Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1.S(OCCCC1C2C=CC=CC=2OC=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:2].[O:7]1[CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[C:5]2[CH:4]=[CH:3][CH:28]=[CH:27][C:6]1=2
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(Cl)cc23)CC1
Agent: COc1cccnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)OCCCc2coc3ccccc23)cc1
Agent: Cl
Product: COc1cccnc1N1CCN(CCCc2coc3ccccc23)CC1

Procedure:
The title compound was prepared (0.73 g, 91%, mp 179.5°-182° C.) in a manner analogous to the preparation of 1-[3-(5-chlorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine (Example 25) by the reaction of 3-benzo[b]furanpropanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:19])([CH3:18])[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.[CH3:21][NH2:22]>>[CH2:11]([O:10][C:8]([NH:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([NH:22][CH3:21])=[O:3])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)C(C)(C)CNC(=O)OCc1ccccc1
Product: CNC(=O)C(C)(C)CNC(=O)OCc1ccccc1

Procedure:
4.19 g of 3-benzyloxycarbonylamino-2,2-dimethylpropionic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are stirred for 8 days at 60° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is purified by FC (220 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf ()dichloromethane/methanol=9:1)=0.51.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].C(NCC)C>C(#N)C>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:36][C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[C:39]#[N:40])[CH:13]=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCNCC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCc1cncn1Cc1ccccc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)-ethyl]-1-trityl-1H-imidazole (2.10 g, 4.48 mmol) in acetonitrile (20 mL) is added 2-bromomethylbenzonitrile (0.967 g, 4.93 mmol). The reaction mixture is stirred at 60° C. for 16 h. It is then cooled to room temperature and diethylamine (5 mL, 44.8 mmol) is added. The reaction mixture is stirred at 60° C. for 30 min. It is then cooled to room temperature and the solvents are removed in vacuo. Methanol (25 mL) is added and stirring is continued for 1 h at room temperature. Methanol is removed by concentration in vacuo. The residue is dissolved in ethyl acetate and washed with water twice. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-{5-[2-(tert-butyldimethylsilanyloxy)-ethyl]-imidazol-1-ylmethyl}-benzonitrile; MS (ESI) m/z 342 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(OC)(O[CH3:14])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C=O)cc1
Yield: 99.7 %

Procedure:
20 g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80° C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1% p-hydroxybenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Product: Nc1cnc(-c2ccc(F)cc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 2-amino-5-bromopyrazine (2.7 g) and 4-fluorophenylboronic acid (3.4 g), 2-amino-5-(4-fluorophenyl)pyrazine was obtained as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.CN(C=O)C.C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[F:13])[C:7](=[O:9])[CH2:6][CH2:5]2
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4-difluorocinnamic acid (5.0 g, 26.9 mmol) in DCM (35 mL) at 0° C., was added DMF (1 drop) and oxalyl chloride (4.7 mL, 53.8 mmol). The reaction mixture was warmed to rt and stirred for 16 h. The solvents were removed in vacuo and the residue azeotroped with toluene (2×20 mL). The residue was redissolved in carbon disulfide (20 mL) and added to a solution of aluminum trichloride (12.4 g, 94.1 mmol) in carbon disulfide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, heated to reflux for 4 h and then cooled to rt. The reaction mixture was poured into ice, extracted with EtOAc (2×500 mL) and the combined organic phase dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 1:9) to give the title compound: δH (CDCl3) 2.73 (2H, t), 3.17 (2H, t), 7.32 (1H, t), 7.43 (1H, t).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[O:30]1[CH:34]=[C:33](C2C=C(C=CC=2)N)[N:32]=[CH:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:33]3[N:32]=[CH:31][O:30][CH:34]=3)[CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Nc1cccc(-c2cocn2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2cocn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(oxazol-4-yl)aniline in step 1. MS: 394.28 (M+H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][CH2:7][CH:8]=O.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[C:1]([NH:5][CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:12][CH3:13]
Reactant: CCC=O
Reactant: CC(C)(C)N
Reactant: CCCC=O
Product: CCCCNC(C)(C)C
Product: CCCNC(C)(C)C

Procedure:
In an analogous manner to that in example 1c, 1.5 mol of tert-butylamine were reacted with n-propionaldehyde (example 2a) or n-butyraldehyde (example 2b) to give the corresponding secondary amines (tert-butylpropylamine and n-butyl-tert-butylamine respectively), and they were then analyzed by gas chromatography. For these reactions too, yields of 93.6 area % (example 2a) and 95.7 area % (example 2b) of the corresponding secondary amines were achieved.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH:8]=[O:9]
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C

