Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:8]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:10])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Yield: 55 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)acetic acid and isobutyl amine. Yield: 55%. 1H NMR (400 MHz, dMSO): δ 0.76-0.78 (d, 6H), 1.38 (s, 9H), 1.63-1.66 (m, 1H), 2.84-2.92 (m, 2H), 5.30-5.22 (d, 1H), 7.25-7.27 (d, 1H), 7.35-7.37 (m, 1H), 7.43-7.51 (m, 4H), 7.61-7.66 (m, 4H), 8.14-8.17 (t, 1H); MS+H (383).
Reaction SMILES: [CH:1]1([CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O1CCCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:8][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH:6]=[CH2:7])[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: C=CCC(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(OCC)OCC)C1CC1
Temperature: 25 °C

Procedure:
1-Cyclopropylbut-3-en-1-ol (C14, see C. Tahtaoui et al., J. Org. Chem. 2010, 75, 3781-3785) (92%, 8.1 g, 66 mmol) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 8.25 g, 206 mmol) in tetrahydrofuran (105 mL). The cooling bath was removed and the suspension was stirred until the internal temperature reached 21° C. The reaction mixture was then cooled in an ice bath, and 2-bromo-1,1-diethoxyethane (97%, 18.5 mL, 119 mmol) was added drop-wise at a rate that maintained the internal temperature below 5° C. After warming to room temperature, the reaction mixture was heated to 58° C. for 27 hours. Sodium hydride (60% in mineral oil, 3.3 g, 83 mmol) and 2-bromo-1,1-diethoxyethane (97%, 10 mL, 64 mmol) were added again, and the reaction mixture was heated at mild reflux for 14 hours. It was then cooled to 0° C., slowly quenched with water (100 mL) and extracted with diethyl ether (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 12.1 g, 53.0 mmol, 80%. 1H NMR (400 MHz, CDCl3) δ 5.87-5.98 (m, 1H), 5.05-5.11 (m, 1H), 5.00-5.04 (m, 1H), 4.61 (t, J=5.3 Hz, 1H), 3.66-3.75 (m, 3H), 3.54-3.62 (m, 2H), 3.47 (dd, J=10.3, 5.5 Hz, 1H), 2.70 (dt, J=8.4, 6.0 Hz, 1H), 2.36-2.41 (m, 2H), 1.22 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H), 0.80-0.90 (m, 1H), 0.54-0.62 (m, 1H), 0.35-0.50 (m, 2H), 0.07-0.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.6 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.34 g, 33.4 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (7.98 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (13.0 g, 100%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[C:11](#[N:13])[CH3:12].Cl>O1CCOCC1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:10])[N:1]=[C:11]([CH3:12])[N:13]=1
Reactant: CC#N
Reactant: Cc1cccc(N)c1C#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)c2c(C)cccc2n1
Temperature: 5 °C
Reaction time: 15 h
Yield: 123.3 %

Procedure:
1. 66.2 g of 2-amino-6-methylbenzonitrile and 22 g of acetonitrile are dissolved in 750 ml of absolute dioxan and the solution is cooled to 5° C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5° to 7° C. The mixture is stirred at room temperature for a further 15 h. and then again cooled to 5° C. A further 11 g of acetonitrile are added thereto, hydrochloric acid gas is introduced for 8 h. and the mixture is stirred at room temperature for a further 15 h. The suspension is subsequently evaporated at 30° C. in a vacuum. The crystalline residue is triturated with 0.71 of water, cooled to 0° to 5° C. neutralized with saturated sodium hydrogen carbonate solution and filtered. The crystals are washed with water and dried in a vacuum. There are obtained 107 g of crude 4-amino-2,5-dimethylquinazoline which still contains inorganic salts. This compound melts at 198°-199° C. after recrystallization from ethanol.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])=[CH:9][NH:10][C:3]=2[CH:2]=1.CS(C)=O.[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH:25]=[N:24][C:23]1=2>CC(C)=O>[O:21]=[C:22]1[NH:30][CH:29]=[N:28][C:27]2[N:26]([CH2:31][CH2:32][C:33]([NH:16][CH:12]([CH2:11][C:8]3[C:4]4[C:3](=[CH:2][CH:1]=[C:6]([OH:7])[CH:5]=4)[NH:10][CH:9]=3)[C:13]([OH:15])=[O:14])=[O:34])[CH:25]=[N:24][C:23]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.3 %

