Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH3:15].[OH-].[K+].Cl>C(O)C.O>[CH3:15][O:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Commercially available 4-hydroxy benzoic acid (10.0 g, 72.4 mmol) and 2-chloroethylmethylether (13.7 g, 144 mmol) wer added to a stirred, room temperature solution of KOH (8.12 g, 144 mmol) in ethanol (90 mL) water (10 mL) and the resulting yellow solution was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated to provide a light yellow powder. The reaction mixtur was diluted with water (100 mL) and addtional KOH (5 g, 89 mmol) was added and the reaction mixture was heated at reflux for two hours. The reaction mixture was cooled to 0° C., and neutralized with 2M HCl (100 mL). The precipitate was filtered and the off white powder (15.5 g) was chromatographed (silica gel, elutent 95:5/methylene chloride: methanol) to provide the title compound as a white powder (8.73 g, 54%): 1HNMR (CDCl3) δ3.37 (s, 3H), 3.69 (t, J=5 Hz, 2H), 4.16 (t, J=5 Hz, 2H), 6.97 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 12.52 (s, 1); MS (ESI): [M−H]− at m/z 196.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:27]=O>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2/[CH:27]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1ccc2[nH]cc(/C=C/C(=O)c3cc(OC)c(OC)c(OC)c3)c2c1
Yield: 52 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (1.2 g) and 5-methoxyindole-3-carboxaldehyde (1 g) except that the obtained crude crystals were recrystallized from 2-propanol, to give Compound 25 (1.09 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:44]5[CH2:45][CH2:46][N:41]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:42][CH2:43]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: CS(=O)(=O)N1CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(S(C)(=O)=O)CC1
Yield: 21.3 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 1-methylsulfonyl-piperazine (187 mg, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (53 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 8.99 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.29-7.51 (m, 5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.14-3.15 (m, 4H), 2.86-2.87 (m, 5H), 2.66-2.67 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 656 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: CC(=O)c1ncccc1Cl
Reactant: Nc1nccc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (312 mg, 2.0 mmol) and 2-acetyl-3-chloropyridine (310 mg, 2.0 mmol) in anhydrous THF (5.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (448 mg, 4.0 mmol) to the reaction mixture and stir the mixture at 10° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with water (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1cccnc1-c1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: ClCc1cccnc1-c1ccccc1Cl
Reaction time: 1 h
Yield: 92 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of [2-(2-chlorophenyl)pyridin-3-yl]methanol (1 g, 4.55 mmol, 1.00 equiv) in thionyl chloride (5 mL). The resulting solution was stirred for 1 h at reflux. The resulting mixture was concentrated under vacuum to yield 1 g (92%) of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH2:30]([OH:33])[C:31]#[CH:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:25])([F:26])[F:24])[N:17]=[C:16]2[O:33][CH2:30][C:31]#[CH:32])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: C#CCO
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and propargyl alcohol with pyridine there is obtained isopropyl 2-chloro-4-fluoro-5-[6-oxo-4-pentafluoroethyl-2-(2-propynyloxy)-1(6H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz): 7.85 ppm (d,1H), 7.41 ppm (d,1H), 6.71 ppm (s,1H), 5.27 ppm (m,1H), 5.00 ppm (d,2H), 2.53 ppm (t,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H);
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([CH:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To S -2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred 4 hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform exrract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, S -2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of S -2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:28]=[C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][C:22]2=[O:27])=[CH:12][CH:13]=1)[CH3:16]
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccc(F)cc32)cc1
Yield: 41 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (161 mg, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100 mg, 0.56 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (88 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH:18]3[C:19](=[O:14])[NH:11][CH2:10][C:9]4[CH:8]=[CH:13][CH:12]=[CH:15][C:16]=4[O:17]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: C1COCCO1
Product: O=C1NCc2ccccc2OC1CCCCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 110 °C
Reaction time: 6 h
Yield: 52.4 %

Procedure:
In 10 ml of dioxane was dissolved 65.2 mg of the compound prepared in Reference Example 2, then 123 mg (3 equivalents) of 4-(4-chlorophenyl)piperidine was added thereto, and the resulting mixture was stirred at 110° C. for 6 hours with heating. Thereafter, the same procedures for reaction, treatment and purification as used in Example 1 were repeated to give 46.7 mg (yield: 52.4%) of the title compound. The hydrochloride of this compound was obtained by converting the compound into hydrochloride in the usual manner, and then recrystallizing the salt from methylene chloride-ether.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12].CCN(CC)CC.[CH3:21][O:22][C:23](=[O:26])[C:24]#[CH:25]>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:26])[CH:24]=[CH:25][O:1][NH:2][C:3](=[NH:13])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOCCOCC(=N)NO
Reactant: C#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCC(=N)NOC=CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of crude N-hydroxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-acetamidine (3.02 g) and NEt3 (2.30 mL) in DCM (40 mL) was added propynoic acid methyl ester (1.43 mL) dropwise. The mixture was stirred for 30 min at RT, washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue, crude 3-({2-[2-(2-Methoxy-ethoxy)-ethoxy]-acetimidoyl}-aminooxy)-acrylic acid methyl ester (4.50 g) was directly used in the next step.
