Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@:6]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[C:7](=[O:21])[NH:8][C:9]1[CH:20]=[CH:19][C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:11]=2[CH:10]=1)[CH:2]=[CH2:3].[C:31]([O:35][CH3:36])(=[O:34])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH3:36][O:35][C:31]([CH:3]=[CH:2][CH2:1][O:4][CH2:5][C@:6]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[C:7](=[O:21])[NH:8][C:9]1[CH:20]=[CH:19][C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:11]=2[CH:10]=1)=[O:34]
Reactant: C=CCOC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Reactant: C=CC(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C=CCOC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Reaction time: 4 h

Procedure:
A mixture of 120 mg (0.226 mmol) tert.butyl(R)—N-[2-(prop-2-enyloxy)-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)ethyl]-carbamate (prepared from (R)—O-allyl-α-methyl-N-butoxycarbonylserine and 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine) in methylene chloride is rinsed for 30 min with argon, combined with 0.42 ml (4.66 mmol) methyl acrylate and 2nd generation Grubbs catalyst and heated to boiling for 4 h. Then the mixture is concentrated by evaporation and purified by chromatography.
Reaction SMILES: CC#C.C=C=C.[C:7](OC(C)=C)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:30]([OH:49])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[C:30]([O:49][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: C=C(C)OC(=O)CCCCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: C#CC
Agent: C=C=C
Product: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
When the reaction was completed, spent MAPP gas was removed from the product mixture in flash chamber 14. Gases were vented overhead and a liquid seal (not shown) was maintained at the bottom drain 15 to prevent leakage of spent gases into the atmosphere. A sight glass was provided in the barricade to permit remote manual control of the liquid level in chamber 14. Liquid exiting from the flash chamber was at a temperature of about 280° F and contained no apparent dissolved gas. Since isopropenyl stearate reacts slowly with stearic acid to form stearic anhydride the reaction was quenched by rapidly solidifying the product on double drum flaker 16. Drum clearance was 0.044 inches and the drums were cooled by circulating water at a temperature of about 50° F at a rate of about 2.9 gallons per minute. The product, an amorphous solid, was scraped from the drums with doctor blades.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:27])=[C:7]([C:9]23[CH2:17][O:16][CH2:15][CH:14]2[CH2:13][S:12][C:11]([NH:18]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:8]=1>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:27])=[C:7]([C:9]23[CH2:17][O:16][CH2:15][CH:14]2[CH2:13][S:12][C:11]([NH2:18])=[N:10]3)[CH:8]=1
Reactant: O=C(NC1=NC2(c3cc(Br)ccc3F)COCC2CS1)c1ccccc1
Agent: Cl
Product: NC1=NC2(c3cc(Br)ccc3F)COCC2CS1
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
5 N Aqueous hydrochloric acid (158 mL) is added to N-(7a-(5-bromo-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (16.35 g, 7.89 mmol) and the mixture is heated to 90° C. After 18 hours, the mixture is allowed to cool to ambient temperature and washed with dichloromethane. The organic layer is extracted once with 5 N aqueous hydrochloric acid. The pH of the aqueous layer is adjusted to basic with 50% aqueous sodium hydroxide and is extracted twice with 10% isopropyl alcohol:dichloromethane. The organic layer is concentrated under reduced pressure. The resulting residue is purified by radial chromatography eluting with 2% to 5% 7 N ammonia in methanol:dichloromethane to give the title compound (2.23 g, 47%). ES/MS m/e (79Br/81Br) 331, 333 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1>[C:24]([CH:6]1[C:2](=[O:1])[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(=O)OC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (370 mg) in tetrahydrofuran (20 mL) at −78° C., sodium bis(trimethylsilyl)amide (4.18 mL, 1.0 M in tetrahydrofuran) was added. The reaction mixture was stirred for 1.5 h, then treated with acetic anhydride (0.21 mL) and stirred at room temperature for 20 min. The reaction mixture was quenched by the dropwise addition of water and concentrated under vacuum. To the basic residue, ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (30 mL) with an equal volume of water were added. The aqueous layer was separated, acidified by careful addition of hydrochloric acid to pH 3 and extracted with ethyl acetate (75 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield desired product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][C:21]([NH:23][CH3:24])=[O:22]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CNC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (described previously in U.S. 2004067939) in DMF were added 2.1 eq. NaH (60% in oil). The mixture was stirred at RT for 30 min. and then the (commercially available) 2-chloro-N-methyl-acetamide (1.1 eq.) was added. The mixture was stirred an additional 14 hours at 60° C. and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by preparative HPLC gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.CCO>[Pd].CCOC(C)=O>[NH2:16][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCNc1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNc1cccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A round bottomed flask was charged with palladium on carbon (0.306 g, 0.287 mmol) and a stirbar. Ethyl 3-(3-fluoro-2-nitrophenylamino)propionate (1.473 g, 5.75 mmol) in 1:1 EtOH:EtOAc (40 mL) was added, and the flask was evacuated and purged with hydrogen three times before being stirred at room temperature overnight. The mixture was filtered, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield ethyl 3-(2-amino-3-fluorophenylamino)propanoate as a brown oil (1.074 g, 4.75 mmol, 83%).
