Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH3:18]>>[CH3:1][CH:2]([N:8]([CH2:16][CH2:17][CH3:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C)Nc1ccccc1
Reactant: CCCBr
Product: CCCCCC(C)N(CCC)c1ccccc1

Procedure:
N-(1-Methylhexyl)-N-propylaniline was prepared from N-(1-methylhexyl)aniline (as in Example 2i)) and 1-bromopropane using the same method as in Example 2ii).
Reaction SMILES: [Cl:1]C1C=CC(C[C@H](N)CO)=CC=1.OCCN.[CH:17]([CH:20]1[NH:24][C@@H:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:22]O1)([CH3:19])[CH3:18].O1CCNC1.[Cl:38]C1C=CC(C[C@H](NCC(C)C)CO)=CC=1.O=S(Cl)Cl>>[Cl-:1].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:23]([NH2+:24][CH2:20][CH:17]([CH3:19])[CH3:18])[CH2:22][Cl:38])=[CH:27][CH:28]=1
Reactant: CC(C)CN[C@H](CO)Cc1ccc(Cl)cc1
Reactant: N[C@H](CO)Cc1ccc(Cl)cc1
Reactant: CC(C)C1N[C@@H](Cc2ccc(Cl)cc2)CO1
Agent: C1COCN1
Solvent: O=S(Cl)Cl
Solvent: NCCO
Product: CC(C)C[NH2+][C@H](CCl)Cc1ccc(Cl)cc1
Product: [Cl-]

Procedure:
(1S)-1-(4-Chlorophenylmethyl)-2-hydroxyethylamine was made from (L)-4-chlorophenylalanine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(4-chlorophenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4-chlorophenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-Hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-chlorophenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(4-chlorophenylmethyl)-2-chloroethyl)-N isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4-chlorophenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](O)=O)[CH:5]=[CH:6][C:7]=1[F:8].[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=O)=[CH:22][C:17]=2[NH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][C:11]1[S:36][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[NH:14][CH:15]=[N:16][C:17]=3[CH:22]=2)=[N:25][N:26]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(F)c(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1F

Procedure:
The compound was synthesized starting from 3-(3,4-difluorophenyl)propionic acid (186 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.02 g (5.8%); MS m/z: 343.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.11 (t, 2H, 3J=7.5 Hz); 3.47 (t, 2H, 3J=7.5 Hz); 6.97-6.99 (m, 1H); 7.32-7.35 (m, 1H); 7.40-7.46 (m, 1H); 7.82 (d, 1H, 3J=8.7 Hz); 7.91 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.22 (d, 1H, 4J=1.7 Hz), 8.87 (s, 1H); HPLC (METHOD [A]): rt 13.09 min (85.7%)
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[F:12]C1C=C(C=CC=1C)N>>[ClH:1].[F:12][C:8]1[CH:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][C:7]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: Cc1ccc(NN)c(Br)c1
Agent: Cl
Product: Cc1ccc(NN)cc1F

Procedure:
3-fluoro-4-methyl-phenylhydrazine hydrochloride (21.4 g -) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 7, except using 3-fluoro-4-methylaniline as starting material. ##STR48##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([O:16]CC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:20][NH2:21])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C1CC1c1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Temperature: 95 °C
Yield: 83.9 %

Procedure:
To a room temperature solution of ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (1.0 g, 0.004 mol) in ethanol (10 mL) was added hydrazine hydrate (2 g, 0.04 mol) and the reaction mixture was then heated at 95° C. for 16 h. The mixture was then concentrated in vacuo and the solid that was obtained was washed with hexanes to afford 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (0.78 g, 82%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([OH:15])=O)([O-])=O.CN(C)C=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[Cl:34])[NH2:30]>>[NH2:7][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([Cl:34])=[C:27]([Cl:26])[CH:28]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Yield: 68.5 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (5.0 mL, 57.31 mmol), 3-nitro-4-methoxybenzoic acid (5.04 g, 25.56 mmol), dimethylformamide (0.5 mL, 6.46 mmol), and 3,4-dichloroaniline (8.3 g, 51 mmol) to afford the product (5.45 g); m.p. 179-182° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=O)[CH2:37][CH2:36]2)=[N:5][CH:6]=[C:7]([C:9](=[O:34])[NH:10][C:11]2[S:12][C:13]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[C:14]([C:16]3[S:17][CH:18]=[C:19]([Cl:21])[CH:20]=3)[N:15]=2)[CH:8]=1.ClC(OC[CH:49]([CH3:51])[CH3:50])=O.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].C([O-])(O)=O.[Na+]>C1COCC1.CN1CCOCC1.C1CCN2C(=NCCC2)CC1>[ClH:2].[Cl:2][C:3]1[C:4]([N:35]2[CH2:36][CH2:37][CH:38]([C:41]([NH:10][CH2:9][CH2:7][CH2:6][N:5]3[CH:51]=[CH:49][CH:50]=[CH:8][CH2:3][C:4]3=[N:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:43])[CH2:39][CH2:40]2)=[N:5][CH:6]=[C:7]([CH:8]=1)[C:9]([NH:10][C:11]1[S:12][C:13]([N:22]2[CH2:23][CH2:24][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:26][CH2:27]2)=[C:14]([C:16]2[S:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[N:15]=1)=[O:34]
Reactant: O=C(Nc1nc(-c2cc(Cl)cs2)c(N2CCN(C3CCCCC3)CC2)s1)c1cnc(N2CCC(C(=O)O)CC2)c(Cl)c1
Reactant: CC(C)COC(=O)Cl
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCOCC1
Product: CS(=O)(=O)N=C1CC=CC=CN1CCCNC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(N4CCN(C5CCCCC5)CC4)s3)cc2Cl)CC1
Reaction time: 1.5 h

