Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:24])[CH2:22][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1NC(=O)CN1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-methyl-phenyl)-2-chloroacetamide (37 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 29.3 mg (63%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.62 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.05 (t, J=6 Hz, 1H), 7.10 (m, 2H), 7.58 (t, J=5 Hz, 1H), 7.78 (d, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 9.40 (s, 1H); MS (ESI/APCI+) m/e 311 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>CCOCC.O>[Cl:29][CH2:30][C:31]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:9]([CH2:16][CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH3:15])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(CC)c1NCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CCc1cccc(CC)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-dioxolan-2-ylmethyl)-2,6-diethylaniline (7.7 grams), sodium bicarbonate (6.0 grams), dioxane (20 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. This mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.0 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from an ether-pentane mixture to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2,6-diethylaniline having a melting point of 86° to 87°C.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:28])([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=2[CH2:29][CH3:30])=[O:7])=[CH:4][C:3]=1[Br:33].[Cl-].[Cl:35][C:36]1[C:40](Cl)=[S+:39][S:38][N:37]=1.N1C=CC=CC=1>O1CCCC1.ClCCl>[Br:33][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:2]=1[N:1]=[C:40]1[S:39][S:38][N:37]=[C:36]1[Cl:35])[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:28])([C:21]([F:26])([F:27])[C:22]([F:23])([F:24])[F:25])[C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=1[CH2:29][CH3:30])=[O:7]
Reactant: Clc1ns[s+]c1Cl
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N)c(Br)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N=c2ssnc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
4-amino-3-bromo-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]benzamide (0.254 g) was dissolved in tetrahydrofuran (20 ml). To the mixture was added 4,5-dichloro-1,2,3-dithiazol-1-ium chloride (0.106 g), and stirred at room temperature for 2 hours. To the reaction mixture was added pyridine (0.091 g) in dichloromethane, and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. To the residue was added water and extracted twice with ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain 3-bromo-4-{[4-chloro-5H-1,2,3-dithiazol-5-ylidene]amino}-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]benzamide (0.270 g, 85%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39](Cl)=[O:40])[CH2:36][O:35]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:33][C:34]1([CH3:42])[O:38][C@H:37]([C:39]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:13]([F:14])=[CH:12][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:10][C:9]=3[F:26])=[CH:4][CH2:3]2)=[O:40])[CH2:36][O:35]1
Reactant: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCNCC3)c(F)c2)C(=O)O1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-acetoxymethyloxazolidin-2-one hydrochloride (14.5 g, 37.3 mM) was suspended in dry dichloromethane (300 ml) under nitrogen at 0°, and treated with pyridine (9.78 g, 0.12 M). A solution of 2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl chloride (9.59 g, 75.6 mM) in dichloromethane (100 ml) was added dropwise, and stirring continued for 3 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 300 ml) was added, and stirring continued for 30 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness after the addition of toluene (20 ml). The solid residue was triturated with a mixture of diethyl ether (250 ml) and isohexane (150 ml), and solid filtered to give the title compound (17.5 g). NMR (DMSO-d6) δ: 1.30 (2×s, 6H); 2.02 (s, 3H); 2.28 (br, 1H); 2.39 (br, 1H); 3.67 (t overlapping m, 2H); 3.83 (dd, 1H); 4.00-4.32 (overlapping m, 7H); 4.90 (overlapping m, 2H); 5.86 (s, 1H); 7.34 (d, 2H). MS (ESP): 481 (MH+) for C23H26F2N2O7
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:12]4[CH2:15][O:14][CH2:13]4)[CH:3]=3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: Nc1ncnc2c1c(Br)cn2C1COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1COC1
Temperature: 100 °C
Yield: 61.7 %