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:7](OCC)=[O:8])C.[NH2:20][C:21]([NH2:23])=[S:22].O>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:6]1[C:5](=[O:4])[NH:23][C:21](=[S:22])[NH:20][C:7]1=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Reactant: NC(N)=S
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1NC(=S)NC(=O)C1c1ccccc1F
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To absolute ethanol (200 ml), sodium (3.62 g, 157 mmol) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred until all the sodium had reacted A solution of diethyl-(2-fluorophenyl)malonate (20 g, 78.7 mmol) in absolute ethanol (50 ml) was then added followed by thiourea (8.38 g, 110 mmol). The reaction mixture was then refluxed under nitrogen atmosphere for 17 hours. The cooled reaction mixture was then poured into water (800 ml), the reswiting mixture stirred for 15 minutes and extracted with diethyl ether (500 ml) The organic phase was extracted with brine (150 ml, ⅓ saturated) and the aqueous layers combined. Now concentrated hydrochloric acid (14 ml) was added to the aqueous phase and the resulting white suspension was stirred gently for 1 hour. The suspension was filtered and the resulting solid washed with water, followed by diethyl ether and dried in vacuo for approximately 12 hours to afford 8.59 g (46% yield) of the title compound as a white solid (melting point: >240° C.).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:27]([F:30])([F:29])[F:28])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][O:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:26])[O:11]2)=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][CH2:9][C@:10]2([C:27]([F:29])([F:28])[F:30])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][O:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:26])[O:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(N3CCOC3=O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CCO
Product: O=C1Nc2ccc(N3CCOC3=O)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
4-Fluoro-N-{[2-oxo-6-(2-oxo-1,3-oxazolidin-3-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:ethanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH:10](O)=[O:11]>>[CH:10]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:11]
Reactant: O=CO
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1NC=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
125 g. of 2,6 dimethyl aniline and 375 ml. of 88% formic acid are mixed in a 1 liter bomb with magnetic stirrer. The temperature (oil bath) is brought to 120° C. The bomb is kept at this temperature for 24 hours. The bomb is then allowed to cool to room temperature and stirring continued for 48 hours. The pressure is released and the mixture is poured into an 800 ml. ice with stirring. The mixture is filtered and the solid washed extensively with water and sucked dry and then dried in vacuo at 90°-95° to give N-formyl-2,6-dimethylaniline (m.p. 163°-164.5° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:10]([C:18](=[O:20])[CH3:19])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (10.0 g, 40.5 mmol) in toluene (225 mL) at room temperature was added acetic anhydride (4.6 mL, 48.6 mmol). Boron trifluoride diethyletherate (5.6 mL, 44.6 mmol) was then added dropwise and the resultant solution was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of aqueous sodium bicarbonate. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the-combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (9.0 g, 77%) as redish needles.1H NMR (CDCl3): δ 8.41 (d, 1 H), 7.59 (m, 2 H). 7.45 (dd,1 H), 7.26–7.13 (m 3 H), 2.15 (s, 3 H); 19F NMR (CDCl3) δ −112.06; MS m/z 289 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:23][OH:24])[C:15]1=[O:25].N1C=CC=CC=1>ClCCl>[C:1]([O:24][CH2:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][CH2:12][CH2:11][Cl:10])[C:15]1=[O:25])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=c1n(CO)c2ccccc2n1CCCCl
