Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][C@H:4]([NH:15]C(OCC1C=CC=CC=1)=O)[CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].P(O)(O)O>CO.[Pd].CCOCC>[NH2:15][C@@H:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)C[C@@H](CNCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: OP(O)O
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@H](N)CNCC(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
A solution of 17.43 g of (S)-N-[4-methyl-2-[[(phenylmethoxy)carbonyl]amino]pentyl]glycine, 1,1-dimethylethyl ester in 150 ml of methanol is reduced at 25°, 50 psi using 1 g of 20% palladium on carbon as the catalyst. The filtered solution is treated with 7.84 g of phosphorous acid in 10 ml of ether and the solvent removed under reduced pressure. The residue is partitioned between ether and 10% sodium hydroxide. The aqueous phase is washed five times with ether and the combined ether washes are washed with saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure at 25° gives 10.28 g of crude (S)-N-(2-amino-4-methylpentyl)-glycine, 1,1-dimethylethyl ester. The crude product is sufficiently pure for use in subsequent reactions.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[C:7]2[C:12]([C:13](=[O:16])[C:14]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:16])[C:14]([N:28]2[CH2:29][CH2:30][N:25]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:26][CH2:27]2)=[C:5]1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: CC(=O)NC1=C(N2CCN(Cc3ccccc3)CC2)C(=O)c2ccccc2C1=O
Yield: 89.7 %

Procedure:
A mixture of 500 mg of 2-acetylamino-3chloro-1,4-naphthoquinone, 800 mg of N-benzylpiperazine and 40 ml of absolute ethanol was heated at reflux for 3 hours, then the solvent was removed. The remainder was passed through a small plug of silica gel and eluted with chloroform. The eluate was concentrated to a solid which was recrystallized from dichloromethane/hexane, giving 700 mg of the desired product, mp 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[CH:8][C:9]=2[CH2:15][OH:16])[N:4]=1.[H-].[Na+].[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27](=[O:30])[CH2:28][O:16][CH2:15][C:9]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2)([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CO)c2nc1OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])cc(COCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.13 mmol) of 2,3-dimethoxy-5-hydroxymethyl-7-nitro-quinoxaline are placed in 8 ml of tetrahydrofuran and cooled to 0° C. 52 mg (1.05 equiv.) of approximately 55% NaH in oil are added and the mixture is stirred for 30 minutes at 0° C. 0.2 ml (1.5 equiv.) of bromo-acetic acid tert-butyl ester is added and after 20 minutes the ice-bath is removed. The reaction mixture is stirred at room temperature for 20 hours, diluted with water and extracted with ethyl acetate. The combined organic phases are washed once with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed (SiO2, ethyl acetate/petroleum ether 1:3) and the title compound is obtained in the form of a solid (340 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(O)cc35)CCC4)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cc2c3c(c1)c(CCN1CCN(c4cc(C)ccn4)CC1)c(C)n3CCC2
Yield: 73.9 %

Procedure:
2.2 g of 5,6-dihydro-2-methyl-8-hydroxy-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 6), 0.884 g of acetyl chloride and 0.78 ml of triethylamine were heated under reflux for 5 hours in 15 ml of toluene. To work up the reaction mixture it was added to 50 ml of 10% strength aqueous sodium hydroxide solution. The toluene phase was separated and washed with water until neutral and concentrated. 2 g of crude product were obtained, which was purified by chromatography on a small silica gel column using first dichloromethane and then dichloromethane/ethanol 98:2. 1.8 g of oily title compound were obtained. This was converted into its hydrochloride as described in Example 1H). 1.72 g of 8-acetoxy-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-4H-pyrrolo-[3,2,1-ij]quinoline 2 HCl 22.5 H2O having a melting point of 220° C. were obtained.
