Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@H:10]([O:17][S:35]([CH3:34])(=[O:37])=[O:36])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 0.44 g (1.3 mmol) of the resultant compound of Example 6 and 0.91 ml (5.2 mmol) of diisopropylethylamine in 20 ml of anhydrous dichloromethane was cooled under N2 atmosphere to -20° C. and treated with 0.2 ml (2.6 mmol) of methanesulfonyl chloride. After 20 minutes, the mixture was treated with 10 % aqueous citric acid, extracted with methylene chloride, dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography provided the desired product. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.73 (m, 1 H), 2.93 (dd, J=14, 5 Hz, 1 H), 3.06 (S, 3 H), 3.77 (s, 3 H), 4.18 (m, 1 H), 4.62 (s, 1 H), 5.47 (m, 1 H), 6.17 (dd, J=16, 2 Hz, 1 H), 6.90 (dd, J=16, 6 Hz, 1 H), 7.15-7.35 (m, 5 H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C=O>[C:34]([NH:1][C@H:2]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19](=[O:26])[C:20](=[CH:24][CH:25]=2)[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)CC[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CCC(N)=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 80.7 %

Procedure:
A solution of 30.6 g (83 m mol) of 6-[4-(L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, 56 ml (0.4 mol) of triethylamine, 19 ml (0.2 mol) of acetic anhydride, and 400 ml dimethylformamide is stirred at room temperature for 3 hrs. The reaction solution is evaporated to dryness under reduced pressure and the residue treated with ice and water. The solid is filtered, washed with water, methanol, ether and dried to give 27.6 g of 6-[4-(N-acetyl-L-glutaminylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +19° (cl, DMSO). ##EQU45##
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH2:5]O.CCOCC.P(Br)(Br)[Br:18]>N1C=CC=CC=1>[Br:18][CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCCCCC(C)=CCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC(C)=CCCBr
Temperature: 25 °C

Procedure:
A solution of 3 g. of 4-methyl-3-nonen-1-ol in a mixture of 20 ml. of ether and 1.25 ml. of pyridine under nitrogen is cooled in an ice-salt bath and stirred while 2.7 ml. of phosphorus tribromide is added slowly. The ice bath is removed and the mixture is allowed to warm to room temperature, then is heated under reflux for about 2.5 hrs. The mixture is then cooled in an ice bath while 10 ml. of water is added slowly. The layers are separated and the ether layer is washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated, giving a residue comprising 1-bromo-4-methyl-3-nonene.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23](CBr)=[CH:22][CH:21]=1>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 802.5 %

Procedure:
N-Boc-4-hydroxy piperidine (2.01 g, 1.0 mmol) was dissolved in DMF (30 mL), added sodium hydride (60%, 0.6 g, 15 mmol) in ice-bath, stirred for 30 min, added p-trifluoromethoxy benzyl bromide (3.06 g, 12 mmol), after which resumed to stir for 15 h at room temperature, added ice water (30 mL) in ice-bath to quench reaction. Extracted by dichloromethane (30 mL*2), combined organic phases, the organic phases were washed by water and saturated saline respectively, dried by anhydrous sodium sulfate, concentrated column chromatography (petroleum ether: ethyl acetate=10:1) to give 2.9 g light yellow liquid, yield was 78%.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:16][CH3:17])=[O:2]
Reactant: O=C(O)CSCCCCC1=CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CSCCCCC1=CCCC1=O

Procedure:
In the manner described in Example 39, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1[CH:17]=[CH:16][C:15]([S-:18])=[CH:14][CH:13]=1.[Na+].[H-].[Na+].C1(S)C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: [S-]c1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
5 G. of 2-amino-4-chloro-1-nitrobenzene is added to a solution of sodium phenyl mercaptide, prepared under nitrogen from 2.53 g. 57% sodium hydride and 6.2 ml. thiophenol in 20 ml. dimethylformamide, with a 10 ml. dimethylformamide rinse. The mixture is stirred under nitrogen for three hours at 20°-30°C and then diluted with water. The crude product is washed with water and hexane, then recrystallized from methanol, yielding 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:15]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH2:16]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])(/[CH:15]=[CH:16]/[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:24])[CH3:20]
Reactant: C=CP(=O)(OCC)OCC
Reactant: CCOC(=O)CNc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cccc(/C=C/P(=O)(OCC)OCC)c1
Temperature: 95 °C
Reaction time: 20 h
Yield: 60.5 %