Procedure:
To acetonitrile (15.0 mL) were added 3-chloro-4-hydroxy-benzaldehyde (556, 0.6 g, 4 mmol), 4-chlorobenzyl bromide (557, 1.2 g, 6 mmol), and potassium carbonate (0.9 g, 7 mmol). The reaction was heated to 150° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate: hexanes) (558, 0.85 g, 76%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
TFA (3 ml) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673 mg, 1.2 mmol) in methylene chloride (10 ml). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pH 10 with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride. The organic layer was dried (MgSO4) and the solvent was removed under vacuum. The solid was triturated with a mixture ether/petroleum ether (1/1), filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (390 mg, 70.5%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].Cl.[C:42]([O:45][CH2:46]C)(=[O:44])[CH3:43]>C1COCC1>[OH:16][C@@:15]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:6]=2)[CH:11]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:21]=1)[CH2:43][C:42]([O:45][CH3:46])=[O:44]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 0.69 g (1.32 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 6.9 mL of THF was added dropwise at −35˜−40° C. The mixture was stirred at −40˜−35° C. for 1 hour. 2.5 mL (1.32 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 was added dropwise at −40° C., and the mixture was stirred at −40˜−35° C. for 1 hour. 20 mL of 1N hydrochloric acid was added dropwise at 0° C. or lower, followed by dilution with 30 mL of ethyl acetate. The layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL of water, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, 4 mL of IPE was added, crystals were loosened, filtered, and washed with 1 mL (×2) of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.72 g of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 92%, enantiomer excess 93.6% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([NH:14][CH3:15])[C:4]=1[C:5]([NH2:7])=[O:6].Cl[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=1)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:6])[N:7]=[C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:27](=[O:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=1)[N:14]2[CH3:15]
Reactant: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Reactant: CNc1cc(OC)cc(OC)c1C(N)=O
Solvent: c1ccncc1
Product: COc1cc(OC)c2c(=O)nc(-c3cc(C)c(OC(C)=O)c(C)c3)n(C)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol) in pyridine (10 mL) was added to acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at room temperature for 14 h. The solvent was removed and the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate. The solvent was removed and the crude was purified by silica gel column chromatography (40 g) employing 1% methanol in dichloromethane to give acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 67%). Acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueous NaOH solution (10 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The compound was extracted with ethyl acetate and washed with ether to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one (0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cccc(Cl)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nn(Cc2cccc(Cl)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCNCC4)cc3)cc12
Product: Cl
Yield: 93.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (12 mg, 0.02 mmol) was deprotected in methanol/1,4-dioxane in (0.3/2 ml). This afforded 5 mg (55% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.72 (s, 1H), 8.669 (s, 1H), 7.85 (s, 1H), 7.71-7.69 (d, 2H), 7.42-7.39 (m, 2H), 7.32 (s, 1H), 7.24-7.18 (m, 3H), 5.52 (s, 2H), 3.53-3.50 (m, 4H), 3.41-3.38 (m, 4H), 2.33-2.32 (d, 6H). MS: m/z=497.2 (M+1), HPLC—95.77% (method-B).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=O.C(O)(=O)C.[NH:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CO.ClCCCl.C(O)(=O)C>[C:31]([O:30][C:28]([CH:26]1[CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[C:12]2[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=2[CH2:7][CH2:6]3)[CH2:27]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: COC(=O)c1noc2c1CCc1cc(C=O)ccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)c1noc2c1CCc1cc(CN3CC(C(=O)OC(C)(C)C)C3)ccc1-2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
To a solution of methyl 7-formyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45C, 72 mg, 0.280 mmol) in methanol (5 mL) and 1,2-dichloroethane (1 mL) was added acetic acid (0.1 mL) and tert-butyl azetidine-3-carboxylate acetic acid salt (73.0 mg, 0.336 mmol). The contents were allowed to stir at room temperature for 40 min. and then sodium triacetoxyborohydride (178 mg, 0.840 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. Additional sodium triacetoxyborohydride (2 eq) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. Additional sodium triacetoxyborohydride (4 eq) was added and the reaction mixture was allowed to stir at room temperature for 3 days. Additional amine (0.5 eq.), followed by additional triacetoxyborohydride (3 eq.) was added and the reaction mixtures was stirred at room temperature for 6 more hours to drive the reaction to about 90% conversion. The solvents were evaporated and the residue was re-dissolved into 80 ml ethyl acetate, washed twice with sat. sodium bicarbonate, dried over sodium sulfate, and concentrated to give 95 mg of product. The compound had an HPLC ret. time=0.75/2.0 min. (condition E); MS:(M+H)=399.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C@@:14]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH4+:37].[OH-].O>C(Cl)Cl.CN(C=O)C>[C:25]([C:24]1[CH:23]=[C:22]([C@:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:30]=[CH:29][CH:28]=1)(=[O:26])[NH2:37]
Reactant: COCCCC[C@@](O)(c1cccc(C(=O)O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COCCCC[C@@](O)(c1cccc(C(N)=O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 52 %

