Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NCCCS(=O)(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCCS(=O)(=O)c2ccc(C3=NNC(=O)CC3)cc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropylsulphonyl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccc(Cc2ccccc2)cc1
Yield: 94.6 %

Procedure:
By using ethyl 4-benzylbenzoate (232.55 g), lithium aluminium hydride (23.00 g) and ether (1.3 l), there was prepared the title compound (181.47 g).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(Cl)Cl>O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7](/[N:8]=[CH:17]/[C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)c1ccc(/N=C/c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
4-Isopropylaniline (5.5 ml, 40.2 mmol) was added to a vigorously stirred mixture of 4-(trifluoromethyl)benzaldehyde (5.5 ml, 40.2 mmol) in H2O (60 ml) at room temperature. After 2 hours, DCM (100 ml) was added and the mixture was stirred for 20 minutes. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated to give the imine (11.6 g, 99%) as a beige solid. 1H NMR (360 MHz, CDCl3) δ: 1.28 (6H, d, J 6.9), 2.95 (1H, septet, J 6.9), 7.18-7.21 (2H, m), 7.25-7.29 (2H, m), 7.71-7.73 (2H, m), 8.00-8.02 (2H, m), 8.52 (1H, s).
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1.C(OC1C2C(=CC(OC)=CC=2)C(C2C=CC=C([F:49])C=2)=C(C#N)N=1)C=C>>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:49])[CH:22]=2)=[C:7]([C:23]#[N:24])[N:6]=1
Reactant: C=CCOc1nc(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc12
Reactant: COc1ccc2c(OCC(O)CO)nc(C#N)c(-c3ccccc3)c2c1
Product: COc1ccc2c(OCC(O)CO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 1-(2,3-dihydroxypropoxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 1-(allyloxy)-6-methoxy-4-(3-fluorophenyl)isoquinoline-3-carbonitrile in place of 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].Cl[C:20](=[O:26])[C:21]([O:23]CC)=[O:22].[OH-].[Na+].Cl>ClCCl.O>[OH:11][CH2:10][C@@H:9]([NH:8][C:20](=[O:26])[C:21]([OH:23])=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N[C@H](CO)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Triethylamine (0.703 mL; 5.01 mmol) was added to the mixture of (S)-2-amino-3-phenylpropan-1-ol (0.515 g; 3.34 mmol) and ethyl 2-chloro-2-oxoacetate (0.400 mL; 3.50 mmol) in dichloromethane (15 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes, diluted with 40 mL of dichloromethane, and washed successively with an aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Water (5 mL) and a 2M solution of sodium hydroxide (5 mL; 10 mmol) were added to the resulting residue and the mixture was stirred at room temperature for 10 minutes. Water (10 mL) was added and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The formed solid was filtered off, and the filtrate was extracted with ethyl acetate (5×20 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 0.692 g (94%) of (S)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][O:23][CH3:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a mechanically stirring solution of (R)-tert-butoxycarbonylamino-(4-hydoxy-phenyl)-acetic acid (37.41 g, 140 mmol) (pepared according to the procedure of Salituro, G. M.; Townsend, C. A. J. Am. Chem. Soc. 1990, 112, 760) in N,N-dimethylformamide (750 mL) cooled in a dry ice/acetone bath was added sodium hydride (60% suspension in mineral oil) (12.32 g, 308 mmol) in small portions. The mixture was stirred while cooling in a dry ice/acetone bath for 30 minutes, then a solution of bromoethyl methyl ether (19.73 mL, 210 mmol) in N,N-dimethylformamide (200 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was diluted with ice-water and extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and acidified using concentrated aqueous hydrochloric acid to pH=1. The resulting mixture was extracted with ethyl acetate (3×), the organic extracts were combined, washed with water, brine and dried over sodium sulfate. Evaporation of the solvents gave (R)-tert-butoxycarbonylamino-{4-[2-(methoxy)-ethoxy]-phenyl}-acetic acid as a white solid (35.7 g, 78%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][N:10]=2)[CH2:5][CH2:4]1.[O:20]=[C:21]1[C:30]2[N:29]=[C:28]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[C:27]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:26][C:25]=2[CH:24]=[CH:23][NH:22]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CO>[C:39]1([C:27]2[C:28]([C:31]3[CH:32]=[CH:33][C:34]([CH2:35][N:3]4[CH2:8][CH2:7][CH:6]([C:9]5[N:13]=[C:12]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=6)[NH:11][N:10]=5)[CH2:5][CH2:4]4)=[CH:37][CH:38]=3)=[N:29][C:30]3[C:21](=[O:20])[NH:22][CH:23]=[CH:24][C:25]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: O=Cc1ccc(-c2nc3c(=O)[nH]ccc3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]ccc2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine dihydro-chloride (46 mg, 0.15 mmol) and 4-(8-oxo-3-phenyl-7,8-dihydro-1,7-naphthyridin-2-yl)benzaldehyde (40 mg, 0.12 mmol) in dry DMF (0.5 mL) was added triethylamine (55 μL, 0.40 mmol). After stirring for 10 minutes acetic acid (70 μL, 1.20 mmol) was added and the mixture was stirred at room temperature over night. Then sodium triacetoxy borohydride (52 mg, 0.24 mmol) was added in one portion. After two hours the reaction was complete and some methanol was added. This reaction mixture was concentrated to a smaller volume and adsorbed on silica gel and purified by column chromatography eluting with 0.5-13% methanol/ethyl acetate (sat'd NH3). The appropriate fractions were combined and the solvents removed in vacuo. The residue was triturated with diethyl ether to give pure title compound as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 14.34 (1H, br s), 11.56 (1H, d, J=5.6 Hz), 8.68 (1H, br s), 8.15 (1H, s), 8.03 (1H, m), 7.96 (1H, m), 7.50 (1H, br s), 7.22-7-38 (10H, m), 6.62 (1H, d, J=6.8 Hz), 3.49 (2H, s), 2.84 (2H, brm), 2.69 (1H, m), 2.07 (2H, brt, J=11 Hz), 1.94 (2H, m), 1.78 (2H, m). m/e (m+1): 540.3, 270.8 [(m+2)/2].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.C(=O)(O)[O-]>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CNCC2)c1ccncc1
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(CCc1ccccc1)CC2)c1ccncc1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
8-Methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.33 mmol) was dissolved in acetonitrile (1 mL) and (2-Bromo-ethyl)-benzene (62 mg, 0.33 mmol) was added to the reaction mixture. The contents were heated to 80° C. for 2 h. The reaction mixture was cooled to RT after 2 h and diluted with saturated bicarbonate (20 mL). The desired compound was extracted with EtOAc (2×50 mL). The organic layer dried over sodium sulfate and concentrated under vacuum to obtain the crude product which was purified by reverse phase chromatography to obtain 8.7 mg of 8-Methyl-2-phenethyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, TFA salt) δ (ppm): 8.82 (d, 2H), 7.90 (d, 2H), 7.42 (s, 1H), 7.38-7.22 (m, 6H)7.16 (d, 1H), 7.02 (d, 1H), 4.90 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 3.60-3.40 (m, 4H), 3.24 (m, 2H), 2.95 (m, 1H), 2.44 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([O:56][Si](C(C)(C)C)(C)C)[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3].F.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:64])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CC[C@H](O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CC[C@H](O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of the product of step (d) (0.28 g) in acetonitrile (10 ml) was added 40% aqueous hydrofluoric acid (2 ml). After stirring for 1 hour at room temperature the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with diethyl ether. The organic extract was then dried (MgSO4), filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with acetone/hexane [1:2] then gave the title compound (0.22 g) as a foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccccc1N
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1