Reaction SMILES: [CH:1]([CH:4]([C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:18][C@H:16]2[CH2:15][C@H:14]([CH:4]([CH:1]([CH3:2])[CH3:3])[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])[CH2:17]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C([C@H]1C[C@@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C([C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(triisopropyl-siloxyethyl)cyclobutanol (0.64 g, 2.3 mmol), 4-nitrobenzoic acid (0.79 g, 4.6 mmol) and Ph3P (1.29 g, 4.83 mmol) inside, dry THF 10 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (1.0 mL, 4.83 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane:EtOAc=20:1 to Hexane:EtOAc=12:1) to give yellow oil contaminated with some DIAD (0.96 g, 97.4%, Rf=0.48 (Hexane:EtOAc=12:1)). 1H NMR (CDCl3, 400 MHz): δ 1.02-1.07 (m, 21H), 1.74-1.79 (m, 2H), 2.24-2.33 (m, 2H), 2.35-2.42 (m, 2H), 2.48-2.60 (m, 1H), 3.67-3.71 (t, J=6.4, 2H), 5.30-5.38 (m, 1H), 8.19-8.28 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 12.13, 18.19, 25.97, 34.87, 39.08, 61.95, 70.81, 123.66, 130.85, 136.01, 150.65, 164.39. MS (FAB): expected for C22H35NO5Si (M+H)+ 422.60. Found 422.23608. IR (neat) νmax 2942, 2865, 1725, 1608, 1530, 1463, 1349, 1276, 1103, 882, 720, 681.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33]>>[CH3:33][C@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C[C@@H]1CNCCN1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.53 (m, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (br. s., 3 H) 2.93-4.70 (m, 7 H) 7.63 (d, J=7.07 Hz, 1 H) 7.71-7.80 (m, 1 H) 7.88-8.77 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:8]([O:33][CH3:34])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:20]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), morpholine (34 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (36 mg, yield 55%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)=[O:4].[BH4-].[Na+]>C(O)C.O.ClCCl>[Cl:1][CH2:2][CH:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:15])[CH:11]=2)[O:6]1)[OH:4]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: OC(CCl)C1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution under stirring of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (0.33 g, 1.28 mmol, 88.4 A %) in ethanol (2.5 ml) was cooled to 0° C. under nitrogen. NaBH4 (60.1 mg, 1.59 mmol) was added to the solution and the reaction mixture stirred for 2 hours. After checking that the starting product had disappeared by GC, the mixture was diluted with demi water (7 ml) and dichloromethane (7 ml) and the phases separated. The organic stratum was dried under anhydrous sodium sulphate, filtered and concentrated under vacuum to give raw 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl) ethanol as a mixture of diastereoisomers 54:46 (0.30 g, 70% yield, 67.9 A %).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[F:14][CH:15]([CH2:18][NH2:19])[CH2:16][NH2:17].[S:20]1(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>>[F:14][CH:15]([CH2:18][NH2:19])[CH2:16][NH:17][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([N:23]2[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:20](=[O:31])[CH2:21][CH2:22]2)[N:11]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC(F)CN
Reactant: O=S1CCNCc2ccccc21
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 414, 1H NMR (400 MHz, CD3OD) δ ppm (d, J=7.6 Hz, 1 H), 7.79 (s, 1 H), 7.70-7.20 (m, 6 H), 5.56 (m, 1 H), 4.85-4.55 (m, 3 H), 4.48-4.32 (brs, 1 H), 3.91-3.71 (brs, 2 H), 3.40-3.11 (m, 2 H), 2.93-2.72 (m, 2 H), 2.24 (s, 3 H), 1.68 (s, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14]([OH:16])=O)[CH2:10]2)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>Cl.CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:13][CH2:12][CH:11]1[CH2:10][CH:9]([C:14](=[O:16])[NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[F:31])[CH2:8]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Reactant: NCc1ccccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(C(=O)NCc1ccccc1F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.9 %

Procedure:
A mixture of 100 mg of 8-aza-bicyclo[3.2.1]octane-3,8-dicarboxylic acid 8-ethyl ester, 0.056 g of HOBt, 0.074 g of EDC, 0.073 mL of triethylamine, 100 mg of 2-fluorobenzylamine and 5 mL of DMF was stirred at room temperature for 24 h, diluted with 50 mL of 1N HCl and extracted into 3×25 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of saturated sodium carbonate and dried over magnesium sulfate. Removal of solvents under reduced pressure gave 150 mg of a resin.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([OH:24])([CH3:23])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[C:10]=1[N+:20]([O-:22])=[O:21].CN(C)C=O.CC(C)=O>O>[CH3:23][C:6]([OH:24])([CH3:5])[CH2:7][NH:8][C:9]1[C:18]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]2[N:2]=[N:3][N:12]=[C:11]2[C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12

Procedure:
Sodium azide (19.5 g, 0.3 moles), 2-methyl-[(2-chloro-3-nitroquinolin-4-yl)amino]-2-propanol (29.6 g, 0.10 mole, U.S. Pat. No. 4,988,815 Example 12) and N,N-dimethylformamide (100 mL) were added to a jacketed 1 liter round bottom flask with the outside portion containing acetone. The reaction mixture was stirred with a stirring bar and the acetone refluxed to provide a constant internal reaction temperature of 53° C. After 18 hours the reaction mixture was diluted with water (100 mL). The resulting yellow precipitate was isolated by filtration then washed with 50% N,N-dimethylformamide/water until the washes became light colored. The yellow/green solid was then washed with water, pressed dry and washed with ether. The solid was air dried to provide 27.2 g of crude product as a yellow/light green solid. This material was recrystallized from ethanol/dichloromethane to provide 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol as a yellow crystalline solid, m.p. 204° C. (dec.). Analysis: Calculated for: C13H14N6O3 : % C, 51.65; % H, 4.67; % N, 27.8; Found: % C, 51.30; % H, 4.69; % N, 27.43.
Reaction SMILES: [CH3:1][C:2]1[S:29][C:5]2=[N:6][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:8]([C@@H:10]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:11])[CH:9]=[C:4]2[CH:3]=1.O.NN>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[S:29][C:5]2=[N:6][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:8]([C@@H:10]([NH2:12])[CH3:11])[CH:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)nc2s1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2cc([C@H](C)N)c(-c3ccccn3)nc2s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Slurried (S)-2-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (60 mg, 0.150 mmol) in 3.5 mL of ethanol was warmed to 60° C. and hydrazine monohydrate (73.0 μL, 1.502 mmol) was added. The reaction was stirred at 60° C. for 2 h, cooled to RT and diluted with ethyl acetate. The reaction was filtered and concentrated. The resulting residue was redissolved in ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated to afford crude (S)-1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine. 1H NMR (400 MHz, CDCl3) δ 8.67 (ddd, J=4.9, 2.7, 1.2 Hz, 1H), 8.19 (s, 1H), 7.85 (m, 2H), 7.32 (ddd J=7.0, 4.9, 1.8 Hz, 1H), 6.93 (q, J=1.2 Hz, 1H), 4.60 (q, J=6.6 Hz, 1H), 2.63 (d, J=1.2 Hz, 3H), 2.20 (br s, 3H), 1.43 (d, J=6.6 Hz, 3H) ppm. LC/MS (M+1, found=270.1).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:22](O)[CH3:23]>>[CH2:22]([O:19][C:18](=[O:20])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH2:17])[CH3:23]
Reactant: CCO
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To Nε-carbobenzoxy-L-lysine (69.7 g) was added ethanol (1000 ml) which had been saturated with anhydrous hydrogen chloride. The resulting solution was stirred at room temperature for three days. Ethanol was evaporated in vacuo and the residue was taken up in chloroform (500-600 ml). The chloroform was washed twice with saturated aqueous sodium bicarbonate, filtered and evaporated to afford the desired product as a colorless oil (69.9 g).