Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][N:32]=[C:33]=[O:34]>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2)=[O:34]
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.226 g, 73%). MS (ESI+) m/z 404 (M+H)+; MS (ESI−) m/z 402 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.96 (s, 3H), 4.44 (d, J 6.0, 2H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H), 7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s, 1H), 9.35 (s, 1H); Anal. Calcd for C19H15Cl2N3O3: C, 56.45; H, 3.74; N, 10.39. Found: C, 56.08; H, 3.67; N, 10.03.
Reaction SMILES: [Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH:3]=[O:4].[BH4-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3][OH:4]
Reactant: O=CC1(Br)C=CC=C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC1(Br)C=CC=C(F)C1
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To 1-bromo-3-fluorobenzaldehyde (1.60 kg, 7.91 mol) in methanol (14 L) at 0° C. add sodium borohydride (284 g, 7.93 mol) in portions over 30 min to control the exotherm and gas evolution. After 15 min, quench with water (500 mL) and concentrate to obtain a yellow oil. Dissolve the oil in ethyl acetate (6 L) and wash with water (3 L). Extract the aqueous layer with ethyl acetate (1 L). Wash the combined organic phases with brine (2 L), dry over sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (1614 g, 100%). 1H NMR (CDCl3) δ 7.40 (d, 1H), 7.18 (m, 1H), 7.07 (t, 1H), 4.86 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]3([CH3:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]3([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][CH:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC3(C)CCCCC3)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C[C@@H]2N[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)[C@H](c3cccc(Cl)c3F)[C@@]2(C#N)c2ccc(Cl)cc2F)CCCCC1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 344 (0.16 g, 0.24 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (0.14 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C@@H:39]([OH:44])[CH2:40][N:41]([CH3:43])[CH3:42])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][N:41]([CH3:42])[CH2:40][C@H:39]([OH:44])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C[C@H](O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C[C@H](O)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), (S)-1-(3-amino-pyrazol-1-yl)-3-dimethylamino-propan-2-ol (158 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-((S)-3-dimethylamino-2-hydroxy-propyl)-1H-pyrazol-3-yl]-amide as an off white powder (63.2 mg, 43.6%). HRMS (ES m/z Calcd. for C31H36Cl2F2N6O2+H [(M+H)+]: 633.2318. found: 633.2313.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:48]1([CH2:54][CH2:55]O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([O:19][CH2:55][CH2:54][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28]
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: OCCN1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(OCCN3CCCCC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 10 mg of 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone (INTERMEDIATE 3) dissolved in 2 mL of anhydrous THF was added 87 mg of Ph3P and 43 mg of 1-piperidine ethanol. The resulting mixture was heated to 65° C. for 10 min. Then 72 mg of diisopropyl azodicarboxylate was added dropwise over 2 min and the mixture was stirred for 1 h at 65° C. The resulting reaction mixture was concentrated and purified by preparative thin-layer chromatography, eluting with 100% EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-[2-(1-piperidinyl)ethoxy]-2(1H)-quinolinone. Mass spectrum (ESI) 531.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8 Hz, 2H); 7.38 (t, J=8 Hz, 1H); 7.31 (q, J=6.5 Hz, 1H); 6.98 (m, 2H); 6.54 (s, 1H); 5.90 (s, 1H); 4.08 (s, 2H); 2.83 (m, 6H); 2.61 (s, 4H); 1.68 (s, 4H); 1.48 (s, 2H).
Reaction SMILES: [IH:1].O.[CH2:3]1[O:11][CH:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[I:1][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:11]
Reactant: I
Reactant: c1ccc(C2CO2)cc1
Solvent: O
Solvent: CCO
Product: OCC(I)c1ccccc1
Temperature: 0 °C

