Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>CC(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:1])=[O:26]
Reactant: CNc1ccc(O)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: CN(C(=O)CCCCCBr)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
A solution of 69 g (0.56 mol) of 4-methylaminophenol and 73.9 g (0.61 mol) of N,N-dimethylaniline in about 1.5 L of acetone was stirred mechanically under nitrogen in a 3 L flask. A solution of 119.6 g (0.56 mol) of 6-bromohexanoyl chloride in 100 mL of acetone was added as rapidly as the exotherm would allow at about 40° C. The reaction was refluxed for 2 hours on a steam bath, allowed to cool and poured into a solution of about 560 mL of 2N HCl in 2 L of ice. The aqueous solution was extracted twice with ethyl acetate and the ethyl acetate extracts were combined and dried over magnesium sulfate. The ethyl acetate solution was stripped to dryness under high vacuum to yield 143.4 g (85%) of greenish-white, low melting, solid 6-bromo-N-(4-hydroxyphenyl)-N-methylhexanamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]([O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1)(=[O:24])[CH3:23].[CH3:42]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:22]([O:25][C@@H:26]1[CH2:30][N:29]([C:19](=[O:21])[CH2:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[O:10][C:11]=3[CH:17]=2)[C@H:28]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:42])=[O:38])=[CH:40][CH:41]=2)[CH2:27]1)(=[O:24])[CH3:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(=O)O[C@@H]1CN[C@H](COc2ccc(C(=O)[O-])cc2)C1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC(C)=O)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 96.8 %

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (318 mg, 1.13 mmol), 4-((2S,4S)-4-acetoxy-2-pyrrolidinylmethoxy)benzoate (330 mg, 1.13 mmol), EDC•HCl (325 mg, 1.70 mmol), HOBt (230 mg, 1.70 mmol) and triethylamine (1.18 ml, 8.50 mmol) was stirred at room temperature for 21 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 40 g), whereby from chloroform/acetone (20/1) eluate fractions, the title compound (610 mg, 97%) was obtained as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)Nc2ccc(OC)nc2)c1
Yield: 98.9 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylacetyl chloride (4.8 g, 26.0 mmol) and 5-amino-2-methoxypyridine (3.23 g, 26.0 mmol) to afford the title compound (7.0 g, 99% yield): ES-MS (m/z) 272.
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27][CH2:26]2)[N:19]=1)(=[O:4])(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.NC>C1COCC1.O>[CH3:45][NH:41][C:31]([CH:28]1[CH2:27][CH2:26][CH:25]([NH:24][C:20]2[N:19]=[C:18]([N:13]3[C:14]4[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:1](=[O:3])(=[O:4])[NH2:2])[CH:17]=[CH:16][CH:15]=4)[CH:11]=[CH:12]3)[CH:23]=[CH:22][N:21]=2)[CH2:30][CH2:29]1)=[O:33]
Reactant: NS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
4-{4-[4-(3-Sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexane-carboxylic acid (75 mg, 0.158 mmol), BOP (105.08 mg, 0.238 mmol), DIEA (55 μL, 0.317 mmol), and H2NMe (0.120 μL, 20% soln. in THF, 0.238 mmol) were combined in THF and allowed to stir at RT overnight. Water was then added to the reaction mixture and the mixture sonicated, and the solid filtered, washed with water, dried and recrystallized to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methylamide (Compound 319, 53.3 mg, 69.3%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:24]=[C:23]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[CH:42]=2)[C:20]=1[C:21]#[N:22]>ClCCl.C(#N)C>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([C:41]2[CH:42]=[C:43]([NH:47][C:9](=[O:11])[CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:44]=[CH:45][CH:46]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[N:26]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a cold (0° C.) solution of 3-(1-piperidinyl)-propanoic acid (0.676 g, 3.601 mmol) in dichloromethane was added oxalyl chloride (0.471 mL, 5.401 mmol) and stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure. The