Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][Mg+].[Br-].B(F)(F)F.CCOCC>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:2]1([C:1]2([NH2:8])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Product: NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To benzonitrile (1.03 g, 10 mmol) in ether (50 ml) at −70° C. was added Ti(OiPr)4 (3.22 ml, 11 mmol) and EtMgBr (3M in ether, 7.34 mL, 22 mmol) dropwise, the resulting yellow suspension was warmed up to room temperature over 1 h. After stirring for additional 30 min, the dark brown solution was added BF3.Et2O (2.47 mL, 20 mL) at room temperature. The mixture was further stirred for 1 h, and was quenched by 1N HCl (30 mL) and 5N NaOH (30 mL), the suspension was extracted with ether, ether layer was combined, concentrated to give crude residue, which was purified by column (Hexanes/EtOAc, 2:1 to 1:9) to give 1-phenylcyclopropanamine (420 mg).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([O:17]C)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.C>O>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C@H:14]([CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
Methyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl )amino]- 3-methylbutanoate hydrochloride (7164 g, 16.7 mol) is added to a solution of water (27 L) and concentrated hydrochloric acid (9 L), and heated to 120° C. for 3 days. After cooling down to room temperature, charcoal (350 g) is added, stirring is continued for 45 minutes, the reaction is filtered, and the solvent is evaporated. The crude solid is re-dissolved in methanol (7.1 L) and ethyl acetate (73 L), and cooled to 3° C. for 2 hours. The precipitated product is collected by filtration to give 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8]C(=O)C)=[CH:4][CH:3]=1.[F:12][C:13](I)([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].O.CCOCC>CS(C)=O.[Cu].II>[F:24][C:19]([F:25])([C:20]([F:21])([F:22])[F:23])[C:18]([F:26])([F:27])[C:17]([F:28])([F:29])[C:16]([F:30])([F:31])[C:15]([F:33])([F:32])[C:14]([F:35])([F:34])[C:13]([F:12])([F:36])[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: II
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(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)cc1
Temperature: 105 °C
Yield: 66.7 %

Procedure:
To a solution of acetic acid 4-iodo-phenyl ester (9 gm, 0.0366 mol) in anhydrous DMSO (75 mL) was added copper powder (5.8 g, 0.091 mol), perfluorooctyl iodide (25 g, 0.046 mol) and iodine (130 mg). The reaction mixture was heated to 105° C. for 18 hr, cooled, combined with 100 ml water and 50 ml ether and filtered to remove insoluble copper salts. The organic and aqueous layers in the filtrate were separated, and the aqueous layer extracted twice with ether (2×100 mL). The combined organics were washed with water and brine, dried over MgSO4, and concentrated. To a solution of the crude product in 50 mL methanol was added 1.5 mL 10N HCl. The mixture was refluxed on a steam bath for 1 hr to hydrolyze the acetate completely to the phenol. After cooling to room temperature, the reaction mixture was poured into a separatory funnel containing 100 mL water, and extracted with ether (3×75 mL). The combined organics were washed with water and brine and dried over MgSO4. Recrystallization of the crude concentrate gave 12.5 g of the phenol at 99% purity by HPLC as a waxy solid mp 63-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([C:17]([CH3:19])=O)=[CH2:16].P(=O)(O)(O)O.[As](=O)(O)(O)O>>[CH3:11][O:10][C:9]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:8]=1[C:17]([CH3:19])=[CH:15][CH:16]=[N:7]2
Reactant: C=CC(C)=O
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Agent: O=P(O)(O)O
Agent: O=[As](O)(O)O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Yield: 30 %

Procedure:
Compound II was treated with commercially-available methyl vinyl ketone in the presence of phosphoric acid and arsenic acid to afford the intermediate 5,6-dimethoxy-4-methyl-8-nitroquinoline (III), a new compound, as a pure crystalline material in 30% yield. This successful reaction is novel in that the steric hindrance provided by the 2-methoxy group of 4-amino-5-nitroveratrole and by the methyl group of methyl vinyl ketone would be expected by those skilled in the art to prevent the ring-closure reaction to form III from occurring.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Br:17]Br>CCOCC>[Br:17][CH2:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: CC(=O)c1cc2cc(C(C)(C)C)ccc2o1
Reactant: BrBr
Solvent: CCOCC
Product: CC(C)(C)c1ccc2oc(C(=O)CBr)cc2c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2-Acetyl-5-tert-butylbenzofuran (86.5 g) was dissolved in 800 ml of ether and, with stirring at room temperature, 63.9 g of bromine was dropped thereinto. When the crystals started to be separated, the reaction mixture was cooled with ice water. After completion of the dropping, the mixture was stirred for 30 minutes, the reaction mixture was poured into ice water and, until the crystals were dissolved, ethyl acetate was added thereto. The organic layer was washed with water for three times, dried over anhydrous magnesium sulfate, concentrated in vacuo and n-hexane was added to the residue to crystallize followed by filtrating to give 100.1 g of crystals. M.p. 100°-102° C.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[CH3:15][NH:16][CH3:17]>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:15][N:16]([CH3:17])[C:12](=[O:14])[CH2:11][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1ccc(CC(=O)O)cc1
Reaction time: 3 h
Yield: 8.5 %

