Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[C:19](=[O:21])=[O:20]>O1CCCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:19]([OH:21])=[O:20])=[CH:3][CH:4]=3)[C:12]=2[CH:13]=1
Reactant: O=C=O
Reactant: Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The product of Step B is reacted in a Grignard reaction with 5 g. of magnesium turnings in 25 ml. of tetrahydrofuran (by adding the product of Step B in 150 ml. of tetrahydrofuran at a rate sufficient to sustain refluxing). Refluxing is continued for an additional 3 hours, after which the mixture is stirred overnight at about 20° C. To this reaction mixture is added gaseous carbon dioxide over a period of 1 hour, the mixture being maintained at reflux during the second half of the hour. The reaction mixture is cooled and cautiously added to 50 ml. of 6N hydrochloric acid, then evaporated to provide a residue which is recrystallized from acetic acid to provide tan crystals of 4-(5-methyl-3-benzofuranyl)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[N:7]=1.C([Li])CCC.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC.O>[CH3:8][C:6]1([CH3:9])[CH2:5][CH:4]([CH3:10])[O:3][C:2]([CH2:1][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)=[N:7]1
Reactant: Fc1ccc(CCl)cc1
Reactant: CC1=NC(C)(C)CC(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1CC(C)(C)N=C(CCc2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5,6-Dihydro-2,4,4,6-tetramethyl-4H-1,3-oxazine (10.98 g) in anhydrous tetrahydrofuran (80 ml) was cooled to -70° under nitrogen. n-Butyllithium in hexane (44 ml) was added dropwise to the stirred solution over approximately 1 hr and the mixture was stirred for a further hour. 4-Fluorobenzyl chloride (12.38 g) in anhydrous tetrahydrofuran (20 ml) was added to the mixture over 30 min and the stirred reaction mixture was allowed to warm to room temperature overnight. The mixture was poured into iced water (100 ml) and adjusted to pH 2-3 with 9 M hydrochloric acid. The solution was extracted with pentane (3×75 ml), then adjusted to pH 14 with 10 M sodium hydroxide, and the resulting oil was extracted with ether (3×75 ml). The solvent was evaporated to give crude 5,6-dihydro-4,4,6-trimethyl-2-[2-(4-fluorophenyl)ethyl]-4H-1,3-oxazine (13.87 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][NH2:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:14]([O:21][C:22]([NH:24][NH:25][C:10](=[O:12])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)NNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88 %

Procedure:
6.95 g of 2-(tert-butoxycarbonyl-methyl-amino)-acetic acid, 6.1 g of hydrazine carboxylic acid benzyl ester, 6.18 g of 1-hydroxybenzotriazole monohydrate and 19.2 mL of N,N-diisopropylethylamine were dissolved in 120 mL of N,N-dimethylformamide, and 10.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under stirring at room temperature. After stirring at room temperature for 17 hours, the reaction solution was added with water and extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (hexane:ethyl acetate=1:1), to obtain 10.9 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:23])[NH:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][CH2:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
[1-(2-Benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (350 mg, 1.04 mmol) was dissolved in TFA:DCM (1:1, 4 mL) and allowed to stir at room temperature for 2 h. After this time, the solution was concentrated down under N2 gas and dissolved in DCM. The solution was washed several times with 1M NaOH (aq). The organic layer was dried with Na2SO4 and concentrated down under N2. The crude material was purified by flash chromatography (DCM to 9:1 DCM/MeOH) to afford 189 mg (77% yield) of (S)-2-amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-propionamide. [M+H]+ 237.10.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([Cl:19])=[O:15]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1C(=O)c2ccccc2C1=O

Procedure:
To 10.25 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid dissolved in 50 ml of dichloromethane are added, at room temperature, 4.6 ml of oxalyl chloride and 2 drops of DMF, and the mixture is left for 18 hours at room temperature. The resulting mixture is evaporated to dryness to give 11 g of the expected product.
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:38]([F:42])([F:41])([F:40])[F:39]>C(OCC)C>[F:39][B-:38]([F:42])([F:41])[F:40].[F:1][CH2:2][S+:3]([C:14]1[CH:13]=[CH:12][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: c1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)CF)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccc3ccccc3c2)cc1

