Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH:5]([CH3:29])[N:6]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([CH3:28])[CH:21]=1)(=[O:19])=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12.B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:6]2[CH:5]([CH3:29])[C:4]3[C:3]([OH:2])=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:19])=[O:18])=[CH:21][C:22]=1[CH3:28]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cccc(OC)c3C2C)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)N2c3ccccc3-c3cccc(O)c3C2C)ccc1O
Yield: 51.4 %

Procedure:
The title compound was prepared from 7-methoxy-5-[(4-methoxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.21 g, 0.51 mmol), tetrabutylammonium iodide (0.47 g, 1.3 mmol), and 1 M boron trichloride in dichloromethane (3.1 mL, 3.1 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 3:2 gradient), followed by trituration from dichloromethane, to yield 5-[(4-hydroxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridin-7-ol as a homogeneous solid (0.10 g, 53%), m.p. 258° C.;
Reaction SMILES: [H-].[Na+].CS([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)(=O)=O.[CH2:25]([CH:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][OH:29])[CH3:26]>[Cl-].[Na+]>[CH2:25]([CH:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][O:29][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)[CH3:26]
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: CCCCC(CC)CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CCCCC(CC)COc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Sodium hydride (60% content, oil dispersion, 0.80 g) was added to a mixture of 4'-methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol) and 2-ethyl-1-hexanol (1.30 g, 0.010 mol) over a period of about 10 minutes. After stirring for 30 minutes at room temperature, the reaction mixture was refluxed and further reacted for 4 hours. After cooling to room temperature, the reaction mixture was poured into an aqueous 4M sodium chloride solution (0.3 liter). The crystal that precipitated was taken out by filtration under suction and then washed with water and hexane. The crystal was dried under reduced pressure (0.1 mm Hg) and then recrysallized from hexane to obtain 3.07 g of the above-entitled product (T-4) as a white crystal. Yield: 85%. m.p. 58.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11](OCC)=[O:12])[CH3:10])[C:5]([N+:16]([O-])=O)=[CH:4][C:3]=1[C:19]1[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.[Sn].Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:19]2[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=2)=[CH:4][C:5]2[NH:16][C:11](=[O:12])[CH:9]([CH3:10])[O:8][C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CC1Oc2cc(Cl)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc2NC1=O
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To 10 ml of ethanol, 0.90 g (2.0 mmol) of 3-[2-chloro-4-(1-ethoxycarbonylethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1 g (8.5 mmol) of tin were added, and 2 ml of concentrated hydrochloric acid was added thereto with stirring at room temperature, followed by stirring for 1 hour. After completion of the reaction, excess ethanol was distilled off under reduced pressure, and the residue was neutralized with a saturated sodium hydrogencarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure to obtain 0.7 g (yield: 91%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12]O.S(=O)(=O)(O)O>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Combine 4-bromo-2-fluorobenzoic acid (10 g, 45.7 mmol), methanol (100 mL), and concentrated sulfuric acid (5.0 mL). Heat to reflux. After 16 h, cool to room temperature and evaporate in vacuo to afford a white solid. Dissolve the solid in ethyl acetate (about 40 mL), extract with 2×80 mL saturated aqueous sodium bicarbonate and 1×80 mL brine, dry over MgSO4, filter, and evaporate in vacuo to yield 9.32 g (88%) of methyl 4-bromo-2-fluorobenzoate as a white solid. 1H NMR (d6-DMSO, 300 MHz) 8.80 (t, J=8.4 Hz, 1H), 7.72 (dd, J=10.8 Hz, 1.8 Hz, 1H), 7.54 (ddd, J=8.4 Hz, 1.8 Hz, 0.6 Hz, 1H), 3.83 (s, 3H); IR (cm−1, KBr): 3010, 2995, 1723, 1603, 1484, 1438, 1406, 1294, 1277, 1095, 885; Anal calc'd for C8H6BrFO2: C, 41.23; H, 2.60; Found: C, 40.97; H, 2.61.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.N#N>C([O-])([O-])=O.[Na+].[Na+].C(#N)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>[Cl:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1ccc(-c2ncccc2Cl)cc1
Temperature: 85 °C