Procedure:
N,N'-Carbonyldiimidazole (11.4 g) was added to a stirred solution of 1,4-phenylenediacetic acid (11.4 g) in dry dimethylformamide (300 ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 2 h as dimethylamine gas (about 10 g) was bubbled through. The reaction mixture was then stirred at 20° for 3 h and evaporated in vacuo to leave a brown oil which was diluted with saturated K2CO3 solution (50 ml). The resulting mixture was evaporated in vacuo to leave an off-white solid which was triturated with EA (2×200 ml). The organic phase was discarded and the aqueous phase was acidified (pH1) with 5M hydrochloric acid to precipitate an off-white solid which was triturated with absolute ethanol (25 ml) and filtered to give the title compound (1.1 g) as a fine white solid m.p. 163°-165° (softening at 160°).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)phenol (1.16 g), ethyl 4-bromo-3-methoxy-2-pentenoate (prepared in accordance with the procedure of Example 10) (1.74 g) and potassium carbonate (0.73 g) in DMF (5 ml.) is heated at about 130° for 2 hours. Thereafter, DMF is removed. The residue is filtered and washed with methylene dichloride. The filtrate is washed, dried and evaporated to dryness. The oily residue is subjected to prep. thin layer chromatography using 20% ethylacetate/hexane to yield the ethyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid, MS m/e 444 (M+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: OCc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(CO)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24.8 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 5-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 106 mg of the target compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]1[O:15][CH:13]1[CH3:14].[CH2:16](N(CC)CC)C>>[CH3:14][CH:13]1[C:12](=[O:15])[C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:16]1
Reactant: COC(=O)c1ccccc1O
Reactant: CCN(CC)CC
Reactant: CC1CO1
Product: CC1COc2ccccc2C(=O)C1=O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a one liter, stainless steel autoclave was added 535 g. (3.52) of methyl salicylate (III) and 6.0 g. triethylamine. The resulting mixture was heated at 120° C, while 260 g. (4.5 moles) of propylene oxide was added over a one hour period. The reaction mixture was then heated up to 150° C and allowed to digest for 8 hr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:24])[CH3:23].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.CCOC(C)=O>[C:27]([NH:26][N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1)[CH:22]([CH3:24])[CH3:23])(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccncc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.70 mmol), N′-isopropylisonicotino hydrazide (188.2 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) for refinement and dried so that ivory (E)-tert-butyl 3-(3-(2-isonicotinoyl-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (108 mg, 34.4%).
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].[Na+].[Cl-]>C(O)CO>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Cc1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
Following a standard procedure (Balasubramanian, T. et al, J. Org. Chem. 2000, 65, 7919-7929), a mixture of 6 (6.81 g, 29.7 mmol) and ethylene glycol (76.0 mL) in a 250-mL Claisen flask was flushed with argon for 10 min, and then powdered NaOH (3.05 g, 76.2 mmol) was added. The flask was placed in an oil bath at 120° C. and the oil bath temperature was raised to 160° C. After 2.5 h, the flask was cooled to room temperature and 10% aqueous NaCl (150 mL) was added. The aqueous layer was extracted with CH2Cl2. The organic layers were collected, washed with 10% aqueous NaCl, dried (Na2SO4), concentrated, and chromatographed (silica, CH2Cl2) to give a light brown solid (3.33 g, 71%): mp 92-93° C.; 1H NMR δ 2.34 (s, 3H), 6.51-6.54 (m, 1H), 6.82-6.84 (m, 1H), 7.05-7.08 (m, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 8.15-8.32 (br, 1H); 13C NMR δ 21.3, 106.7, 114.4, 119.0, 125.1, 125.4, 129.5, 133.1, 135.2; FAB-MS obsd 157.0885, calcd 157.0891 (C11H11N).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]([C:9]1[NH:25][C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:11]=2[CH:10]=1)=O.C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH:17][C:16]1[C:11]2[CH:10]=[C:9]([C:7]#[N:6])[NH:25][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
13 ml of phosphorus oxychloride are added to 1.048 g (3.6 mmol) of 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see Stage 10.1) and 0.7 ml of N,N-dimethylacetamide. After stirring at RT for 1 h and at 100° C. for 4 h, the reaction mixture is poured into an ice-cooled saturated solution of NaHCO3. Extraction with ethyl acetate (3 times), washing the organic layers with saturated NaHCO3 solution, water and saturated sodium chloride solution, drying (Na2SO4) and concentrating leads to a solid. Column chromatography (SiO2; ethyl acetate), and stirring the crude product in diethyl ether and hexane yields 4-(3-chloroanilino)-6-cyano-7H-pyrrolo[2,3-d]pyrimidine; m.p. 284-287° C.; TLC-Rf=0.71 (CH2Cl2/methanol [10:1]);HPLC: tRet(Grad20)=11.8.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1>>[C:1]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 63.8 %