residue was added to the solution of 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)nicotinonitrile (starting compound 2, 1.500 g, 3.601 mmol) in acetonitrile (3 mL), and the resulting mixture was stirred at 0° C. for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was carried out by silica gel column chromatography (chloroform/methanol=10/1) to give N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white solid (0.860 g, yield 45%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]C(O)=O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25]C=1.Cl.C(N=C=NC(C)(C)CC)C.[OH:51]N1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[O:4]=[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:2][NH:1][C:36](=[O:51])[C:33]1[CH:32]=[CH:31][C:30]([O:29][C:22]2[CH:23]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:35][CH:34]=1
Reactant: NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1ccc(Oc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1
Reaction time: 6 h

Procedure:
A mixture of 2-amino-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-yl]-acetamide (HCl salt, 0.0600 g, 0.186 mmol), (4-benzyloxy-phenyl)-acetic acid (0.0470 g, 0.190 mmol), ethyldimethylpropylcarbodiimide hydrochloride (0.0430 g, 0.225 mmol), N-hydroxybenzotriazole (0.0300 g, 0.222 mmol), N-methyl morpholine (0.0460 g, 0.455 mmol) in 2 mL of DMF was stirred for 6 hours. The mixture was concentrated under reduced pressure, the residue dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.87 (t, 2H, J=6.78), 2.95 (s, 2H), 4.20 (d, 2H, J=5.76), 4.48 (t, 2H, J=6.78), 6.99–7.47 (m, 9H), 7.65 (m, 1H), 7.96 (m, 2H), 8.27 (m, 1H), 8.83 (m, 1H), 10.13 (s, 1H); MS (DCI/NH3) m/z 484 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[C:6]([C:19]2[CH:20]=[C:21](C=CC(Cl)=O)[CH:22]=[CH:23][CH:24]=2)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.Cl.[CH2:31]1C[O:34][CH2:33][CH2:32]1>>[CH2:1]([NH:3][C:33](=[O:34])[C:32]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:6]2[C:5]([CH3:4])=[CH:14][C:13]3[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)[CH:20]=1)=[CH2:31])[CH3:2]
Reactant: Cc1cc2c(cc1-c1cccc(C=CC(=O)Cl)c1)C(C)(C)CCC2(C)C
Reactant: CCN
Reactant: C1CCOC1
Agent: Cl
Product: C=C(C(=O)NCC)c1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of THF are introduced into a round-bottomed flask and 2.8 ml (35 mmol) of ethylamine solution (70%) are added. A solution of 1.2 g (3.2 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacryloyl chloride in 40 ml of THF is added dropwise and the mixture is stirred at room temperature for one hour. The reaction medium is acidified with hydrochloric acid and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 817 mg (68%) of N-ethyl-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-phenylacrylamide are collected, with a melting point of 158-9° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.[OH-].[Na+].C(O)(=[O:41])C>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:21])=[O:41])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (120 mg) in dimethyl sulfoxide (2.5 ml) was added 30% hydrogen peroxide (0.26 ml), and the mixture was stirred at room temperature for 15 minutes. Then, to the reaction mixture was added a 5N sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added acetic acid. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 127 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][O:22]CC3C=CC=CC=3)=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:21][OH:22])=[O:20])[O:16][C:15]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(NOCc1ccccc1)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: O=C(NO)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