Reactant: CCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC(=O)OCn1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Heptanoyl chloride (0.64 mL, 4.15 mmol) was added dropwise at 0° C. to 1-(3-chloropropyl)-3-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 4.15 mmol) and pyridine (0.50 mL, 6.23 mmol) in dichloromethane (20 mL) and then allowed to warm to room temperature. The mixture was washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (30% ethyl acetate/hexanes) to give product as an oil (1.35 g, 92%); NMR (DMSO-d6); δ0.80 (t, J=6.8 Hz, 3H); 1.15-1.19 (m, 6H); 1.46-1.49 (m, 2H); 2.08-2.12 (m, 2H); 2.30 (t, J=7.2 Hz, 2H); 3.67 (t, J=6.4 Hz, 2H); 3.97 (t, J=6.8 Hz, 2H); 5.88 (s, 2H); 7.10-7.16 (m, 2H); 7.24-7.29 (m, 2H); MS for C18H25ClN2O3 m/z 353 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])[N:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14]=2[CH:34]=1.[OH-].[Li+]>>[C:28]1([N:15]2[C:14]3[CH:34]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[S:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:19])=[O:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCCCCOc1ccc2nc(S(=O)(=O)Cc3ccccc3)n(-c3ccccc3)c2c1

Procedure:
175 mg of 6-[[1-phenyl-2-(phenylmethanesulfonyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with lithium hydroxide according to general operating instructions 3. 143 mg was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:11](=[O:17])[C:12](OCC)=[O:13])=[CH:9][N:10]=1.[BH4-].[Na+].Cl>C(O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:17])[CH2:12][OH:13])=[CH:9][N:10]=1
Reactant: CCOC(=O)C(=O)c1cnc(C2OCCO2)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of ethyl [2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl](oxo)acetate (2.00 g) in ethanol (20 mL) was slowly added sodium borohydride (0.50 g). The reaction mixture was stirred at room temperature for 1 hr, 6M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (1.50 g, yield 89%) as a colorless oil. MS: 218 (MH+).
Reaction SMILES: C[O:2][C:3](OC)([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH3:4].O1CCOCC1.S(=O)(=O)(O)O>O>[C:6]1([O:5][C:3](=[O:2])[CH3:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COC(C)(OC)Oc1nccc2ccccc12
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1nccc2ccccc12
Temperature: 85 °C
Yield: 57.4 %

Procedure:
A mixture of 1-isoquinolinyloxyacetaldehyde dimethyl acetal (0.93 g, 4 mmol), dioxane (10 mL), water (15 mL) and conc. sulfuric acid (2 mmol) was heated at 85° C. for 2 h, then was quenched with saturated aqueous sodium hydrogen carbonate (100 mL). The resulting mixture was extracted with dichloromethane (2×100 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50 mL), dried over sodium sulfate and evaporated in vacuo to give the title compound (0.43 g, 57%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:25][C:26](=[O:47])[C@H:27]([CH3:46])[CH2:28][C@H:29]([N:43]=[C:44]=[O:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:25][C:26]([C@H:27]([CH3:46])[CH2:28][C@H:29]([NH:43][C:44]([N:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1)=[O:45])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][CH:36]=1)=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 1H-pyrazole-3-carboxylic acid (20.5 mg, 0.183 mmol) in DMF (1 mL) is added diisopropylethylamine (0.032 mL, 0.183 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CO[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH2:13][CH2:12]1)=O.O>C1COCC1>[Br:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([CH:14]3[CH2:15][CH2:16][N:11]([CH3:9])[CH2:12][CH2:13]3)=[N:18][NH:19]2)=[CH:24][CH:23]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Yield: 55.3 %

Procedure:
To a stirred suspension of LiAlH4 (6.2 g, 0.083 mol of a 50-55% oil dispersion) in THF (175 ml), under nitrogen, was added, dropwise, 4-(6-bromo-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester (28.1 g, 0.083 mol) of Example 106 (a). The reaction was refluxed for 1 hour, cooled in an ice bath, and water was added. The reaction was filtered and the filtrate was concentrated to yield 13.5 g of a solid. The solid was recrystallized from toluene to yield 10.2 g (42%) of a solid, mp 203°-205° C. An analytical sample was obtained by chromatography of a 3.4 g sample on a preparative HPLC (silica gel column) utilizing CH2Cl2 --CH3OH--(C2H5)2NH (95:4:1) as eluent. After evaporation of the appropriate fractions there remained 2.8 g of 6-bromo-3-(1-methyl-4-piperidinyl)-1H-indazole, mp 205°-207° C.