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (481 mg, 2.79 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under argon atmosphere. Naphthalene (393.8 mg, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature below −50° C., trifluoromethanesulfonic anhydride (0.47 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether (54%, 0.77 mL, 2 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a yellow oily solid (1.873 g) after heating at room temperature.
Reaction SMILES: C1(O)C=CC=CC=1.COC(=O)C[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]#[N:21])=[CH:15][CH:14]=1>>[S:19]([C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[C:20]#[N:21]
Reactant: COC(=O)COc1ccc(SC#N)cc1
Solvent: Oc1ccccc1
Product: N#CSc1ccc(O)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1B using phenol. MS m/z 152 (M+1) Preparation of [(4-Thiocyanato-phenoxy)-acetic acid methyl ester (Compound ZZB)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](Cl)(=[O:42])[CH3:41]>>[C:40]([NH:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][OH:12])=[O:4])(=[O:42])[CH3:41]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using acetyl chloride. The final product was obtained in 26% yield.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:10][OH:11]
Reactant: NO
Reactant: O=Cc1sccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1sccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
3-Bromothiophene-2-carbaldehyde (Maybridge) (28.7 gm, 0.15 mol) in ethanol (50 ml) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 gm, 0.2 mole), sodium hydroxide (8 gm, 0.2 mol) in water (30 ml) and ethanol (100 ml). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight. The reaction mixture was diluted with cold water (600 ml), and the precipitated solids were collected by filtration to provide 20.5 gm, (67%) of product. The aqueous layer was further extracted with ethyl acetate and, the combined organic layers were washed with brine, dried with magnesium sulfate filtered and concentrated in vacuo to leave an additional 6.9 g of product.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=[O:19])=[O:18])=[O:4].O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([S:17]([N:6]2[CH2:7][C@@H:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:19])=[O:18])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](Oc3ccccc3)C[C@H]2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-(3,4-Dimethoxybenzenesulfonyl)-[(2S,4S)-4-phenoxy-2-pyrrolidinecarboxylic acid] methyl ester (9) (0.95 g, 2.25 mmol) is dissolved in 11 mL of 2:2:1 tetrahydrofuran:water:methanol. Lithium hydroxide (0.54 g, 22.5 mmol) is added and the solution stirred at ambient temperature for 6 hours. The reaction mixture is poured onto saturated citric acid solution (20 mL) and extracted with ethyl acetate (40 mL). The organic layer is isolated and washed successively with water (2×20 mL) and brine (20 mL). The solution is then dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product as a white solid. CIMS: MH+ 408
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I-].[Na+].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=4)[CH:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[C:19]=3[NH:20][C:21]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=4)[CH:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[C:19]=3[N:20]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=3)[C:21]=2[CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nc2c1[nH]c1cc(Cl)ccc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Yield: 60.4 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.72 ml, 5.36 mmol) and sodium iodide (0.80 g, 5 4 mmol) were added to a stirred suspension of methyl 7-chloro-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.03 g, 2.68 mmol) and K2CO3 (1.11 g, 8.03 mmol) in DMF (10 ml) at RT. After 2 days this was diluted with EtOAc, washed with water (5×) and brine, and then dried with sodium sulfate. Removal of the solvent followed by radial silica gel chromatography (step gradient elution with hexane containing 0 to 50% DCM) afforded impure methyl 7-chloro-2-(3-fluoro-4-methoxyphenyl)-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (820 mg, 1.62 mmol, 61% yield) as a yellow solid that was used as such. MS (ESI) m/z 505.29 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.38 (2H, d, J=8.24 Hz), 7.92-7.97 (3H, m), 7.85 (1H, dd, J=8.55, 1.22 Hz), 7.46 (1H, s), 7.34 (1H, dd, J=8.24, 1.53 Hz), 7.06 (1H, t, J=8.70 Hz), 6.86 (2H, d, J=8.24 Hz), 6.75 (2H, d, J=8.55 Hz), 5.66 (2H, s), 3.95 (3H, s), 3.81 (3H, s), 3.73 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: C1CNCCN1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)N2CCNCC2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and piperazine were reacted by a procedure similar to Example 47 to give 253. MS: (ESI+) 482.1
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9]([OH:18])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>>[CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:14]1(=[O:16])[O:18][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCCCC(=O)O
Agent: OCCCCCCO
Product: O=C1CCCCCO1