Procedure:
The sulfonamide was synthesized from 4-acetamidophenyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mmol) by general Method C. It was purified by recrystallization from EtOH (1.27 g, 40%) EI-MS m/z 304 (M-H)-.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][CH:10]=2.[CH2:18]1COCC1.C[Mg]Br>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH:16]([OH:17])[CH3:18])=[CH:11][CH:10]=2
Reactant: COCCOc1cnc2ccc(C=O)cc2c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: COCCOc1cnc2ccc(C(C)O)cc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(3-(2-methoxyethoxy quinolin-6-yl)ethanol. 3-(2-methoxyethoxy)quinoline-6-carbaldehyde (1.7 g, 7.4 mmol) was dissolved in THF (29 mL, 7.4 mmol) and cooled to −78° C. To the solution was added methylmagnesium bromide (7.4 mL, 22 mmol), and the reaction was allowed to warm to RT. After 1 h, the reaction was quenched with sat. aq ammonium chloride. The material was extracted with DCM (×3) and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was then purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH4OH in DCM). 1-(3-(2-methoxyethoxy)quinolin-6-yl)ethanol was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:20][CH:21]=1
Reactant: ClCCCCSc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chlorophenylmercapto)-butylchloride.
Reaction SMILES: C([NH:8][CH2:9][CH:10]([Cl:23])[CH2:11][S:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:13])(OC(C)(C)C)=O.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].O.C(Cl)Cl>C1(OC)C=CC=CC=1>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:8][CH2:9][CH:10]([Cl:23])[CH2:11][S:12]([C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCC(Cl)CS(=O)c1ccc([N+](=O)[O-])cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(Cl)CS(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The product from Step C, 78 mg, is dissolved in 0.4 ml of anisole and treated at 0° C. for 10 minutes with 2.0 ml of trifluoroacetic acid (TFA). The TFA and anisole are pumped off at 20° C., and water and CH2Cl2 are added to the residue. The water layer is separated and evaporated, affording 66 mg of pure product.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[C:4]#[C:5][CH:6]([O:8][CH3:9])[CH3:7].[Cl:12][C:13]1[CH:14]=[C:15]([O:19][CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:16]=[N:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([O:19][CH:20]([CH2:24][CH3:25])[C:21]([NH:2][C:3]([CH3:11])([CH3:10])[C:4]#[C:5][CH:6]([O:8][CH3:9])[CH3:7])=[O:22])[CH:16]=[N:17][CH:18]=1
Reactant: COC(C)C#CC(C)(C)N
Reactant: CCC(Oc1cncc(Cl)c1)C(=O)O
Agent: Cl
Product: CCC(Oc1cncc(Cl)c1)C(=O)NC(C)(C)C#CC(C)OC