Procedure:
100 mg (0.500 mmol) of DL-5-hydroxytryptophan and 3 ml of dry dimethylsulfoxide were placed in a 25 ml round bottom flask equipped with a magnetic stirring bar and stopper. Then 150 mg (0.456 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) were added and the heterogeneous mixture was stirred for 2.5 hours at room temperature in the closed flask. The mixture became completely homogeneous. The reaction mixture was poured into 20 ml of acetone and a semi-solid precipitate was obtained by filtration. The crude product was washed twice with 2 ml of acetone. The solid was resuspended in 10 ml of acetone and the insoluble material was removed by filtration. The acetone solution was evaporated to dryness. The yield of product 2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-3-(5-hydroxyl-1H-indol-3-yl)-propionic acid (AIT-0111) was 15 mg. Yield: 7.3% (Purity 93 %).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([O:3][CH3:4])=[O:2].IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:18])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(CC(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(CC(C)=O)ccc1OC
Yield: 99.9 %

Procedure:
A mixture of 1-(3-carbomethoxy-4-hydroxyphenyl)propan-2-one (3.0 g), iodomethane (5.0 g), potassium carbonate (7.0 g) was refluxed in acetone until tlc showed no starting material (~6 hours). The mixture was cooled, filtered and evaporated. The residue was partitioned between ether and water and the layers separated. The ether layer was dried (MgSO4) and evaporated to give the title compound (3.2 g). τ (CDCl3) 7.84 (3H, s), 6.35 (2H, s), 6.1 (3H, s), 3.05 (1H, d, J=8 Hz), 2.68 (1H, dd, J=8 Hz, J=2 Hz), 2.36 (1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1>C1COCC1.O>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of sodium thiomethoxide in THF (53 mL) and H2O (20 mL) cooled to 0° C. was added 2-chloro-5-nitropyridine (LXV) (5.09 g, 32.09 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was poured into ice water and stirred for 10 minutes, filtered, washed with water, dried under vacuum to yield 2-(methylthio)-5-nitropyridine (CVII) as a yellow solid (5.14 g, 30.20 mmol, 94.1%). 1H NMR (DMSO-d6) δ ppm 2.62 (s, 3H), 7.57 (d, J=8.9 Hz, 1H), 8.38 (d, J=8.9 Hz, 1H), 9.22 (d, J=2.7 Hz, 1H); ESIMS found for C6H6N2O2S m/z 171.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH3:11])=[O:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([F:26])[C:24]=1F.Cl>CS(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]([O:10][CH3:11])=[O:9])[N:3]=1
Reactant: COC(=O)n1nc(O)cc1C
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 40 °C
Yield: 45.4 %

Procedure:
To a DMSO (15 mL) solution of methyl 3-hydroxy-5-methylpyrazole-1-carboxylate (1.56 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) was added 3-chloro-4,5-difluorobenzotrifluoride (2.21 g, 10.0 mmol), and the mixture was stirred under heating at 40° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid (30 mL) and extracted with ethyl acetate. The organic layers combined were washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The thus-obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give a white solid of methyl 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxylate (1.60 g, yield: 45.4%). Melting point: 123˜125° C., 1H-NMR (CDCl3, TMS, ppm): δ2.55 (d, J=0.8 Hz, 3H), 3.94 (s, 3H), 5.87 (d, J=0.8 Hz, 1H), 7.38 (dd, J=2.0 Hz, JHF=9.4 Hz, 1H), 7.50˜7.60 (m, 1H).
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Li+].[Li+].[CH2:24]([O:31][C:32](=[O:35])[CH2:33]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:31][C:32](=[O:35])[CH2:33][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1O
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cc1cc(Cl)ccc1O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,2′-Methylene-bis(4-chloro-phenol) (12 g, 44.6 mmol) is dissolved in DMF (100 mL). Lithium carbonate (3.3 g, 44.6 mmol) is added, followed by benzyl-2-bromoacetate (7.7 mL, 49 mmol). The suspension is stirred at 80° C. for 8 hours. Further benzyl-2-bromoacetate (1 mL, 6.4 mmol) is added and stirring continued at 100° C. for 4 hours. The reaction mixture is evaporated to dryness, water is added to the residue which is acidified to pH 1 with 2 M aqueous HCl and extracted with EtOAc. The organic layer is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash column chromatography over silica gel eluting with 4:1 iso-hexane:EtOAc. The product is suspended in iso-hexane, dissolved in the minimum volume of EtOAc, seeded and left to stand. The resultant solid is collected by filtration, washed with iso-hexane and dried to give [4-chloro-2-(5-chloro-2-hydroxy-benzyl)-phenoxy]-acetic acid benzyl ester; m.p.=135-137° C.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[C:8]1([C:6]2[N:7]=[CH:2][C:3]3[NH:20][C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:4]=3[N:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1nc(-c2ccccc2)nc2c1[nH]c1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(-c2ncc3[nH]c4ccccc4c3n2)cc1