Procedure:
To 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.186 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (104 mg, 0.260 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 solution (1 mL) in a 5 ml sealable vial. N2 gas was bubbled through the mixture for 10 minutes then Pd(Ph3P)4 (21.47 mg, 0.019 mmol) was added and bubbled N2 for 5 minutes. The mixture was then capped and heated 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (4×5 ml). The organics were then combined, washed with brine, dried over MgSO4, filtered and concentrated. The residual was then diluted with 3 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 15% ACN/H2O, 0.1% TFA to 40% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (53 mg, 61.8% yield) as a white power. LC-MS (ES) m/z=462.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=3.28 Hz, 1H), 8.08-8.13 (m, 1H), 7.70 (d, J=3.03 Hz, 1H), 7.41 (br. s., 1H), 7.15-7.33 (m, 4H), 6.17 (br. s., 2H), 5.82-5.93 (m, 1H), 4.95-5.07 (m, 4H), 4.30 (br. s., 2H), 3.96 (br. s., 2H), 3.29 (d, J=1.01 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:15])[C@@H:12]([NH2:14])[CH3:13])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[C:4](=[O:20])[N:3]1[CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:14][C@@H:12]([CH3:13])[C:11]([NH:10][CH:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[C:4](=[O:20])[N:3]([CH:21]([CH3:23])[CH3:22])[N:2]([CH3:1])[C:8]2=[O:9])=[O:15])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)N1C(=O)c2ccccc2C(NC(=O)[C@H](C)N)C(=O)N1C
Product: CC(C)N1C(=O)c2ccccc2C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N1C
Yield: 75 %

Procedure:
In a manner similar to example 1, the title compound was prepared by the reaction of 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-amino-1-oxopropyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione with 3,5-difluorophenylacetic acid. The compound was purified on prep HPLC using the column YMC S5 ODS (20×100 mm) with a flow rate of 40 ml/min and gradient time of 10 min., starting with solvent A (10% MeOH—90% H2O—0.1% TFA), and ending with solvent B (90% MeOH—10% H2O—0.1% TFA). (75% yield). MS (ESI) 473.09 (M+H); Rf 1.31
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@:5]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:6].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:13][C:9]1[CH:8]=[C:7]([C@@:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)([O:4][CH2:3][CH2:2][NH:1][C:37]([O:39][CH3:40])=[O:38])[CH3:6])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN)c2cccc(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate (0.410 g, 1.07 mmol), DMAP (0.380 g), DIPEA (4 mL), and methyl chloroformate (0.960 g) in CH2Cl2 was stirred at rt for 20 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methoxycarbonylamino)ethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 465 (M+Na).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1CCCCC1>O1CCCC1>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=[CH:14][O:15][CH3:16])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COC=C1CCN(Cc2ccccc2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of di-isopropylamine (11.1 g, 15.4 mL, 110 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to 0° C. under a nitrogen atmosphere. A solution of n-butyl lithium in hexanes (2.5 M, 44 mL, 110 mmol) was added dropwise with stirring. The pale yellow solution was stirred for 15 minutes at 0° C., then transferred via cannula to a suspension of methoxymethyl-triphenylphosphonium chloride (37.7 g, 110 mmol) in dry tetrahydrofuran (300 mL) stirred at -20° C. After 30 minutes, the reaction mixture was cooled to -40° C. and a solution of 1-benzylpiperid-4-one (18.9 g, 18.5 mL, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise over 15 minutes. The reaction mixture was warmed gradually to ambient temperature over 23 h. The reaction mixture was then poured onto water, mixed and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered; solvent was removed in vacuo. Column chromatography (ethyl acetate) gave starting piperidine (Rf =0.7, 0.5 g) and the product (Rf =0.51, 11.6 g), an orange-yellow liquid:1HNMR:7.4-7.25(m,5H), 5.8(s,1H), 3.5(s,2H), 3.45(s,3H), 2.5-2.3(m,5H), 2.05(t,2H,J=7); MS:217.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([SH:13])[CH3:12]>>[CH:11]([S:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([CH3:12])[CH3:10]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)S
