Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][C:28]3OC[CH2:31][O:32][C:27]=3[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=NC(SC)=NC=1.[CH3:35][C:36]1[C:37]([C:42]([OH:44])=O)=[N:38][CH:39]=[CH:40][N:41]=1.COC1C=C(C=CC=1)C=O>>[CH3:35][C:36]1[C:37]([C:42]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][CH:28]=[C:27]([O:32][CH3:31])[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:44])=[N:38][CH:39]=[CH:40][N:41]=1
Reactant: Cc1nccnc1C(=O)O
Reactant: CSc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nccnc2C)c1

Procedure:
This was prepared in the same manner as the product from example 242 using 3-methylpyrazine-2-carboxylic acid (JOC, 2002, p556) and 3-methoxybenzaldehyde as the acid and aldehyde components to give the title compound as a foam, 0.5 g, (63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].O>O1CCCC1.ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)=[O:29]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A solution of 5.58 g (29 mmol) 1-(4-aminophenyl)-4-methylpiperazine and 3.77 g (29 mmol) N-ethyldiisopropylamine in 30 ml tetrahydrofuran was cooled in an ice bath and 3.518 g (29 mmol) pivaloyl chloride were added dropwise. The suspension was stirred for 18 h at room temperature. Water (30 ml) and dichloromethane (50 ml) were added and the organic layer was separated. The aqueous phase was re-extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated to give a white solid. Washing with a mixture of hexane and ethyl acetate (4:1) yielded 6.69 g (83%) of a white crystalline compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1ccc(CBr)nc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 6-methylnicotinonitrile (1.0 g, 8.47 mmol) in 1,2-dichloroethane (30 mL) was added N-bromosuccinimide (NBS; 1.52 g, 8.54 mmol) and followed by 2,2′-azobis(isobutyronitrile) (AIBN; 0.14 g, 0.85 mmol) at RT. The reaction mixture was then heated to 80° C. and stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10% EtOAc/Hexane) afforded compound I-4 (0.6 g, 3.05 mmol, 36%) as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.67-7.62 (m, 2H), 7.21 (dd, J=9.0, 2.0 Hz, 1H), 4.44 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)c(F)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(Br)cc1F
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylbenzoic acid (i-2a) (1.87 g, 8 mmol) in CH3OH (50 mL) at 0° C. was added SOCl2 (6 mL, 80 mmol) dropwise. Then the mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with H2O, brine, dried over anhydrous Na2SO4, and concentrated. The resulting crude solid was washed with PE to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, d), 7.37 (1H, d), 3.92 (3H, s), 2.39 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:12])[N:7]([C:24]2[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][CH2:36][OH:37].CCN(CC)CC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:12])[N:7]([C:24]2[CH:25]=[C:26]([CH2:30][C:31]([NH:34][CH2:35][CH2:36][OH:37])=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)O)c2)n1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)NCCO)c2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 2-(3-(3-t-butyl-5-(3-(naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)acetic acid (200 mg, 0.43 mmol) in THF (10 mL) was added 2-amino-ethanol (260 mg, 4.3 mmol) and Et3N (0.5 mL), then this mixture was heated to 40° C. and stirred overnight. After removal of the solvent, this mixture was extracted with EtOAc and washed with 1N HCl aqueous solution and the organic layer was dried over Na2SO4. After removal of the solvent, a crude product was obtained, which was purified by preparative HPLC to afford 2-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)pyrazol-1-yl]phenyl}-N-(2-hydroxy-ethyl)acetamide (104 mg, 50% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.81 (s, 1H), 8.12 (m, 1H), 7.98 (d, J=9.3 Hz, 1H), 7.92-7.87 (m, 2H), 7.61 (d, J=8.1 Hz, 1H), 7.53-7.49 (m, 2H), 7.47-7.38 (m, 4H), 7.29 (d, J=7.5 Hz, 1H), 6.39 (s, 1H), 3.49 (s, 2H), 3.35 (t, J=6.0 Hz, 2H), 3.07 (q, J=6.0 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 487 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([O:23]C)=[O:22])[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([OH:23])=[O:22])[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
Methyl 8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoline-2-carboxylate (0.84 g, 2.62 mmol) was dissolved in THF (25 mL), NaOH 1.00 N (2.62 mL, 2.62 mmol) was added, and the resulting solution was stirred at RT for 3 h, then at 40° C. for 2 h. The reaction mixture was then concentrated in vacuo the pH was adjusted to <4 using 5 N HCl. A precipitate formed and was isolated by filtration to give 8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoline-2-carboxylic acid (647 mg, 2.11 mmol, 80% yield) as a dark-brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.71 (br. s., 1H), 12.72 (br. s., 1H), 8.59 (d, J=8.4 Hz, 1H), 8.26 (d, J=7.4 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.30-7.34 (m, 1H), 7.04 (br. s., 1H), 3.46 (t, J=6.5 Hz, 2H), 2.90 (t, J=6.7 Hz, 2H). m/z (ESI, +ve ion) 308.0 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1.N1CCCC1>C(Cl)Cl>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1cccc(OC2CCN(C(=O)Cl)C2)c1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a stirred solution of 9.5 g (0.097 mole) of phosgene in 100 ml of methylene chloride under nitrogen gas was added dropwise 23.84 g (0.088 mole) of 1-benzyl-3-(3-methylphenoxy)pyrrolidine in 50 ml of methylene chloride. When the addition was complete, thin-layer chromatography showed no starting pyrrolidine remained. The reaction mixture was stirred overnight and concentrated in vacuo to give an oil. The oil was triturated with 30/60 petroleum ether to remove benzyl chloride. A white solid, 14.4 g of crude product was obtained. A portion was recrystallized from hexane.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[C:21]([C:25]1[O:29][C:28]([C:30]2[C:31]([NH2:40])=[N:32][CH:33]=[C:34]([Sn](C)(C)C)[N:35]=2)=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].[Cl-].[Li+]>CC(C)CC(O)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>[NH2:40][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:6]([CH3:7])[N:5]=[C:4]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[N:3]=2)=[N:35][C:30]=1[C:28]1[O:29][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:26][N:27]=1
Reactant: CC(C)(C)c1nnc(-c2nc([Sn](C)(C)C)cnc2N)o1
Reactant: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)CC(C)O
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 140 °C
Yield: 79.3 %