To a mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-N-benzyloxy-2-oxo-5-oxazolidinecarboxamide (Step 1, 300 mg, 0.722 mmol) in methanol (28.8 mL) was added 5% palladium-on-carbon (77 mg) under nitrogen. The resulting mixture was degassed and stirred under a hydrogen atmosphere (balloon) for 1 hour. The catalyst was then removed by filtration through Celite, rinsing with methanol (60 mL), and the filtrate was concentrated under reduced pressure. Trituration of this residue with (5% methanol/methylene chloride)/diethyl ether gives the title compound, mp 141-143° C.; MS (ESI+) for C14H16FN3O5 m/z 326 (M+H)+; [α]25D=−70° (c 0.99, DMSO).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[N+]([O-])=O)#[N:12]>CS(C)=O>[C:11]([C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[N:12]
Reactant: N#Cc1ccc([N+](=O)[O-])c(C#N)c1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C#N)cc2C#N)cc1

Procedure:
The sodium salt of p-hydroxybenzonitrile (1 ml) was heated with 2,4-dicyanonitrobenzene (1 mole) in dry dimethyl sulphoxide for 18 hours at 105° to form 4-(2,4-dicyanophenoxy) benzonitrile m.p. 222°-223°, which was recovered by dilution with water, and purified by crystallisation from acetic acid. This compound was hydrolysed with 60 w/w aqueous sulphuric acid (25 pts.) mixed with glacial acetic acid (10 parts), refluxing the mixture for 24 hours; on cooling, diphenyl ether 2,4,4'-tricarboxylic acid separated. The tricarboxylic acid was cyclized either (a) by heating to 300° for 5 minutes, or (b) dissolving in concentrated sulphuric acid, heating at 100° for 3 hours and subsequently diluting with water. The solid resulting from (a) or from (b) was recrystallised from dimethyl formamide to give xanthone-2,7-dicarboxylic acid identical with that prepared by Methods (i) and (ii).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Na+].CC(O)=O>CCO>[CH3:15][N:14]1[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2ccncc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(C(=O)O)cc2ccncc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
NaH (60% dispersion in mineral oil, 51 mg, 1.26 mmol) was added to a solution of 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (200 mg, 1.05 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was stirred for 1 h, before being treated with MeI (79 μL, 1.26 mmol) and allowed to warm to 20° C. After 16 h, saturated aqueous NH4Cl (10 mL) was added, then the suspension was stirred vigorously for 1 h. The mixture was partitioned between H2O (10 mL) and EtOAc (30 mL), then the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated, then the residue was purified by flash chromatography (IH-EtOAc, 1:1) to provide 1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester: δH (CDCl3): 1.45 (t, 3H), 4.20 (s, 3H), 4.42 (q, 2H), 7.25 (s, 1H), 7.58 (d, 1H), 8.36 (d, 1H), 8.95 (s, 1H). A solution of this ester (36 mg, 180 μmol) in EtOH (3 mL) was treated with 2 M NaOH (270 μL, 540 μmol), then the mixture was stirred at 60° C. for 4 h. On cooling to ambient temperature, the mixture was treated dropwise with dilute AcOH to adjust the pH to 4. The resulting suspension was allowed to stand at ambient temperature for 7 d, then the precipitated solid was collected, washed with H2O, and dried to furnish the title compound: δH(CD3OD): 4.23 (s, 3H), 7.20 (s, 1H), 8.01 (d, 1H), 8.17 (d, 1H), 9.12 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]([CH2:44][OH:45])[C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@@H:35]([CH2:44][OH:45])[C@@H:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1>O1CCCC1.C(OCC)(=O)C>[I:25][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCI)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a stirred solution of triphenylphosphine (1.178 g, 4.49 mmol) and imidazole (0.611 g, 8.98 mmol) in tetrahydrofuran (10 mL) at 0° C. was added iodine (1.292 g, 5.09 mmol). The resulting dark mixture was stirred at 0° C. After 5 minutes, tert-butyl 4-(2-(2-hydroxyethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (1.19 g, 2.99 mmol) was added as a solution in tetrahydrofuran (5 mL). The mixture was then warmed to room temperature and stirred for 1 hour. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, saturated sodium thiosulfate, water, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 1:2 ethyl acetate:hexanes, giving the desired product (1.50 g, 99%) as an orange foam. 1H NMR (DMSO-d6) δ 7.59-7.54 (m, 1H), 7.45-7.38 (m, 2H), 5.45-5.37 (m, 1H), 3.98-3.85 (m, 2H), 3.73-3.61 (m, 1H), 3.35-3.27 (m, 5H), 3.19-3.03 (m, 1H), 3.02-2.82 (m, 2H), 1.92-1.84 (m, 2H), 1.45-1.34 (m, 11H); ESI-MS (m/z, %): 530 (M+Na, 6), 452 (25), 279 (100).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]CC)=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[I-].[Na+]>C(#N)C>[Br:1][CH2:2][C:3]([O-:5])=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: O=C([O-])CBr