Procedure:
To a solution of 300 mg of the compound of Example 16 in 6 ml of THF, 56 μl of N-methylmorpholine were added, 60 μl of isobutyl chloroformate was added at −15° C., and the mixture was stirred for 1.5 hours. And, to a solution of 96 mg of methanesulfonamide in 4 ml of THF, 348 μl of 1,8-diazabicyclo[5,4,0]-7-undecene was added, and the mixture was stirred at room temperature for 19 hours and at 50° C. for 2 days. The reaction solution was mixed with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The residue obtained by the evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane-THF=2:1˜0:1) and then by silica gel column chromatography (chloroform-MeOH=100:0˜100:3), and the obtained compound was dissolved in chloroform-EtOH. A 0.1M HCl-EtOAc solution was added thereto, the solvent was evaporated under reduced pressure, EtOH-diethylether was added thereto, and the thus-produced precipitate was collected by filtration to obtain 30 mg of 5-chloro-N-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-6-(4-(3-[2-(methanesulfonylimino)azepin-1-yl]propylaminocarbonyl)piperidin-1-yl)nicotinamide hydrochloride.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[SH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C(#N)C.CCOCC>[CH3:23][CH:22]([CH3:24])[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[C:11]1[CH:10]=[CH:9][N:8]=[C:7]([S:6][C:2]([F:4])([F:3])[F:1])[N:12]=1)=[O:25]
Reactant: FC(F)(F)I
Reactant: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S)n2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(SC(F)(F)F)n2)c1
Reaction time: 4 h
Yield: 73.2 %

Procedure:
2 g trifluoromethyl iodide was condensed into a solution of 0.57 g (0.002 mol) N-[2-(2-mercapto-4-pyrimidinyl)-4-methylphenyl]-2-methylpropanamide and 2.5 g triethylamine in 20 mL anhydrous acetonitrile, and the reaction mixture was stirred under a dry ice condenser while exposed to a sun lamp for 4 h. The reaction mixture was diluted with 100 mL ether and washed successively with water, 1N sodium hydroxide solution, and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 40:1 chlorobutane/ethyl acetate mixture as eluent to yield 0.52 g of the title compound as yellow crystals melting at 114°-116° C. 1H NMR (CDCl3): δ 1.21 (d,6H), 2.40 (s,3H), 2.55 (m,1H), 7.40-8.70 (5H), 10.7(s,1H,NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:7]=1.[CH3:18][I:19]>CO>[IH:19].[CH3:18][S:10][C:9](=[NH:11])[NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CI
Reactant: Cc1ccc(N2CCOCC2)c(NC(N)=S)c1
Solvent: CO
Product: CSC(=N)Nc1cc(C)ccc1N1CCOCC1
Product: I

Procedure:
A mixture of 1-(5-methyl-2-morpholinophenyl)thiourea (14 g), methyl iodide (7.9 g) in methanol (50 ml) was heated at reflux for 2 hours to give 2-methyl-1-(5-methyl-2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, m.p. 157°-159° C.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[NH:5].C(OCC)C.[OH-].[Na+].[CH2:21]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][CH3:34])[CH:29]=[C:28]([O:35][CH2:36][CH3:37])[C:25]=1[CH:26]=O)[CH3:22]>C(Cl)Cl.CCCCCC>[CH2:7]([NH:6][C:4]([NH:3][N:2]=[CH:26][C:25]1[C:24]([O:23][CH2:21][CH3:22])=[CH:31][C:30]([O:32][CH2:33][CH3:34])=[CH:29][C:28]=1[O:35][CH2:36][CH3:37])=[NH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Reactant: N=C(NN)NCc1ccccc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOc1cc(OCC)c(C=NNC(=N)NCc2ccccc2)c(OCC)c1