Procedure:
To a stirred suspension of tert-butyl 4-(5-bromo-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (2700 mg, 7.82 mmol) and 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(trimethylstannyl)pyrazin-2-amine (2988 mg, 7.82 mmol) in 4-methyl-2-pentanol (28 mL) were added lithium chloride (995 mg, 23.46 mmol) and bis(triphenylphosphine) palladium (II) chloride (220 mg, 0.31 mmol). The mixture was degassed with argon and heated at 140° C. for 2 h. The reaction was cooled down and the resulting precipitate was collected by filtration, washed with isopropanol (25 mL), water (25 mL) and dried under suction. The isopropanol organic fraction was concentrated and the precipitate formed was collected and combined with the main precipitate affording tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (3.0 g, 79%): 1H NMR Spectrum: (DMSO-d6) 1.41 (9H, s), 1.45 (9H, s), 1.50-1.68 (2H, m), 1.95 (3H, dd), 2.78-3.05 (1H, m), 3.96 (3H, d), 4.21 (3H, s), 8.86 (1H, s); Mass Spectrum [M+H]+=484.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH:28]=O)[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>C1CCCCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH:28]2[O:4][CH2:1][CH2:2][O:3]2)[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCO
Reactant: CC(C)(C)c1cccc(CCC=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)(C)c1cccc(CCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Ethylene glycol (15 mL, 0.27 mol, 1.2 eq), paratoluene sulfonic acid (430 mg, 1% w/w) and cyclohexane (50 mL) were charged into a 1 L three-necked round-bottom flask, equipped with a dean and stark, a reflux condenser and a mechanical stirrer. 3-(3-tert-butylphenyl)propanal (50.6 g, gc purity of 85%, 0.22 mol) was added dropwise at ambient temperature. After stirring for 2 h at reflux, the reaction mixture was cooled to ambient temperature and washed twice with water (50 mL), saturated aqueous NaHCO3, dried over magnesium sulphate and concentrated to give 2-[2-(3-tert-butylphenyl)ethyl]-1,3-dioxolane in the form of a pale yellow coloured oil (60 g, gc purity>84%; yield>95%). The material was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:26](OC)([O:29]C)[O:27]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:26]([OH:29])[OH:27])[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CC(C)c1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)c1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-iso-propyl-2,3-dihydro-benzofuran (0.8 g, 3 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 6 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3-dimethyl-7-iso-propyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:8]=[N:9][CH:10]=2)[C:4](=[S:7])[NH:5][N:6]=1.[CH3:11][O-].[Na+].CI>C(O)C>[CH3:11][S:7][C:4]1[N:3]2[CH:8]=[N:9][CH:10]=[C:2]2[CH:1]=[N:6][N:5]=1
Reactant: C[O-]
Reactant: S=c1[nH]ncc2cncn12
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nncc2cncn12
Temperature: 0 °C

