Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)#[N:12].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(C[C@H](Nc2ccc(C#N)c(Cl)c2)C(=O)O)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (0.90 g) in dimethyl sulfoxide (20 mL) were added 4-cyanophenylalanine (1.00 g) and cesium carbonate (2.23 g), and the mixture was stirred at 90° C. overnight. After warming to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 1.57 g, 92%).
Reaction SMILES: C(O)(=O)C.[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6].C(N)(=O)C>O.C(OCC)C.[Fe]>[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:7])[CH3:6]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: CC(N)=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1ccc(N)c(F)c1
Reaction time: 1 h

Procedure:
A stirred flask containing 350 mL of acetic acid was heated to 80°-85° C. under a nitrogen atmosphere. To this flask was added 39.10 g (0.700 mole) of powdered iron, and this mixture was stirred for one hour. A solution of 4-isopropoxy-2-fluoronitrobenzene in 250 mL was added to the mixture dropwise. Upon completion of addition, the reaction mixture was heated at 80°-85° C. for one hour. After being cooled below 40° C., the mixture was filtered, and the solvent was evaporated under reduced pressure, leaving a residue. This residue was dissolved in a mixture of water and diethyl ether. The organic layer was separated and was washed in succession with saturated aqueous solutions of sodium bicarbonate and sodium chloride. It was then dried over anhydrous magnesium sulfate, filtered through a short column of silica gel, and the solvent was evaporated under reduced pressure, leaving an impure residue which contained significant amounts of acetamide in addition to the desired product. This residue was suspended in 500 mL of 2N hydrochloric acid for one hour. The hydrochloric acid mixture was then extracted with diethyl ether, and the two phases were separated. Aqueous sodium hydroxide solution was added to the aqueous hydrochloride solution until it was basic. This basic solution was extracted with diethyl ether, and the extract was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent under reduced pressure, the residue was recrystallized from diethyl ether/petroleum ether to yield 16.90 g of 4-isopropoxy-2-fluoroaniline as an oil, which darkened on standing. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])C=O.F[C:27]1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[C:5]([Cl:13])([C:19]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:17]([CH3:16])[CH:18]=1)[C:6]1[CH:11]=[C:10]([CH3:27])[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(C=O)cc1C
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)(c1cccc(C)c1)c1ccc(C)c(C)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3,4-dimethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27]C(=O)C)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Yield: 79 %

Procedure:
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 72 mg of 20-(1,3-dioxolan-2-yl)-3β-(methoxymethyl)oxypregna-5,7-dien-1α-ol showing the following physical properties.
Reaction SMILES: O[CH2:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:6]3)[CH2:4]2.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH2:2][C:3]12[CH2:11][CH:7]3[CH2:6][C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])([CH2:4]1)[CH:9]([CH2:8]3)[CH2:10]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CO)(C3)C2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Temperature: 90 °C
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl [1-(hydroxymethyl)tricyclo[3.3.1.03,7]non-3-yl]carbamate (as obtained in step VI preparation 3) (0.67 g, 2.5 mmol) in toluene (10 mL) was added phthalimide (0.52 g, 3.5 mmol), triphenylphosphine (1.05 g, 4.0 mmol), and diisopropylazodicarboxylate (0.8 mL, 4.0 mmol). The reaction mixture was heated to 90° C. for 4 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl [2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate (0.45 g) as a viscous liquid in 46% yield. m/z (M+1) 397; 1H NMR (CDCl3) 300 MHz δ 7.90-7.80 (m, 2H), 7.77-7.68 (m, 2H), 4.75 (s (br), 1H), 3.60 (s, 2H), 2.47-2.35 (m, 1H), 2.36-2.29 (m, 1H), 2.02-1.84 (m, 4H), 1.77-1.65 (m, 2H), 1.64-1.35 (m, 5H), 1.41 (s, 9H), 1.34-1.24 (m, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16](N[C@H](C(O)=O)CO)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][O:12][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Product: COCC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Boc-homoserine (0.51 g) was methylated as described for Boc-serine in Example 73. This afforded 0.45 g crude product which was carried on without further purification. NMR (300 MHz, CDCl3) delta 1.40 (s, 9H), 3.16 (s, 3H), 3.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.Cl.[CH2:27]([O:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH3:28].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:9][CH2:10][C:11](=[O:13])[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:30][O:29][CH2:27][CH3:28])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCOCCNCCOCC
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCN(CCOCC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 14.7 %

Procedure:
Following general procedure B2,2-[(2E)-3-(methoxycarbonyl) prop-2-enoyloxy]acetic acid (23) (0.80 g, 6.14 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (1.40 g, 7.37 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. bis(2-Ethoxyethyl)amine hydrochloride (1.18 g, 7.37 mmol) (1.18 g, 7.37 mmol) and diisopropylethylamine (DIEA) (1.34 mL, 0.99 g, 7.67 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (1:1) afforded 0.30 g (15% yield) of the title compound (27) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=15.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.56-3.43 (m, 12H), 1.19 (q, J=7.6 Hz, 6H). MS (ESI): m/z 332.20 (M+H)+.
Reaction SMILES: O.[C:2]1(C)[CH:7]=[CH:6][C:5]([S:8](O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])O.[Na+]>CO>[S:8]1[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:2]([CH2:7][CH2:6][CH2:13][OH:16])=[CH:3]1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCc1csc2ccccc12

