Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH:17]([CH3:19])[CH3:18]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]#[N:11])=[CH:7][CH:8]=1
Reactant: CC(C)Br
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)C(C#N)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 4-trifluoromethyl-phenylacetonitrile (5.00 g, 27.0 mmoles), 50% aqueous sodium hydroxide solution (1.9 g), sodium hydroxide (270 mg), and tetra n-butylammonium chloride (1.2 g) stirring in a 60° oil bath was added 2-bromopropane (3.32 g, 27.0 mmoles). The resulting mixture was stirred at 80° for 0.5 hours, and then at 90°-95° for 1.0 hours longer. After cooling, the mixture was partitioned between toluene and water. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and then evaporated. Chromatography of the residue over silica gel using 10% ethyl acetate-hexane as eluent gave the title compound (3.95 g) as an orange oil which was characterized by NMR as follows: 1H NMR (CDCl3) d 7.67 (d, 2H), 7.48 (d, 2H), 3.77 (d, 1H), 2.18 (m, 1H), 1.13 (d, 3H), 1.06 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:10][OH:11].[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Into a solution wherein 12 g of (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol obtained in Example 40 was dissolved in 120 ml of ethyl acetate was added dropwise 10 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 6.92 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 400 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 15.2 g of oily (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 22.5 minutes ((R)-form) and 24.7 minutes ((S)-form)).
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=O)[CH3:6].Cl.C([O-])(O)=O.[Na+]>CO.O>[CH2:1]([O:3][N:4]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CCON
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
0.42 g of a 40% strength aqueous O-ethylhydroxylamine solution was added to a solution of 0.4 g (1.3 mmol) of the compound from Example 1 in 20 ml of methanol. Using 10% strength hydrochloric acid, the mixture was acidified to pH 4, and the solution was then stirred at 20-25° C. for about 18 hours. The reaction solution was poured into water and adjusted to pH 8 using NaHCO3. The mixture was then extracted with methyl tert-butyl ether (MtBE), and the combined organic phases were washed with water and dried. Removal of the solvent gave 0.4 g of the title compound as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[CH:6]=1.N[C:19]1([C:31]#[N:32])[CH:24]=[CH:23][C:22](C2C=CC=CC=2)=[CH:21][CH2:20]1.COC1C(CC(OC)=O)CC(OC)O1>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:22]3[CH:23]=[CH:24][C:19]([C:31]#[N:32])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=1
Reactant: N#CC1(N)C=CC(c2ccccc2)=CC1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: COC(=O)CC1CC(OC)OC1OC
Product: COC(=O)Cc1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 60 %

Procedure:
According to the procedure described in Example 14(a) for the preparation of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)acetate were condensed in 6 hours at 80° C. to give a crude product. Successive flash column chromatography with EtOAc/CH2Cl2Cl2 /hex gave in 60% yield 2-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid. 1 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.8 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.10-7.09 (m, 2H), 6.33 (t, 1H, J=2.2 Hz), 3.73 (s, 3H), 3.58 (s, 2H). Anal. Calculated for C20H16N2O2 : C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86; H, 5.14; N, 8.90.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:22]O>>[CH3:1][C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:22])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cccc(C(F)(F)F)c1C
Temperature: 75 °C
Yield: 88 %

Procedure:
To a 500 mL round bottom equipped with an Airflux Condenser and stir bar was added 2-methyl-3-(trifluoromethyl)benzoic acid (30 g, 147 mmol). The solid was taken up in Methanol (101 ml) and to that solution was slowly added sulfuric acid (8.22 ml, 154 mmol). The reaction was then fitted with the condenser and heated to 75° C. overnight. The reaction was cooled back to room temperature, and neutralized by slow addition of 1N NaOH (˜155 mL). The solution was then extracted with 3×300 mL Et2O, the organic layer dried over magnesium sulfate, and concentrated to an oil, which solidified under vacuum to give off white solid methyl 2-methyl-3-(trifluoromethyl)benzoate (28.25 g, 129 mmol, 88% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (d, J=1.77 Hz, 3H) 3.89 (s, 3H) 7.53 (t, J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.97 (d, J=7.83 Hz, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>CO.O1CCCC1>[Cl:37][C:21]1[CH:22]=[C:23]([CH:26]([OH:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:5]([OH:39])=[O:4])=[O:38]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
An aqueous solution of sodium hydroxide (1N; 0.5 mL, 0.5 mmol) was added to a solution of rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 228; 82 mg, 0.16 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). The solution was stirred at room temperature for 16 h and the solvent was evaporated. Water (3 mL) was added and the mixture was acidified with 1N hydrochloric acid solution (0.25 mL). The precipitated solids were recovered by filtration, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (53 mg, 66% yield) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[C:20]3[CH3:30])=[C:15](C)[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:32][C:33]1[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:34]=1[CH:35]=O>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[C:20]3/[CH:30]=[CH:35]/[C:34]3[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:33]=3[OH:32])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1-n1c(C)nc2ccccc2c1=O
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C#Cc2ccc(-n3c(/C=C/c4ccc(O)cc4O)nc4ccccc4c3=O)cc2)cc1
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([O:23][C:21]([CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To 30 ml of acetone were added 200 mg of 2-(trans-3-hydroxystyryl)benzothiazole, 0.11 ml of ethyl bromoacetate and 131 mg of potassium carbonate, and the mixture was refluxed for 4 hours. After cooled to room temperature, the mixture was extracted with ethyl ether, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. After the crude crystals of the residue were washed with ethyl ether and n-hexane, they were dried under reduced pressure to give 207 ml (yield 77%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(OC)cc3)C2)nc1
Reaction time: 18 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (350 mg) and 4-methoxybenzaldehyde (145 mg) in dichloromethane (5 ml) was added sodium triacetoxyborohydride (410 mg) at 20° C., and then it was stirred at the same temperature for 18 hours. The reaction was quenched with saturated aq NaHCO3 solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (11 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (362 mg) was obtained as colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(O)C.O.NN>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(N)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4-(2-methoxy-5-nitrobenzyl)morpholine (252 mg, 1.0 mmol) in THF:ethanol mixture (1:1) (25 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (450 mg; 9.0 mmol) and the mixture was stirred for 1 hour at ambient temperature, filtered through a Celite/silica gel pad. The filtrate was evaporated to yield the pure 4-methoxy-3-morpholin-4-ylmethylphenylamine (149 mg, 67%), which was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.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.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.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:15]=[C:16]([F:18])[CH:17]=2)[O:9][N:8]=1
Reactant: Fc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: Fc1cc(-c2cccnc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 19.1 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4, 35.8 mg, 0.031 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with chloroform, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 19 mg (19%) 3-(2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.92 (s, 1H), 8.84 (d, 1H), 8.70 (d, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.00 (m, 2H), 7.90 (td, 1H), 7.65 (m, 1H), 7.55 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[Br:11][C:12]1[C:20]2[O:19][CH2:18][C:17](=[O:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>C(Cl)Cl.O>[Br:11][C:12]1[C:20]2[O:19][CH2:18][CH:17]([OH:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1COc2c(Br)cccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1COc2c(Br)cccc21
Yield: 94.1 %