Procedure:
To 1.52 gm. of imidazo[1,5-d]-as-triazine-4(3H)-thione in 25 ml. of ethanol is added 0.54 gm. of sodium methoxide. Then 0.63 ml. of methyl iodide is added and the mixture is stirred and heated under reflux for 80 minutes. The mixture is cooled to 0° C. giving a precipitate which is collected. This product is recrystallized from 25 ml. of methanol and treated with charcoal giving the desired product, m.p. 186°-190° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[NH:10][C:7](=[O:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[C:18]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1cccs1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cccs1
Yield: 55 %

Procedure:
from thiophen-2-yl acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 55%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[NH2:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 102.3 %

Procedure:
To the product from Step A (5.08 g) in MeOH (75 mL) was added 10% Pd/C (900 mg) in a Parr bottle. This was then shaken on a Parr shaker under 50 psi H2 at room temperature for 4.5 hours. The catalyst was filtered through celite, the solvent removed under vacuum and the crude product purified by reverse phase preparatory HPLC to yield 4.5 g of p-amino-phenylalanine methyl ester, N-isobutyl carbamate, trifluoroacetate as a hygroscopic yellow solid.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([CH3:26])[C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]([CH3:26])[C@H:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN[C@@H](CCSC)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Condensation of BocLeuOH (5.00 g.) and HMeMetNH2 (4.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocLeu-MeMetNH2 in 81% yield. De-t-butoxycarbonylation of BocLeu-MeMetNH2 (5.96 g.) using hydrogen chloride in ethyl acetate gave HLeu-MeMetNH2 hydrochloride salt in 98% yield. Condensation of BocDTrpOPFP (7.56 g.) and HLeu-MeMetNH2 hydrochloride salt (5.00 g.) by the activated ester method gave BocDTrp-Leu-MeMetNH2 in 56% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeMetNH2 (2.0 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeMetNH2 trifluoroacetate salt in 79% yield.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(Nc2ccc3ccccc3c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Nc2ccc3ccccc3c2)c1C(=O)O
Yield: 93 %

Procedure:
A mixture of 3-(naphthalen-2-ylamino)phthalic acid dimethyl ester (0.75 g, 2.2 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 3 hours. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.64 g in 93% yield: 1H NMR (DMSO-d6) δ 7.29-7.54 (m, 7H), 7.68 (d, J=8.1 Hz, 1H), 7.76-7.81 (m, 2H), 8.16 (br, 1H).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]=1[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=O)C.[OH-].[Na+].Cl.C(=O)=O>C(OCC)(=O)C>[C:17]([CH2:16][CH2:15][C:14]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c1CCCC2
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)CCc1c[nH]c2c1CCCC2