Procedure:
A solution of 2,3-dichloropyridine (0.9663 g, 6.5 mmol), p-tolylboronic acid (0.8569 g, 6.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3618 g, 0.31 mmol) in 0.5 M Na2CO3 (25 mL) and acetonitrile (25 mL) was flushed with N2, sealed and heated at 85° C. for 16 hours. The reaction mixture was cooled to room temperature and the volume reduced by half under vacuum. The concentrate was extracted with dichloromethane (3×20 mL), dried (MgSO4) and condensed to yellow-green oil. The residue was purified by column chromatography, eluted with hexanes:ethyl acetate:dichloromethane (7:2:1)) to provide the title compound as a yellow-orange oil. MS (ESI+) m/z 203 (M+H)+; 1H NMR (DMSO-d6) δ 2.38 (s, 3H), 7.30 (d, J 8.2, 2H), 7.42 (d, J 8.2, 1H), 7.59 (d, J 8.2, 2H), 8.03 (d, J 8.1, 1H), 8.62 (d, J 6.1, 1H); Anal. Calc'd for C12H10ClN.0.1H2O: C, 70.15; H, 5.00; N, 6.82. Found: C, 70.06; H, 4.67; N, 6.67.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.[C:18](#[N:21])[CH:19]=[CH2:20]>>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:20][CH2:19][C:18]#[N:21])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2)cc1
Reactant: C=CC#N
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
A mixture of (E)-3-(4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (1.0 g, 4.3 mmol), acrylonitrile (1.1 g, 22 mmol) and silica gel (4 g, grade 62 60-200 mesh 150 Å) was stirred at room temperature for 24 h. The reaction mixture was purified via silica gel column chromatography to give (E)-3-{4-[1-(2-cyano-ethyl)-pyrrolidin-2-yl]-phenyl}-acrylic acid methyl ester (1.2 g, 98%) as a colorless oil. LCMS (m/z): 285.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](OC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
An 18-mL vial was charged with methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate (20.7 mg, 0.053 mmol) and THF (2 ml). To the mixture was added LiAlH4 (20 mg, 0.53 mmol, 10 eq.) portion-wise at 0° C. After the addition was complete, the resulting mixture was stirred under Ar at rt overnight. 2N HCl aq. (2 ml) was added followed by saturated NaHCO3 aq. The mixture was extracted with ethyl acetate (3×5 ml). The organic layer was combined and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent to afford the desired product (15 mg), of which 1H NMR indicates it contains impurities. The product thus obtained was re-purified by chromatography on silica gel using DCM followed by DCM/EA with a ratio of 9:1 to 2:1 in favor of DCM as eluent to give 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]ethanol (3.5 mg, 18% yield). MW=264.87. 1H NMR (CDCl3, 360 MHz) δ 7.84 (m, 2H), 7.41 (m, 3H), 7.21 (m, 3H), 7.16 (s, 1H), 5.95 (brs, 1H), 3.90 (m, 2H), 3.18 (m, 2H), 2.87 (m, 4H), 2.24 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][OH:28])[N:16]=[C:15]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][OH:38])[CH:14]=2)=[CH:8][C:7]=1[CH3:39].Cl.O.C(OCC)(=O)C>C1COCC1.C(O)C.[OH-].[Na+]>[OH:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]#[C:19][C:17]1[CH:18]=[C:13]([S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:40])=[O:2])=[C:7]([CH3:39])[CH:8]=2)[CH:14]=[C:15]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][OH:38])[N:16]=1
Reactant: COC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3CO)nc(C#Cc3ccccc3CO)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Sc2cc(C#Cc3ccccc3CO)nc(C#Cc3ccccc3CO)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[2,6-Bis-(2-hydroxymethyl-phenylethynyl)-pyridin-4-ylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (51 mg; 0.090 mmol) was dissolved in a mixture of THF and ethanol (2:1) (10 ml) and 1N sodium hydroxide (0.5 ml) was added. The reaction mixture was stirred for about 1 h and 1N aqueous hydrogen chloride (3 ml), water (10 ml) and ethyl acetate (20 ml) was added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (10 ml). The pooled organic phases were washed with water (10 ml), dried and evaporated to dryness. The crude product was purified by prep. HPLC to give {4-[2,6-bis-(2-hydroxymethyl-phenylethynyl)-pyridin-4-ylsulfanyl]-2-methyl-phenoxy}-acetic acid. Yield: 23 mg.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH2:15][C:16]([NH2:18])=[O:17])[CH:2]=[CH2:3].[CH2:19]([O:22]N1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O)C=C>>[CH2:1]([O:4][N:5]1[C:19](=[O:22])[N:10]2[CH2:11][C@H:6]1[C:7]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCONC1CN[C@@H](C(N)=O)C=C1CC(N)=O
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C(CC(N)=O)=C[C@H]2C(N)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from (R)-5-(allyloxyamino)-4-(2-amino-2-oxoethyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 177, 132 mg, 0.52 mmol) following the procedure described for Intermediate 16. The reaction mixture was stirred at 0° C. for 2 h. The volatile was removed under vacuum and the crude was subjected to silica column eluting with 0-100% ethyl acetate/hexanes and then 95% ethyl acetate/5% MeOH to give a pale yellow solid. 62 mg, 43%.
Reaction SMILES: [F:1][C:2]([F:28])([C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])C(O)=O.[Br:29]Br.FF>>[F:1][C:2]([Br:29])([F:28])[C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Yield: 142.9 %