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=O)C.CCOC(C)=O>C1COCC1>[CH2:1]([NH:13][C:22]([C:24]1[CH:25]=[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[C:27]([O:31][CH2:32][CH2:33][OH:34])=[C:28]([Br:30])[CH:29]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of dodecyl amine (3.22 g, 17.64 mmol) in 50 mL anhydrous THF was added n-BuLi (7.05 mL, 17.64 mmol) dropwise. When the addition was complete, the mixture was stirred for 10 min at 0° C. then at room temperature for 30 min. This lithiated amine was added dropwise to a cooled (0° C.) solution of 5-bromo-3′-chloro-6-(2-hydroxy-ethoxy)-biphenyl-3-carboxylic acid ethyl ester (2.5 g, 5.78 mmol) in 40 mL anhydrous THF via cannula. The reaction was stirred for 10 min at 0° C. when the addition was complete then at room temperature overnight. Then the reaction mixture was heated to 35° C. for 1 hour then more n-BuLi was added (0.7 mL, 1.75 mmol). The reaction was then worked up as in Step 2 of Example 135. There yielded 2.5 g, 80% of a yellow oil as desired product after flash chromatography (25% EtOAc:75% Hexanes) on silica gel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@:8]([CH2:26][OH:27])([CH3:25])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:16][C:15]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].N1C=NN=N1.C(N(CC)[P:37]1[O:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[CH2:39][O:38]1)C.OO.[O-:52]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@:8]([CH3:25])([CH2:26][O:27][P:37]1(=[O:52])[O:38][CH2:39][C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[CH2:42][O:43]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:16][C:15]=2[CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S([O-])([O-])=S
Reactant: CCCCCc1nc2cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc2o1
Reactant: CCN(CC)P1OCc2ccccc2CO1
Agent: OO
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCc1nc2cc(CC[C@](C)(COP3(=O)OCc4ccccc4CO3)NC(=O)OC(C)(C)C)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon a solution of [(R)-1-Hydroxymethyl-1-methyl-3-(2-pentyl-benzoxazol-5-yl)-propyl]-carbamic acid tert-butyl ester (151 mg, 0.387 mmol) and tetrazole (85 mg, 1.21 mmol) in dry THF (3 ml) was treated with N,N-diethyl-1,5-dihydro-2,4,3-benzo-dioxaphosphepin-3-amine (185 mg, 0.77 mmol) and stirred for 1 hours at RT. After cooling the reaction mixture to 0° C., aqueous hydrogen peroxide (0.4 ml of a 30 w/w % solution) was added and the reaction was allowed to stir for one hour at RT. The reaction mixture was distributed between a 10% aqueous Na2S2O3 solution and AcOEt. The organic layer was dried over MgSO4, concentrated in vacuum and purified over silica gel (eluent (DCM/methanol 30/1). The title compound was obtained as an colorless amorphous solid. 1H-NMR (DMSO-d6) δ: 7.52 (d, J=8.3 Hz; 1H), 7.50-7.40 (m; 5H), 7.15 (dd, J=8.3, 1.5 Hz; 1H), 6.8 (bs; 1H), 5.32-5.26/5.16-5.04 (m; 4H), 4.17/4.06 (AB-system, J=9.5, 4.5 Hz; 2H), 2.88 (t, J=7.5 Hz; 2H), 2.71-2.58 (m; 2H), 2.14-2.08 (m; 1H), 1.81-1.68 (m; 3H), 1.38 (s; 9H); 1.28 (s; 3H), 1.38-1.28 (m; 4H), 0.85 (m; 3H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[NH2:30][C@H:31]([C:39]([CH2:41][F:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.Cl>C1COCC1.CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:30][C@H:31]([C:39]([CH2:41][F:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)CF
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CF)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of Z-PheOH (0.207 g, 0.69 mmol) in THF (4 mL), cooled to -20° C., were added NMM (76 uL, 0.69 mmol) and IBCF (90 uL, 0.69 mmol). After 10 minutes, a chilled (-10° C.) solution of PheCH2F hydrochloride (0.15 g, 0.69 mmol) in DMF (1 mL) was added, followed by NMM (76 uL, 0.69 mmol). The mixture was stirred for 30 minutes. 1M HCl (5 mL) was added. The solution was extracted with ethyl acetate (30 mL), washed with saturated aqueous NaHCO3 (6 mL), brine (4 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/hexane, yielding 0.22 (53%) of Z-Phe-PheCH2F.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][C:20]#N.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[OH:39]S(O)(=O)=O>CC(OC)(C)C.O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH:20]=[O:39]
Reactant: O=S(=O)(O)O
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC=O)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile (178 mg, 0.59 mmol) was dried azeotropically with toluene in vacuo (3×2 mL), redissolved into toluene (3 mL) and cooled to 0° C. DIBALH (1.0 M in heptane, 0.9 mmol) was added over 3 minutes dropwise. After 1 h, H2O (2 ml) and aqueous H2SO4 (6 mL 2.5 M) were added and the mixture let warm to room temperature for 2.5 h. MTBE (5 mL) was added, the layers separated and the aqueous phase extracted 3×5 mL MTBE. The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enal as a colorless oil.