parts of dibutyltin oxide were added. The mixture was subjected to a reaction for 8 hours at 230° C. under normal pressure, and subsequently reacted for 5 hours under a reduced pressure of from 10 mmHg to 15 mmHg. Further, 44 parts of trimellitic anhydride were added thereto, and the mixture was reacted for 2 hours at 180° C. under normal pressure. Thus a [low-molecular weight polyester 1] was obtained. The [low-molecular weight polyester 1] was found to have a number average molecular weight of 2,500, a mass average molecular weight of 6,700, a glass transition temperature (Tg) of 43° C., an acid value of 25 mgKOH/g and an SP value of 10.8.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[CH:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[Br:22])[CH2:7][CH2:8]1)=[O:2]
Reactant: BrBr
Reactant: COc1ccc(N2CCN(C=O)CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(C=O)CC2)c(Br)c1

Procedure:
Sodium acetate (VI, 9.702 g, 0.1182 mol) is added to a mixture of 1-formyl-4-(4-methoxyphenyl)piperazine (VI, 5.17 g, 23.5 mmol) and acetic acid (102 ml). When the sodium acetate had completely dissolved, a solution of bromine (7.912 g, 49.5 mmol) in acetic acid (9.5 ml) is added over 14 min. After 35 min the mixture is poured into water poured into water and extracted exhaustively with dichloromethane. The combined organic extracts are backwashed with water, followed by saturated sodium bicarbonate, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting first with ethyl acetate/dichloromethane (10/90) and then ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give 1-formyl-4-(2-bromo-4-methoxyphenyl)piperazine (VII), NMR (CDCl3) 2.94, 3.55, 3.74, 3.78, 6.83, 6.97, 7.16 and 8.10 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[Sn].[OH-].[Na+]>C(O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(/C=C/c2ccc(N)cc2)cc1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 68.2 %

Procedure:
A mixture of 10.1 g (40 mmol) of (E)-1-methoxy-4-[2-(4-nitrophenyl)ethenyl]-benzene in 70 ml of ethanol and 130 ml of hydrochloric acid (25%) is heated to 110° C. Portionwise, 15 g of tin are added and stirring is continued for 4.5 hours at 110° C. For the working-up, the reaction mixture is cooled and neutralised with a solution of sodium hydroxide. The mixture is transferred to a separatory funnel where it is extracted with dichloromethane. The organic layer is separated, dried over sodium sulfate and evaporated. The residue is triturated in ether and, thereafter, the remaining solid is collected on a filter funnel. There are obtained 6.15 g (69% of theory) of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine as a yellow crystals; MS: m/e=226 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15]
Reactant: OCCCCCCCOC1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 20.37 g of 7-(tetrahydropyran-2-yloxy)-1-heptanol in 200 ml of methylene chloride was added, whilst ice-cooling, to a mixture of 40.60 g of pyridinium chlorochromate, 3.86 g of sodium acetate and 200 ml of methylene chloride. The resulting mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours, after which was diluted with 1.5 liter of diethyl ether and passed through a column containing 250 g of silica gel. The eluate was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through 400 g of silica gel. 14.11 g of 7-(tetrahydropyran-2-yloxy)heptanal were obtained, as a colorless oil, from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 40:1 to 9:1 by volume.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:10]2=[O:27])[CH:5]=[CH:4][N:3]=1.Br[C:29]1[CH:30]=[CH:31][C:32]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:33][CH:34]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29]4[CH:34]=[N:33][C:32]([CH2:35][N:36]5[CH2:37][CH2:38][CH2:39][CH2:40]5)=[CH:31][CH:30]=4)[CH:7]=3)[C:10]2=[O:27])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Brc1ccc(CN2CCCC2)nc1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4ccc(CN5CCCC5)nc4)c3)C(C)(C)C2=O)cc1
Yield: 8.9 %