Procedure:
A mixture of 4-Chloro-2-phenyl-5H-indolo[3,2-d]pyrimidine (650 mg), triethylamine (1.0 g), 10% palladium on carbon catalyst (110 mg) and ethanol (30 mL) was stirred under 1 atm of hydrogen for 1 h. The catalyst was filtered through celite and the ethanol is removed in vacuo. the residue is suspended in saturated ammonium chloride solution and the product was extracted with methylene chloride. After drying over magnesium sulfate the solvent was removed in vacuo to afford 2-Phenyl-5H-indolo[3,2-d]pyrimidine (Compound 4) after trituration with ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: BrCCC1CCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(CCC3CCOc4ccccc43)CC2)cc1
Yield: 45.7 %

Procedure:
The procedure of Example 1 is followed, but starting with 4-(2-bromoethyl)-3,4-dihydro-(2H)-benzopyran (5 g), 1-(4-nitrophenyl)piperazine (4.3 g) and from dry potassium carbonate (1.43 g), followed by potassium iodide (3.43 g) in 2-butanone (200 cc). The residue obtained is chromatographed on a column 4.4 cm in diameter, containing silica gel (100 g), using a dichloromethane-ethyl acetate mixture (50-50 by volume) as eluent, and collecting 20-cc fractions. The fractions between 100 and 300 cc are concentrated to dryness. The residue obtained is crystallized from isopropyl acetate (30 cc). 1-[2-(3,4-Dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(4-nitrophenyl)-piperazine (3.48 g) is thus obtained in the form of a yellow solid melting at 110° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([O:31][C:32]2[N:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[F:50][C:51]([F:64])([F:63])[C:52]1[NH:53][C:54]2[C:59]([CH:60]=1)=[CH:58][C:57]([CH2:61][NH2:62])=[CH:56][CH:55]=2>CN(C=O)C>[O:31]([C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:62][CH2:61][C:57]2[CH:58]=[C:59]3[C:54](=[CH:55][CH:56]=2)[NH:53][C:52]([C:51]([F:64])([F:50])[F:63])=[CH:60]3)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(Oc2ccccc2)nc1
Reaction time: 24 h
Yield: 16.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 6-(phenyloxy)-3-pyridinecarboxylic acid (Maybridge; 51.5 mg, 0.239 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge, the organic layer evaporated to dryness and purified using MDAP to give the title compound as a white solid (11 mg);
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH2:38][O:39][CH3:40])(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:43](O)C>O1CCCC1.ClCCl>[CH2:40]([O:39][CH2:38][CH2:37][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH3:43]
Reactant: COCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 99 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-[1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (320 mg, 0.55 mmol) in ethanol (4 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 5 h. The mixture diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (250 mg, 99%) which was used in the next step without further purification: LC/MS m/e calcd for C24H27FN2O4S [M+H]+ 459.56, observed 459.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([S:38][CH2:39][CH:40]([CH3:44])[C:41](O)=[O:42])(=[O:37])[CH3:36]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[N:9]([C:41](=[O:42])[CH:40]([CH3:44])[CH2:39][S:38][C:35](=[O:37])[CH3:36])[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: COC(=O)C1NCCS1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Temperature: 0 °C

Procedure:
2-Thiazolidinecarboxylic acid methyl ester (C.A. 53, 12,281d) (4.4 l g.) and 3-hydroxybenzotriazole (4.0 g.) are dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipitate is filtered off and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-(3-acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:6]([CH3:34])[CH:5]=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])=[CH:19][CH:20]=3)=[CH:13][CH:12]=[C:11]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:6]([CH3:34])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N3CCOC3=O)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
To a solution of ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate (67 mg, 0.15 mmol) in THF/H2O (1 mL, v/v=1/1) was added lithium hydroxide monohydrate (7 mg, 0.15 mmol). The mixture was stirred at room temperature for 6 h. THF was evaporated in vacuo. The residue was acidified to pH=5 with 5% hydrochloric acid, concentrated and purified by prep-TLC to afford the titled compound as a brown solid (24 mg, yield 39%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 ml) were added triethylamine (0.08 mL) and acetyl chloride (45 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (177 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I:22]I.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 85.7 %

Procedure:
To acetic acid (263.7 L, 6.8 rel vol) was charged 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (38.6 kg, 1 mol eq, limiting reagent), iodine (17.4 kg, 0.53 mol eq) and concentrated sulfuric acid (3.7 L, 0.1 rel vol). The temperature was adjusted to 50° C.-55° C. and 90% nitric acid (4.1 kg, 0.6 mol eq) charged over 15 minutes. The reaction was stirred until deemed to be complete as judged by HPLC analysis. The reaction was cooled, stirred and the product collected by filtration. The solid was washed twice with water (2×77.0 L, 2×2 rel vol) and acetone (2×38.6 kg, 2×1 rel vol). The solid was dried under vacuum to constant weight to yield the title compound (47.0 kg, 111.0 mol, 85.7%).