Procedure:
Perfluorononanoic acid 100 g (0.215 mole), bromine 21.0 g (0.129 mole) and Freon 113 (500 ml) were mixed in the plastic reactor. The mixture was treated with fluorine in the same manner as described in Example 1. Approximately 1.7 fold excess fluorine was used, producing 92 grams of perfluorooctyl bromide (86% yield). Thus, using approximately half the amount of bromine as used in Example 1 produced a lower yield of the perfluoroalkyl halide.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[O:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.[OH-].[K+].O>CCO>[CH:14]1([O:13][C:5]2[C:6]([CH3:12])=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[C:3]([OH:18])=[O:2])[CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(CO)cc(C)c1OC1CCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CO)cc(C(=O)O)c1OC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
2-Cyclobutoxy-5-hydroxymethyl-3-methyl-benzoic acid methyl ester (410 mg, 1.64 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.90 g, 32.8 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 1 h then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with conc. HCl then extracted with EtOAc (3×10 mL). The combined organic layers are dried over anhydrous MgSO4 and concentrated in vacuo to give product (284) as viscous yellow oil (387 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]([O:16][CH:17]1[CH2:20][NH:19][CH2:18]1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]([O:16][CH:17]1[CH2:20][N:19]([C:32]([NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:18]1)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: CS(=O)(=O)c1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylsulfonyl)benzhydryloxy]azetidine (171) (222 mg, 0.58 mmol) in anhydrous DCM (7 mL) was added molecular sieves and tert-butyl isocyanate (68 μL, 0.58 mmol). After shaking at ambient temperature for 16 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (24 mL) and evaporation afforded the desired product as a pale yellow solid (188 mg, 67%).
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](O)C(=O)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-hydroxypropionate G-3 (5 mmol) in DCM (5 mL) was added pyridine (15 mmol), the reaction was cooled to −20° C., then triflic anhydride was added (7.5 mmol). The solution was stirred for 1 hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then dried (Na2SO4) and concentrated. The intermediate triflate was then resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(R)-fluoropropionate G-4.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH3:24])=[O:10].[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])=[N:13][C:12]=3[CH2:23][CH3:24])=[O:10])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: CCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (174 mg, 0.5 mmol) and 6-morpholin-4-yl-pyridin-3-ylamine (90 mg, 0.5 mmol) in 5 mL of acetonitrile was stirred at 85° C. overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30 min) to yield 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (107 mg, 52% yield) as a light yellow solid. LCMS calcd for C21H21ClN4O3 (m/e) 412, obsd 413 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]([C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:28]=2)=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Br)c(Br)c(Br)c(Br)c2C(=O)O)ccc1Cl
Yield: 87 %