Reaction SMILES: [C:1]1(=[S:6])[S:5][CH2:4][CH2:3][S:2]1.F[B-](F)(F)F.[H+].[S:13]([CH2:18][CH:19]1[CH2:21][S:20]1)[CH2:14][CH:15]1[CH2:17][S:16]1>ClCCl>[S:13]([CH2:14][CH:15]1[CH2:17][S:16][C:1]2([S:5][CH2:4][CH2:3][S:2]2)[S:6]1)[CH2:18][CH:19]1[CH2:21][S:20][C:1]2([S:5][CH2:4][CH2:3][S:2]2)[S:6]1
Reactant: S=C1SCCS1
Reactant: C(SCC1CS1)C1CS1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: C1CSC2(S1)SCC(CSCC1CSC3(SCCS3)S1)S2
Temperature: -5 °C
Yield: 4.7 %

Procedure:
A mixture of ethylene trithiocarbonate (5.04 g, 0.037 moles) and tetrafluoroboric acid (1.0 ml) in anhydrous dichloromethane (50.0 ml) cooled to −5° C. and stirred under nitrogen, was treated dropwise with a solution of 2,2′-[thiobis(methylene)]bis-thiirane (3.34 g, 0.019 moles) in anhydrous dichloromethane (30.0 ml). The resulting mire was allowed to warm to room temperature and quenched with 5% sodium bicarbonate solution (50.0 ml). The separation of the organic layer followed by water washing, drying and evaporation afford a wet yellow solid. Purification of which by short-path chromatography (20% ethyl acetate/hexane over silica) afforded 2,2′-[thiobis(methylene)]bis-1,4,6,9-tetrathiaspiro[4.4]nonane (4.7% yield).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][CH:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([F:15])[CH2:3][CH2:4][CH:5]([C:8]([CH3:17])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)C1CCC(F)(F)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 232A (0.27 g, 1.226 mmol) in THF (5 mL) was added LDA (1.226 mL, 2.452 mmol, 2M in THF) dropwise at −78° C. and the resulting solution was stirred at the same temperature for 45 min. MeI (0.307 mL, 4.90 mmol) was then added at −78° C. and the reaction mixture was allowed to warmed to RT and stir for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% EtOAc in hexane.) Fractions containing the product were combined and evaporated to afford Intermediate 232B as a pale yellow liquid. (0.15 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.07 (q, J=7.2 Hz, 2H), 2.01 (d, J=12.1 Hz, 2H), 1.92-1.74 (m, 2H), 1.73-1.53 (m, 4H), 1.31-1.20 (m, 2H), 1.11 (br. s., 4H), 1.03 (d, J=2.6 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](/B(O)O)=[CH:25]\[CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC/C=C/B(O)O
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.45 mmol), trans-1-hexen-1-ylboronic acid (77 mg, 0.676 mmol), resin-bound PPh3Pd (692 mg, loading 0.13 mmol/g) and aqueous Na2CO3 (0.9 mL of a 2M solution) in DME (3 mL) is placed in a microwave vial and heated at 110° C. for 30 min. The mixture is filtered, diluted with EtOAc and washed with 1N HCl. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 128.5 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (12.5 g, 31.1 mmol), 2-chloro-4-fluoronitrobenzene (10.9 g, 62.1 mmol) and potassium carbonate (12.9 g, 93.0 mmol) in 130 mL of 4:1 DME/water in a sealed flask was heated to 100° C. with stirring. An identical 12.5 g scale reaction was set up in a second sealed vessel. The reaction vessels were maintained at 100° C. for 70 hours, cooled to RT, and stirred for an additional 18 hours. The combined reaction mixtures were partitioned between EtOAc (300 mL) and water (600 mL), and the phases separated. The aqueous solution was extracted with two additional 150 mL portions of EtOAc. The combined EtOAc solutions were washed with half saturated brine (1×), saturated brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The resulting yellow-brown solid was recrystallized from EtOAc/ether to give the title compound (22.3 g, 64%) as an off-white solid. LCMS (m/z, ES+)=558 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[N:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:16]=[C:17]4[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]4[CH:2]=3)=[CH:10][N:9]=2)[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2cccn2)nc1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cccn4)nc3)cn2c1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
