Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[O:11][C:10](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cc2ccc(F)cc2)o1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Cc2ccc(F)cc2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A mixture of 5-(4-fluoro-benzyl)-furan-2-carbaldehyde (1 g, 4.89 mmol) described in Manufacturing Example 208-1-2, nitromethane (1.32 mL, 24.5 mmol), ammonium acetate (754 mg, 9.78 mmol), and acetic acid (10 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.21 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:30][C:31]1[C:32]([F:42])=[CH:33][C:34]([F:41])=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:36]=1>O1CCCC1>[Cl:30][C:31]1[C:32]([F:42])=[CH:33][C:34]([F:41])=[C:35]([S:37]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[N:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:36]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ncc(F)cn2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
N-(2,4-Dimethoxybenzyl)-5-fluoropyrimidin-2-amine (Preparation 18, 4.00 g, 15.2 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to −78° C. A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (17 mL, 17 mmol) was added drop-wise to the solution and the solution was stirred for 30 minutes at −78° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (3.42 g, 13.8 mmol) in tetrahydrofuran was added drop-wise to the reaction mixture and it was stirred at −78° C. for 1 h then allowed to warm gradually to ambient temperature. The reaction mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride (50 mL). The aqueous phase was extracted with ethyl acetate (×2). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto diatomaceous earth and purified by silica gel column chromatography (hexanes to dichloromethane gradient elution) to afford the title compound as a white solid (1.73 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][C@@H:29]5[CH2:33][CH2:32][O:31][CH2:30]5)[CH:21]=4)=[CH:18][CH:17]=[N:16]3)=[CH:11][CH:10]=2)C=CC=CC=1.O1CCCC1.Cl.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([NH2:8])=[CH:14][CH:13]=3)[N:16]=[CH:17][CH:18]=2)=[CH:21][C:22]=1[O:28][C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)cc1O[C@@H]1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnn2-c2ccc(N)cc2)cc1O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Into a 1-neck round-bottom flask was added N-(diphenylmethylene)-4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl) aniline (52.0 mg, 0.101 mmol), 1.0 mL of tetrahydrofuran, and 0.1 mL of 2.0 M aqueous HCl. The reaction was stirred at room temperature for 2 hours and 10 mL of 0.5 N HCl in water and 10 mL of a 2:1 mixture of hexanes and ethyl acetate were added. The clear aqueous layer was basified with 1 N NaOH and extracted with 3×10 mL of ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure to yield 4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline (28 mg, 79%) as a tan solid. LC/MS (EI) tR 3.11 (Method C), m/z 352.1 (M++1)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24]([OH:26])=[O:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]1[C:24]([OH:26])=[O:25])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
A solution of 4.00 g (10.98 mmole) of (S)-4-(benzyloxycarbonyl)-1-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid in 40 ml of methanol was hydrogenated over 1.0 g of 10% pd/c with rocking at 25° under 40 psi of hydrogen for 16 hr. The mixture was filtered and the cake was washed with a mixture of 100 ml of dichloromethane, 50 ml of methanol and 1.0 g of diisopropylethyl amine. Concentration in vacuo followed by Pumping in vacuo for 2 hr left 2.39 g (95%) of white solid which was homogeneous by tlc (silica gel, 1:1:1:1 ethyl acetate:n-butanol:acetic acid:water, Rf =0.70).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27]Br>>[CH3:33][O:32][C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COc1cc(Cn2c(C(=O)c3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 67.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (296 mg, yield: 67.8%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.[IH:24]>>[I:24][C:17]1[CH:22]=[C:21]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:8][CH:9]=2)[N:20]=[CH:19][N:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: CC(C)(C)OCc1ccc(B(O)O)cc1
Product: CC(C)(C)OCc1ccc(-c2cc(I)ncn2)cc1

Procedure:
The compound was prepared according to Example 1 using 4-tert-butyloxymethylphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91 M, 3 ml) (Louw et. al. Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc.1) in THF (3 ml). The solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and purified by chromatography on silica gel eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%. Evaporation of the fractions gave (2S,3R)-1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine. MS (ES+) m/z 424 (M+H), 324 (M+2H-tBuOCO--), 368 (M+2H-tBu). 1H NMR (360 MHz, CDCl3) δ 7.48 (2H, d, J 6.9 Hz), 7.35-7.2 (6H, m) 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J 13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J 14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.36 (9H, s).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][CH:13]1[N:19]=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11])=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH2:8][C@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH3:30])[C:14]1=[O:31])=[O:11]