Procedure:
Tetrabromophthalic anhydride (7.03 g, 0.015 mole), 1-methylethyl 5-amino-2-chlorobenzoate (3.24 g, 0.015 mole) and toluene (about 150 ml) were heated almost to reflux over 30 minutes. The reaction mixture was cooled and filtered to give the title compound, m.p. 169°-171° C. (decomp.) (8.92 g, 87% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[N:3]1.Cl[Sn]Cl>Cl>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[CH:10]=1
Reactant: Cn1nnc2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cn1nnc2cc(N)ccc21
Yield: 68.7 %

Procedure:
1-Methyl-5-nitrobenzotriazole (0.7 g) was reduced by SnCl2 (4.0 g) at 0° C. in 5 mL of conc. HCl. The pH of the reaction mixture was adjusted to basic and the mixture was extracted with EtOAc. The product 5-amino-1-methylbenzotriazole (0.4 g) obtained after removal of the solvent was used for the next reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=4)[CH:27]([C:39]4[CH:44]=[CH:43][C:42]([NH:45][C:46]([C@H:48]5[CH2:52][CH2:51][CH2:50][N:49]5C(OC(C)(C)C)=O)=[O:47])=[CH:41][CH:40]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:17]=1)=O)(C)(C)C.[ClH:60]>O1CCOCC1>[ClH:60].[C:35]([C:32]1[CH:31]=[CH:30][C:29]([N:28]2[CH:24]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[N:17]=[C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[NH:14][CH:15]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26][CH:27]2[C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([C@H:48]3[CH2:52][CH2:51][CH2:50][NH:49]3)=[O:47])=[CH:43][CH:44]=2)=[CH:34][CH:33]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)N2c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(c3ccc(NC(=O)[C@H]4CCCN4)cc3)CCC2c2ccc(-c3c[nH]c([C@@H]4CCCN4)n3)cc2)cc1

Procedure:
The product from Example 40E (610 mg, 0.76 mmol), in 2M hydrochloric acid in dioxane solution (10 mL) was reacted according to the procedure in Example 39I to provide the title compound (495 mg) as a hydrochloride salt and a mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([OH:11])=[O:10])[N:3]=1.[NH2:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.C(=O)([O-])[O-].[Na+:23].[Na+]>O>[Na+:23].[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[CH:5]=[C:4]([C:9]([O-:11])=[O:10])[N:3]=1
Reactant: O=C(O)c1cc(Cl)nc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2cc(C(=O)[O-])nc(Cl)n2)n[nH]1
Yield: 57.1 %

Procedure:
A mixture of 2,4-dichloropyrimidin-6-yl carboxylic acid (Method 45) (528 mg, 2.73 mmol), 3-amino-5-methylpyrazole (279 mg, 2.87 mmol) and sodium carbonate (578 mg, 5.46 mmol) was heated in water (10 ml) at 50° C. for 18 hours. The mixture was allowed to cool and the product was collected by filtration, washed with water and dried to give the title compound (430 mg, 77%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13]([CH:21]=[CH:22][CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1.O>N(CCO)(CCO)CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][N:9]1[CH2:25][CH2:24][C:12]2[N:13](/[C:21](/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:22]\[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=3[C:11]=2[CH2:10]1
Reactant: CC=Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C/C=C(/c1ccccc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 100 °C
Reaction time: 14 h
Yield: 39.5 %

Procedure:
Iodo benzene (0.5 g, 2.4 mmol) and 2,8-dimethyl-5-(prop-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (588 mg, 2.4 mmol) were charged in triethanolamine (4 mL). Palladium (II)acetate (5 mg, 0.024 mmol) was added and stirred at 100° C. for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added. The desired compound was extracted with diethyl ether twice. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 0.3 g of product. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.18 (m, 3H), 6.96-6.82 (m, 4H), 6.62 (m, 1H), 4.66 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.42 (m, 1H), 3.0 (s, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.36 (s, 3H), 1.50 (d, 3H).