Procedure:
A solution of compound 80-2 (2.04 g) and p-toluenesulfonic acid monohydrate (10.0 mg) in methanol (80 ml) was stirred at room temperature for 20 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and methanol was evaporated under reduced pressure. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to give the object product (1.48 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)=[O:22])=[C:8]2[CH3:25])=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CC(C)CC(=O)N1CCN(C)CC1)c(C)n2Cc1ccc(Br)cc1

Procedure:
To a solution of the acid from Example 7, Step 6 (300 mg) in DMF (4 mL) was added triethylamine (0.13 mL), diethyl cyanophosphonate (0.13 mL) and 1-methylpiperazine (0.08 mL) at r.t. After 4 h the reaction mixture was diluted with EtOAc and the organic phase was washed with HCl 1M, 5% aqueous NaHCO3 and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; CH2Cl2 /MeOH, 95:5) afforded the title compound as a white solid.
Reaction SMILES: [NH:1]([S:10]([C:13]1[CH:19]=[CH:18][C:16](C)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:20]([Li])CCC.[CH2:25]([Mg]Br)[CH2:26][CH:27]([CH3:29])[CH3:28].Cl>C1COCC1.CCCCCC>[CH3:6][CH:4]([CH2:3][C@H:2]([NH:1][S:10]([C:13]1[C:14]([CH3:20])=[CH:15][CH:16]=[CH:18][CH:19]=1)(=[O:11])=[O:12])[C:7](=[O:9])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Reactant: [Li]CCCC
Reactant: CC(C)CC[Mg]Br
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)N[C@@H](CC(C)C)C(=O)CCC(C)C

Procedure:
To a stirred -78° C. solution of Ts-Leu (15 g, 53 mmol) in dry THF (240 ml) was added n-butyl lithium (57.8 ml of a 0.91M solution in hexane) followed 15 minutes later by isopentyl magnesium bromide (185 ml of a 0.8M solution in THF). The mixture was heated at reflux for 3 days, then cooled and poured into 0° C. 1M HCl (500 ml). The layers were separated and the aqueous phase was extracted with ether (3×150 ml). The combined organic layers were washed with saturated NaHCO3 (2×150 ml) and brine (150 ml). Drying and evaporating provided a residue which was chromatographed on silica gel to give 7.43 (41%) of the desired product. Mass spectrum: (M+H)+ =340.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:9]3[CH:11]=[CH:12][C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:19].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CC(C)C(=O)C>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N+:4]1[C:5]2[CH:6]=[CH:7][C:8]3[CH:14]=[C:13]([S:15]([O-:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]([CH3:20])([CH3:1])[C:3]=1[CH3:19])([OH:29])=[O:28]
Reactant: O=C(O)CCCCBr
Reactant: CC1=Nc2ccc3cc(S(=O)(=O)[O-])ccc3c2C1(C)C
Agent: [K+]
Solvent: CC(=O)C(C)C
Product: CC1=[N+](CCCCC(=O)O)c2ccc3cc(S(=O)(=O)[O-])ccc3c2C1(C)C
Temperature: 140 °C
Yield: 7.2 %

Procedure:
To a solution of 1,1,2-trimethyl-1H-benzo[e]indole-7-sulfonic acid (723 mg, 2.5 mmol) in methanol (5 mL) was added a saturated solution of potassium hydroxide in isopropanol (3.134%, 4.913 g, 1.1 eq.) and the resulting suspension was heated at reflux for 2 h. Then the mixture was concentrated and the corresponding potassium salt was obtained. Under nitrogen atmosphere, a mixture of potassium 1,1,2-trimethyl-1H-benzo[e]indole-7-sulfonate and 5-bromovaleric acid (585 mg, 3 mmol) in 3-methyl-2-butanone (5 mL) was heated at 140° C. for 20 h. Removal of the solvent and purification by chromatography (dichloromethane/methanol) afforded 3-(4-carboxybutyl)-1,1,2-trimethyl-1H-benzo[e]indolium-7-sulfonate (70 mg, isolated yield 7.2%). LC-MS: 390.18 [M+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH3:13]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:13])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Product: Nc1nc(N)c(NC=O)c(Cl)n1
Yield: 89 %