Reaction SMILES: [H-].[K+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][C@H:14]1[C@@H:18]([OH:19])[CH2:17][O:16][C@@H:15]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:29][C:28]([CH2:27][O:19][C@H:18]2[CH2:17][O:16][C@H:15]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C@@H:14]2[CH2:13][CH2:12][CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4])=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1[C@@H](c2cccnc2)OC[C@@H]1O
Reactant: ICc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Temperature: -15 °C

Procedure:
A 0.694 g (0.00346 mole) suspension of 20% potassium hydride in mineral oil is washed twice with petroleum ether and resuspended in 5 ml of tetrahydrofuran. The suspension is cooled with stirring at -15 ° C. and a solution of 1.169 g (0.00346 mole) of (2S,3S,4R)-3-(3-t-butyldimethylsilyloxyprop-1-yl)-4-hydroxy-2-(3-pyridyl)tetrahydrofurane in 10 ml of tetrahydrofurane is added dropwise. After stirring the mixture for 2 min, 1.37 g (0.00346 mole) of 4-iodomethylbiphenyl is added at once and the mixture is stirred at -15° C. for 75 min. Concentrated ammonium chloride is added and the mixture is extracted with ether (2×20 ml). The combined extracts are washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (1:1) to give (2S,3S,4R)-4-(biphenyl-4-ylmethoxy)-3-(3-t-butyldimethylsilyloxyprop-1-yl)-2 -(3-pyridyl)tetrahydrofuran as an oil having [α]D25 =+71.99 MeOH).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:2][CH:3]3[CH2:7][CH2:6][CH2:5][O:4]3)=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCC1CCCO1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCC3CCCO3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 42 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use 2-(bromomethyl)tetrahydrofuran in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 42% yield: mp 181-183° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.66-8.62 (m, 1H), 7.38-7.26 (m, 5H), 6.22-6.18 (m, 1H), 6.14-6.12 (m, 1H), 5.95-5.94 (m, 1H), 4.58-4.54 (m, 2H), 4.33-4.20 (m, 1H), 3.99-3.78 (m, 4H), 2.67 (s, 3H), 2.13-1.90 (m, 3H), 1.77-1.66 (m, 1H); MS (ES+) m/z 426.3 (M+1), 448.3 (M+23).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.ClC1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].O>[N+:30]([C:27]1[CH:28]=[CH:29][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 66 %

Procedure:
A mixture of toluene (15 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (0.80 g, 4.54 mmol) was added and the mixture was degassed with argon gas for 5 minutes. Phenyl boronic acid (0.59 g, 4.54 mmol) and 2-chloro-5-nitro-pyridine (0.6 g, 3.78 mmol) were added and the mixture was again degassed with argon gas for 5 minutes. Tetrakis palladium triphenyl phosphine (0.88 g, 0.76 mmol) was added and the mixture was degassed with argon gas for 5 minutes. The resulting mixture was heated to reflux for 3 hours. The mixture was then diluted with ethyl acetate, washed with water then brine solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford a residue which was purified by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) to afford 0.5 g (66%) of 5-nitro-2-phenyl-pyridine. LCMS purity: 201 (M+1)+, 98.2%, 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 8.55 (dd, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.55 (m, 3H).