Procedure:
To a solution of 3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoic acid (51.0 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (17.3 mg, 0.13 mmol) followed by DMF (1 drop). The resulting mixture was stirred until gas evolution ceased (˜10 min), and completion of reaction was confirmed by LC-MS. To the reaction flask was added excess NH4OH, and reaction was stirred at rt for another 10 min. Water (5 mL) was added and organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give (R)-tert-butyl 3-((S)-1-(3-carbamoylphenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (26.2 mg, 52%). MS m/z 443 (M+Na+).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][C@H:6]([CH3:17])[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][C@H:6]1[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](O)CCNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a stirred solution of thionyl chloride (2.9 g, 24.3 mmol) in acetonitrile (15 mL) is cooled to −45° C. is added a solution of tert-butyl [(3R)-3-hydroxybutyl]carbamate (1.8 g, 9.7 mmol) in acetonitrile (20 mL) by syringe over 10 min, keeping the internal temperature below −40° C. 4-Dimethylaminopyridine (119 mg, 0.97 mmol) is added followed by the slow addition of pyridine (3.9 mL, 48.6 mmol), keeping the temperature below −40° C. Ethyl acetate (50 mL) is added to the suspension and the mixture at −35° C. is filtered. The solid is washed with EtOAc and the filtrates are combined. Saturated Na2HPO4 solution (20 mL) is added into the filtrates and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4, dried (MgSO4) and concentrated to afford the title compound (2.3 g, 99%) which is used in the next step without purification.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14].[O-]CC.[Na+]>C(O)C>[C:3]([CH2:2][S:1][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[OH:14])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: OC(CCCCCl)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCCCC(O)c1ccco1

Procedure:
To a stirred, refluxing mixture of 76 g of ethyl mercaptoacetate, 79.5 g of 5-chloro-1-(2-furyl)-1-pentanol (Example), and 10 ml of 1.5 M sodium ethoxide in ethanol is added an additionan 300 ml of 1.5 M sodium ethoxide during 15 minutes. The resulting mixture is stirred at reflux for 3 hours, cooled, and concentrated to remove most of the ethanol. The residue is partitioned with ether and water. The ether phase is washed with brine and dried over potassium carbonate. The solution is concentrated, diluted with xylene, and again concentrated to give an oil, pmr spectrum (CDCl3): δ3.24 (singlet, --S--CH2CO2C2H5) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C@H:10]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:32].C1[CH2:37][O:36][CH2:35]C1.C(N(CC)C(C)C)(C)C>CCOC(C)=O.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:35]([O:36][CH3:37])=[O:32])[CH:25]=2)[C@H:11]([C:13](=[O:23])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(Br)c2)C1
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cccc([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)Nc2cccc(C#N)c2)c1
Temperature: 150 °C

Procedure:
Split a solution of trans-3-(3-bromo-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.53 g, 1.13 mmol) in a 1:1 mixture of MeOH/THF (10 mL) into three microwave pressure tubes. Add to each tube molybedinum hexacarbonyl (0.06 g, 0.23 mmol) followed by N,N-diisoproylethyl amine (0.15 mL, 0.80 mmol) and Herrmann's palladacycle (0.16 g, 0.17 mmol). Heat each mixture in a microwave reactor at 150° C. for 15 minutes then cool to room temperature. Combine the mixtures, dilute with EtOAc and load onto silica gel. Purify the residue by flash silica gel chromatography to provide 0.20 g of trans-3-(3-cyano-phenylcarbamoyl)-4-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a foam.