Procedure:
To prepare hexane-1,6-diol, for example, it is known to hydrogenate adipic acid or its salts directly, in aqueous solution or in an organic solvent, by a batchwise (DE-A-26 05 107; GB 1,300,889) or continuous (DE-A-23 21 101) procedure in which, alongside hexane-1,6-diol, relatively large proportions of caprolactone, ω-hydroxy-caproic acid and monoalcohols with carbon numbers from 1 to 6 are always formed. For the same purpose, it is also known to esterify adipic acid with monoalcohols, to give a di-n-alkyl adipate which is hydrogenated in the gas phase to give hexane-1,6-diol (WO 82/03854). It is also known to esterify adipic acid with diols, such as hexane-1,6-diol, by a batchwise procedure to give a mixture of higher esters, which is hydrogenated in a batchwise autoclave process to give hexane-1,6-diol and ω-hydroxy-caproic esters, the hydrogenation catalyst employed being a pulverulent copper chromite catalyst (DE-B-10 23 750).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][N:3]1[CH2:13][C:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)=[O:16]
Reactant: O=C(O)CN1CCN(c2ccccn2)C1=O
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(c2ccccn2)C1=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of (2-oxo-3-pyridin-2-ylimidazolidin-1-yl)acetic acid (22 mg, 0.10 mmol, described in Intermediate 14), (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (25 mg, 0.10 mmol, described in Intermediate 4), EDC (19 mg, 0.10 mmol), HOBT (15 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.0138 mL, 0.10 mmol) is stirred in DMF (0.5 mL) at ambient temperature for 18 h. The crude mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provides the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(CS(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylsulfonylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.O>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:7][N:6]2[C:8]=1[C:12]1[S:13][C:14]([C:23]2[N:27]=[CH:26][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(-c3cnn(C)c3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 95 °C
Reaction time: 12 h
Yield: 40.8 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl}-1,3-thiazol-2-yl]imidazo[1,2-a]pyridine (157 mg, 0.3 mmol) obtained in Example 117-B(i) in DME (10 mL) and water (2 mL), were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (93.6 mg, 0.45 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (24.5 mg, 0.03 mmol) and cesium carbonate (293 mg, 0.9 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 12 h. The reaction mixture was allowed to cool to rt, and then were added water (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (40 mL) and then a 1:1 mixture of EtOAc and THF (60 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with THF to give the title compound (64.0 mg, 41%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 12 mL of DMF to the stirred solvent was added K2CO3 (2.2 g, 16 mmol), 4-methoxyphenol (1 g, 8 mmol) and ethyl bromoacetate (1.1 mL, 9.6 mmol) Then the reaction mixture was Stirred at RT for 5 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to get the compound (2 g, Yield: 90%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH2:15]1[CH:19]2[CH2:20][C:21](=[O:22])[CH:17]([CH2:18]2)[CH2:16]1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOCC>[O:29]=[C:23]([CH:20]1[C:21](=[O:22])[CH:17]2[CH2:18][CH:19]1[CH2:15][CH2:16]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CC2CCC1C2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1C(=O)C2CCC1C2

Procedure:
The title product was prepared by a procedure similar to that described in step 1 of intermediate 1, from hexamethyldisilazane (4.2 ml, 20.0 mmol), ether (91 ml), nBuLi (2.3M in hexane, 11.63 ml, 27.3 mmol), norcamphor (2.0 g, 18.2 mmol) and diethyl oxalate (2.96 ml, 21.82 mmol) the title product was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
4-Trifluoromethylphenylboronic acid (255 mg) and ethyl 2-chloroisonicotinate (200 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([NH:27][CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Reactant: NCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNC2CCC(Nc3cccc4cnccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and 2-phenylethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (24 mg) and a syn-form compound (11 mg).