Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][N:19]1[CH2:18][C:17](=[O:16])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12]
Reactant: CCOC(=O)CNC
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1N1C(=O)CN(C)C1=S
Yield: 80 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.2 g of 2-isopropylphenyl-isothiocyanate, 12.29 g of sarcosine ethyl ester hydrochloride, 16.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.9 g) as a peach solid, m.p. 129°-131° C. Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.89; H, 6.38; N, 11.28. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: BrC1C=C(NC2C=CC(N3CCN([CH:23]4[CH2:26][O:25][CH2:24]4)CC3)=CN=2)C(=O)N(C)C=1.[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[N:42]=[CH:41][C:40]([N:43]3[C@@H:48]([CH3:49])[CH2:47][N:46](C(OC(C)(C)C)=O)[C@H:45]([CH3:57])[CH2:44]3)=[CH:39][CH:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>>[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:44][C@@H:45]([CH3:57])[N:46]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:47][C@@H:48]3[CH3:49])=[CH:41][N:42]=2)[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Yield: 91 %

Procedure:
Following the procedures as described for compound 101k, reaction of 122d (700 mg, 1.79 mmol), afforded 122e as a yellow solid (723 mg, 91%). LCMS: [M+H]+ 448
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2
Reactant: O=[N+]([O-])c1cc(CCl)ccc1O
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Temperature: 23 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
In a 100 mL round-bottomed flask was added 4-(chloromethyl)-2-nitrophenol (1.0 g, 5.33 mmol), 1H-indazole (0.630 g, 5.33 mmol), and potassium carbonate (0.884 g, 6.40 mmol) in DMF (26.7 mL). The mixture was stirred at 23° C. for 18 h. The reaction was diluted with water (100 mL) and the resulting solid was isolated by filtration, washed with water, and dried in vacuo. The crude solid was purified via ISCO flash chromatography (0-75% EtOAc in hexanes; 40 g column) to give the title compound as a yellow solid (341 mg, 24% yield): 1H NMR (DMSO-d6, 400 MHz): δ=8.50 (d, J=1.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.68-7.72 (m, 1H), 7.56-7.61 (m, 1H), 7.48 (dd, J=8.6, 2.3 Hz, 1H), 7.10 (dd, J=8.5, 7.2 Hz, 2H), 7.00-7.06 (m, 1H), 5.62 ppm (s, 2H). ESI-MS: m/z 270.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13](Br)([CH3:15])[CH3:14].[I-].[Na+].O>CN(C)C=O>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.2 g, 0.10 mol) in N,N-dimethylformamide (100 ml) were added isopropyl bromide (12.1 ml, 0.13 mol) and sodium iodide (19.5 g, 0.13 mol), and the mixture was stirred at 70° C. for 15 hrs. To the reaction solution was added water (500 ml), and the mixture was extracted with ethyl acetate (500,200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (12.4 g, 64%) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])=[CH:17][C:16]=4[F:33])[CH:14]=3)[CH:11]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:25])[CH3:35])[CH3:22])=[CH:17][C:16]=4[F:33])[CH:14]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)pyrazolo[1,5-a]pyridin-2-yl]-3-fluorophenoxy}-1-methylethyl]carbamate (200 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (2 mL) was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (2 mL) and acetic anhydride (2 ml). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and by preparative HPLC (C18, water/acetonitrile (containing 0.1% trifluoroacetic acid)). The desired fraction was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (60.6 mg) as off-white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:32])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 2.4 g (9.72 mmol) 4-chloro-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, 2.56 g (10.7 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 1.2 g (10.38 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (30 mL) at 110°0 C. for 1 hour to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile as a pink solid, mp 251-254° C.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C-:8].[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH2:18]([C:19]1[O:20][CH:8]=[N:7][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCC(=O)Cl
Reactant: [C-]#[N+]CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCc1ocnc1C(=O)OC
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
50.1 g of potassium t-butoxide are dissolved in 500 ml of tetrahydrofuran, and 37.0 g of methyl α-isocyanoacetate are added dropwise thereto at -50° C. to -40° C. The mixture is stirred at the same temperature for 30 minutes. 50.0 g of n-caproyl chloride are gradually added to the mixture at -50° C. to -40° C., and the mixture is stirred at the temperature below -30° C. for 20 hours. After the reaction, the mixture is treated in the same manner as described in Preparation 1-(1). 40 g of 5-n-pentyl-4-methoxycarbonyloxazole are thereby obtained as oil. Yield: 54.3%.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.O>C1COCC1>[F:17][C:18]([F:40])([F:41])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Ethyl diethoxyphosphorylacetate (30 mL, 150 mmol) was dropped into a suspension of sodium hydride (60% oily) (6.00 g, 150 mmol) in THF (300 mL) at room temperature during 30 minutes. After the dropping, the mixture was stirred at room temperature for 1 hour more, a solution of 2-(3,5-bis(trifluoromethyl)-benzyloxy)-1-phenylethanone (48.90 g, 135 mmol) in THF (100 mL) was dropped thereinto at room temperature during 30 minutes and the mixture was stirred for 1 hour more. The reaction mixture was added to water (1000 mL) followed by extracting with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residual oily product was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 4-(3,5-bis(trifluoromethyl)-benzyloxy)-3-phenyl-2-butenoate (40.00 g, 69%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.23 (t, J=7.1 Hz, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.63 (s, 2H), 5.08 (s, 2H), 6.24 (s, 1H), 7.39-7.43 (m, 3H), 7.57-7.61 (m, 2H), 7.79 (s, 2H), 7.96 (s, 1H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C([O:29][N:30]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NO>CN(C=O)C.C(OCC)(=O)C>[OH:29][NH:30][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][N:10]2[CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: O=C(O)c1ccc2ccn(CCOc3ccccc3)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NO)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.8 %