Procedure:
In a manner similar to that described in Example 3, butyryl chloride (0.033 g, 0.00031 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.042 g of 4-[4-(butyrylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) M+264.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:17](=[O:19])=[O:18]>C1CCCCC1.C1COCC1.O>[F:8][C:4]1[N:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:17]([OH:19])=[O:18]
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1F
Reaction time: 2 h
Yield: 97 %

Procedure:
2,6-Difluoropyridine (7.89 mL, 0.087 mmol) is added dropwise under N2 at 78° C. to a stirred solution of lithium diisopropylamide (59.0 mL of a 1.5N solution in cyclohexane, 0.089 mmol) in THF (250 mL). After 2 h at 78° C., a stream of dry CO2 is passed through the solution and the mixture is diluted with water and washed with EtOAc. The aqueous portion is neutralized with 3N HCl, extracted with EtOAc and worked up to give 2,6-difluoronicotinic acid (13.4 g, 97%). 1H NMR (DMSO) δ 8.59 (1H, dd, J=9.2, 8.2 Hz), 7.30 (1H, dd, J=8.2, 2.1 Hz), 4.03 (1H, brs).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:37]#[C:36][CH2:35][O:34][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: C#CCOC
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=S)[CH2:33]C)[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH3:3].C(Cl)(=[O:42])C>C(N(CC)CC)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:42])[CH3:33])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:17][CH2:18]2)=[O:12])=[CH:38][CH:39]=1)[CH3:3]
Reactant: CC(=O)Cl
Reactant: CCC(=S)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)COc4ccc(CN(C)C)cc4)CC3)c(F)c2)C(=O)O1

Procedure:
As described for the preparation of 27, the reaction of 26 (prepared from 264 mg of 25) with acetyl chloride and triethylamine gave the acetamide which was purified by silica gel chromatography with 5% MeOH-0.5%NH4OH—CH2Cl2 followed by crystallization from Et2OAc to give 73 mg of 29, a white solid; 1HNMR [300 MHz, (CD3)2SO] δ 1.81 (s, 3H), 2.45 (s, 6H), 2.93. 3.00 (s, s, 4H), 3.38 (t, 2H), 3.60 (s, 4H), 3.68 (dd, 1H), 3.85 (s, 2H), 4.06 (t, 1H), 4.69 (m, 1H), 4.88 (s, 2H), 6.94 (d, 2H), 7.06 (t, 1H), 7.16 (dd, 1H), 7.33 (d, 2H), 7.49 (dd, 1H), 8.24 (t, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethyl-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=0.91 min; Mass spectrum (ESI+): m/z=484 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[NH2:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH:3]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(N)cc(NCCNC(=O)OC(C)(C)C)n1
Temperature: 180 °C

Procedure:
6-Chloro-2-methylsulfanyl-pyrimidin-4-amine (176 mg, 1 mmol) was dissolved together with tert-butyl N-(2-aminoethyl)carbamate (200 mg, 1.25 mmol) and triethylamine (174 μl, 1.25 mmol) in THF (2 ml). The mixture was stirred at 180° C. under microwave heating for 8 hours. The mixture was diluted with ethyl acetate and the resulting solution was washed with a solution of sodium bicarbonate (5%) and brine, dried over magnesium sulfate, the volatiles were removed under reduced pressure. The residue dissolved in DCM and purified by filtration over silica to yield 105 mg (0.35 mmol, 35%) MS (ESI) m/z=300.2 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.C(O)C.[OH-].[K+:20].[K+].NC1[C:31]2[C:26](=C[CH:28]=[CH:29][CH:30]=2)[NH:25]C=1C([O-])=O>O.C(#N)C>[K+:20].[N:25]1[CH:26]=[CH:31][C:30]([NH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:4]([O-:3])=[O:5])=[CH:29][CH:28]=1
Reactant: Nc1c(C(=O)[O-])[nH]c2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 140 %

Procedure:
Charge a mixture of 7.50 kg (26.66 mol) of 3-amino-1H-indole-2-carboxylic acid ethyl ester, 37.5L of ethanol and 37.5 L of 4M KOH to a 30-gal reactor and heat to 75° C. over 30 min. Monitor the progress of the reaction by HPLC (Column—150×3.9 mm Waters Symmetry C18, 5 micron; mobile phase—20% acetonitrile/80% 0.1% TFA in water; flow rate—1.0 mL/min; wavelength—225 nm; RT: 3-amino-1H-indole-2-carboxylic acid potassium salt—3.3 min; 3-amino-1H-indole-2-carboxylic acid ethyl ester—6.0 min). Typically achieve, a 100% conversion within 3 h. Cool the mixture to 25° C. over 2 h and concentrate at 50–60° C./50 torr to a residue. Add a total of 37.5 L of water and heat the mixture to and hold at 85° C. for 30 min. Cool the mixture to 10° C. over 2 hours, and then further cool to and hold at 5° C. for 2 hours. Filter off the solid that forms, wash with a total of 10 L of 4M KOH solution and air dry. Further dry the solid at 35° C. in a forced air oven for 72 h to give 10.9 kg, 140% yield of the title compound: HPLC analysis 70.7% pure.