Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2cc(Br)cnc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.0 eq.) (see J. Am. Chem. Soc. 1957, 6421.) in DMF (0.2M) was added NaH (1.4 eq.). The mixture was stirred for 30 min then SEM-Cl (2.0 eq.) was added. The final mixture was stirred for 2 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with water (3×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 7:3) afforded the title compound as a foam.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([O:29][C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]5([C:42](=[O:50])[NH:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)[CH2:41][CH2:40]5)=[O:38])=[CH:32][C:31]=4[F:51])=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:52]>CCOC(C)=O>[ClH:52].[NH2:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([O:29][C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]5([C:42](=[O:50])[NH:43][C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)[CH2:40][CH2:41]5)=[O:38])=[CH:32][C:31]=4[F:51])=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:15]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)OC1(CCOc2ccc3c(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)cc4F)ccnc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)OC1(CCOc2ccc3c(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)cc4F)ccnc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-(2-(4-(2-fluoro-4-(1-(phenylcarbamoyl)cyclopropane-carboxamido)phenoxy)quinolin-7-yloxy)ethyl)cyclopropyl 2-(tert-butoxycarbonylamino)acetate (23 mg, 0.03 mmol) in EtOAc (1 mL) was added HCl (2 mol/L in EtOAc, 1 mL). The mixture was stirred at rt for 2 h, and then concentrated in vacuo to give the title compound as a white solid (15 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[OH:45][CH2:46][C:47](O)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([C:46](=[O:45])[CH2:47][OH:48])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was coupled with 2-hydroxyacetic acid (14 mg, 0.185 mmol) using HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.494 mmol) in DMF (2 mL) to get 60 mg (73.1%) yield of the title compound. MS: m/z=665.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O.C(O)(C)C>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:17])[C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(Oc2cc(Cl)c(N)c(Cl)c2)ccn1
Yield: 15 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (700 mg), N-chlorosuccinimide (0.44 g) and isopropanol (10 ml) were stirred at 80° C. for 1 hour. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate), to obtain 120 mg of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:14]([O-])=O.[Na+].O.O.Cl[Sn]Cl.C(Cl)Cl.CO>C(O)(C(F)(F)F)=O.O.Cl>[Cl:1][C:2]1[C:3]([S:9][CH2:10][CH2:11][CH2:12][Cl:13])=[C:4]([NH:5][NH2:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(Cl)c1SCCCCl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: NNc1cccc(Cl)c1SCCCCl
Temperature: 0 °C
Yield: 159.3 %