Procedure:
N-2-Amino-4,6-dichloro-5-pyridinyl)formamide (Example 3, 500 mg, 2.14 mmol) and ammonia (150 mL) was stirred in a Parr bomb at 50° C. for 18 hours. The ammonia was evaporated and the residual solid triturated with water (10 mL). The solid was dried to give the title compound as red powder (400 mg, 89%), m.p.>300° C.; mass spectrum (CI/CH4): 190, 188 (M+1); 1H-NMR(DMSO-d6)δ: 9.05 and 8.60 (both br s, total 1, NHCHO), 8.1 and 7.8 (both br s, total 1, NCHO), 6.80-6.20 (4 br s, total 4, 2 NH2).
Reaction SMILES: C(O[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]3)=[C:18]([F:32])[CH:17]=2)[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)C.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].[C:41](#[N:43])C>>[F:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([F:32])[C:19]=1[N:23]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[N:24]1)[O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:43][CH2:41][CH2:36][C:34]([OH:40])=[O:35])=[O:33])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1)c1ccc(C(=O)OCC)cc1
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Product: CCCC(Oc1cc(F)c(-n2cc(C(F)(F)F)cn2)c(F)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Example 20 using (+/−)-4-{1-[3,5-difluoro-4-(4-trifluoromethyl-pyrazol-1-yl)-phenoxy]-butyl}benzoic acid ethyl ester. Column: Waters Atlantis d C18 4.6×50 mm, 5 μm; Modifier: TFA 0.05%; Gradient: 95% H20/5% acetonitrile linear to 5% H20/95% acetonitrile over 4.0 min, hold at 5% H20/95% acetonitrile to 5.0 min. Flow: 2.0 mL/min.; Retention time: 3.31 minutes. MS (M+1): 512.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:29][C:30]1[CH:66]=[CH:65][CH:64]=[CH:63][C:31]=1[CH2:32][NH:33][C:34]([C@@H:36]1[C:40]([CH3:42])([CH3:41])[S:39][CH2:38][N:37]1[C:43](=[O:62])[C@@H:44]([OH:61])[C@@H:45]([NH:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:35]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][C:30]1[CH:66]=[CH:65][CH:64]=[CH:63][C:31]=1[CH2:32][NH:33][C:34]([C@@H:36]1[C:40]([CH3:42])([CH3:41])[S:39][CH2:38][N:37]1[C:43](=[O:62])[C@@H:44]([OH:61])[C@@H:45]([NH:53][C:54](=[O:60])[C@@H:55]([NH:56][C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH:57]([CH3:59])[CH3:58])[CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:35]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Methoxyacetic acid (23 μl), HOBt (48 mg), and EDC.HCl (63 mg) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (149 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[C:20]([Br:19])[CH:28]=3)[CH2:24][CH2:25]2)=[O:17])[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc2c(c1)NCC2
Reactant: C[C@@H]1CN(CC(=O)O)CCN1C(=O)OC(C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
(R)-4-Carboxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol), 6-bromo indoline (100 mg, 0.43 mmol) and triethylamine (0.148 mL, 1.06 mmol) were dissolved in DCM (1.94 mL) at ambient temperature. PyBrop (199 mg, 0.43 mmol) was added and the reaction stirred for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (97 mg, 52%) as a pale yellow oil. 1H NMR (Me-d3-OD): 8.32 (1H, s), 7.24-7.10 (2H, m), 5.50 (1H, s), 4.38-4.17 (3H, m), 3.83 (1H, d), 3.31 (1H, s), 3.17 (2H, t), 2.91 (1H, d), 2.81 (1H, d), 2.33 (1H, dd), 2.20-2.09 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:21].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C:34](=[O:37])([O-])[O-].[Na+].[Na+].[Cl:40][C:41]1[N:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1>ClCCl.O>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][O:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:47][C:44]3[CH:45]=[N:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[O:37])=[C:3]([Br:21])[CH:4]=2)[CH2:9]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)nc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)Nc3ccc(Cl)nc3)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.8 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (100 mg, example 28a) in dichloromethane (2 ml) was added triphosgene (31 mg). A solution of sodium carbonate (59 mg) in water (2 ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all the starting material had reacted. A solution of 6-chloropyridin-3-amine (36 mg, CAS 5350-93-6) in dichloromethane (2 ml) was then added and the reaction mixture was stirred at room temperature for a further 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 80% EtOAc in heptanes) to give (RS)-2-{3-bromo-4-[3-(6-chloro-pyridin-3-yl)-ureido]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (47 mg, 33%) as an off-white solid. MS (ISP): 515.2 ([{37Cl81Br}M+H]+), 513.2 ([{37Cl79Br or 35Cl81Br}M+H]+), 511.0 ([{35Cl79Br}M+H]+), 459.0 ([{37Cl81Br}M+H—C4H8]+), 457.0 ([{37Cl79Br or 35Cl81Br}M+H—C4H8]+), 454.9 ([{35Cl79Br}M+H—C4H8]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:31][C:32]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:33]=1[CH:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50]C(NC3C=CC=CC=3)=O)=[CH:46][CH:45]=2)=[O:42])[CH2:37][CH2:36]1.CCN(CC)CC>ClCCl.O>[F:31][C:32]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:33]=1[CH:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:7](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:46][CH:45]=2)=[O:42])[CH2:37][CH2:36]1
Reactant: O=C(Nc1ccccc1)Nc1ccc(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)cc1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Picolinic acid (69.0 mg, 0.56 mmol) was dissolved in dichloromethane (4.0 mL), and then HOBt (70.0 mg, 0.56 mmol), WSC (107 mg, 0.56 mmol), the compound (200 mg, 0.37 mmol) obtained in Example 73 (1) and Et3N (103 μL, 0.74 mmol) were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50), thereby giving the title compound (132 mg, 79%) as a white solid.