Procedure:
A solution of ethyl N-(3-bromophenyl)glycinate (Example B) (4 g, 15.5 mmol), diethyl vinylphosphonate (4.92 g, 30 mmol), and bis(triphenylphosphine) palladium (II) chloride (1 g) in dimethylformamide (15 ml) and triethyamine (5 ml) is immersed in an oil bath (95° C.) and stirred for 20 hours. After cooling the dimethylformamide is removed in vacuo and the oily brown residue is dissolved in a saturated solution of sodium chloride and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered and evaporated to give a residue (3.2 g). Purification is accomplished by silica gel chromatography (ethyl acetate as eluant, a single fluorescent spot on tlc, Rf=0.5 (ethyl acetate)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:38]1[CH2:39][CH2:40][C:35]2([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=3[O:42][CH2:41]2)[CH2:36][CH2:37]1)=[O:26]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 99.6 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.347 mmol) obtained in Example 66, step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.079 g, 0.382 mmol), the title compound (0.195 g, 100%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccn1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccn1)C2
Yield: 95.2 %

Procedure:
A mixture of 4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.28 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.41 ml), water (0.41 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 75) (0.37 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Cl)=[CH:9][CH:8]=1.C(O)C>O>[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:8]=1
Reactant: CS(=O)[O-]
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 1 L volume four-necked flask, sodium methanesulfinate (31.3 g), 4-fluorophenacyl chloride (21-b) (4.8.1 g), and ethanol (300 ml) were added under a nitrogen atmosphere, and heated to reflux for 1 hour. After the mixture was cooled to room temperature, water (500 ml) was added. The precipitated solids were collected by filtration, washed with water, and dried. The solids were dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization (hexane-ethyl acetate) to give 51.9 g of 1-(4-fluorophenyl)-2-methylsulfonylethan-1-one (7-2-3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22].CO>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)=CCBr
Reactant: O=C1C=C(NCc2ccc(Cl)nc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(CC=C(Cl)Cl)Cc2ccc(Cl)nc2)CO1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
350 mg (1.56 mmol) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (Ia-1; cf. EP 0539588 A1) and 124 mg (3.12 mmol) of a 60% dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 3 h. After cooling to room temperature, 592 mg (3.12 mmol) of 3-bromo-1,1-dichloroprop-1-ene (cf. WO 8800183 A1) are added and the mixture is heated under reflux for a further 5 h. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 264 mg (50% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](3,3-dichloroprop-2-en-1-yl)amino]furan-2(5H)-one.
Reaction SMILES: [F:1][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:2]([F:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)F
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Product: CCOC(=O)C(C)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Ethyl 2-fluoropropionate and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one were treated in the same manner as in Reference Example 7, and the residue thus obtained was purified by a column chromatography (eluant: ethyl acetate/toluene=1/4) to obtain ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Mg]Cl)[CH3:16]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:14])[C:15]#[CH:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Mg]Cl
Reactant: CC(C)(C)OC(=O)n1cccc1C=O
Solvent: C1CCOC1
Product: C#CC(O)c1cccn1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-formyl-pyrrole-1-carboxylic acid tert-butyl ester (23.4 g, 120 mmol) (prepared as described below) in dry THF (275 mL) was added ethylmagnesium chloride (Aldrich, 0.5 M solution in THF, 480 mL, 240 mmol) dropwise at −65° C. and the reaction mixture was stirred at the same temperature for 0.5 hour. The cooling bath was then removed and the reaction mixture was stirred for another 1 hour to give a clear solution. The reaction was quenched by slowly adding EtOH (60 mL) and a saturated aqueous solution of NH4Cl (200 mL) at 5° C., and extracted with ethyl acetate (3×250 mL). The combined organic extracts were successively washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage, 75-S, 92/8 hexanes/ethyl acetate) purification of the crude oil afforded 2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester as a light amber oil. (Yield 25.0 g, 94.2%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].C(N(CC)CC)C.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(OCC)(=O)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:8][C:1](=[O:9])[C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 97.5 %