Procedure:
To a solution of 1(2-phenoxyethyl)-1H-indole-6-carboxylic acid (0.66 g, 1.31 mmol) and TEA (0.92 mL, 6.6 mmol) in DMF (10 mL) was added HATU (0.52 g, 1.37 mmol). The solution was stirred 1 hr at room temperature, then NH2OH (50% wt/wt in H2O; 2 mL) was added and the solution was stirred 1 hr. The reaction solution was then diluted with ethyl acetate (150 mL) and washed with 1N HCl (100 mL) and then aq. NaHCO3 (100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.57 g (93%) of N-hydroxy-1-(2-phenoxyethyl)-1H-indole-6-carboxamide a light yellow solid. 1H NMR (300 MHz, DMSO) δ 11.11 (s, 1H), 8.94 (s, 1H), 8.06 (s, 1H), 7.56 (m, 2H), 7.66 (dd, 1H, J=8.5 Hz, J=1.5 Hz), 7.24 (m, 2H), 6.88 (m, 3H), 6.48 (d, 1H, J=3.0 Hz), 4.61 (t, 2H, J=5.2 Hz), 4.30 (t, 2H, J=5.2 Hz). EM (calc.): 296.12; MS (M+H): 297.06.
Reaction SMILES: [Cl-].[NH4+:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11]>O.CO.[Fe]>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:2])=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: [NH4+]
Reactant: COc1ccccc1Br
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COc1cc(N)ccc1Br
Temperature: 75 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A suspension of iron powder (40.8 g, 0.730 mol), ammonium chloride (64.7 g, 1.21 mol) and 2-bromoanisole (50 g, 0.215 mol) in water (1.5 L) and MeOH (1 L) was stirred overnight at 75° C. The solid was filtered off and the liquid was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 43.1 g of the title compound were obtained. Brown solid, ISP-MS: m/e=203.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:13]([O:20][C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[N:28]1[S:32](=[O:34])(=[O:33])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:30](=[O:41])[CH2:29]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][C:25]1[CH:24]=[CH:23][C:22]([N:28]2[CH2:29][C:30](=[O:41])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[S:32]2(=[O:34])=[O:33])=[C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)NCCI
Agent: [I-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3 g, 46 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (25 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.25 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.3 mL) is added, followed after 30 min with (2-iodoethyl)-carbamic acid tert-butyl ester (4.5 g, 16.5 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.20 g) and tri-o-tolylphosphine (0.30 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methoxyaniline (38 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (18 mg, 25%). 1H NMR (CDCl3): 8.82 (dd, J=1.4, 4.7 Hz, 2H), 8.32 (dd, J=1.7, 4.4 Hz, 2H), 7.84 (d, J=2.1 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 6.77 (dd, J=3.3, 9.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:4][PH:5](Cl)=[O:6])[CH:2]=[CH2:3].[O-:8][C:9]#[N:10].[Na+]>C(#N)C>[CH2:1]([CH2:4][PH:5]([N:10]=[C:9]=[O:8])=[O:6])[CH:2]=[CH2:3]
Reactant: N#C[O-]
Reactant: C=CCC[PH](=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=CCC[PH](=O)N=C=O
Reaction time: 5.5 h
Yield: 70.6 %