Procedure:
A mixture of 10.0 g. of 1-amino-3-benzylguanidine hydroiodide and 100 ml. each of diethyl ether, n-hexane and methylene chloride is shaken with 10 ml. of 5N NaOH. To this is added 8.15 g. of 2,4,6-triethoxybenzaldehyde and the mixture is shaken for 15 minutes. The organic layer is washed with saturated aqueous sodium chloride, passed through hydrous sodium magnesium silicate and concentrated to dryness under reduced pressure. The residue is crystallized from aqueous ethanol, giving the desired product as nearly colorless crystals, m.p. 140°-141° C.
Reaction SMILES: C1(=O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24]([O:36][C:37](=[O:41])[CH:38]([CH3:40])[NH2:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C(O)(C)C>[NH2:39][C@H:38]([C:37]([O:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:41])[CH3:40]
Reactant: CCCCCCCCCCCCOC(=O)C(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 60 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
A 100 ml round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (7.0 g, 0.04 mole) and isopropanol (30 g). The suspension was heated to 60° C. over 15 minutes. A mixture of DL-alanine dodecyl ester p-toluenesulfonate salt (16.9 g, 0.04 mole), triethylamine (4.0 g 0.04 mole) and isopropanol (20 g) were added dropwise over 15 minutes from an addition funnel. The reaction mixture was stirred rapidly for about 6 hrs and then cooled to room temperature. The white product was filtered, washed with chloroform (3×150 ml) and dried under high vacuum at 35° C. giving 12.5 g (73% yield) of N-D-gluconyl dodecyl alaninate with a melting point of 97°-98° C. and 98.8% purity.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH2:26]([C:27]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc2oc(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.5 g, 2.14 mmol) and triethylamine (0.90 mL, 6.42 mmol) in dichloromethane (15 mL) was added phenylacetyl chloride (0.28 mL, 2.14 mmol) dropwise, then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (537 mg, 2.83 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (3×100 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-benzylbenzoxazole-4-carboxylic acid (277 mg, 51%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 13.08 (br s, 1H), 7.91 (dd, J=7.1, 1.0 Hz, 1H), 7.85 (dd, J=7.7, 1.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 1H), 4.40 (s, 2H); MS (ESI+) m/z 254 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:25][CH2:24][CH2:23][Cl:22])[C:9]=2[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 49.3 %

Procedure:
6-tert-Butyl-4H-benzo[1,4]oxazin-3-one (81MF2248a) (2.07 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) to give the title compound (81MF2248b) (1.39 g, 49%). 1H NMR (CDCl3) δ 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCl3) δ 164.8, 146.4, 143.1, 127.9, 120.9, 116.7, 112.2, 67.8, 42.6, 38.9, 34.8, 31.6, 30.2.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)Br
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 97 and 2-bromopropane, white solid N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][N:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([NH:15][C:16]3[NH:20][N:19]=[CH:18][CH:17]=3)[N:9]=2)[CH2:5][C@@H:4]([C:21]([O:23][CH3:24])=[O:22])[CH2:3]1.[C:25](=O)([O:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])[O:26]C1C=CC([N+]([O-])=O)=CC=1>C(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>[CH3:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:9]=[C:8]([N:6]2[CH2:7][C@H:2]([NH:1][C:25]([O:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:26])[CH2:3][C@H:4]([C:21]([O:23][CH3:24])=[O:22])[CH2:5]2)[N:13]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: COC(=O)[C@H]1C[C@@H](N)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)O[C@@H](C)C(F)(F)F)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude methyl cis-5-amino-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]piperidine-3-carboxylate prepared in Step 4 of Example 6 was dissolved into CHCl3 (6 ml). To the solution was added the solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (203.3 mg) in CHCl3 and DIEA (125.0 μl). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved into EtOAc, poured into 1 M aqueous solution of NaOH and extracted with EtOAc. The extract was washed with saturated aqueous solution of NaHCO3, dried over MgSO4 and concentrated to give the crude methyl cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-[({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)amino]piperidine-3-carboxylate as a pale orange amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:52])=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:44][CH:43]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.8 %