Procedure:
10.45 g of D-leucic acid was dissolved in 150 ml of ethyl acetate. 11 ml of triethylamine and 18.78 g of 4-nitrobenzyl bromide were added and the mixture was heated under reflux for 3 hours. The mixture was washed in sequence with water, 10% citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation, there were obtained 20.6 g (98%) of D-leucic acid 4-nitrobenzyl ester as a gum. Rf (chloroform) 0.37.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:16]([C:19]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([S:16]([C:19]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)([CH3:20])[CH3:21])(=[O:17])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Phenyl chloroformate (0.635 mL, 5.06 mmol) was added to 4-[4-(2-cyclopentylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.5 g, 3.37 mmol) and sodium hydrogen carbonate (0.425 g, 5.06 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.30 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCn1c(-c2nc(-c3ccccc3)cnc2N)nc2cnccc21
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
5-Bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.038 g, 0.12 mmol) (see Example 2), phenyl boronic acid (0.034 g, 0.27 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.009 g, 0.012 mmol), potassium carbonate (0.045 g, 0.32 mmol), and an 8:1 mixture of acetonitrile:water (3 mL) were combined and subjected to 150° C. for 5 minutes in a SmithSynthesizer microwave. The resulting heterogeneous, black mixture was filtered through a celite pad, which was then washed with ethyl acetate and water. The mixture is extracted into ethyl acetate (×3) and washed with water and saturated sodium chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated. The residue is purified on silica, eluting with 2.5% methanol in chloroform to afford the title compound (0.009 g, 23%).
Reaction SMILES: C(O)C.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:30]CC2C=CC=CC=2)=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:13])(=[O:6])[CH3:5]>[Pd].O1CCCC1>[C:4]([C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:13])(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethanol (6 mL) and tetrahydrofuran (72 mL) were added to 5-acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (602 mg, 1.25 mmol) and 5% palladium on carbon (60 mg), and the mixture was hydrogenated at room temperature for 30 minutes. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure and the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (230 mg, 47.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.O.[NH2:16][NH2:17]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
To a solution of 2,4-dichloro-6-phenylpyrimidine (224 mg, 1 mmol) in 1 mL of 1,4-dioxane was added 300 uL of hydrazine hydrate. Stirring was continued at room temperature and the reaction monitored by thin layer chromatography (30% ethyl acetate/hexanes). When the starting material was consumed, 2 mL of water was added and the resultant precipitate was collected on a filter to afford 2-chloro-4-hydrazinyl-6-phenylpyrimidine as a yellow solid. The damp solid was suspended in 2 mL of ethanol, to which was added 220 mg of 4-trifluoromethoxybenzaldehyde. Within 5 minutes the solution became clear and then reprecipitated material. The product, 2-chloro-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidine (XX), was collected by filtration and dried to afford 150 mg of a solid. ESI/MS 392.973, 395.002 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH:29]=[CH:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:26][CH:27]=[CH:28][CH2:29][CH2:30]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C1=CCNCC1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CC=CCC4)cc3c2)cc1

Procedure:
The product from Example 1C and 1,2,3,6-tetrahydropyridine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 329 (M+H)+;
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.[F:13][CH2:14][C:15](=O)[CH2:16][F:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:13][CH2:14][CH:15]([N:1]1[CH2:2][CH:3]([NH2:5])[CH2:4]1)[CH2:16][F:17]
Reactant: O=C(CF)CF
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NC1CN(C(CF)CF)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (0.256 g) and 1,3-difluoropropan-2-one (0.154 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.473 g) and the reaction was allowed to stirred at room temperature. After 16 hours, the reaction was quenched with saturated NaHCO3 solution (10 mL) and extracted into dichloromethane (25 mL). The organic layer was dried and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.5% to 3.5% methanol/dichloromethane followed by treatment with HCl (4.0M in dioxane, 3 mL) and methanol (0.5 mL) for 2 hours gave the title compound after concentration.