Procedure:
Crude 2-ethoxycarbonyl-3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydroindole (30 g) and 80 mL of 5 N sodium hydroxide were refluxed for 80 min in a round bottom flask heated in an oil bath and equipped with magnetic stirring. The heater was turned off, but the flask was left in the hot bath, and about 44 mL of 10 N hydrochloric acid was cautiously added via a dropping funnel through the reflux condenser with vigorous stirring. When approximately 80% of the acid had been added, a large amount of carbon dioxide was evolved. The addition was continued until the pH was 2-3. The mixture was cooled in a water bath, and 200 mL of ethyl acetate was added to dissolve the oil that was present. The ethyl acetate layer was isolated and was washed 3 times with 50 mL of water each time, twice with 30 mL of brine each time, and was dried over 5 g of anhydrous sodium sulfate and was evaporated to give 15.5 g (80%) yield of crude 3-(2-carboxyethyl)-4,5,6,7-tetrahydroindole as a very dark sticky syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: Cc1ccc(CC(=O)NC(C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure B′ and using 4methylphenylacetic acid (Aldrich) and D,L-alanine isobutyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 102°-104° C. The reaction was monitored by tlc on silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(Nc2nccc(C(C)O)n2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(=O)c1ccnc(Nc2cc(C)cc(Br)c2)n1

Procedure:
1-(2-((3-Bromo-5-methylphenyl)amino)pyrimidin-4-yl)ethanol (3.27 g, 10.59 mmol) was dissolved in dichloromethane (14 mL). Dess-Martin Periodinane (9.0 g, 21.2 mmol) was added, and the resultant suspension was stirred vigorously for 14 h at room temperature. The mixture was diluted with saturated aqueous sodium bicarbonate and sodium thiosulfate. The heterogeneous mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10-40% ethyl acetate/hexanes) to afford 1-(2-((3-bromo-5-methylphenyl)amino)pyrimidin-4-yl)ethanone as a yellow solid. MS ESI calc'd. for C13H13BrN3O [M+H]+ 306, 308. found 306, 308. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=4.9 Hz, 1H), 7.93 (s, 1H), 7.35-7.30 (m, 2H), 7.05 (s, 1H), 2.71 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]1([NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]1[N:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:2]2=[N:3][C:4]([O:11][CH3:12])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: O=C(CCCCCCl)Nc1ccccc1
Product: COc1ccc2nc(CCCCCCl)n(-c3ccccc3)c2n1
Yield: 57 %

Procedure:
Method B applied to 2-chloro-6-methoxy-3-nitropyridine (94 mg, 0.5 mmol) and 6-chlorohexanoic acid phenylamide (113 mg, 0.6 mmol) afforded the title compound as viscous oil (94 mg, 57%). 1H NMR (DMSO) δ 1.34-1.41 (m, 2H), 1.62-1.71 (m, 6H), 2.78 (t, J=6.8Hz, 2H), 3.73 (s, 3H), 6.73 (d, J=8.6Hz, 1H), 7.53-7.63 (m, 5H), 7.98 (d, J=8.6Hz, 1H).
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(NC1CCN(C2SC=CN=2)CC1)=O.[Cl:23][C:24]1[C:28]([Cl:29])=[C:27]([CH3:30])[NH:26][C:25]=1[C:31]([NH:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[C:44]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[N:43]=[C:42]([C:51]([O:53]C)=[O:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:32]>>[Cl:23][C:24]1[C:28]([Cl:29])=[C:27]([CH3:30])[NH:26][C:25]=1[C:31]([NH:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[C:44]([N:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)[N:43]=[C:42]([C:51]([OH:53])=[O:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:32]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCCC2)n1
Agent: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCCC4)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesized by an analogous method to Intermediate 3 starting from methyl 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-pyrrolidin-1-ylpyrimidine-4-carboxylate (Example 316).