Procedure:
3-Chloro-2-[(3-chloropropyl)sulfanyl]aniline (4.2 g, 15.4 mmol) was dissolved in TFA (24 mL) at 23° C. With stirring concentrated HCl (24 mL) was added. This mixture was cooled in an ice bath. A solution of NaNO2 (1.17 g, 10 mmol) in water (6 mL) was added dropwise over 10 min. The internal temperature of the reaction was maintained at <5° C. during this addition, and then maintained at 0° C. for 1 h at which time it was transfered via cannula over 10 min to a stirred solution (8 mL) of SnCl2.2H2O (7.65 g, 34 mmol) in concentrated HCl cooled in an ice bath. The cooling bath was then removed and the reaction was allowed to warm to 23° C. for 1 h. It was recooled in an ice bath. Aqueous NaOH solution (50%) was added dropwise until pH>12 affording a heterogeneous product which was treated with CH2Cl2-MeOH (20:1, 250 mL). This mixture was filtered and the resulting two-phase filtrate was extracted with CH2Cl2 (2×200 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. to afford 3-Chloro-2-(3′-chloropropylthio)phenyl hydrazine (4.0 g, 90%) as a brown oil. The resulting oil was dissolved in CH2Cl2 (100 mL),and a stream of HCl gas was bubbled into this solution for 5 min. The resultant purple solid was isolated after evaporation of the solvent to afford 1-{3-chloro-2-[(3-chloropropyl)sulfanyl]phenyl}hydrazine hydrochloride and used without further purification. 1H NMR (CD3OD, 300 MHz) δ7.37 (t, 1H, J=8.0 Hz), 7.15 (dd, 1H, J=8.1, 1.1 Hz), 6.95 (dd, 1H, J=8.5, 1.1 Hz), 3.67 (t, 2H, J=6.3 Hz), 2.95 (t, 2H, J=7.0 Hz), 1.90 (quintet, 2H, J=6.6 Hz) ppm
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])=[O:15]>O.CO>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:18]([OH:20])=[O:19])[CH:11]=[CH:12][C:13]=1[S:14]([CH3:16])(=[O:2])=[O:15]
Reactant: CS(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of potassium permanganate (101 mg, 0.64 mmol) in water (1.83 mL) was treated with a solution of 2(R)-(3-chloro-4-methanesulfinyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (191.5 mg, 0.58 mmol) in methanol (5.8 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was diluted with methanol and then was filtered through a pad of celite. The filtrate was concentrated in vacuo and was azeotroped with acetonitrile. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 methylene chloride/methanol with glacial acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (87 mg, 43%) as an off-white foam: EI-HRMS m/e calcd for C15H17ClO5S (M−H2O)+ 326.0379, found 326.0378.
Reaction SMILES: C(OO[CH:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7]1)(=O)C.[K].[Cl:20][C:21]1[C:22]2[C:23]3[C:24](=[C:32]([CH3:35])[O:33][N:34]=3)[C:25](=[O:31])[NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.C(OCC)(=O)C.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>[Si:12]([O:11][CH:9]1[CH2:10][CH:6]([N:26]2[C:27]3[CH:28]=[CH:29][CH:30]=[C:21]([Cl:20])[C:22]=3[C:23]3=[N:34][O:33][C:32]([CH3:35])=[C:24]3[C:25]2=[O:31])[CH:7]=[CH:8]1)([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: Cc1onc2c1c(=O)[nH]c1cccc(Cl)c12
Reactant: CC(=O)OOC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1onc2c1c(=O)n(C1C=CC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 55 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-(t-butyldimethylsilanyloxy)cyclopent-2-enyloxy acetate (3.4 g, 13.3 mmol) in DMF (140 mL) was added tetrakis(triphenylphosphine)palladium (1.54 g, 1.3 mmol) and 9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one potassium salt (4.4 g, 16.2 mmol). The reaction mixture was stirred at 55° C. for 6 hours. It was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave desired product (5.7 g, 67%). 1H NMR (CDCl3, 400 MHz) δ; 7.83 (m, 1H); 7.22 (m, 2H); 6.50 (t, 1H); 5.84 (m, 2H); 4.85 (t, 1H); 2.82 (s, 3H); 2.78 (m, 1H); 2.02 (m, 1H); 0.81 (s, 9H); 0.02 (s, 3H); 0.00 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.[CH2:27]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][S:34][CH2:33][NH:32]1)[CH3:28]>C(Cl)Cl>[CH2:27]([O:29][C:30](=[O:36])[C@@H:31]1[CH:35]([C:12](=[O:14])[CH2:11][CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[S:34][CH2:33][NH:32]1)[CH3:28]
Reactant: CCOC(=O)[C@@H]1CSCN1
Reactant: O=C(O)CC1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a mixture of 2.85 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 13.45 g of WSC.HCl was added 45 ml of methylene chloride under ice-cooling. The mixture was stirred for 5 minutes at room temperature. To this was added a solution of 2.4 g of L-thioproline ethyl ester in 7 ml of methylene chloride at room temperature, and the mixture was stirred for a further 18 hours at the same temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 3.4 g of 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline ethyl ester as a colorless oil (yield: 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CC(N(C)C)=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]([CH3:26])[C:14](=[O:18])[CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc[nH]c(=O)c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CI
Product: Cc1ccccc1C(CC(=O)c1ccn(C)c(=O)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one (150 mg) in DMA (1 mL) was added potassium carbonate (58 mg) and methyl iodide (0.06 mL). The mixture was stirred at rt for 6 h, water and TBME were added. The phases were separated and the inorganic phase was extracted with TBME and EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:10 to EtOAc) to yield the title compound as a light yellow foam, MS (ESI+): m/z=410.2 ([M+H]+, 1Br).
Reaction SMILES: ClC1C=CC(C(=O)[CH2:7][CH:8]([CH3:11])[CH:9]=O)=CC=1.S(C1[CH:25]=[CH:24][C:22]([NH2:23])=CC=1)(=O)(=O)N>>[CH2:7]([N:23]([CH:22]=[CH:24][CH3:25])[CH2:9][CH:8]([CH3:7])[CH3:11])[CH:8]([CH3:11])[CH3:9]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C=O)CC(=O)c1ccc(Cl)cc1
Product: CC=CN(CC(C)C)CC(C)C

