Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][N:15]1[C:24](=[O:25])[CH:23]2[CH:17]([N:18]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:19][CH:20]=[CH:21][CH2:22]2)[C:16]1=[O:37])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1([Mg]Br)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.C(OCC)C>[CH:1]([O:14][NH:15][C:16]([CH:17]1[CH:23]([C:24](=[O:25])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:22][CH:21]=[CH:20][CH2:19][N:18]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:37])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC3C(=O)N(OC(c4ccccc4)c4ccccc4)C(=O)C32)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
7-Benzhydryloxy-1-(4-methoxybenzenesulfonyl)-2,5,5a,8a-tetrahydro-1H-pyrrolo[3,4-b]azepine-6,8-dione (100 mg, 0.19 mmol) was dissolved in THF (2 mL) and cooled to -78° C. This solution was treated dropwise with a 3 M solution of phenyl magnesium bromide in diethyl ether and then warmed to ambient temperature. The reaction mixture was stirred another 2.5 hrs at room temperature, cooled to 0° C., and quenched with saturated aqueous NH4Cl (2 mL). This mixture was then diluted with H2O and diethyl ether and the layers were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 5 to 10% ethyl acetate in toluene) to give 3-benzoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide; MS: (M+H)+ 596.9, (M+NH4)+ 614.2.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12]C(C)(C)C)[C:9]([OH:17])=[CH:8][N:7]=1)(=O)C>Cl>[OH:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]([OH:17])=[C:10]([SH:12])[CH:11]=1
Reactant: CC(=O)OCc1cc(SC(C)(C)C)c(O)cn1
Agent: Cl
Product: OCc1cc(S)c(O)cn1
Temperature: 80 °C
Yield: 87.6 %

Procedure:
{4-[(1,1-dimethylethyl)thio]-5-hydroxy-2-pyridinyl}methyl acetate (2.5 g, 9.8 mmol) was dissolved in concentrated HCl and the mixture was heated at 80° C. for 18 hours. The solvent was evaporated under vacuum and the residue was triturated with diethyl ether to afford the product as a solid (1.35 g, 88%); MS (+ve ion electrospray) m/z 158 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[OH:11].[CH2:12]([O:14][C:15](N1C2C(=C(Br)C=CC=2)C(O)=N1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([OH:11])=[N:6]1)=[O:16])[CH3:13]
Reactant: Oc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Product: CCOC(=O)n1nc(O)c2cc(Br)ccc21

Procedure:
5-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CCVIII was prepared from 5-bromo-1H-indazol-3-ol using the procedure described for preparation of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (Example 37).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH3:33])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)C(C)=O)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
60 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0 ml of CH2Cl2 and 16 mg of acetylchloride (0.2 mmol) is added. The vial is capped with a Teflon® lined cap and shaken at room temperature for 2 h. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1 and Hexane:AcOEt=2:1) to give 33.8 mg of the title compound. Yield 50%: mass spectrum (m/e): 386 (M+1); 1H-NMR (CDCl3): 7.03 (s, 1H), 3.79 (s, 3H), 3.47 (m, 1H), 2.54 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 1.86 (m, 4H), 0.91 (t, 6H, J=7.4 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: CCOC(=O)OCCOC(=O)C(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (ethoxycarbonyloxy)ethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (37a) (4.5 g max.) dissolved in 50 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.88 g (13.5 mmol) of sodium azide (NaN3). After work-up, the crude title compound (37b) was obtained and used in the next step without further purification. The analytical data was consistent with the data obtained for (ethoxycarbonyloxy)ethyl (2R)-4-[(3-azidopropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (32b).
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[Cl:35][C:36]1[C:43]([O:44][CH3:45])=[CH:42][C:39]([CH:40]=[O:41])=[C:38]([F:46])[CH:37]=1>>[Cl:35][C:36]1[C:43]([O:44][CH3:45])=[CH:42][C:39]([CH:40]([C:28]2[N:24]([CH3:23])[N:25]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[OH:41])=[C:38]([F:46])[CH:37]=1
Reactant: COc1cc(C=O)c(F)cc1Cl
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: COc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1Cl
Yield: 67.6 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (65 mg, 0.40 mmol) and Intermediate 392.1 (80 mg, 0.45 mmol) afforded 94 mg of Intermediate 392.2 as a white solid. LCMS 348.25 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH2:27][CH2:26]2.Cl[CH2:34][C:35](=[O:37])[CH3:36].[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH:27]([CH2:34][C:35](=[O:37])[CH3:36])[CH2:26]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CC(=O)CCl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(CC(C)=O)C2=O
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 56 %