Procedure:
Triethylamine (0.2 ml) was added to formic acid (63 ml), to the resultant mixture, a solution in methylene chloride (2.1 ml) of 7-bromo-2,3-dihydrobenzofuran-3-one (0.10 g) that is commercially available or can be obtained by a publicly known method was added, chloro[(1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]-(mesitylene) ruthenium (II) (8.8 mg) was added, and the resultant mixture was stirred at room temperature for 3 hours. To the resultant mixture, ethyl acetate and water were added, followed by extracting the resultant mixture with ethyl acetate, and the organic phase was washed with a saturated saline, and then was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=5:1 to 3:1), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (95 mg) as pale orange oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:75])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([NH:73][CH3:74])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:75])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:68]([NH:73][CH3:74])[CH:67]=1
Reactant: CNc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 44.5 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.56 g, 4.3 mmol), diphenylphosphinic chloride (0.41 g, 1.7 mmol), then reacted with 4-amino-3-methylamino-benzoic acid methyl ester prepared in Example 165 (0.19 g, 1 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methylamino-benzoic acid methyl ester as a light yellow solid (Yield 0.24 g, 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: COC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 33.2 %

Procedure:
Following the method of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (2.00 g, 7.71 mmol), methyl 4-chloro-3-oxo-butanoate (1.63 g, 10.8 mmol), and triethylamine (1.83 mL, 13.1 mmol) were reacted in methanol (40 mL) to provide methyl 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetate (910 mg, 33%) as a yellow oil. 1H NMR (d6-DMSO) δ 10.10 (s, 1H), 7.86 (d, 1H), 7.58 (d, 2H), 7.30-7.42 (m, 4H), 6.90 (d, 1H), 6.80 (s, 1H), 5.25 (s, 2H), 3.62 (s, 3H). Mass spectrum (apci) m/z=356 (100) (M+H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:14]([CH2:18]C)[N:15]=[CH:16][N:17]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:4])[CH3:3].CN1C(CO)=NC=N1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:4][C:2]([C:5]1[C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:18])[N:15]=[CH:16][N:17]=2)=[N:9][N:8]2[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[N:21][N:22]=[C:7]2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCn1ncnc1COc1nn2c(-c3c(F)ccc(F)c3F)nnc2cc1C(C)(C)C
Agent: Cn1ncnc1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1ncnc1COc1nn2c(-c3c(F)ccc(F)c3F)nnc2cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To the product of Example 4 Step a) (2.67 g) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared as described in EP-A-421210) (0.93 g) in dry dimethylsulfoxide (10 ml) was added caesium carbonate (3.14 g), and the mixture stirred at 50° C. under an atmosphere of dry nitrogen for 24 hours. On cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, evaporated at reduced pressure, and the residue chromatographed on silica gel (eluent 2.5% methanol-dichloromethane). The product was crystallised from ethyl acetate/diethyl ether/isohexane, to afford the title compound as a colourless solid. 1H NMR (500 MHz, DMSO-6) δ1.39 (9H, s), 3.74 (3H, s), 5.50 (2H, s), 7.46 (1H, m), 7.88 (1H, m), 7.90 (1H, s), 8.17 (1H, s); MS (ES+) m/z 418 [MH]+.
Reaction SMILES: C([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([CH2:10][C:9]([OH:20])=[O:8])[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1
Reactant: [H][H]
Reactant: O=C(Cn1ccc2ccncc21)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)Cn1ccc2ccncc21
Yield: 89.1 %

Procedure:
To a stirred solution of pyrrolo[2,3-c]pyridin-1-yl-acetic acid benzyl ester (1.0 g, 3.6 mmol) in MeOH (20 mL) in a Parr shaker vessel (250 mL), palladium-charcoal (100 mg) is added under nitrogen atmosphere. Nitrogen is flashed with hydrogen and the solution is hydrogenated at room temperature at 10 psi hydrogen pressure. Reaction is monitored by TLC. After complete consumption of starting material, the reaction mixture is taken out from the Parr shaker and diluted with water. The solution is filtered through a pad of diatomaceous earth and washed successively with hot water. Volatiles are removed under reduced pressure and crude solid obtained is washed with EtOAc (3×50 mL). It is concentrated and dried in vacuum to yield pyrrolo[2,3-c]pyridin-1-yl-acetic acid as a solid (0.565 g).