Procedure:
To a solution of 0.5 g of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) of Example 7 in 15 mL of dioxane are successively added, under argon, 0.32 g of 5-bromo-2-(pyrrolidin-1-ylmethyl)pyridine obtained in stage a) below, 77 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos), 38 mg of palladium acetate and 1.75 g of caesium carbonate. The reaction mixture is refluxed for 7 hours and then filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (87/13 by volume) to give 62 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-{[6-(pyrrolidin-1-yl-methyl)pyridin-3-yl]amino}pyridin-4-yl)methyl]imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[CH:5][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cccc2oc(-c3ccc[nH]c3=O)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc[nH]c4=O)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
A mixture of 2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxylic acid (102 mg, 0.40 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.80 mmol), 1-hydroxybenzotriazole (108 mg, 0.80 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (135 mg, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.22 mL, 1.60 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (3×100 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2-oxo-1,2-dihydropyridin-3-yl)benzoxazole-4-carboxamide (21 mg, 13%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (br s, 1H), 8.53 (dd, J=7.3, 1.7 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 7.76-7.69 (m, 2H), 7.48 (t, J=7.9 Hz, 1H), 6.58 (t, J=6.7 Hz, 1H), 4.64-4.55 (m, 1H), 3.15-3.10 (m, 2H), 2.68-2.62 (m, 2H), 2.54 (s, 3H), 2.15-1.95 (m, 3H), 1.60-1.47 (m, 4H), 1.15-1.10 (m, 2H); MS (ESI+) m/z 393(M+H); HPLC>99% (AUC), tR=12.23 min.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>COCCOC.O.CCO>[C:37]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9](=[O:14])[CH:8]=[C:7]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Reactant: OB(O)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(-c3ccccc3)ccc2o1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
Into a dry microwave vial under N2 was added 6-bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (about 1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). Phenyl boronic acid (5.6 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 5.86 mg (23%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 435 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.83-1.91 (m, 2H), 2.24 (br d, 2H), 3.15-3.23 (m, 2H), 3.61 (br d, 2H), 3.82-3.97 (m, 3H), 5.45 (s, 1H), 6.36-6.42 (m, 1H), 6.90 (d, 1H), 7.34-7.56 (m. 10H), 7.74 (d, 2H), 7.89 (dd, 1H), 8.40 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:37]([CH3:45])=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=5[CH3:45])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1c(F)cccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-methyl-phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(Br)c1)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
1-(3-Bromo-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (1.8 g, 5.3 mmol) prepared in Step 1, 2,4-difluorophenylhydrazine hydrochloride (1.2 g, 6.4 mmol) and conc. hydrochloric acid (100.0 uL) were added to ethanol (15.0 mL). The reaction mixture was stirred at 100° C. for 8 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 2.3 g of the titled compound as a yellow liquid.
Reaction SMILES: [Br-].[C:2]([O:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:7]1[S:25][C:26](N)=[NH2+])(=[O:4])[CH3:3].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].ClC[C:46]#[N:47]>CC(C)=O.O>[C:2]([O:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:7]1[S:25][CH2:26][C:46]#[N:47])(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](SC(N)=[NH2+])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](SCC#N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-S-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-2-thiouronium bromide (7; 16.11 g, 31.07 mmol), sodium metabisulphite (11.81 g, 62.14 mmol), potassium carbonate (4.72 g, 34.18 mmol), and chloroacetonitrile (8.21 g, 108.7 mmol) were dissolved in acetone/water (50:50 v/v, 200 mL), and stirred for 1 hour at room temperature. The reaction mixture was poured in ice-water (300 mL), and stirred for an additional 2 hours. The white precipitate was collected by filtration and recrystallized from hot methanol (30 mL). The product was filtered off as a white crystalline solid (9.61 g, 77%). M.p.=97° C. (Lit: 95-97° C.). 1H-NMR (400 MHz, CDCl3): δ=2.00 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.17 (s, 3H, CH3), 3.35 (d, J=17 Hz, 1H, S—CH), 3.64 (d, J=17 Hz, 1H, S—CH′), 4.01 (t, J=6.9 Hz, 1H, H5), 4.16 (m, 2H, H6, H6′), 4.7 (d, J1,2=10 Hz, 1H, H1), 5.11 (dd, J3,4=3.2 Hz, J2,3=10 Hz, 1H, H3), 5.24 (t, J=10 Hz, 1H, H2), 5.47 (d, J=2.4 Hz, 1H, H4). FT-IR (ATR): ν=2249 (CN, w), 1739 (C═O, s).
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH:19]=O)=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[ClH:74]>Cl.CCOCC.CCO.O.C1(C)C=CC=CC=1>[ClH:74].[CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.2 %

Procedure:
To a 2 L Erlenmeyer flask was added 6-chrysenecarbaldehyde (21.2 g, 82.7 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 9.13 g, 86.8 mmol), p-toluenesulfonic acid.H2O (Eastman, 0.5 g, 2.5 mmol), and PhCH3 (500 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting golden colored solution was allowed to cool to RT, diluted with abs. EtOH (500 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 2.51 g, 42 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M ethanolic HCl every 15 min. After 3 days the indicator turned green then yellow and a voluminous white precipitate was present in the flask. To the flask was then added 1M ethanolic HCl (10 mL). The reaction was diluted to 4 L with abs. Et2O and stirred for 1 h. The precipitate was then filtered through a medium porosity glass fritted funnel and pressed dry. The filter cake was washed thoroughly with 20% HCl (5×250 mL), pressed dry and then washed with CH2Cl2 (4×500 mL), pressed and sucked dry. The solid was dissolved in abs. EtOH (1400 mL). 1M ethanolic HCl (1 mL) and 5 g of Calgon® (a trademark of Calgon Corporation, a subsidiary of Merck and Co., Pittsburgh, PA, 15230) brand of activated charcoal were added, and the mixture boiled and filtered through a pad of Celite® (a trademark of Johns Manville Co., P.O. Box 5108, Denver, CO, 80217) brand of filtered aid. The clear yellow solution was concentrated to 500 mL and diluted to 2 L with abs. Et2O which was then filtered to give the crude product. Further crystallization (2×) from CH3OH/Et2O (1:3) gave 18.07 g (57.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 241°-243° (dec), (C, H, Cl, N).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Yield: 87.8 %

Procedure:
A suspension of 1-benzyl-cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (5.37 g) and 10% palladium-on-charcoal (2.70 g) in ethanol (50 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at room temperature for 22 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.25 g). The compound was gradually solidified at room temperature.