Procedure:
A lithium diisopropylamide solution, freshly prepared from 4.25 ml of diisopropylamine and 18.7 ml of 1.6N n-butyllithium in hexane, in 60 ml of anhydrous tetrahydrofuran was added dropwise while stirring to a solution, cooled to -70°, of 3.24 g of 5-methoxy-1-indanone in 350 ml of anhydrous tetrahydrofuran. The mixture was stirred at this temperature for an additional 30 minutes and a solution of 1.6 ml of chloroacetone dissolved in 60 ml of anhydrous tetrahydrofuran was subsequently added dropwise over 15 minutes. The reaction mixture was left to come to room temperature over 100 minutes and was stirred at this temperature for an additional 45 minutes. Subsequently, the reaction mixture was poured on to 150 ml of ice, 150 ml of saturated sodium chloride were added and the organic phase was separated. The aqueous phase was extracted once with 400 ml of diethyl ether. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. The red oil obtained was purified by column chromatography on silica gel (hexane/diethyl ether 3:7). There were obtained 1.67 g of crude product which was crystallized from diethyl ether/hexane. The crystallization gave 1.21 g (56%) of (RS)-5-methoxy-2-(2-oxopropyl)-1-indanone as a light yellow solid with m.p. 73°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:22]([NH:21][CH2:19][CH3:20])=[O:23])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2-amino-6-bromo-benzothiazole (6.12 g, 26.2 mmol), triethylamine (7.30 mL, 52.4 mmol, 2.0 eq), and ethyl isocyanate (4.15 mL, 52.4 mmol, 2.0 eq) in 50 mL toluene was heated at about 90° C. for about 15 hours. The precipitate was filtered off, washed with Et2O, and dried under vacuum to give the desired compound 7.39 g (94%). LC/MS 300.0 (M−1); LC retention time 3.01 min.
Reaction SMILES: [CH:1](=[N:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CNCc1ccccc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (15.00 g, 116.00 mmol, 1.0 eq) in CH2Cl2 (150 mL) was added Et3N (20 mL, 143.3 mmol, 1.2 eq) and PhCHO (14.6 mL, 143.3 mmol, 1.2 eq) in turn. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo to afford the crude product methyl 2-(benzylideneamino)acetate, which was used for the next step without further purification. To a solution of methyl 2-(benzylideneamino)acetate in MeOH (200 mL) at −5° C. was added NaBH4 (2.80 g, 72.8 mmol, 0.55 eq) slowly. The reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was then quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (21.30 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[N+:14]([O-:17])([OH:16])=[O:15]>C(OC(=O)C)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[N+:14]([O-:17])([OH:16])=[O:15].[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])([CH3:9])[CH3:11])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:12][CH3:13]
Reactant: COc1ccc(C(C)(C)C)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1c(Br)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
2-Bromo-4-tert-butylanisole (4.54 g, 18.67 mmol) was dissolved in acetic anhydride (15 mL) and the solution was cooled to 0° C. A solution of nitric acid (70%, 2.5 mL) in acetic anhydride (2.5 mL) was prepared by the dropwise addition of HNO3 (70%, 2.5 mL) to Ac2O at 0° C. The HNO3 solution was pre-cooled to 0° C., and added dropwise to the stirred solution of the 2-bromo-4-tert-butylanisole over 5 min. The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (150 mL) and saturated NaHCO3 (50 mL) This mixture was then neutralized by gradual addition of solid NaHCO3 until the pH was between 7-8. The organic layer was separated, washed with brine (50 mL) and dried over anhydrous Na2SO4. The solvents were removed in vacuo, the residue was purified by column chromatography (eluting with 3:1 hexane-EtOAc) to give 2-bromo-4-tert-butyl-6-nitroanisole (2 g, 37%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[C:19]2[C:20]([OH:28])=[C:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:23]([Cl:24])[C:18]=2[O:17][CH:16]=1>C(Cl)CCl>[C:1]([C:16]1[O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([CH2:25][CH2:26][CH3:27])=[C:20]([O:28][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]=2[C:15]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccccc3)c(C)c2c1OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A solution of benzoyl chloride (3.03 gm; 21.6 mmoles) in ethylene dichloride (20 mL) was added slowly to a cooled suspension of aluminium chloride (5.8 gm; 43 mmoles) in ethylenedichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.62 gm; 7.2 mmoles) in dichloroethylene (20 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.18 gm (63%) of 2-benzoyl-3-methyl-4-benzoyloxy-5-propyl-7-chlorobenzofuran, mp. 141°-142° C.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:33][CH:34]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)C2CCCCN2C(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(C(=O)N2CCCCC2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 700 mg of t-butyl [[1-[[1-(p-amidinobenzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxy]acetate in 20ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at room temperature for 3 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate and chromatography on silica gel (RP-18, water/THF 9:1) gives 111 mg of [[1-[[1-(p-amidinobenzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxyacetic acid. M.p. 233°-234° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.[CH2:42]([NH:46][CH3:47])[CH2:43][CH2:44][CH3:45]>>[CH2:42]([N:46]([CH3:47])[CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:40][CH:41]=1)[CH2:43][CH2:44][CH3:45]
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: CCCCNC
Product: CCCCN(C)CCc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 18.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and butylmethylamine (22 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: C[C:2]1[C:11]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-]>CO.O>[N:14]1([C:12]([C:11]2[CH:2]=[C:3]([CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[O:13])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cccc(C(=O)N2CCOCC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(C(=O)N2CCOCC2)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
To a solution of methyl methyl-3-(morpholine-4-carbonyl)benzoate (300 mg, 1.11 mmol) in MeOH (2 mL) and water (2 mL) was added LiOH (100 mg, 2.38 mmol) at 20° C. The mixture was heated to 60° C. for 1 h under N2. The reaction solution was concentrated in vacuo and diluted with water. The pH was adjusted to 4 with 2N HCl and the aqueous layer was extracted with DCM. The organic layer was concentrated to dryness and obtained the title product that was used in the next reaction without further purification (250 mg, Yield 96%). LCMS (m/z): 236.2 (M+1).
Reaction SMILES: C[O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([C@H:34]([OH:36])[CH3:35])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][C:14]2[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=2)[CH:12]=1)[CH3:5].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:36][C@@H:34]([C@@H:32]1[CH2:31][O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([O:13][C:14]4[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=4)[CH:10]=3)[O:6][C@@H:4]([CH3:5])[CH2:3][OH:2])=[CH:25][CH:26]=2)=[N:33]1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (213 mg, 0.412 mmol) synthesized in Example (114d) was dissolved in methylene chloride (5.0 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.80 mL, 0.80 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1.5 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with 1N aqueous sodium hydroxide solution (10 mL), and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=4%-5%) to afford the desired compound (147 mg, yield 71%) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[CH2:13]([SiH:16]([Cl:18])[Cl:17])[CH:14]=[CH2:15]>>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH:14]([CH3:15])[CH2:13][SiH:16]([Cl:18])[Cl:17]
Reactant: Cc1ccc(C)cc1
Reactant: C=CC[SiH](Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(C)C[SiH](Cl)Cl)c1
Yield: 52.6 %