Product: CC(C)Sc1ccc(C#N)cc1

Procedure:
2 g of 4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 4-(isopropylthio)benzonitrile. 900 mg of 4-(isopropythio)benzonitrile was reacted via Procedure T to give 4-(isopropylthio)benzoic acid. 730 mg of 4-(isopropylthio)benzoic acid was reacted via Procedure R to give 4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 43 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (43%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (258 mg, 67%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1C2C(CO[C:47]([NH:49][C@H:50]([C:67]([O:69][CH3:70])=[O:68])[CH2:51][S:52][CH2:53][CH:54]([C:59](=[O:66])[C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)[CH2:55][C:56]([OH:58])=[O:57])=[O:48])C3C(=CC=CC=3)C=2C=CC=1.[Cl:71][C:72]1[CH:77]=[CH:76][C:75]([N:78]=C=O)=[CH:74][CH:73]=1>C1COCC1.ClCCl>[Cl:71][C:72]1[CH:77]=[CH:76][C:75]([NH:78][C:47]([NH:49][C@H:50]([C:67]([O:69][CH3:70])=[O:68])[CH2:51][S:52][CH2:53][CH:54]([C:59](=[O:66])[C:60]2[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=2)[CH2:55][C:56]([OH:58])=[O:57])=[O:48])=[CH:74][CH:73]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccc(Cl)cc1
Yield: 12 %

Procedure:
Wang resin (100-200 mesh, 0.66 mmol/g, 70 mg) was treated with triphenylphosphine (34.5 mg), diethyl azodicarboxylate (20.8 μL) and 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid (72.3 mg) in THF (0.5 mL) at room temperature for 3 days. The resin was filtered, washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 20% piperidine-dichloromethane (1 mL) solution for 1 h. The resin was filtered, and washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 10 eq of 4-chlorophenyl isocyanate in dichloromethane (6 mL) for two days. The resin was washed with washed with dimethyl formamide, isopropanol, dichloromethane and ether and dried. The resin was treated with 20% trifluoroacetic acid in dichloromethane (5 mL). The solution was filtered, concentrated and purified on HPLC (C-18 prep column, 10% to 90% acetonitrile in water both containing 0.1% TFA) to give 12% of the title compound; ESMS, (M+1)+480.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.6 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (300 mg, 0.593 mmol) in dry DMF (6 mL), was added (2-bromoethoxy)(tert-butyl)dimethylsilane (423 mg, 1.78 mmol) and cesium carbonate (578 mg, 1.78 mmol). The reaction mixture was stirred at r.t. for 36 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (310 mg, 78.8%) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:25]1([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:28][C:27](=[O:30])[O:26]1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][O:15][N:14]([C:25]2([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:28][C:27](=[O:30])[O:26]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Reactant: COC(=O)C1(Cl)CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
In 3 ml of N,N-dimethylformamide was dissolved 236 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution was added 326 mg of cesium carbonate. The mixture was stirred at room temperature for 20 minutes, to which was added 179 mg of the Compound (13) obtained in Example 13, followed by stirring for two hours. To the reaction solution was added a dilute saline solution. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, which was dried (Na2SO4), then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 101 mg of the subject Compound (12). The IR and NMR spectra of this product were in complete agreement with those of the Compound (12) obtained in Example 12.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1.C(N(CC)CC)C.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)=[O:37])[CH:15]=2)[N:10]=1
Reactant: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Reactant: CSc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NC(=O)Nc2ccc3nc(N4CC5CCC4CC5)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-azabicyclo[2.2.2]oct-2-yl)quinolin-6-amine (21 mg, 0.08 mmol, Example 119, Step B), triethylamine (0.013 mL, 0.09 mmol) in 1 mL methylene chloride was added 4-(methylthio)phenylisocyanate (15 mg, 0.09 mmol). The resulting mixture was stirred at r.t. for 2 h. The solvent was removed under vacuum and the residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate (1:1) to afford the product, MS: m/z 419 (MH+), as an off-white solid.