Procedure:
2-Iodo-2-phenylethanol was synthesized as described in Golumbic, C. and Cottle, D. L. J. Am. Chem. Soc. 61, 996 (1939). An aqueous HI solution (81.7 grams, 54.7%) and 556 ml of water were added to a 1L reaction flask equipped with an addition funnel, which was cooled to zero degrees C. Styrene oxide (40 grams) and 50 grams of ethanol were added to the addition funnel. The styrene oxide solution was added dropwise to the flask over a 40-minute period during which a white precipitate was formed. Filtration over a fritted glass funnel followed by drying under vacuum for four hours yielded 69.8 grams of a white solid having a melting point of 62-66° C. The solid was dissolved in 560 ml of ethanol and poured into rapidly stirred water (2.5L containing 100 ml of 5% NaHSO3). The white precipitate was collected on a fritted glass funnel and dried in a vacuum oven at room temperature for four hours in the presence of P2O5 as a desiccant. The white solid (24 grams) had a melting point of 75.5-76° C. NMR analysis was consistent with the reports in the above-cited literature.
Reaction SMILES: [O:1]1[CH:6]2[CH2:7][N:8](C(OCC3C=CC=CC=3)=O)[CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1>CO.C(O)=O.[OH-].[OH-].[Pd+2]>[O:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[O:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CC2OCCOC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: C1COC2CNCC2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (0.46 g, 1.94 mmol) in MeOH (20 mL) was added two drops of HCO2H followed by 20% Pd(OH)2 (50 mg). The reaction mixture was stirred under H2 for 4 h at rt and was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for the next step without further purification.
Reaction SMILES: C(=O)=O.CC(C)=O.[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:21](Cl)([Cl:23])=[O:22].Cl.CC1C=CC=CC=1NCCC(O)=O>C(Cl)Cl>[Cl:23][C:21]([N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[CH3:8])=[O:22]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1NCCC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1N(CCC(=O)O)C(=O)Cl
Temperature: 40 °C
Reaction time: 0.42 h
Yield: 97.9 %

Procedure:
In a 100 cc round-bottomed flask equipped with magnetic stirring, a thermometer, a dry ice/acetone reflux condenser, a device for introducing gas and a dropping funnel, there is introduced 3-(2-methylanilino)propionic acid (5.29 g; 29.6 mmol) and methylene chloride (30 cc). The mixture maintained under an atmosphere of argon is heated to a temperature in the region of 40° C., and phosgene (5.20 g; 52.6 mmol) is then added with stirring in the course of 25 minutes, while maintaining the temperature between 36° C. and 40° C. During the introduction of phosgene, a white precipitate of 3-(2-methylanilino)propionic acid hydrochloride forms. The reaction mixture is heated to a temperature in the region of 40° C. for a further hour. The white precipitate is then almost completely dissolved. After cooling to 20° C. and the removal of the phosgene which has not reacted, the light precipitate which remains is separated by filtration. The filtrate is concentrated to dryness. N-Chloroformyl-3-(2-methylanilino)propionic acid (7 g) is thus obtained almost pure, m.p. 112° C., the structure of which is confirmed by the infrared spectrum, mass spectrum and proton nuclear magnetic resonance spectrum. The product, after recrystallisation in a toluene/hexane mixture (70:30 by volume), melts at 113° C.
Reaction SMILES: C1([CH2:4][CH2:5][NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])CC1.[OH-].[Na+].O1[CH2:36][CH2:35][CH2:34]C1>C(O)C>[CH:34]1([N:6]([CH2:7][C:8]2[C:9](=[C:27]([CH3:29])[CH3:28])[CH2:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:12][CH:13]=2)[CH2:5][CH3:4])[CH2:35][CH2:36]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CNCCC3CC3)c(C(C)C)c2)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC1=CC=C(C#Cc2ccc(C(=O)O)cc2)CC1=C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropylethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][C:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]([CH3:10])([CH3:9])[CH2:11][C:19]2([CH3:18])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)CC(C)(C)C
Product: CC(C)(C)CC1(C)CC(C)(C)c2ccc(O)cc21

Procedure:
57 g (0.25 mol) of 2,2-bis-(4-hydroxyphenyl)-propane, 10 g of an acid-activated fuller's earth and 84 g (0.75 mol) of diisobutylene are stirred in an autoclave for 8 hours at around 150° C. The catalyst is then filtered off and the reaction mixture subjected to fractional distillation, giving 25.2 g (44% of the theoretical) of 5-hydroxy-1,1,3-trimethyl-3-neopentyl indane.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (example B.18) (227 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 43%). MS (ISP) 507.3 [(M+H)+]; mp 265-267° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1C(=O)CCC1>[C:20]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:30][CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 125 °C
Yield: 51.6 %