Procedure:
In the same apparatus and procedures as Example 1, 0.9 g (0.007 mol) of aluminum chloride and 37 g (0.349 mol) of p-xylene were reacted with 10 g (0.07 mol) of allyldichlorosilane at 0° C. for 1.5 hrs. Vacuum distillation of the solution gave 9.1 g (81%) of 3-(2,5-dimethylphenyl)-1,1-dichloro-1-silabutane (boiling point: 86°-9° C./0.6 mmHg).
Reaction SMILES: CC(C)=[O:3].C1OC1CCCCCCC.[CH2:15]1[O:25][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:15]([OH:25])[CH:16]([OH:3])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)=O
Reactant: CCCCCCCCC1CO1
Agent: CCCCCCCC1CO1
Product: CCCCCCCCC(O)CO

Procedure:
A homogeneous clear solution is prepared by adding 3 moles of acetone to 1 mole of a mixture of 1-nonene oxide and 1-decene oxide at room temperature. After 50 grams of 5% aqueous sulfuric acid to the solution, the acetone is evaporated off and the resulting solution is neutralized by adding an aqueous sodium hydroxide. The neutralized solution is extracted with pet ether and the extract dried over anhydrous magnesium sulfate. The pet ether is stripped off and a mixture of 1,2-nonanediol and 1,2-decanediol is obtained by distilling under vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:28]([N:27]([CH3:33])[CH3:26])[CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C1CCNC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(N(C)C)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-3-dimethylaminopyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C23H25Cl2N5O2 (474.39); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16](O)[CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[Cl:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(Oc2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenol (0.1 mL, 0.903 mmol) was added to 10 mL of tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (150 mg, 0.452 mmol) and triphenylphosphine (237 mg, 0.903 mmol) dissolved in distilled tetrahydrofuran solution, and diisopropyl azocarboxylate (0.18 mL, 0.903 mmol) was slowly added at 0° C., and the mixture was stirred at room temperature for one day. The solvent of the reaction mixture was removed by reduced pressure evaporation to obtain a yellow liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (4:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (4:1, v/v)).