Procedure:
5-Amino-2-methoxy-5-methylhex-3-yne hydrochloride was reacted with 2-(5-chloro-3-pyridyloxy)butyric acid in a similar procedure to Example 1, Stage 3 to give 2-(5-chloro-3-pyridyloxy)-N-(2-methoxy-5-methylhex-3-yn-5-yl)butyramide as a yellow oil.
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])C.[CH2:21](N)CC>>[CH3:12][C:9]([CH3:10])([CH3:11])[C@@H:8]([C:13]([OH:15])=[O:14])[NH:7][C:5]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:1][CH2:3][CH3:21])=[O:6]
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Reactant: CCCN
Product: C=CCCCN(CCC)C(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine was prepared according to the procedure described for N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using n-propylamine in Step 1. LRMS (ESI) m/z 285 [(M+H)+; calcd for C15H29N2O3: 285.2].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].I[CH2:34][CH2:35][CH3:36]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH3:36])[CH2:14][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CCCN1CCC(N(C(=O)Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred and refluxing mixture of 5 parts of 4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodium carbonate, 0.4 parts of potassium iodide and 200 parts of butanol is added 4.7 parts of 1-iodopropane and the whole is stirred and refluxed for 22 hours. Then a second portion of 4.5 parts of 1-iodopropane is added and stirring and refluxing is continued for 27h.30. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in methylbenzene. The solution is filtered from some impurities and the filtrate is evaporated again. The residue is crystallized from 1,1'-oxybisethane at -10° C., yielding 0.9 parts of 4-chloro-N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide; mp. 118.6° C.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>>[CH2:6]1[O:7][C:8]2[CH:9]=[CH:10][C:2]([C:1]([Cl:15])=[O:12])=[CH:3][C:4]=2[O:5]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)OCO2

Procedure:
20 g (0.12 mole) of piperonylic acid are suspended in 170 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[C:24](=[O:36])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:61]([O:63][CH3:64])=[O:62].[NH4+].[Cl-]>O1CCCC1.O.C(Cl)Cl>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[C:24](=[O:36])[CH:23]([C:61]([O:63][CH3:64])=[O:62])[CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@]2(CCC(=O)N2C(=O)OCc2ccccc2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1C[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N(C(=O)OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of phenylmethyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-1-carboxylate (Intermediate 33, 85 mg) in Tetrahydrofuran (THF) (2 ml), at −78° C., LiHMDS (0.257 ml, 0.257 mmol) was added and left stirring at this temperature for 1 hr. methyl chloroformate (0.019 ml, 0.245 mmol) was added at the same temperature and the reaction was left at this temperature for 2 hrs. To the solution was added NH4Cl saturated solution, followed by DCM and water. The two phases were separated and the aqueous one was extracted with DCM. The combined organic layers were filtered through a phase separator tube and the solvent was removed in vacuo obtaining the title compound (83 mg) as a white foam. This batch was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (s, 1H) 7.67 (s, 2H) 7.24-7.48 (m, 5H) 6.85-7.00 (m, 2H) 6.70-6.84 (m, 1H) 5.09-5.29 (m, 3H) 4.34 (d, 1H) 3.99 (t, 1H) 3.70 (s, 3H) 2.65 (s, 3H) 2.58-3.44 (m, 2H) 2.34 (s, 3H) 1.54-2.45 (m, 6H) 1.47 (d, 3H); Mixture of two diastereoisomers ratio ˜50:50 (for example visible on the signal of CH(6) see annotation in the spectrum). The atom numbering shown in the following structure is included for the purpose of correlation with the NMR data only.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=2[C:13]=1[CH3:14])=O.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: COCCCCC(=O)c1oc2ccc(OC)cc2c1C
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 84 h
Yield: 90.2 %

Procedure:
To a mixture of 5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (797 mg) synthesized above, methyl 4-aminobenzoate (479 mg), triethylamine (3.21 mL) and methylene chloride (10 mL) was added a 1.0M solution (3.46 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred under argon atmosphere at room temperature for 3.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (10 mL) of the obtained oil in tetrahydrofuran were added acetic acid (824 μL) and sodium cyanoborohydride (362 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (1.07 g, 90%) as a brown oil.