Procedure:
166 g (1.2 mol) of allylmethylphosphinic acid chloride were dissolved in 300 ml of acetonitrile and heated with 78 g (1.2 mol) of sodium cyanate to 50°-55° C. with stirring. After 5.5 hours, the precipitate was filtered off by suction and washed with acetonitrile; the filtrate was concentrated and the residue distilled at a temperature of 78°-80° C. and at a pressure of 25 Pa. 123 g of allylmethylphosphinic acid isocyanate (71% of theory) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(=O)C1C=CC([C@@H](N2CCN(CC=C)CC2)C2C=CC=C(N[CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)C=2)=CC=1)C.C(O)(C(F)(F)F)=O>CO>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13](=[O:14])[C:12]1[CH:20]=[CH:21][C:9]([C@@H:8]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:51][C:52]3[S:53][CH:54]=[CH:55][CH:56]=3)[CH:3]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: C=CCN1CCN([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NCc3cccs3)c2)CC1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CC=C(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(NCc3cccs3)c2)N2CCN(CC=C(C)C)CC2)cc1

Procedure:
Synthesized using COMPOUND 67 and the method described for COMPOUND 69. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; (400 MHz, CD3OD) 1.06 (t, J=6.61 Hz, 3H), 1.19 (t, J=6.61 Hz, 3H), 1.76 (s, 3H), 1.82 (s, 3H), 2.11-2.27 (m, 2H), 2.89-3.14 (m, 4H), 3.14-3.26 (m, 2H), 3.32-3.42 (m, 2H), 3.45-3.54 (m, 2H), 3.71 (d, J=7.93 Hz, 2H), 4.27 (s, 1H), 4.47 (s, 2H), 5.22-5.29 (m, 1H), 6.56 (ddd, J=7.94 Hz, 2.37 Hz, 1.02Hz, 1H), 6.68-6.71 (m, 1H), 6.77 (t, J=2.20Hz, 1H), 6.91 (dd, J=5.07 Hz, 3.38 Hz, 1H), 6.95-6.97 (m, 1H), 7.02 (t, J=7.77 Hz, 1H), 7.21 (dd, J=5.07 Hz, 1.19 Hz, 1H), 7.26 (d, J=8.05 Hz, 1H), 7.47 (d, J=8.12 Hz, 2H). Found: C, 59.49; H, 6.40; N, 7.85. C32H42N4O×0.7H2O 1.4 CF3COOH has C, 59.46; H, 6.42; N, 7.97%. [a]D20=−20.30 deg [c 0.650, MeOH]
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: Nc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCNc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.15 g) is reacted with aniline following the procedure outlined in example 10 and reduced with lithium aluminium hydride (0.15 g) in THF at room temperature. Aqueous work-up and crystallization from methanol gives 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-phenylamino-5α-chola-8,14-dien (106 mg). 1H-NMR (CDCl3, 300 MHz)): δ=7.17 (2H, t); 6.69 (1H, t); 6.6 (2H, d); 5.35 (1H, s); 3.6 (1H, s); 3.2 (1H, m); 3.09 (2H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][OH:17]>CO>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:16][OH:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Reactant: NO
Solvent: CO
Product: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Temperature: 60 °C

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-formylbenzoate (1.1 g, 4.0 mmol) in MeOH (5 mL) was added (aq. solution) hydroxylamine (4 mL) and the reaction mixture was heated at 60° C. for 2-3 h. The reaction mass was concentrated and extracted with EtOAC. The organic layer was washed with brine and concentrated to afford 0.900 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, J=6.9 Hz, 3H), 4.40 (q, J=6.6 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 8.20 (s, 1H), 11.89 (br s, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].CO>C(OCC)(=O)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH2:22][C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-4-(4-trifluoromethylphenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 49% overall yield. FDMS m/e=510 (M+ of free base). α[D]589 =-11.99 (c=0.42, methanol).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 109.5 %

Procedure:
(R)-tert-butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (1.10 g, 2.60 mmol) was dissolved in anhydrous toluene (30 mL) and cooled to 0° C. Red-Al (65% in toluene, 2.6 mL, 8.64 mmol) was added dropwise. After the addition, the reaction was stirred at rt for 12 h and quenched by adding water slowly. The resulting mixture was filtered through Celite and washing with THF. The filtrate was evaporated under reduced pressure to give crude product 1.05 g. It was used for next step without further purification.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:34])([CH3:33])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:23][C:24]1[CH:25]=[C:26]([C:30](=O)[CH3:31])[CH:27]=[CH:28][CH:29]=1)[CH:20]([CH3:22])[CH3:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]([CH3:34])([CH3:33])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH3:1])=[CH2:31])[CH:25]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Yield: 90.4 %

Procedure:
The procedure described in Example 9 was repeated, except that methyl triphenylphosphonium bromide (2.88 g; 8.1 mmol), n-butyl lithium in n-hexane (1.56 M: 5.2 ml; 8.1 mmol), and Compound 40 (1.67 g; 5.4 mmol) were used, to thereby yield 1.50 g of the target compound (yield: 90.4%).