Reactant: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@@H](NC(=O)[C@H](N)Cc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 0 °C
Yield: 19.5 %

Procedure:
3(R,S)-[2(R)-(tert-Butyloxycarbonyl)amino-3-phenylpropionylamino]- 5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (12.7 g, 24.5 mmol) [Example 27, Step 2] was dissolved in ethyl acetate (20 ml) and cooled to 0° C. This solution was then saturated with hydrogen chloride gas. After 1.5 h the resulting precipitate was collected by filtration. After recrystallisation twice from ethanol, the precipitate was partitioned between ethyl acetate (50 ml) and 10% sodium carbonate solution (50 ml). The organic phase was separated and the aqueous extracted with further ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to afford the title compound (2 g, 20%) as a pale yellow solid. mp 75°-78° C. 1H NMR (360 MHz, CDCl3) δ 1.03-1.41 (4H, m), 1.48-1.72 (4H, m), 1.82-1.92 (1H, m), 1.97-2.06 (1H, m), 2.70-2.84 (2H, m), 3.28-3.42 (4H, m), 3.76-3.82 (1H, m), 5.36 (1H, d, J=8.2 Hz), 7.21-7.33 (7H, m), 7.50 (1H, t, J=8.4 Hz), 7.56 (1H, d, J=8.1 Hz), 8.67-8.72 (1H, m). [α]D -13.5° (c=0.63, CH3OH).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1
Reactant: C1COCCN1
Reactant: Fc1cc(Br)ccn1
Solvent: CCN(CC)CC
Product: Brc1ccnc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2-fluoro-4-bromopyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then heated in an oil bath at 100° C. for 66 hr. LCMS analysis indicated the formation of the desired product (m/z=244.9, Rt=0.36 min). The reaction mixture was concentrated in vacuo to yield 4-(4-bromopyridin-2-yl)morpholine as a light brown solid, (>100%, TEA impurity). LCMS (m/z) (M+H)=244.9, Rt=0.36 min. 1H NMR (400 MHz, <dmso>) δ ppm 3.39-3.55 (m, 4H) 3.59-3.75 (m, 4H) 6.87 (dd, J=5.28, 1.37 Hz, 1H) 7.05 (d, J=1.17 Hz, 1H) 8.00 (d, J=5.48 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(CCl)c(Cl)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 21 h
Yield: 27 %

Procedure:
To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.; Dorn, Conrad P.; Frankshun, Robert A.; O'Grady, Laura A.; Bailey, Philip J.; et al.; JMCMAR; J.Med.Chem.; EN; 29; 8; 1986; 1436-1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44 ml, 66 mmol) at room temperature. The mixture was stirred at 80° C. for 21 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (6:1/4:1) to afford 2.8 g (27%) of the title compound as pale yellow oil.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:29])([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CS(C)=O>[CH3:28][C:18]([N:29]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=NC(C)(C)Cc1ccc(OC)cc1)C(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
632 mg of 2-n-butoxyphenylglyoxal hydrate are dissolved in 0.5 ml of dimethylsulfoxide, and a solution of 440 mg of α,α-dimethyl-4-methoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 20° C. for one hour, whereby a solution of α-(α,α-dimethyl-4-methoxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cccc2c1NC(C)(C)C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cccc(C(=O)O)c2N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,2-dimethyl-1,2-dihydroquinoline-8-carboxylate (0.188 g, 0.865 mmol) in THF (5 mL) and H2O (5 mL) was added a 1N aqueous solution of sodium hydroxide (3.46 mL, 3.46 mmol). After stirring at 60° C. overnight the reaction mixture was acidified to pH 2 using 1N aqueous HCl, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired compound that was used without further purification.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][CH:35]=1>C(#N)CCC>[NH2:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CCOC(=O)c1cnc(N)cn1
Solvent: CCCC#N
Product: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2cn1
Temperature: 120 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (245 mg, 0.44 mmol, 1.0 eq) and ethyl 5-aminopyrazine-2-carboxylate (CAS-Nr. 54013-06-8, 81.1 mg, 0.49 mmol, 1.1 eq.) in 2.7 mL butyronitrile was heated at 120° C. for 1.5 h. A substantial amount of the deprotected free amine was detected by UPLC analysis. For isolation, the volatile components were removed using a rotary evaporator and the resulting crude material was purified via MPLC [Biotage Isolera, 25 g Snap-cartridge; eluent: DCM→DCM/ethanol (95/5)] to deliver 38 mg (21%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc2ccccc2c1CCN