Procedure:
3-Fluoro-5-morpholin-4-yl-benzoic acid (4.45 g, 19.8 mmol) and HBTU (8.19 g, 21.6 mmol) are stirred at room temperature in dry DMF (40 ml) for 1 hour. 4-Bromo-naphthalen-1-ylamine (4.0 g, 18.0 mmol) and diisopropylethylamine (4.8 ml, 27 mmol) are then added and the mixture is stirred at room temperature for 16 hours. The mixture is poured into ethyl acetate (300 ml) and washed with water (250 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is crystallized from ethyl acetate and hexanes to give N-(4-bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide as a pink powder (1.688 g). Mp: 195-6° C. 1H NMR 300 MHz (DMSO-d6) δ 10.5 (s, 1H), 8.19 (d, 1H, J=6 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=8.4 Hz), 7.71 (m, 2H), 7.53 (d, 1H, J=8.1Hz), 7.47 (s, 1H), 7.25 (d, 1H, J=8.4 Hz), 7.05 (d, 1H, J=12.3 Hz), 3.76 (s, 4H), 3.26 (s, 4H). MS: 429 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.O>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1[S:5][CH2:4][CH2:3][NH2:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCS
Reactant: CS(=O)(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1c(SCCN)n(Cc2ccccc2)c2ccccc12

Procedure:
2-Aminoethanethiol hydrochloride (0.419 g, 3.12 mmol) was added to a stirred suspension of sodium hydride (0.314 g, 50% in mineral oil, 6.56 mmol) in anhydrous dimethylformamide (30 ml) and after 1 hour, 1-benzyl-2-chloro-3-methylsulfonylindole (1.0 g, 3.29 mmol) was added. One half hour thereafter the solution was diluted with water, the product extracted with ether, the extract dried over sodium sulfate and evaporated in vacuo. The product was obtained as a solid, M.P.-95°-96°.
Reaction SMILES: [OH2:1].[OH2:2].O.O.[C:5]([O-:8])(=[O:7])[CH3:6].[Gd+3].[C:10]([O-:13])(=[O:12])[CH3:11].[C:14]([O-])(=[O:16])C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(Cl)(Cl)Cl.CO>[CH3:5][OH:7].[C:11]([OH:2])(=[O:1])[C:10]([OH:13])=[O:12].[OH:16][CH2:14][CH:6]([CH2:5][OH:8])[OH:12]
Reactant: O
Reactant: CC(=O)[O-]
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: [Gd+3]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)O
Product: OCC(O)CO

Procedure:
The sp3 form of ligand 11 (42 mg, 0.08 mmol) was stirred with gadolinium acetate tetrahydrate (122 mg, 0.3 mmol) and proton sponge (54 mg, 0.25 mmol) in chloroform/methanol (150 ml, v/v 1/2) for one day. The dark green reaction mixture was concentrated under reduced pressure and chromatographed through silica gel (25 cm.×1.5 cm.) which was pretreated with chloroform/triethylamine (50 ml, v/v 25/1). Chloroform/triethylamine (25/1) and chloroform/methanol/triethylamine 25/2.5/1 v/v) was used as eluents. A dark red band was first collected followed by two green bands. The last green band, which showed a clear aromatic pattern by UV/VlS, was concentrated and recrystallized from chloroform/n-hexane to give 14 mg (22%) of the Gd complex 7BFor 7BFAB MS (methanol/oxalic acid/glycerol matrix): m/e (relative intensity) 671 (155G, 58), 672 (156Gd, 78), 673 (157Gd, 94), 674 (158Gd, 100), 676 (160Gd, 64); HRMS, M+ 674 2366 (calcd. for C34H38N5158Gd 674.2368): UV/VIS (CHCl3) λmax nm (ε) 339.5 (14,850), 450.5 (36,350), 694.5 (6,757), 758.0 (23,767); IR (KBr) ν2990, 2960, 2900, 2830, 2765, 2700, 2620, 2515, 1710, 1550, 1440, 1410, 1395, 1365, 1265, 1220, 1180, 1150, 1105, 1090, 1060, 1040, 1095, 1045, 1015, 680 cm-1 ; Anal. calc. for C34H38N5Gd.(OH)2.2H2O: C, 54.89; H, 5.96; N, 9.41. Found: C, 54.49; H, 5.95; N, 8.97.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.O=[Pt]=O.C(O)C>[CH:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C1(C2CCCCC2)CC1
Yield: 57.8 %

Procedure:
To 1-phenyl-cyclopropanecarboxylic acid (0.500 g) in acetic acid (2 mL) was added Adams catalyst (0.050 g) in ethanol (0.3 mL). The reaction was left to stir for 48 hours under 5 bar of hydrogen. The reaction was filtered, washing with ethanol (10 mL) and water (10 mL). The resulting solid was collected by filtration and subsequently washed with water (10 mL) to afford the sub-titled compound (0.3 g).