100.0 mg (corresponding to 0.38 mmol) of 5-(2-bromoacetyl)-2-(pyrazole-1-yl)pyridine and 83.6 mg (corresponding to 0.38 mmol) of 2-amino-5-iodopyridine were dissolved in 3.8 mL of acetonitrile. The resulting solution was heated under reflux for 4 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 50 mL of water and 50 mL of methanol. Then, about 50 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for an hour using an ultrasonic washing machine. Precipitates were filtered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 80.2 mg (corresponding to 0.21 mmol) of 2-[2-(pyrazole-1-yl)pyridine-5-yl]-6-iodoimidazo[1,2-a]pyridine (FIG. 5, step 3).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[S:24][C:23]([CH2:25]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:25][C:23]2[S:24][C:20]([Br:19])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: ClCc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(Br)s2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
6.64 g of 4-(sec-butyloxy)-phenol and 5.52 g of potassium carbonate are heated in 50 ml of anhydrous dimethylformamide for one hour at 70° C. Subsequently, 8.46 g of 5-bromo-2-chloromethylthiophene in 20 ml anhydrous dimethylformamide is dripped in. The mixture is stirred for 6 hours at 80° C. and overnight at room temperature (about 20° C.). It is then poured into 100 ml of ice water and extracted three times with ethyl acetate, and the organic phases are dried over magnesium sulfate. The solvent is evaporated off to give a crude product which is purified by chromatography on silica gel using n-hexane/ethyl acetate (4:1) as eluant. There is obtained 6.3 g of 2-[4-(sec-butyloxy)-phenoxymethyl]-5-bromothiophene as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][C@@H:7]1[OH:17])=[O:4].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C=O)C>[CH2:24]([O:17][C@H:7]1[CH2:8][C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Step AE (2): To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide in DMF (4.5 mL) at rt was added sodium hydride (95% purity, 205 mg). The resulting mixture was stirred at rt for 5 min. Allyl bromide (0.26 mL) was added, and the reaction mixture was stirred for 30 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give N-((1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as a slightly yellowish oil (660 mg). 1H NMR (400 MHz, CDCl3) δ 7.14 (1H, d), 6.85 (1H, d), 6.83 (1H, s), 5.88 (1H, m), 5.44 (1H, d), 5.28 (1H, dt), 5.12 (1H, dt), 4.38 (1H, q), 4.06 (1H, m), 3.76 (3H, s), 3.05 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21]>>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared by the general method of Preparation 1 using 198 g (0.79 mole) of t-butoxycarbonyl-D-methionine (Boc-D-Met) and 99.5 g (0.79 mole) glycine methyl ester (Gly-OMe) hydrochloride. The title compound was isolated as an analytically pure solid without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11](O)=[O:12].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([Cl:24])=[O:12]
Reactant: COc1cc(F)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(F)c(C(=O)Cl)cc1Cc1cccc(Cl)c1F
Temperature: 25 °C

Procedure:
5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (10 g) was suspended in toluene (50 ml) with stirring at room temperature, thionyl chloride (4.57 g) was added dropwise at 65-75° C., and the mixture was stirred for 1.5 hr. After cooling, the solvent was concentrated under reduced pressure, toluene (50 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in toluene (20 ml) to give a solution of 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride in toluene. This was identified as the title compound by HPLC.