Procedure:
The bis(methylhydrazine)terpyridine of Part A (3.50 g, 82 mmol), ethyl bromoacetate (13.2 mL, 820 mmol), 2,6-lutidine (9.6 mL, 820 mmol), and sodium iodide (0.35 g, 2 mmol) were added to 350 mL of acetonitrile, and the solution was refluxed under N2 for 48 hours, when an additional 4.1 mL (370 mmol) of ethyl bromoacetate and 4.8 mL (410 mmol) of 2,6-lutidine were added. The reaction solution was refluxed for an additional 48 hours, and cooled. A copious amount of white salt resulting from excess bromoacetate and lutidine was filtered and discarded. The filtrate was concentrated, and the concentrated material was dissolved in dichloromethane, and extracted two times with dilute aqueous sodium chloride. The organic phase was concentrated under high vacuum until free of odors of bromoacetate and lutidine. The crude oil was purified on a Woelm silica gel column (36×2 in.). The column was eluted initially with 100% dichloromethane followed by 50/1 dichloromethane/acetone, with gradual increase of the concentration of acetone to 25/1 dichloromethane/acetone. Concentration of purified fractions gave 2.91 g (46%) of light straw-colored oil. A fraction of the purified oil, upon standing at room temperature, crystallized, and after trituration with methanol gave a white solid, mp 100°-103° C. Anal. calcd for C40H49N7O9 : C, 62.24; H, 6.40; N, 12.70. Found: C, 62.31; H, 6.32; N, 12.69. The NMR and IR spectra were consistent with the assigned structure, and the product was homogeneous by TLC.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH2:9]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH:9][CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: N#CCNc1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 30 %

Procedure:
Chloroacetonitrile (45.3 grams (g)) and 97.2 g of 3,4-dichloroaniline were heated with stirring in a 250 milliliter (ml) round-bottomed three-necked flask at about 120°-125° C. for 2 hours. The reaction mixture was cooled, then diluted with methylene chloride and then filtered to remove the 3,4-dichloroaniline hydrochloride (52.4 g) which had formed. The filtrate was concentrated to dryness under vacuum, leaving a black gummy residue that crystallized on cooling. The residue was put in solution in hot toluene, the solution was then cooled and filtered, which gave 38.3 g of crude product. Recrystallization from cyclohexane gave 36.2 g of purified 3,4-dichloroanilinoacetonitrile as pink crystals, having a melting point (m.p.) of 95°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25](SC)=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32].C(O)(C(F)(F)F)=[O:34].OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25]([OH:34])=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32]
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(SC)n(C)c4=O)cc3F)c2cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2nccc(Oc3ccc(-c4cnc(O)n(C)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 1, 1.048 g, 2.3 mmol) was dissolved in CH3CN (15 mL) and TFA (1.7 mL) and cooled to 0° C. Urea hydrogen peroxide (290 mg, 3.09 mmol) was added, and the reaction was stirred for 5 min. trifluoroacetic anhydride (0.43 mL, 3.09 mmol) was added, and the reaction was warmed to RT and stirred for 40 min. The mixture was quenched with H2O (10 mL) and EtOAc (25 mL) and allowed to stand overnight. Saturated NaHCO3 (10 mL) and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (EtOAc→1:1 EtOAc/MeOH) to give title compound. MS (ESI pos. ion) m/z: 411. Calc'd for C21H17FN3O5: 410.39.