Procedure:
N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 0.9 mmol) and benzoylpiperazine (0.53 g, 3.00 mmol) were dissolved in 15 NMP and heated at 125° C. for 16 hours. The reaction was quenched with 100 ml water after cooling to room temperature. The mixture was extracted with 50 ml acetyl acetate and washed by water (3×20 ml). N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)benzamide (0.20 g, 50%) was obtained after flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.06 (s, br, 4H), 3.85 (d, br, 4H), 7.31 (d, J=8.8 Hz, 1H), 7.48 (m, 5H), 7.62 (m, 2H), 7.65 (m, 1H), 7.95 (d, J=7.1 Hz, 2H), 8.06 (dd, J=2.6, 8.8 Hz, 1H), 9.12 (s, 1H), 9.47 (d, J=2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 52.4, 115.9, 119.9, 121.0, 127.3, 127.6, 129.2, 129.7, 130.7, 133.0, 134.2, 134.5, 135.5, 145.9, 146.7, 165.3, 171.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](Cl)=[O:51]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:50](=[O:51])[C:49]4[CH:53]=[CH:54][CH:55]=[CH:56][C:48]=4[F:47])=[CH:31][C:30]=3[F:36])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM (10 mL) at 0° C. was added DIPEA (0.199 mL, 1.137 mmol) and 2-fluorobenzoyl chloride (135 mg, 0.853 mmol) and the suspension was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was collected, dried and concentrated. The residue was purified using Biotage (eluent EtOAc, 25 g Silicycle HR column) to provide the title compound 356 (400 mg, 0.616 mmol, quantitative yield) as a white solid.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Cl:5][C:6](=[C:10]([Cl:12])[Cl:11])[C:7](Cl)=[O:8]>C(Cl)Cl>[Cl:11][C:10]([Cl:12])=[C:6]([Cl:5])[C:7]([O:4][CH:1]([CH3:3])[CH3:2])=[O:8]
Reactant: CC(C)O
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Solvent: ClCCl
Product: CC(C)OC(=O)C(Cl)=C(Cl)Cl

Procedure:
A solution of 6.5 gms (0.108 moles) isopropyl alcohol, 20 gms (0.013 moles) trichloro acryloyl chloride and 100 ml methylene chloride was stirred for 72 hours. The solvent was stripped and the product was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH2:17]([C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:25])([NH:1][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH3:35])=[O:34])[CH3:24])=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1

Procedure:
2-Amino-N-(benzyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide (100 mg, 0.3 mmol) and o-tolyl isocyanate (36 mg, 0.3 mmol) were stirred as a solution in DCM (5 mL). Purification via HPLC afforded the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.58 (s, 6H) 2.22 (s, 3H) 4.13 (s, 2H) 5.76 (s, 1H) 7.15, (s, 5H) 7.32 (s, 4H) 7.50 (s, 6H). m/z 485.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Yield: 87 %

Procedure:
A solution of 2.15 g of 5,6-dihydro-5-(4-nitrobenzoyl)phenanthridine in 50 ml of ethyl acetate and 0.5 g of 10% palladium-on-carbon is hydrogenated in a Parr apparatus under an atmosphere of hydrogen for three hours. The mixture is filtered through diatomaceous earth and the solvent removed to give 1.7 g of the product as a yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:17]([O-])=O)[C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:17][C:8]1[C:9]([CH3:16])=[C:10]([CH:15]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COCCOc1cc(C(=O)OC)c(C)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCOc1cc(N)c(C)c(C(=O)OC)c1
Temperature: 80 °C
Yield: 106.4 %

Procedure:
To stirred solution of methyl 5-(2-methoxyethoxy)-2-methyl-3-nitrobenzoate (1.35 g, 4.83 mmol) in ethanol (20 mL) were added ammonium chloride (1.35 g, 25.0 mmol) dissolved in water (20 mL) and iron powder (1.07 g, 19.3 mmol). The resulting reaction mixture was heated at 80° C. for 3 h. On completion, the reaction mixture was filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified by aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, concentrated under reduced pressure to give the crude title compound (1.23 g) which was used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:6]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:7]([C:25](N(OC)C)=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Li]C1SC=CN=1.Cl.C1C[O:48]CC1>CCCCCC>[NH:6]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C@H:7]([C:25]([OH:48])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16].[S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]c1nccs1
Agent: c1cscn1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at −78° C. was added n-Budi (1.6 M in hexane, 19 mL) dropwise. The mixture was stirred for 30 minutes. Then a solution of Boc-Arg(Tos)N(Me)OMe, from Example 1, (1.7 g, 3.6 mmol) in THF (50 mL) was added to the lithiothiazole mixture at −78° C. The solution was stirred for 2 hours. 1 M HCl (30 mL) was added to the reaction mixture and warmed to room temperature. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with sat NaCl (30 mL), dried over MgSO4, filtered and evaporated. The crude oily residue was purified by flash column chromatography over SiO2 (50% EtOAc in CH2Cl2) to give Boc-Arg(Tos)-thiazole, shown above, (1.5 g, 84% yield) as a powder.