Procedure:
Following a procedure similar to that described in Example 64(iii), but using 2-(4-chlorophenacyl) propionaldehyde [prepared as described in step (ii) above] and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale brown powder (yield 35%), melting at 196-198° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31]C(=O)C)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=O)C>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)Oc1ccc(CCc2ccc(OC(C)=O)cc2)cc1
Agent: O=C(O)c1cccc(C(=O)O)c1
Product: Oc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 250 °C

Procedure:
A charge consisting of 8.2 parts of isophthalic acid and 14.8 parts of 1,2-bis(4-acetoxyphenyl)ethane is placed in a reaction vessel equipped with a stirrer, condenser and receiver. The vessel is evacuated and purged with nitrogen three times. A nitrogen blanket is maintained in the reactor while it is heated to 250° C. for about three hours during which period approximately 3.5 to 4.0 parts of acetic acid distills. Thereupon the vessel is evacuated to a pressure of about 125 mm and heating at 275° C. is continued for one half hour during which period an additional 1 to 1.5 parts of acetic acid distills. The vacuum is then increased to reduce the pressure to about 0.1 to 0.2 mm and the temperature is raised to 290° C. for an additional hour. At this point the reaction mixture becomes so viscous that further stirring is difficult. Heating is stopped, the reaction mixture is again blanketed with nitrogen and allowed to cool. The resultant polymer is light yellow in color, crystalline and demonstrates an inherent viscosity of 0.57 in the phenol-tetrachloroethane solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][O:35]3)=[O:23])=[CH:17][C:9]1=2
Reactant: NCC1CCCO1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCC1CCCO1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z=530.97 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[C:42]([CH:46]=O)[NH:43]2)=[CH:39][CH:38]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[C:42]([CH:46]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH:43]2)=[CH:39][CH:38]=1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC=Cc1cc2ccc(Cl)cc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of Pentyl-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes. A solution of 6-Chloro-1H-indole-2-carbaldehyde in THF was added to the reaction mixture and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of acetic anhydride are added in the cold to a suspension of 30 g (0.22 mole) of 1-(3-aminophenyl)ethanone in 200 ml of toluene, and the mixture is stirred for 1 h at room temperature, then heated for 1 h to 60° C. and left to stand overnight. The precipitate obtained is drained, ground in ether and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>CO.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1ccc(N3CCOCC3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a light orange, homogeneous solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (0.1705 g, 0.302 mmol) in methanol (3.59 mL) and THF (10.78 mL) was added LiOH (0.029 g, 1.208 mmol) in water (5.44 μL, 0.302 mmol). After 1.5 hr, the reaction was concentrated in vacuo. Water was added to the residue and acidified to pH ˜6 with 1 N aqueous HCl. The insoluble material was filtered and dried over Drierite to give the desired product (0.14098 g, 0.263 mmol, 87% yield) as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH-].[K+]>C(COC)OC>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 89 %

Procedure:
1-(p-toluenesulphonyl)indole was prepared according to the procedure described in Y. Kikugawa Synthesis 1981, 460-461, by reaction of indole with p-toluenesulphonyl chloride in the presence of potassium hydroxide in dimethoxyethane at ambient temperature for 30 minutes. Yield: 89%.
Reaction SMILES: [F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=O)[CH2:6][CH2:5][C:4]1([F:11])[F:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=[S:32])[CH2:6][CH2:5][C:4]1([F:11])[F:10]
Reactant: O=C1CCC(F)(F)[C@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 172.9 %

Procedure:
To a solution of (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidin-2-one (1.00 g, 3.08 mmol) in toluene (5 mL) was added Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithia-diphosphetane-2,4-disulfide) (686 mg, 1.70 mmol). The mixture was stirred at 100° C. for 2 hours. TLC analysis showed no starting material remained. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=5:1) to give (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidine-2-thione (1.00 g, 2.94 mmol, 95.4% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(Cl)CCl>CN(C=O)C>[CH3:23][N:24]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: CN(c1ccncc1)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N(C)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (53 mg, 0.17 mmol) and 4-(N-methyl-N-pyridin-4-yl-amino)phenylamine (47 mg, 0.24 mmol) in DMF (3 mL), EDC (73 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (28 mg). MS 500.2 and 502.2 (M+H, Cl pattern).