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
0.59 g (2.93 mmol) of 2-(2-methoxy-1-naphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, is introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 0.61 cm3 (4.37 mmol) of triethylamine dried over potassium hydroxide, is introduced, followed by 0.42 cm3 (3.54 mmol) of valeryl chloride. After the introduction of the reactants, the ice bath is removed and reaction is allowed to proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.39 g (1.37 mmol) of N-[2-(2-methoxynaphthyl)ethyl]pentanamide (white solid) is obtained, equivalent to a yield after purification of 47%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[O:12].[P:14]([Cl:19])(Cl)(Cl)(Cl)[Cl:15].Cl.C(O)=[O:22]>C(Cl)(Cl)(Cl)Cl>[Cl:15][P:14]([Cl:19])([NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])=[O:22]
Reactant: O=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
A mixture of 40 g (0.23 mole) of 2-naphthalene carboxamide, 48.7 g (0.23 mole) of phosphorus pentachloride and 400 ml of AR carbon tetrachloride was heated at 70° for 30 min. at which time the HCl evolution had ceased. It was cooled to 30° and 11.1 g (0.23 mole) of 97% formic acid added dropwise. Continued to stir for 30 min., then filtered, washed with AR carbon tetrachloride and air-dried to give 43 g, m.p. 110°-111°.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]([NH:10]C(=O)OC(C)(C)C)[CH2:8][CH2:7][C@@H:6]([C:18]2[N:19]([CH3:26])[N:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[O:5][CH2:4]1.C(OC([NH:34][C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[N:37][C:36]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:34][C:35]1[S:39][C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])=[N:37][C:36]=1[C:47]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:26])[C:18]=1[C@@H:6]1[CH2:7][CH2:8][C@@H:9]([NH2:10])[C@@H:3]([O:2][CH3:1])[CH2:4][O:5]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: CO[C@H]1CO[C@H](c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4ccccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-methoxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 93), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 183 as the hydrochloride salt as a dark salmon pink solid (68 mg, 45%). 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.18-8.09 (m, 5H), 7.74 (s, 1H), 7.52-7.36 (m, 4H), 4.96 (dd, J=9.9, 2.8 Hz, 1H), 4.19 (dd, J=13.6, 5.0 Hz, 1H), 4.00 (dd, J=13.6, 5.3 Hz, 1H), 3.86 (d, J=4.5 Hz, 1H), 3.78 (s, 3H), 3.62-3.49 (m, 1H), 3.33 (s, 3H), 2.14-1.97 (m, 2H), 1.98-1.74 (m, 2H). LCMS (ES+) m/z 461 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.24 g) and 1N NaOH (1.5 ml) in ethanol (4 ml) was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization of the crystals from ethyl acetate--methanol afforded colorless crystals (0.15 g, 67%), m.p. 183°-185° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH:15]=[CH2:16]>O1CCOCC1>[O:13]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1([CH2:16][CH2:15][C:14]#[N:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC#N
Reactant: O=C1CCCCC1c1ccccc1
Solvent: C1COCCO1
Product: N#CCCC1(c2ccccc2)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
Triton B surfactant (500 μL) was added to a stirred solution of 2-phenylcyclohexanone (5 g, 28.7 mmol) in dioxane (40 mL). A solution of acrylonitrile (1.8 g, 33.9 mmol) in dioxane (5 mL) was added dropwise. A slight exotherm was observed. The solution was stirred at room temperature for 3 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with water (20 mL, 2×). The EtOAc extract was dried (MgSO4), filtered, and concentrated. The residual oil was chromatographed on a silica gel column. Elution with 2% EtOAc in heptane, followed by 5% EtOAc in heptane afforded 3-(2-oxo-1-phenylcyclohexyl)propanenitrile (Int. 2-A, 5.05 g, 77% yield) as a colorless oil. HPLC: tR=2.73 min, YMC Combi S5 ODS 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.2% H3PO4; Final solvent: 90% aq. MeOH-0.2% H3PO4. LC/MS: m/e 228.26 (M+H)+, 250.14 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B(O)O)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:29][C:30]1[C:34]2[CH:35]=[C:36]([OH:39])[CH:37]=[CH:38][C:33]=2[O:32][N:31]=1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:16]1[C:15]2[CH:24]=[CH:25][C:12]([O:11][C@H:9]3[C:10]4[C:6](=[C:5]([O:39][C:36]5[CH:37]=[CH:38][C:33]6[O:32][N:31]=[C:30]([CH3:29])[C:34]=6[CH:35]=5)[CH:4]=[CH:3][C:2]=4[F:1])[CH2:7][CH2:8]3)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Cc1noc2ccc(O)cc12
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6onc(C)c6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (R)-7-fluoro-1-[(S)-3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yloxy]-2,3-dihydro-1H-inden-4-ylboronic acid and 3-methyl-benzo[d]isoxazol-5-ol following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.68 min; Mass spectrum (ESI+): m/z=490 [M+H]+.